Protein variants in Hiroshima and Nagasaki: tales of two cities.

PubMed Central

Neel, J V; Satoh, C; Smouse, P; Asakawa, J; Takahashi, N; Goriki, K; Fujita, M; Kageoka, T; Hazama, R

1988-01-01

The results of 1,465,423 allele product determinations based on blood samples from Hiroshima and Nagasaki, involving 30 different proteins representing 32 different gene products, are analyzed in a variety of ways, with the following conclusions: (1) Sibships and their parents are included in the sample. Our analysis reveals that statistical procedures designed to reduce the sample to equivalent independent genomes do not in population comparisons compensate for the familial cluster effect of rare variants. Accordingly, the data set was reduced to one representative of each sibship (937,427 allele products). (2) Both chi 2-type contrasts and a genetic distance measure (delta) reveal that rare variants (P less than .01) are collectively as effective as polymorphisms in establishing genetic differences between the two cities. (3) We suggest that rare variants that individually exhibit significant intercity differences are probably the legacy of tribal private polymorphisms that occurred during prehistoric times. (4) Despite the great differences in the known histories of the two cities, both the overall frequency of rare variants and the number of different rare variants are essentially identical in the two cities. (5) The well-known differences in locus variability are confirmed, now after adjustment for sample size differences for the various locus products; in this large series we failed to detect variants at only three of 29 loci for which sample size exceeded 23,000. (6) The number of alleles identified per locus correlates positively with subunit molecular weight. (7) Loci supporting genetic polymorphisms are characterized by more rare variants than are loci at which polymorphisms were not encountered. (8) Loci whose products do not appear to be essential for health support more variants than do loci the absence of whose product is detrimental to health. (9) There is a striking excess of rare variants over the expectation under the neutral mutation/drift/equilibrium theory. We suggest that this finding is primarily due to the relatively recent (in genetic time) agglomeration of previously separated tribal populations; efforts to test for agreement with the expectations of this theory by using data from modern cosmopolitan populations are exercises in futility. (10) All of these findings should characterize DNA variants in exons as more data become available, since the finding are the protein expression of such variants. PMID:3195587

Protein variants in Hiroshima and Nagasaki: tales of two cities.

PubMed

Neel, J V; Satoh, C; Smouse, P; Asakawa, J; Takahashi, N; Goriki, K; Fujita, M; Kageoka, T; Hazama, R

1988-12-01

The results of 1,465,423 allele product determinations based on blood samples from Hiroshima and Nagasaki, involving 30 different proteins representing 32 different gene products, are analyzed in a variety of ways, with the following conclusions: (1) Sibships and their parents are included in the sample. Our analysis reveals that statistical procedures designed to reduce the sample to equivalent independent genomes do not in population comparisons compensate for the familial cluster effect of rare variants. Accordingly, the data set was reduced to one representative of each sibship (937,427 allele products). (2) Both chi 2-type contrasts and a genetic distance measure (delta) reveal that rare variants (P less than .01) are collectively as effective as polymorphisms in establishing genetic differences between the two cities. (3) We suggest that rare variants that individually exhibit significant intercity differences are probably the legacy of tribal private polymorphisms that occurred during prehistoric times. (4) Despite the great differences in the known histories of the two cities, both the overall frequency of rare variants and the number of different rare variants are essentially identical in the two cities. (5) The well-known differences in locus variability are confirmed, now after adjustment for sample size differences for the various locus products; in this large series we failed to detect variants at only three of 29 loci for which sample size exceeded 23,000. (6) The number of alleles identified per locus correlates positively with subunit molecular weight. (7) Loci supporting genetic polymorphisms are characterized by more rare variants than are loci at which polymorphisms were not encountered. (8) Loci whose products do not appear to be essential for health support more variants than do loci the absence of whose product is detrimental to health. (9) There is a striking excess of rare variants over the expectation under the neutral mutation/drift/equilibrium theory. We suggest that this finding is primarily due to the relatively recent (in genetic time) agglomeration of previously separated tribal populations; efforts to test for agreement with the expectations of this theory by using data from modern cosmopolitan populations are exercises in futility. (10) All of these findings should characterize DNA variants in exons as more data become available, since the finding are the protein expression of such variants.

Allelic Expression of Deleterious Protein-Coding Variants across Human Tissues

PubMed Central

Kukurba, Kimberly R.; Zhang, Rui; Li, Xin; Smith, Kevin S.; Knowles, David A.; How Tan, Meng; Piskol, Robert; Lek, Monkol; Snyder, Michael; MacArthur, Daniel G.; Li, Jin Billy; Montgomery, Stephen B.

2014-01-01

Personal exome and genome sequencing provides access to loss-of-function and rare deleterious alleles whose interpretation is expected to provide insight into individual disease burden. However, for each allele, accurate interpretation of its effect will depend on both its penetrance and the trait's expressivity. In this regard, an important factor that can modify the effect of a pathogenic coding allele is its level of expression; a factor which itself characteristically changes across tissues. To better inform the degree to which pathogenic alleles can be modified by expression level across multiple tissues, we have conducted exome, RNA and deep, targeted allele-specific expression (ASE) sequencing in ten tissues obtained from a single individual. By combining such data, we report the impact of rare and common loss-of-function variants on allelic expression exposing stronger allelic bias for rare stop-gain variants and informing the extent to which rare deleterious coding alleles are consistently expressed across tissues. This study demonstrates the potential importance of transcriptome data to the interpretation of pathogenic protein-coding variants. PMID:24786518

Fast single-pass alignment and variant calling using sequencing data

USDA-ARS?s Scientific Manuscript database

Sequencing research requires efficient computation. Few programs use already known information about DNA variants when aligning sequence data to the reference map. New program findmap.f90 reads the previous variant list before aligning sequence, calling variant alleles, and summing the allele counts...

A new detection method for the K variant of butyrylcholinesterase based on PCR primer introduced restriction analysis (PCR-PIRA).

PubMed Central

Shibuta, K; Abe, M; Suzuki, T

1994-01-01

The K variant of human butyrylcholinesterase is caused by a G/A transition in the butyrylcholinesterase gene, which neither creates nor destroys any restriction site. In an attempt to detect the K variant both simply and rapidly, we developed a two step method of "PCR primer introduced restriction analysis" (PCR-PIRA). The first step was used to introduce a new Fun4HI site into the normal allele for a screening test, while the second step was performed to create a new MaeIII site on the variant allele for a specific test. This method thus enabled us to distinguish clearly the K variant from the normal allele, and also showed that the frequency of the K variant allele is 0.164 in the Japanese population. Images PMID:7966197

Systematic Cell-Based Phenotyping of Missense Alleles Empowers Rare Variant Association Studies: A Case for LDLR and Myocardial Infarction

PubMed Central

Schuberth, Christian; Won, Hong-Hee; Blattmann, Peter; Joggerst-Thomalla, Brigitte; Theiss, Susanne; Asselta, Rosanna; Duga, Stefano; Merlini, Pier Angelica; Ardissino, Diego; Lander, Eric S.; Gabriel, Stacey; Rader, Daniel J.; Peloso, Gina M.; Kathiresan, Sekar; Runz, Heiko

2015-01-01

A fundamental challenge to contemporary genetics is to distinguish rare missense alleles that disrupt protein functions from the majority of alleles neutral on protein activities. High-throughput experimental tools to securely discriminate between disruptive and non-disruptive missense alleles are currently missing. Here we establish a scalable cell-based strategy to profile the biological effects and likely disease relevance of rare missense variants in vitro. We apply this strategy to systematically characterize missense alleles in the low-density lipoprotein receptor (LDLR) gene identified through exome sequencing of 3,235 individuals and exome-chip profiling of 39,186 individuals. Our strategy reliably identifies disruptive missense alleles, and disruptive-allele carriers have higher plasma LDL-cholesterol (LDL-C). Importantly, considering experimental data refined the risk of rare LDLR allele carriers from 4.5- to 25.3-fold for high LDL-C, and from 2.1- to 20-fold for early-onset myocardial infarction. Our study generates proof-of-concept that systematic functional variant profiling may empower rare variant-association studies by orders of magnitude. PMID:25647241

Sensory Gating and Alpha-7 Nicotinic Receptor Gene Allelic Variants in Schizoaffective Disorder, Bipolar Type

PubMed Central

Martin, Laura F.; Leonard, Sherry; Hall, Mei-Hua; Tregellas, Jason R.; Freedman, Robert; Olincy, Ann

2011-01-01

Objectives Single nucleotide allelic variants in the promoter region of the chromosome 15 alpha-7 acetylcholine nicotinic receptor gene (CHRNA7) are associated with both schizophrenia and the P50 auditory evoked potential sensory gating deficit. The purpose of this study was to determine if CHRNA7 promoter allelic variants are also associated with abnormal P50 ratios in persons with schizoaffective disorder, bipolar type. Methods P50 auditory evoked potentials were recorded in a paired stimulus paradigm in 17 subjects with schizoaffective disorder, bipolar type. The P50 test to conditioning ratio was used as the measure of sensory gating. Mutation screening of the CHRNA7 promoter region was performed on the subjects’ DNA samples. Comparisons to previously obtained data from persons with schizophrenia and controls were made. Results Subjects with schizophrenia, regardless of allele status, had an abnormal mean P50 ratio. Subjects with schizoaffective disorder, bipolar type and a variant allele had an abnormal mean P50 ratio, whereas those schizoaffective subjects with the common alleles had a normal mean P50 ratio. Normal control subjects had a normal mean ratio, but controls with variant alleles had higher P50 ratios. Conclusions In persons with bipolar type schizoaffective disorder, CHRNA7 promoter region allelic variants are linked to the capacity to inhibit the P50 auditory evoked potential and thus are associated with a type of illness genetically and biologically more similar to schizophrenia. PMID:17192894

Association between sex, systemic iron variation and probability of Parkinson's disease.

PubMed

Mariani, S; Ventriglia, M; Simonelli, I; Bucossi, S; Siotto, M; Donno, S; Vernieri, F; Squitti, R

2016-01-01

Iron homeostasis appears altered in Parkinson's disease (PD). Recent genetic studies and meta-analyses have produced heterogeneous and inconclusive results. In order to verify the possible role of iron status in PD, we have screened some of the main metal gene variants, evaluated their effects on iron systemic status, and checked for possible interactions with PD. In 92 PD patients and 112 healthy controls, we screened the D544E and R793H variants of the ceruloplasmin gene (CP), the P589S variant of the transferrin gene (TF), and the H63D and C282Y variants of the HFE gene, encoding for homologous proteins, respectively. Furthermore, we analyzed serum concentrations of iron, copper and their related proteins. The genetic investigation revealed no significant differences in allelic and genotype distributions between patients and controls. Two different multivariable forward stepwise logistic models showed that, when the effect of sex is considered, an increase of the probability of having PD is associated with low iron concentration and Tf-saturation. This study provides new evidence of the involvement of iron metabolism in PD pathogenesis and reveals a biological effect of sex.

Common colorectal cancer risk alleles contribute to the multiple colorectal adenoma phenotype, but do not influence colonic polyposis in FAP.

PubMed

Cheng, Timothy H T; Gorman, Maggie; Martin, Lynn; Barclay, Ella; Casey, Graham; Saunders, Brian; Thomas, Huw; Clark, Sue; Tomlinson, Ian

2015-02-01

The presence of multiple (5-100) colorectal adenomas suggests an inherited predisposition, but the genetic aetiology of this phenotype is undetermined if patients test negative for Mendelian polyposis syndromes such as familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). We investigated whether 18 common colorectal cancer (CRC) predisposition single-nucleotide polymorphisms (SNPs) could help to explain some cases with multiple adenomas who phenocopied FAP or MAP, but had no pathogenic APC or MUTYH variant. No multiple adenoma case had an outlying number of CRC SNP risk alleles, but multiple adenoma patients did have a significantly higher number of risk alleles than population controls (P=5.7 × 10(-7)). The association was stronger in those with ≥10 adenomas. The CRC SNPs accounted for 4.3% of the variation in multiple adenoma risk, with three SNPs (rs6983267, rs10795668, rs3802842) explaining 3.0% of the variation. In FAP patients, the CRC risk score did not differ significantly from the controls, as we expected given the overwhelming effect of pathogenic germline APC variants on the phenotype of these cases. More unexpectedly, we found no evidence that the CRC SNPs act as modifier genes for the number of colorectal adenomas in FAP patients. In conclusion, common colorectal tumour risk alleles contribute to the development of multiple adenomas in patients without pathogenic germline APC or MUTYH variants. This phenotype may have 'polygenic' or monogenic origins. The risk of CRC in relatives of multiple adenoma cases is probably much lower for cases with polygenic disease, and this should be taken into account when counselling such patients.

Functional PMS2 Hybrid Alleles Containing a Pseudogene-Specific Missense Variant Trace Back to a Single Ancient Intrachromosomal Recombination Event

PubMed Central

Ganster, Christina; Wernstedt, Annekatrin; Kehrer-Sawatzki, Hildegard; Messiaen, Ludwine; Schmidt, Konrad; Rahner, Nils; Heinimann, Karl; Fonatsch, Christa; Zschocke, Johannes; Wimmer, Katharina

2012-01-01

Sequence exchange between PMS2 and its pseudogene PMS2CL, embedded in an inverted duplication on chromosome 7p22, has been reported to be an ongoing process that leads to functional PMS2 hybrid alleles containing PMS2- and PMS2CL-specific sequence variants at the 5′-and the 3′-end, respectively. The frequency of PMS2 hybrid alleles, their biological significance, and the mechanisms underlying their formation are largely unknown. Here we show that overall hybrid alleles account for one-third of 384 PMS2 alleles analyzed in individuals of different ethnic backgrounds. Depending on the population, 14–60% of hybrid alleles carry PMS2CL-specific sequences in exons 13–15, the remainder only in exon 15. We show that exons 13–15 hybrid alleles, named H1 hybrid alleles, constitute different haplotypes but trace back to a single ancient intrachromosomal recombination event with crossover. Taking advantage of an ancestral sequence variant specific for all H1 alleles we developed a simple gDNA-based polymerase chain reaction (PCR) assay that can be used to identify H1-allele carriers with high sensitivity and specificity (100 and 99%, respectively). Because H1 hybrid alleles harbor missense variant p.N775S of so far unknown functional significance, we assessed the H1-carrier frequency in 164 colorectal cancer patients. So far, we found no indication that the variant plays a major role with regard to cancer susceptibility. PMID:20186689

Functional PMS2 hybrid alleles containing a pseudogene-specific missense variant trace back to a single ancient intrachromosomal recombination event.

PubMed

Ganster, Christina; Wernstedt, Annekatrin; Kehrer-Sawatzki, Hildegard; Messiaen, Ludwine; Schmidt, Konrad; Rahner, Nils; Heinimann, Karl; Fonatsch, Christa; Zschocke, Johannes; Wimmer, Katharina

2010-05-01

Sequence exchange between PMS2 and its pseudogene PMS2CL, embedded in an inverted duplication on chromosome 7p22, has been reported to be an ongoing process that leads to functional PMS2 hybrid alleles containing PMS2- and PMS2CL-specific sequence variants at the 5'-and the 3'-end, respectively. The frequency of PMS2 hybrid alleles, their biological significance, and the mechanisms underlying their formation are largely unknown. Here we show that overall hybrid alleles account for one-third of 384 PMS2 alleles analyzed in individuals of different ethnic backgrounds. Depending on the population, 14-60% of hybrid alleles carry PMS2CL-specific sequences in exons 13-15, the remainder only in exon 15. We show that exons 13-15 hybrid alleles, named H1 hybrid alleles, constitute different haplotypes but trace back to a single ancient intrachromosomal recombination event with crossover. Taking advantage of an ancestral sequence variant specific for all H1 alleles we developed a simple gDNA-based polymerase chain reaction (PCR) assay that can be used to identify H1-allele carriers with high sensitivity and specificity (100 and 99%, respectively). Because H1 hybrid alleles harbor missense variant p.N775S of so far unknown functional significance, we assessed the H1-carrier frequency in 164 colorectal cancer patients. So far, we found no indication that the variant plays a major role with regard to cancer susceptibility. (c) 2010 Wiley-Liss, Inc.

Detection of Allelic Variants of the POLE and POLD1 Genes in Colorectal Cancer Patients

PubMed Central

LA, Pätzold; D, Bērziņa; Z, Daneberga; J, Gardovskis; E, Miklaševičs

2017-01-01

Abstract Incidence of colorectal cancer is high worldwide and it mostly occurs as an accumulation of environmental factors and genetic alterations. Hereditary colorectal cancer can develop as a part of a hereditary syndrome. There is a suspected correlation between colorectal cancer and allelic variants of the POLE and POLD1 genes. The aim of the present study was to look for associations between the allelic variants in the POLE and POLD1 genes and colorectal cancer. One thousand, seven hundred and forty-nine DNA samples from colorectal cancer patients were collected from 2002 to 2013. Samples were divided in three groups: hereditary colorectal cancer patients, patients with different hereditary cancer syndromes in their families and patients with no cancer history in their families. The DNA samples were screened for allelic variants of POLE rs483352909 and POLD1 rs39751463 using denaturing high performance liquid chromatography (DHPLC). All patients were negative for allelic variants rs483352909 of the POLE gene and rs397514632 of the POLD1 gene. One allelic variant rs373243003 in the POLE gene and one novel duplication of four nucleotides at the excision site between intron and exon (c.1384-5dupCCTA) in the POLD1 gene, was found. We could not detect or confirm the connection between the genetic variants in the POLD1 and POLE genes and colorectal cancer patients, but we detected a novel genetic variant with an unknown significance. PMID:29876237

Genetic variants of serum butyrylcholinesterase in Chilean Mapuche Indians.

PubMed

Acuña, M; Eaton, L; Ramírez, N R; Cifuentes, L; Llop, E

2003-05-01

We estimated the frequencies of serum butyrylcholinesterase (BChE) alleles in three tribes of Mapuche Indians from southern Chile, using enzymatic methods, and we estimated the frequency of allele BCHE*K in one tribe using primer reduced restriction analysis (PCR-PIRA). The three tribes have different degrees of European admixture, which is reflected in the observed frequencies of the atypical allele BCHE*A: 1.11% in Huilliches, 0.89% in Cuncos, and 0% in Pehuenches. This result is evidence in favor of the hypothesis that BCHE*A is absent in native Amerindians. The frequencies of BCHE*F were higher than in most reported studies (3.89%, 5.78%, and 4.41%, respectively). These results are probably due to an overestimation of the frequency of allele BCHE*F, since none of the 20 BCHE UF individuals (by the enzymatic test) individuals analyzed showed either of the two DNA base substitutions associated with this allele. Although enzymatic methods rarely detect the presence of allele BCHE*K, PCR-PIRA found the allele in an appreciable frequency (5.76%), although lower than that found in other ethnic groups. Since observed frequencies of unusual alleles correspond to estimated percentages of European admixture, it is likely that none of these unusual alleles were present in Mapuche Indians before the arrival of Europeans. Copyright 2003 Wiley-Liss, Inc.

Genomic Features That Predict Allelic Imbalance in Humans Suggest Patterns of Constraint on Gene Expression Variation

PubMed Central

Fédrigo, Olivier; Haygood, Ralph; Mukherjee, Sayan; Wray, Gregory A.

2009-01-01

Variation in gene expression is an important contributor to phenotypic diversity within and between species. Although this variation often has a genetic component, identification of the genetic variants driving this relationship remains challenging. In particular, measurements of gene expression usually do not reveal whether the genetic basis for any observed variation lies in cis or in trans to the gene, a distinction that has direct relevance to the physical location of the underlying genetic variant, and which may also impact its evolutionary trajectory. Allelic imbalance measurements identify cis-acting genetic effects by assaying the relative contribution of the two alleles of a cis-regulatory region to gene expression within individuals. Identification of patterns that predict commonly imbalanced genes could therefore serve as a useful tool and also shed light on the evolution of cis-regulatory variation itself. Here, we show that sequence motifs, polymorphism levels, and divergence levels around a gene can be used to predict commonly imbalanced genes in a human data set. Reduction of this feature set to four factors revealed that only one factor significantly differentiated between commonly imbalanced and nonimbalanced genes. We demonstrate that these results are consistent between the original data set and a second published data set in humans obtained using different technical and statistical methods. Finally, we show that variation in the single allelic imbalance-associated factor is partially explained by the density of genes in the region of a target gene (allelic imbalance is less probable for genes in gene-dense regions), and, to a lesser extent, the evenness of expression of the gene across tissues and the magnitude of negative selection on putative regulatory regions of the gene. These results suggest that the genomic distribution of functional cis-regulatory variants in the human genome is nonrandom, perhaps due to local differences in evolutionary constraint. PMID:19506001

Structure of allelic variants of subtype 5 of histone H1 in pea Pisum sativum L.

PubMed

Bogdanova, V S; Lester, D R; Berdnikov, V A; Andersson, I

2005-06-01

The pea genome contains seven histone H1 genes encoding different subtypes. Previously, the DNA sequence of only one gene, His1, coding for the subtype H1-1, had been identified. We isolated a histone H1 allele from a pea genomic DNA library. Data from the electrophoretic mobility of the pea H1 subtypes and their N-bromosuccinimide cleavage products indicated that the newly isolated gene corresponded to the H1-5 subtype encoded by His5. We confirmed this result by sequencing the gene from three pea lines with H1-5 allelic variants of altered electrophoretic mobility. The allele of the slow H1-5 variant differed from the standard allele by a nucleotide substitution that caused the replacement of the positively charged lysine with asparagine in the DNA-interacting domain of the histone molecule. A temperature-related occurrence had previously been demonstrated for this H1-5 variant in a study on a worldwide collection of pea germplasm. The variant tended to occur at higher frequencies in geographic regions with a cold climate. The fast allelic variant of H1-5 displayed a deletion resulting in the loss of a duplicated pentapeptide in the C-terminal domain.

Mining the LIPG Allelic Spectrum Reveals the Contribution of Rare and Common Regulatory Variants to HDL Cholesterol

PubMed Central

Raghavan, Avanthi; Neeli, Hemanth; Jin, Weijun; Badellino, Karen O.; Demissie, Serkalem; Manning, Alisa K.; DerOhannessian, Stephanie L.; Wolfe, Megan L.; Cupples, L. Adrienne; Li, Mingyao; Kathiresan, Sekar; Rader, Daniel J.

2011-01-01

Genome-wide association studies (GWAS) have successfully identified loci associated with quantitative traits, such as blood lipids. Deep resequencing studies are being utilized to catalogue the allelic spectrum at GWAS loci. The goal of these studies is to identify causative variants and missing heritability, including heritability due to low frequency and rare alleles with large phenotypic impact. Whereas rare variant efforts have primarily focused on nonsynonymous coding variants, we hypothesized that noncoding variants in these loci are also functionally important. Using the HDL-C gene LIPG as an example, we explored the effect of regulatory variants identified through resequencing of subjects at HDL-C extremes on gene expression, protein levels, and phenotype. Resequencing a portion of the LIPG promoter and 5′ UTR in human subjects with extreme HDL-C, we identified several rare variants in individuals from both extremes. Luciferase reporter assays were used to measure the effect of these rare variants on LIPG expression. Variants conferring opposing effects on gene expression were enriched in opposite extremes of the phenotypic distribution. Minor alleles of a common regulatory haplotype and noncoding GWAS SNPs were associated with reduced plasma levels of the LIPG gene product endothelial lipase (EL), consistent with its role in HDL-C catabolism. Additionally, we found that a common nonfunctional coding variant associated with HDL-C (rs2000813) is in linkage disequilibrium with a 5′ UTR variant (rs34474737) that decreases LIPG promoter activity. We attribute the gene regulatory role of rs34474737 to the observed association of the coding variant with plasma EL levels and HDL-C. Taken together, the findings show that both rare and common noncoding regulatory variants are important contributors to the allelic spectrum in complex trait loci. PMID:22174694

Rare Coding Variants in ANGPTL6 Are Associated with Familial Forms of Intracranial Aneurysm.

PubMed

Bourcier, Romain; Le Scouarnec, Solena; Bonnaud, Stéphanie; Karakachoff, Matilde; Bourcereau, Emmanuelle; Heurtebise-Chrétien, Sandrine; Menguy, Céline; Dina, Christian; Simonet, Floriane; Moles, Alexis; Lenoble, Cédric; Lindenbaum, Pierre; Chatel, Stéphanie; Isidor, Bertrand; Génin, Emmanuelle; Deleuze, Jean-François; Schott, Jean-Jacques; Le Marec, Hervé; Loirand, Gervaise; Desal, Hubert; Redon, Richard

2018-01-04

Intracranial aneurysms (IAs) are acquired cerebrovascular abnormalities characterized by localized dilation and wall thinning in intracranial arteries, possibly leading to subarachnoid hemorrhage and severe outcome in case of rupture. Here, we identified one rare nonsense variant (c.1378A>T) in the last exon of ANGPTL6 (Angiopoietin-Like 6)-which encodes a circulating pro-angiogenic factor mainly secreted from the liver-shared by the four tested affected members of a large pedigree with multiple IA-affected case subjects. We showed a 50% reduction of ANGPTL6 serum concentration in individuals heterozygous for the c.1378A>T allele (p.Lys460Ter) compared to relatives homozygous for the normal allele, probably due to the non-secretion of the truncated protein produced by the c.1378A>T transcripts. Sequencing ANGPTL6 in a series of 94 additional index case subjects with familial IA identified three other rare coding variants in five case subjects. Overall, we detected a significant enrichment (p = 0.023) in rare coding variants within this gene among the 95 index case subjects with familial IA, compared to a reference population of 404 individuals with French ancestry. Among the 6 recruited families, 12 out of 13 (92%) individuals carrying IA also carry such variants in ANGPTL6, versus 15 out of 41 (37%) unaffected ones. We observed a higher rate of individuals with a history of high blood pressure among affected versus healthy individuals carrying ANGPTL6 variants, suggesting that ANGPTL6 could trigger cerebrovascular lesions when combined with other risk factors such as hypertension. Altogether, our results indicate that rare coding variants in ANGPTL6 are causally related to familial forms of IA. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Distortion of maternal-fetal angiotensin II type 1 receptor allele transmission in pre-eclampsia.

PubMed Central

Morgan, L; Crawshaw, S; Baker, P N; Brookfield, J F; Broughton Pipkin, F; Kalsheker, N

1998-01-01

OBJECTIVE: To investigate the fetal angiotensin II type 1 receptor genotype in pre-eclampsia. DESIGN: Case-control study. POPULATION: Forty-one maternal-fetal pairs from pre-eclamptic pregnancies and 80 maternal-fetal pairs from normotensive pregnancies. METHODS: Maternal and fetal DNA was genotyped at three diallelic polymorphisms, at nucleotides 573, 1062, and 1166, in the coding exon of the angiotensin II type 1 receptor gene, and at a dinucleotide repeat polymorphism in its 3' flanking region. RESULTS: Allele and genotype frequencies at the four polymorphic regions investigated did not differ between pre-eclamptic and normotensive groups, in either fetal or maternal samples. Mothers heterozygous for the dinucleotide repeat allele designated A4 transmitted this allele to the fetus in 15 of 18 informative pre-eclamptic pregnancies and in eight of 26 normotensive pregnancies. This was greater than the expected probability in pre-eclamptic pregnancies (p=0.04) and less than expected in normotensive pregnancies (p<0.005). The 573T variant, which is in partial linkage disequilibrium with the A4 allele, showed a similar distortion of maternal-fetal transmission. CONCLUSION: Angiotensin II type 1 receptor gene expression in the fetus may contribute to the aetiology of pre-eclampsia. It is unclear whether susceptibility is conferred by the fetal genotype acting alone, or by allele sharing by mother and fetus. Possible mechanisms for the effect of the angiotensin II type 1 receptor gene are suggested by the association of the 573T variant with low levels of surface receptor expression on platelets. If receptor expression is similarly genetically determined in the placenta, responsiveness to angiotensin II may be affected, with the potential to influence placentation or placental prostaglandin secretion. PMID:9719367

Preferential Allele Expression Analysis Identifies Shared Germline and Somatic Driver Genes in Advanced Ovarian Cancer

PubMed Central

Halabi, Najeeb M.; Martinez, Alejandra; Al-Farsi, Halema; Mery, Eliane; Puydenus, Laurence; Pujol, Pascal; Khalak, Hanif G.; McLurcan, Cameron; Ferron, Gwenael; Querleu, Denis; Al-Azwani, Iman; Al-Dous, Eman; Mohamoud, Yasmin A.; Malek, Joel A.; Rafii, Arash

2016-01-01

Identifying genes where a variant allele is preferentially expressed in tumors could lead to a better understanding of cancer biology and optimization of targeted therapy. However, tumor sample heterogeneity complicates standard approaches for detecting preferential allele expression. We therefore developed a novel approach combining genome and transcriptome sequencing data from the same sample that corrects for sample heterogeneity and identifies significant preferentially expressed alleles. We applied this analysis to epithelial ovarian cancer samples consisting of matched primary ovary and peritoneum and lymph node metastasis. We find that preferentially expressed variant alleles include germline and somatic variants, are shared at a relatively high frequency between patients, and are in gene networks known to be involved in cancer processes. Analysis at a patient level identifies patient-specific preferentially expressed alleles in genes that are targets for known drugs. Analysis at a site level identifies patterns of site specific preferential allele expression with similar pathways being impacted in the primary and metastasis sites. We conclude that genes with preferentially expressed variant alleles can act as cancer drivers and that targeting those genes could lead to new therapeutic strategies. PMID:26735499

Extremely hypomorphic and severe deep intronic variants in the ABCA4 locus result in varying Stargardt disease phenotypes.

PubMed

Zernant, Jana; Lee, Winston; Nagasaki, Takayuki; Collison, Frederick T; Fishman, Gerald A; Bertelsen, Mette; Rosenberg, Thomas; Gouras, Peter; Tsang, Stephen H; Allikmets, Rando

2018-05-30

Autosomal recessive Stargardt disease (STGD1, MIM 248200) is caused by mutations in the ABCA4 gene. Complete sequencing of the ABCA4 locus in STGD1 patients identifies two expected disease-causing alleles in ~75% of patients and only one mutation in ~15% of patients. Recently, many possibly pathogenic variants in deep intronic sequences of ABCA4 have been identified in the latter group. We extended our analyses of deep intronic ABCA4 variants and determined that one of these, c.4253+43G>A (rs61754045), is present in 29/1155 (2.6%) of STGD1 patients. The variant is found at statistically significantly higher frequency in patients with only one pathogenic ABCA4 allele, 23/160 (14.38%), MAF=0.072, compared to MAF=0.013 in all STGD1 cases and MAF=0.006 in the matching general population (P<1x10-7). The variant, which is not predicted to have any effect on splicing, is the first reported intronic "extremely hypomorphic allele" in the ABCA4 locus; i.e., it is pathogenic only when in trans with a loss-of-function ABCA4 allele. It results in a distinct clinical phenotype characterized by late-onset of symptoms and foveal sparing. In ~70% of cases the variant was allelic with the c.6006-609T>A (rs575968112) variant, which was deemed non-pathogenic. Another rare deep intronic variant, c.5196+1056A>G (rs886044749), found in 5/834 (0.6%) of STGD1 cases is, conversely, a severe allele. This study determines pathogenicity for three non-coding variants in STGD1 patients of European descent accounting for ~3% of the disease. Defining disease-associated alleles in the non-coding sequences of the ABCA4 locus can be accomplished by integrated clinical and genetic analyses. Cold Spring Harbor Laboratory Press.

TaGW2-6A allelic variation contributes to grain size possibly by regulating the expression of cytokinins and starch-related genes in wheat.

PubMed

Geng, Juan; Li, Liqun; Lv, Qian; Zhao, Yi; Liu, Yan; Zhang, Li; Li, Xuejun

2017-12-01

Functional allelic variants of TaGW2 - 6A produce large grains, possibly via changes in endosperm cells and dry matter by regulating the expression of cytokinins and starch-related genes via the ubiquitin-proteasome system. In wheat, TaGW2-6A coding region allelic variants are closely related to the grain width and weight, but how this region affects grain development has not been fully elucidated; thus, we explored its influence on grain development based mainly on histological and grain filling analyses. We found that the insertion type (NIL31) TaGW2-6A allelic variants exhibited increases in cell numbers and cell size, thereby resulting in a larger (wider) grain size with an accelerated grain milk filling rate, and increases in grain width and weight. We also found that cytokinin (CK) synthesis genes and key starch biosynthesis enzyme AGPase genes were significantly upregulated in the TaGW2-6A allelic variants, while CK degradation genes and starch biosynthesis-negative regulators were downregulated in the TaGW2-6A allelic variants, which was consistent with the changes in cells and grain filling. Thus, we speculate that TaGW2-6A allelic variants are linked with CK signaling, but they also influence the accumulation of starch by regulating the expression of related genes via the ubiquitin-proteasome system to control the grain size and grain weight.

Influence of cytarabine metabolic pathway polymorphisms in acute myeloid leukemia induction treatment.

PubMed

Megías-Vericat, Juan Eduardo; Montesinos, Pau; Herrero, María José; Moscardó, Federico; Bosó, Virginia; Martínez-Cuadrón, David; Rojas, Luis; Rodríguez-Veiga, Rebeca; Boluda, Blanca; Sendra, Luis; Cervera, José; Poveda, José Luis; Sanz, Miguel Ángel; Aliño, Salvador F

2017-12-01

Cytarabine is considered the most effective chemotherapeutic option in acute myeloid leukemia (AML). The impact of 10 polymorphisms in cytarabine metabolic pathway genes were evaluated in 225 adult de novo AML patients. Variant alleles of DCK rs2306744 and CDA rs602950 showed higher complete remission (p = .024, p = .045), with lower survival rates for variant alleles of CDA rs2072671 (p = .015, p = .045, p = .032), rs3215400 (p = .033) and wild-type genotype of rs602950 (p = .039, .014). Induction death (p = .033) and lower survival rates (p = .021, p = .047) were correlated to RRM1 rs9937 variant allele. In addition, variant alleles of CDA rs532545 and rs602950 were related to skin toxicity (p = .031, p = .049) and mucositis to DCK rs2306744 minor allele (p = .046). Other toxicities associated to variant alleles were hepatotoxicity to NT5C2 rs11598702 (p = .032), lung toxicity (p = .031) and thrombocytopenia to DCK rs4694362 (p = .046). This study supports the interest of cytarabine pathway polymorphisms regarding efficacy and toxicity of AML therapy in a coherent integrated manner.

CYP3A4 allelic variants with amino acid substitutions in exons 7 and 12: evidence for an allelic variant with altered catalytic activity.

PubMed

Sata, F; Sapone, A; Elizondo, G; Stocker, P; Miller, V P; Zheng, W; Raunio, H; Crespi, C L; Gonzalez, F J

2000-01-01

To determine the existence of mutant and variant CgammaP3A4 alleles in three racial groups and to assess functions of the variant alleles by complementary deoxyribonucleic acid (cDNA) expression. A bacterial artificial chromosome that contains the complete CgammaP3A4 gene was isolated and the exons and surrounding introns were directly sequenced to develop primers to polymerase chain reaction (PCR) amplify and sequence the gene from lymphocyte DNA. DNA samples from Chinese, black, and white subjects were screened. Mutating the affected amino acid in the wild-type cDNA and expressing the variant enzyme with use of the baculovirus system was used to functionally evaluate the variant allele having a missense mutation. To investigate the existence of mutant and variant CgammaP3A4 alleles in humans, all 13 exons and the 5'-flanking region of the human CgammaP3A4 gene in three racial groups were sequenced and four alleles were identified. An A-->G point mutation in the 5'-flanking region of the human CgammaP3A4 gene, designated CgammaP3A4*1B, was found in the three different racial groups. The frequency of this allele in a white population was 4.2%, whereas it was 66.7% in black subjects. The CgammaP3A4*1B allele was not found in Chinese subjects. A second variant allele, designated CgammaP3A4*2, having a Ser222Pro change, was found at a frequency of 2.7% in the white population and was absent in the black subjects and Chinese subjects analyzed. Baculovirus-directed cDNA expression revealed that the CYP3A4*2 P450 had a lower intrinsic clearance for the CYP3A4 substrate nifedipine compared with the wild-type enzyme but was not significantly different from the wild-type enzyme for testosterone 6beta-hydroxylation. Another rare allele, designated CgammaP3A4*3, was found in a single Chinese subject who had a Met445Thr change in the conserved heme-binding region of the P450. These are the first examples of potential function polymorphisms resulting from missense mutations in the CgammaP3A4 gene. The CgammaP3A4*2 allele was found to encode a P450 with substrate-dependent altered kinetics compared with the wild-type P450.

Searching for missing heritability: Designing rare variant association studies

PubMed Central

Zuk, Or; Schaffner, Stephen F.; Samocha, Kaitlin; Do, Ron; Hechter, Eliana; Kathiresan, Sekar; Daly, Mark J.; Neale, Benjamin M.; Sunyaev, Shamil R.; Lander, Eric S.

2014-01-01

Genetic studies have revealed thousands of loci predisposing to hundreds of human diseases and traits, revealing important biological pathways and defining novel therapeutic hypotheses. However, the genes discovered to date typically explain less than half of the apparent heritability. Because efforts have largely focused on common genetic variants, one hypothesis is that much of the missing heritability is due to rare genetic variants. Studies of common variants are typically referred to as genomewide association studies, whereas studies of rare variants are often simply called sequencing studies. Because they are actually closely related, we use the terms common variant association study (CVAS) and rare variant association study (RVAS). In this paper, we outline the similarities and differences between RVAS and CVAS and describe a conceptual framework for the design of RVAS. We apply the framework to address key questions about the sample sizes needed to detect association, the relative merits of testing disruptive alleles vs. missense alleles, frequency thresholds for filtering alleles, the value of predictors of the functional impact of missense alleles, the potential utility of isolated populations, the value of gene-set analysis, and the utility of de novo mutations. The optimal design depends critically on the selection coefficient against deleterious alleles and thus varies across genes. The analysis shows that common variant and rare variant studies require similarly large sample collections. In particular, a well-powered RVAS should involve discovery sets with at least 25,000 cases, together with a substantial replication set. PMID:24443550

Rare and low-frequency coding variants alter human adult height

PubMed Central

Marouli, Eirini; Graff, Mariaelisa; Medina-Gomez, Carolina; Lo, Ken Sin; Wood, Andrew R; Kjaer, Troels R; Fine, Rebecca S; Lu, Yingchang; Schurmann, Claudia; Highland, Heather M; Rüeger, Sina; Thorleifsson, Gudmar; Justice, Anne E; Lamparter, David; Stirrups, Kathleen E; Turcot, Valérie; Young, Kristin L; Winkler, Thomas W; Esko, Tõnu; Karaderi, Tugce; Locke, Adam E; Masca, Nicholas GD; Ng, Maggie CY; Mudgal, Poorva; Rivas, Manuel A; Vedantam, Sailaja; Mahajan, Anubha; Guo, Xiuqing; Abecasis, Goncalo; Aben, Katja K; Adair, Linda S; Alam, Dewan S; Albrecht, Eva; Allin, Kristine H; Allison, Matthew; Amouyel, Philippe; Appel, Emil V; Arveiler, Dominique; Asselbergs, Folkert W; Auer, Paul L; Balkau, Beverley; Banas, Bernhard; Bang, Lia E; Benn, Marianne; Bergmann, Sven; Bielak, Lawrence F; Blüher, Matthias; Boeing, Heiner; Boerwinkle, Eric; Böger, Carsten A; Bonnycastle, Lori L; Bork-Jensen, Jette; Bots, Michiel L; Bottinger, Erwin P; Bowden, Donald W; Brandslund, Ivan; Breen, Gerome; Brilliant, Murray H; Broer, Linda; Burt, Amber A; Butterworth, Adam S; Carey, David J; Caulfield, Mark J; Chambers, John C; Chasman, Daniel I; Chen, Yii-Der Ida; Chowdhury, Rajiv; Christensen, Cramer; Chu, Audrey Y; Cocca, Massimiliano; Collins, Francis S; Cook, James P; Corley, Janie; Galbany, Jordi Corominas; Cox, Amanda J; Cuellar-Partida, Gabriel; Danesh, John; Davies, Gail; de Bakker, Paul IW; de Borst, Gert J.; de Denus, Simon; de Groot, Mark CH; de Mutsert, Renée; Deary, Ian J; Dedoussis, George; Demerath, Ellen W; den Hollander, Anneke I; Dennis, Joe G; Di Angelantonio, Emanuele; Drenos, Fotios; Du, Mengmeng; Dunning, Alison M; Easton, Douglas F; Ebeling, Tapani; Edwards, Todd L; Ellinor, Patrick T; Elliott, Paul; Evangelou, Evangelos; Farmaki, Aliki-Eleni; Faul, Jessica D; Feitosa, Mary F; Feng, Shuang; Ferrannini, Ele; Ferrario, Marco M; Ferrieres, Jean; Florez, Jose C; Ford, Ian; Fornage, Myriam; Franks, Paul W; Frikke-Schmidt, Ruth; Galesloot, Tessel E; Gan, Wei; Gandin, Ilaria; Gasparini, Paolo; Giedraitis, Vilmantas; Giri, Ayush; Girotto, Giorgia; Gordon, Scott D; Gordon-Larsen, Penny; Gorski, Mathias; Grarup, Niels; Grove, Megan L.; Gudnason, Vilmundur; Gustafsson, Stefan; Hansen, Torben; Harris, Kathleen Mullan; Harris, Tamara B; Hattersley, Andrew T; Hayward, Caroline; He, Liang; Heid, Iris M; Heikkilä, Kauko; Helgeland, Øyvind; Hernesniemi, Jussi; Hewitt, Alex W; Hocking, Lynne J; Hollensted, Mette; Holmen, Oddgeir L; Hovingh, G. Kees; Howson, Joanna MM; Hoyng, Carel B; Huang, Paul L; Hveem, Kristian; Ikram, M. Arfan; Ingelsson, Erik; Jackson, Anne U; Jansson, Jan-Håkan; Jarvik, Gail P; Jensen, Gorm B; Jhun, Min A; Jia, Yucheng; Jiang, Xuejuan; Johansson, Stefan; Jørgensen, Marit E; Jørgensen, Torben; Jousilahti, Pekka; Jukema, J Wouter; Kahali, Bratati; Kahn, René S; Kähönen, Mika; Kamstrup, Pia R; Kanoni, Stavroula; Kaprio, Jaakko; Karaleftheri, Maria; Kardia, Sharon LR; Karpe, Fredrik; Kee, Frank; Keeman, Renske; Kiemeney, Lambertus A; Kitajima, Hidetoshi; Kluivers, Kirsten B; Kocher, Thomas; Komulainen, Pirjo; Kontto, Jukka; Kooner, Jaspal S; Kooperberg, Charles; Kovacs, Peter; Kriebel, Jennifer; Kuivaniemi, Helena; Küry, Sébastien; Kuusisto, Johanna; La Bianca, Martina; Laakso, Markku; Lakka, Timo A; Lange, Ethan M; Lange, Leslie A; Langefeld, Carl D; Langenberg, Claudia; Larson, Eric B; Lee, I-Te; Lehtimäki, Terho; Lewis, Cora E; Li, Huaixing; Li, Jin; Li-Gao, Ruifang; Lin, Honghuang; Lin, Li-An; Lin, Xu; Lind, Lars; Lindström, Jaana; Linneberg, Allan; Liu, Yeheng; Liu, Yongmei; Lophatananon, Artitaya; Luan, Jian'an; Lubitz, Steven A; Lyytikäinen, Leo-Pekka; Mackey, David A; Madden, Pamela AF; Manning, Alisa K; Männistö, Satu; Marenne, Gaëlle; Marten, Jonathan; Martin, Nicholas G; Mazul, Angela L; Meidtner, Karina; Metspalu, Andres; Mitchell, Paul; Mohlke, Karen L; Mook-Kanamori, Dennis O; Morgan, Anna; Morris, Andrew D; Morris, Andrew P; Müller-Nurasyid, Martina; Munroe, Patricia B; Nalls, Mike A; Nauck, Matthias; Nelson, Christopher P; Neville, Matt; Nielsen, Sune F; Nikus, Kjell; Njølstad, Pål R; Nordestgaard, Børge G; Ntalla, Ioanna; O'Connel, Jeffrey R; Oksa, Heikki; Loohuis, Loes M Olde; Ophoff, Roel A; Owen, Katharine R; Packard, Chris J; Padmanabhan, Sandosh; Palmer, Colin NA; Pasterkamp, Gerard; Patel, Aniruddh P; Pattie, Alison; Pedersen, Oluf; Peissig, Peggy L; Peloso, Gina M; Pennell, Craig E; Perola, Markus; Perry, James A; Perry, John R.B.; Person, Thomas N; Pirie, Ailith; Polasek, Ozren; Posthuma, Danielle; Raitakari, Olli T; Rasheed, Asif; Rauramaa, Rainer; Reilly, Dermot F; Reiner, Alex P; Renström, Frida; Ridker, Paul M; Rioux, John D; Robertson, Neil; Robino, Antonietta; Rolandsson, Olov; Rudan, Igor; Ruth, Katherine S; Saleheen, Danish; Salomaa, Veikko; Samani, Nilesh J; Sandow, Kevin; Sapkota, Yadav; Sattar, Naveed; Schmidt, Marjanka K; Schreiner, Pamela J; Schulze, Matthias B; Scott, Robert A; Segura-Lepe, Marcelo P; Shah, Svati; Sim, Xueling; Sivapalaratnam, Suthesh; Small, Kerrin S; Smith, Albert Vernon; Smith, Jennifer A; Southam, Lorraine; Spector, Timothy D; Speliotes, Elizabeth K; Starr, John M; Steinthorsdottir, Valgerdur; Stringham, Heather M; Stumvoll, Michael; Surendran, Praveen; Hart, Leen M ‘t; Tansey, Katherine E; Tardif, Jean-Claude; Taylor, Kent D; Teumer, Alexander; Thompson, Deborah J; Thorsteinsdottir, Unnur; Thuesen, Betina H; Tönjes, Anke; Tromp, Gerard; Trompet, Stella; Tsafantakis, Emmanouil; Tuomilehto, Jaakko; Tybjaerg-Hansen, Anne; Tyrer, Jonathan P; Uher, Rudolf; Uitterlinden, André G; Ulivi, Sheila; van der Laan, Sander W; Van Der Leij, Andries R; van Duijn, Cornelia M; van Schoor, Natasja M; van Setten, Jessica; Varbo, Anette; Varga, Tibor V; Varma, Rohit; Edwards, Digna R Velez; Vermeulen, Sita H; Vestergaard, Henrik; Vitart, Veronique; Vogt, Thomas F; Vozzi, Diego; Walker, Mark; Wang, Feijie; Wang, Carol A; Wang, Shuai; Wang, Yiqin; Wareham, Nicholas J; Warren, Helen R; Wessel, Jennifer; Willems, Sara M; Wilson, James G; Witte, Daniel R; Woods, Michael O; Wu, Ying; Yaghootkar, Hanieh; Yao, Jie; Yao, Pang; Yerges-Armstrong, Laura M; Young, Robin; Zeggini, Eleftheria; Zhan, Xiaowei; Zhang, Weihua; Zhao, Jing Hua; Zhao, Wei; Zhao, Wei; Zheng, He; Zhou, Wei; Rotter, Jerome I; Boehnke, Michael; Kathiresan, Sekar; McCarthy, Mark I; Willer, Cristen J; Stefansson, Kari; Borecki, Ingrid B; Liu, Dajiang J; North, Kari E; Heard-Costa, Nancy L; Pers, Tune H; Lindgren, Cecilia M; Oxvig, Claus; Kutalik, Zoltán; Rivadeneira, Fernando; Loos, Ruth JF; Frayling, Timothy M; Hirschhorn, Joel N; Deloukas, Panos; Lettre, Guillaume

2016-01-01

Summary Height is a highly heritable, classic polygenic trait with ∼700 common associated variants identified so far through genome-wide association studies. Here, we report 83 height-associated coding variants with lower minor allele frequencies (range of 0.1-4.8%) and effects of up to 2 cm/allele (e.g. in IHH, STC2, AR and CRISPLD2), >10 times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (+1-2 cm/allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes mutated in monogenic growth disorders and highlight new biological candidates (e.g. ADAMTS3, IL11RA, NOX4) and pathways (e.g. proteoglycan/glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate to large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways. PMID:28146470

Quantifying penetrance in a dominant disease gene using large population control cohorts

PubMed Central

Minikel, Eric Vallabh; Vallabh, Sonia M.; Lek, Monkol; Estrada, Karol; Samocha, Kaitlin E.; Sathirapongsasuti, J. Fah; McLean, Cory Y.; Tung, Joyce Y.; Yu, Linda P.C.; Gambetti, Pierluigi; Blevins, Janis; Zhang, Shulin; Cohen, Yvonne; Chen, Wei; Yamada, Masahito; Hamaguchi, Tsuyoshi; Sanjo, Nobuo; Mizusawa, Hidehiro; Nakamura, Yosikazu; Kitamoto, Tetsuyuki; Collins, Steven J.; Boyd, Alison; Will, Robert G.; Knight, Richard; Ponto, Claudia; Zerr, Inga; Kraus, Theo F.J.; Eigenbrod, Sabina; Giese, Armin; Calero, Miguel; de Pedro-Cuesta, Jesús; Haïk, Stéphane; Laplanche, Jean-Louis; Bouaziz-Amar, Elodie; Brandel, Jean-Philippe; Capellari, Sabina; Parchi, Piero; Poleggi, Anna; Ladogana, Anna; O'Donnell-Luria, Anne H.; Karczewski, Konrad J.; Marshall, Jamie L.; Boehnke, Michael; Laakso, Markku; Mohlke, Karen L.; Kähler, Anna; Chambert, Kimberly; McCarroll, Steven; Sullivan, Patrick F.; Hultman, Christina M.; Purcell, Shaun M.; Sklar, Pamela; van der Lee, Sven J.; Rozemuller, Annemieke; Jansen, Casper; Hofman, Albert; Kraaij, Robert; van Rooij, Jeroen G.J.; Ikram, M. Arfan; Uitterlinden, André G.; van Duijn, Cornelia M.; Daly, Mark J.; MacArthur, Daniel G.

2016-01-01

More than 100,000 genetic variants are reported to cause Mendelian disease in humans, but the penetrance - the probability that a carrier of the purported disease-causing genotype will indeed develop the disease - is generally unknown. Here we assess the impact of variants in the prion protein gene (PRNP) on the risk of prion disease by analyzing 16,025 prion disease cases, 60,706 population control exomes, and 531,575 individuals genotyped by 23andMe, Inc. We show that missense variants in PRNP previously reported to be pathogenic are at least 30× more common in the population than expected based on genetic prion disease prevalence. While some of this excess can be attributed to benign variants falsely assigned as pathogenic, other variants have genuine effects on disease susceptibility but confer lifetime risks ranging from <0.1% to ~100%. We also show that truncating variants in PRNP have position-dependent effects, with true loss-of-function alleles found in healthy older individuals, supporting the safety of therapeutic suppression of prion protein expression. PMID:26791950

Triglyceride associated polymorphisms of the APOA5 gene have very different allele frequencies in Pune, India compared to Europeans

PubMed Central

Chandak, Giriraj R; Ward, Kirsten J; Yajnik, Chittaranjan S; Pandit, Anand N; Bavdekar, Ashish; Joglekar, Charu V; Fall, Caroline HD; Mohankrishna, P; Wilkin, Terence J; Metcalf, Bradley S; Weedon, Michael N; Frayling, Timothy M; Hattersley, Andrew T

2006-01-01

Background The APOA5 gene variants, -1131T>C and S19W, are associated with altered triglyceride concentrations in studies of subjects of Caucasian and East Asian descent. There are few studies of these variants in South Asians. We investigated whether the two APOA5 variants also show similar association with various lipid parameters in Indian population as in the UK white subjects. Methods We genotyped 557 Indian adults from Pune, India, and 237 UK white adults for -1131T>C and S19W variants in the APOA5 gene, compared their allelic and genotype frequency and determined their association with fasting serum triglycerides, total cholesterol, HDL and LDL cholesterol levels using univariate general linear analysis. APOC3 SstI polymorphism was also analyzed in 175 Pune Indian subjects for analysis of linkage disequilibrium with the APOA5 variants. Results The APOA5 -1131C allele was more prevalent in Indians from Pune (Pune Indians) compared to UK white subjects (allele frequency 20% vs. 4%, p = 0.00001), whereas the 19W allele was less prevalent (3% vs. 6% p = 0.0015). Patterns of linkage disequilibrium between the two variants were similar between the two populations and confirmed that they occur on two different haplotypes. In Pune Indians, the presence of -1131C allele and the 19W allele was associated with a 19% and 15% increase respectively in triglyceride concentrations although only -1131C was significant (p = 0.0003). This effect size was similar to that seen in the UK white subjects. Analysis of the APOC3 SstI polymorphism in 175 Pune Indian subjects showed that this variant is not in appreciable linkage disequilibrium with the APOA5 -1131T>C variant (r2 = 0.07). Conclusion This is the first study to look at the role of APOA5 in Asian Indian subjects that reside in India. The -1131C allele is more prevalent and the 19W allele is less prevalent in Pune Indians compared to UK Caucasians. We confirm that the APOA5 variants are associated with triglyceride levels independent of ethnicity and that this association is similar in magnitude in Asian Indians and Caucasians. The -1131C allele is present in 36% of the Pune Indian population making it a powerful marker for looking at the role of elevated triglycerides in important conditions such as pancreatitis, diabetes and coronary heart disease. PMID:17032446

Hfq variant with altered RNA binding functions

PubMed Central

Ziolkowska, Katarzyna; Derreumaux, Philippe; Folichon, Marc; Pellegrini, Olivier; Régnier, Philippe; Boni, Irina V.; Hajnsdorf, Eliane

2006-01-01

The interaction between Hfq and RNA is central to multiple regulatory processes. Using site-directed mutagenesis, we have found a missense mutation in Hfq (V43R) which strongly affects2 the RNA binding capacity of the Hfq protein and its ability to stimulate poly(A) tail elongation by poly(A)-polymerase in vitro. In vivo, overexpression of this Hfq variant fails to stimulate rpoS–lacZ expression and does not restore a normal growth rate in hfq null mutant. Cells in which the wild-type gene has been replaced by the hfqV43R allele exhibit a phenotype intermediate between those of the wild-type and of the hfq minus or null strains. This missense mutation derepresses Hfq synthesis. However, not all Hfq functions are affected by this mutation. For example, HfqV43R represses OppA synthesis as strongly as the wild-type protein. The dominant negative effect of the V43R mutation over the wild-type allele suggests that hexamers containing variant and genuine subunits are presumably not functional. Finally, molecular dynamics studies indicate that the V43R substitution mainly changes the position of the K56 and Y55 side chains involved in the Hfq–RNA interaction but has probably no effect on the folding and the oligomerization of the protein. PMID:16449205

Rare and low-frequency coding variants alter human adult height.

PubMed

Marouli, Eirini; Graff, Mariaelisa; Medina-Gomez, Carolina; Lo, Ken Sin; Wood, Andrew R; Kjaer, Troels R; Fine, Rebecca S; Lu, Yingchang; Schurmann, Claudia; Highland, Heather M; Rüeger, Sina; Thorleifsson, Gudmar; Justice, Anne E; Lamparter, David; Stirrups, Kathleen E; Turcot, Valérie; Young, Kristin L; Winkler, Thomas W; Esko, Tõnu; Karaderi, Tugce; Locke, Adam E; Masca, Nicholas G D; Ng, Maggie C Y; Mudgal, Poorva; Rivas, Manuel A; Vedantam, Sailaja; Mahajan, Anubha; Guo, Xiuqing; Abecasis, Goncalo; Aben, Katja K; Adair, Linda S; Alam, Dewan S; Albrecht, Eva; Allin, Kristine H; Allison, Matthew; Amouyel, Philippe; Appel, Emil V; Arveiler, Dominique; Asselbergs, Folkert W; Auer, Paul L; Balkau, Beverley; Banas, Bernhard; Bang, Lia E; Benn, Marianne; Bergmann, Sven; Bielak, Lawrence F; Blüher, Matthias; Boeing, Heiner; Boerwinkle, Eric; Böger, Carsten A; Bonnycastle, Lori L; Bork-Jensen, Jette; Bots, Michiel L; Bottinger, Erwin P; Bowden, Donald W; Brandslund, Ivan; Breen, Gerome; Brilliant, Murray H; Broer, Linda; Burt, Amber A; Butterworth, Adam S; Carey, David J; Caulfield, Mark J; Chambers, John C; Chasman, Daniel I; Chen, Yii-Der Ida; Chowdhury, Rajiv; Christensen, Cramer; Chu, Audrey Y; Cocca, Massimiliano; Collins, Francis S; Cook, James P; Corley, Janie; Galbany, Jordi Corominas; Cox, Amanda J; Cuellar-Partida, Gabriel; Danesh, John; Davies, Gail; de Bakker, Paul I W; de Borst, Gert J; de Denus, Simon; de Groot, Mark C H; de Mutsert, Renée; Deary, Ian J; Dedoussis, George; Demerath, Ellen W; den Hollander, Anneke I; Dennis, Joe G; Di Angelantonio, Emanuele; Drenos, Fotios; Du, Mengmeng; Dunning, Alison M; Easton, Douglas F; Ebeling, Tapani; Edwards, Todd L; Ellinor, Patrick T; Elliott, Paul; Evangelou, Evangelos; Farmaki, Aliki-Eleni; Faul, Jessica D; Feitosa, Mary F; Feng, Shuang; Ferrannini, Ele; Ferrario, Marco M; Ferrieres, Jean; Florez, Jose C; Ford, Ian; Fornage, Myriam; Franks, Paul W; Frikke-Schmidt, Ruth; Galesloot, Tessel E; Gan, Wei; Gandin, Ilaria; Gasparini, Paolo; Giedraitis, Vilmantas; Giri, Ayush; Girotto, Giorgia; Gordon, Scott D; Gordon-Larsen, Penny; Gorski, Mathias; Grarup, Niels; Grove, Megan L; Gudnason, Vilmundur; Gustafsson, Stefan; Hansen, Torben; Harris, Kathleen Mullan; Harris, Tamara B; Hattersley, Andrew T; Hayward, Caroline; He, Liang; Heid, Iris M; Heikkilä, Kauko; Helgeland, Øyvind; Hernesniemi, Jussi; Hewitt, Alex W; Hocking, Lynne J; Hollensted, Mette; Holmen, Oddgeir L; Hovingh, G Kees; Howson, Joanna M M; Hoyng, Carel B; Huang, Paul L; Hveem, Kristian; Ikram, M Arfan; Ingelsson, Erik; Jackson, Anne U; Jansson, Jan-Håkan; Jarvik, Gail P; Jensen, Gorm B; Jhun, Min A; Jia, Yucheng; Jiang, Xuejuan; Johansson, Stefan; Jørgensen, Marit E; Jørgensen, Torben; Jousilahti, Pekka; Jukema, J Wouter; Kahali, Bratati; Kahn, René S; Kähönen, Mika; Kamstrup, Pia R; Kanoni, Stavroula; Kaprio, Jaakko; Karaleftheri, Maria; Kardia, Sharon L R; Karpe, Fredrik; Kee, Frank; Keeman, Renske; Kiemeney, Lambertus A; Kitajima, Hidetoshi; Kluivers, Kirsten B; Kocher, Thomas; Komulainen, Pirjo; Kontto, Jukka; Kooner, Jaspal S; Kooperberg, Charles; Kovacs, Peter; Kriebel, Jennifer; Kuivaniemi, Helena; Küry, Sébastien; Kuusisto, Johanna; La Bianca, Martina; Laakso, Markku; Lakka, Timo A; Lange, Ethan M; Lange, Leslie A; Langefeld, Carl D; Langenberg, Claudia; Larson, Eric B; Lee, I-Te; Lehtimäki, Terho; Lewis, Cora E; Li, Huaixing; Li, Jin; Li-Gao, Ruifang; Lin, Honghuang; Lin, Li-An; Lin, Xu; Lind, Lars; Lindström, Jaana; Linneberg, Allan; Liu, Yeheng; Liu, Yongmei; Lophatananon, Artitaya; Luan, Jian'an; Lubitz, Steven A; Lyytikäinen, Leo-Pekka; Mackey, David A; Madden, Pamela A F; Manning, Alisa K; Männistö, Satu; Marenne, Gaëlle; Marten, Jonathan; Martin, Nicholas G; Mazul, Angela L; Meidtner, Karina; Metspalu, Andres; Mitchell, Paul; Mohlke, Karen L; Mook-Kanamori, Dennis O; Morgan, Anna; Morris, Andrew D; Morris, Andrew P; Müller-Nurasyid, Martina; Munroe, Patricia B; Nalls, Mike A; Nauck, Matthias; Nelson, Christopher P; Neville, Matt; Nielsen, Sune F; Nikus, Kjell; Njølstad, Pål R; Nordestgaard, Børge G; Ntalla, Ioanna; O'Connel, Jeffrey R; Oksa, Heikki; Loohuis, Loes M Olde; Ophoff, Roel A; Owen, Katharine R; Packard, Chris J; Padmanabhan, Sandosh; Palmer, Colin N A; Pasterkamp, Gerard; Patel, Aniruddh P; Pattie, Alison; Pedersen, Oluf; Peissig, Peggy L; Peloso, Gina M; Pennell, Craig E; Perola, Markus; Perry, James A; Perry, John R B; Person, Thomas N; Pirie, Ailith; Polasek, Ozren; Posthuma, Danielle; Raitakari, Olli T; Rasheed, Asif; Rauramaa, Rainer; Reilly, Dermot F; Reiner, Alex P; Renström, Frida; Ridker, Paul M; Rioux, John D; Robertson, Neil; Robino, Antonietta; Rolandsson, Olov; Rudan, Igor; Ruth, Katherine S; Saleheen, Danish; Salomaa, Veikko; Samani, Nilesh J; Sandow, Kevin; Sapkota, Yadav; Sattar, Naveed; Schmidt, Marjanka K; Schreiner, Pamela J; Schulze, Matthias B; Scott, Robert A; Segura-Lepe, Marcelo P; Shah, Svati; Sim, Xueling; Sivapalaratnam, Suthesh; Small, Kerrin S; Smith, Albert Vernon; Smith, Jennifer A; Southam, Lorraine; Spector, Timothy D; Speliotes, Elizabeth K; Starr, John M; Steinthorsdottir, Valgerdur; Stringham, Heather M; Stumvoll, Michael; Surendran, Praveen; 't Hart, Leen M; Tansey, Katherine E; Tardif, Jean-Claude; Taylor, Kent D; Teumer, Alexander; Thompson, Deborah J; Thorsteinsdottir, Unnur; Thuesen, Betina H; Tönjes, Anke; Tromp, Gerard; Trompet, Stella; Tsafantakis, Emmanouil; Tuomilehto, Jaakko; Tybjaerg-Hansen, Anne; Tyrer, Jonathan P; Uher, Rudolf; Uitterlinden, André G; Ulivi, Sheila; van der Laan, Sander W; Van Der Leij, Andries R; van Duijn, Cornelia M; van Schoor, Natasja M; van Setten, Jessica; Varbo, Anette; Varga, Tibor V; Varma, Rohit; Edwards, Digna R Velez; Vermeulen, Sita H; Vestergaard, Henrik; Vitart, Veronique; Vogt, Thomas F; Vozzi, Diego; Walker, Mark; Wang, Feijie; Wang, Carol A; Wang, Shuai; Wang, Yiqin; Wareham, Nicholas J; Warren, Helen R; Wessel, Jennifer; Willems, Sara M; Wilson, James G; Witte, Daniel R; Woods, Michael O; Wu, Ying; Yaghootkar, Hanieh; Yao, Jie; Yao, Pang; Yerges-Armstrong, Laura M; Young, Robin; Zeggini, Eleftheria; Zhan, Xiaowei; Zhang, Weihua; Zhao, Jing Hua; Zhao, Wei; Zhao, Wei; Zheng, He; Zhou, Wei; Rotter, Jerome I; Boehnke, Michael; Kathiresan, Sekar; McCarthy, Mark I; Willer, Cristen J; Stefansson, Kari; Borecki, Ingrid B; Liu, Dajiang J; North, Kari E; Heard-Costa, Nancy L; Pers, Tune H; Lindgren, Cecilia M; Oxvig, Claus; Kutalik, Zoltán; Rivadeneira, Fernando; Loos, Ruth J F; Frayling, Timothy M; Hirschhorn, Joel N; Deloukas, Panos; Lettre, Guillaume

2017-02-09

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

Characterization of genetic sequence variation of 58 STR loci in four major population groups.

PubMed

Novroski, Nicole M M; King, Jonathan L; Churchill, Jennifer D; Seah, Lay Hong; Budowle, Bruce

2016-11-01

Massively parallel sequencing (MPS) can identify sequence variation within short tandem repeat (STR) alleles as well as their nominal allele lengths that traditionally have been obtained by capillary electrophoresis. Using the MiSeq FGx Forensic Genomics System (Illumina), STRait Razor, and in-house excel workbooks, genetic variation was characterized within STR repeat and flanking regions of 27 autosomal, 7 X-chromosome and 24 Y-chromosome STR markers in 777 unrelated individuals from four population groups. Seven hundred and forty six autosomal, 227 X-chromosome, and 324 Y-chromosome STR alleles were identified by sequence compared with 357 autosomal, 107 X-chromosome, and 189 Y-chromosome STR alleles that were identified by length. Within the observed sequence variation, 227 autosomal, 156 X-chromosome, and 112 Y-chromosome novel alleles were identified and described. One hundred and seventy six autosomal, 123 X-chromosome, and 93 Y-chromosome sequence variants resided within STR repeat regions, and 86 autosomal, 39 X-chromosome, and 20 Y-chromosome variants were located in STR flanking regions. Three markers, D18S51, DXS10135, and DYS385a-b had 1, 4, and 1 alleles, respectively, which contained both a novel repeat region variant and a flanking sequence variant in the same nucleotide sequence. There were 50 markers that demonstrated a relative increase in diversity with the variant sequence alleles compared with those of traditional nominal length alleles. These population data illustrate the genetic variation that exists in the commonly used STR markers in the selected population samples and provide allele frequencies for statistical calculations related to STR profiling with MPS data. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Two MC1R loss-of-function alleles in cream-coloured Australian Cattle Dogs and white Huskies.

PubMed

Dürig, N; Letko, A; Lepori, V; Hadji Rasouliha, S; Loechel, R; Kehl, A; Hytönen, M K; Lohi, H; Mauri, N; Dietrich, J; Wiedmer, M; Drögemüller, M; Jagannathan, V; Schmutz, S M; Leeb, T

2018-06-22

Loss-of-function variants in the MC1R gene cause recessive red or yellow coat-colour phenotypes in many species. The canine MC1R:c.916C>T (p.Arg306Ter) variant is widespread and found in a homozygous state in many uniformly yellow- or red-coloured dogs. We investigated cream-coloured Australian Cattle Dogs whose coat colour could not be explained by this variant. A genome-wide association study with 10 cream and 123 red Australian Cattle Dogs confirmed that the cream locus indeed maps to MC1R. Whole-genome sequencing of cream dogs revealed a single nucleotide variant within the MITF binding site of the canine MC1R promoter. We propose to designate the mutant alleles at MC1R:c.916C>T as e 1 and at the new promoter variant as e 2 . Both alleles segregate in the Australian Cattle Dog breed. When we considered both alleles in combination, we observed perfect association between the MC1R genotypes and the cream coat colour phenotype in a cohort of 10 cases and 324 control dogs. Analysis of the MC1R transcript levels in an e 1 /e 2 compound heterozygous dog confirmed that the transcript levels of the e 2 allele were markedly reduced with respect to the e 1 allele. We further report another MC1R loss-of-function allele in Alaskan and Siberian Huskies caused by a 2-bp deletion in the coding sequence, MC1R:c.816_817delCT. We propose to term this allele e 3 . Huskies that carry two copies of MC1R loss-of-function alleles have a white coat colour. © 2018 Stichting International Foundation for Animal Genetics.

Allelic Variants of Complement Genes Associated with Dense Deposit Disease

PubMed Central

Abrera-Abeleda, Maria Asuncion; Nishimura, Carla; Frees, Kathy; Jones, Michael; Maga, Tara; Katz, Louis M.; Zhang, Yuzhou

2011-01-01

The alternative pathway of the complement cascade plays a role in the pathogenesis of dense deposit disease (DDD). Deficiency of complement factor H and mutations in CFH associate with the development of DDD, but it is unknown whether allelic variants in other complement genes also associate with this disease. We studied patients with DDD and identified previously unreported sequence alterations in several genes in addition to allelic variants and haplotypes common to patients with DDD. We found that the likelihood of developing DDD increases with the presence of two or more risk alleles in CFH and C3. To determine the functional consequence of this finding, we measured the activity of the alternative pathway in serum samples from phenotypically normal controls genotyped for variants in CFH and C3. Alternative pathway activity was higher in the presence of variants associated with DDD. Taken together, these data confirm that DDD is a complex genetic disease and may provide targets for the development of disease-specific therapies. PMID:21784901

Complex analysis of urate transporters SLC2A9, SLC22A12 and functional characterization of non-synonymous allelic variants of GLUT9 in the Czech population: no evidence of effect on hyperuricemia and gout.

PubMed

Hurba, Olha; Mancikova, Andrea; Krylov, Vladimir; Pavlikova, Marketa; Pavelka, Karel; Stibůrková, Blanka

2014-01-01

Using European descent Czech populations, we performed a study of SLC2A9 and SLC22A12 genes previously identified as being associated with serum uric acid concentrations and gout. This is the first study of the impact of non-synonymous allelic variants on the function of GLUT9 except for patients suffering from renal hypouricemia type 2. The cohort consisted of 250 individuals (150 controls, 54 nonspecific hyperuricemics and 46 primary gout and/or hyperuricemia subjects). We analyzed 13 exons of SLC2A9 (GLUT9 variant 1 and GLUT9 variant 2) and 10 exons of SLC22A12 by PCR amplification and sequenced directly. Allelic variants were prepared and their urate uptake and subcellular localization were studied by Xenopus oocytes expression system. The functional studies were analyzed using the non-parametric Wilcoxon and Kruskall-Wallis tests; the association study used the Fisher exact test and linear regression approach. We identified a total of 52 sequence variants (12 unpublished). Eight non-synonymous allelic variants were found only in SLC2A9: rs6820230, rs2276961, rs144196049, rs112404957, rs73225891, rs16890979, rs3733591 and rs2280205. None of these variants showed any significant difference in the expression of GLUT9 and in urate transport. In the association study, eight variants showed a possible association with hyperuricemia. However, seven of these were in introns and the one exon located variant, rs7932775, did not show a statistically significant association with serum uric acid concentration. Our results did not confirm any effect of SLC22A12 and SLC2A9 variants on serum uric acid concentration. Our complex approach using association analysis together with functional and immunohistochemical characterization of non-synonymous allelic variants did not show any influence on expression, subcellular localization and urate uptake of GLUT9.

A novel MLPH variant in dogs with coat colour dilution.

PubMed

Bauer, A; Kehl, A; Jagannathan, V; Leeb, T

2018-02-01

Coat colour dilution may be the result of altered melanosome transport in melanocytes. Loss-of-function variants in the melanophilin gene (MLPH) cause a recessively inherited form of coat colour dilution in many mammalian and avian species including the dog. MLPH corresponds to the D locus in many domestic animals, and recessive alleles at this locus are frequently denoted with d. In this study, we investigated dilute coloured Chow Chows whose coat colour could not be explained by their genotype at the previously known MLPH:c.-22G>A variant. Whole genome sequencing of such a dilute Chow Chow revealed another variant in the MLPH gene: MLPH:c.705G>C. We propose to designate the corresponding mutant alleles at these two variants d 1 and d 2 . We performed an association study in a cohort of 15 dilute and 28 non-dilute Chow Chows. The dilute dogs were all either compound heterozygous d 1 /d 2 or homozygous d 2 /d 2 , whereas the non-dilute dogs carried at least one wildtype allele D. The d 2 allele did not occur in 417 dogs from diverse other breeds. However, when we genotyped a Sloughi family, in which a dilute coloured puppy had been born out of non-dilute parents, we again observed perfect co-segregation of the newly discovered d 2 allele with coat colour dilution. Finally, we identified a blue Thai Ridgeback with the d 1 /d 2 genotype. Thus, our data identify the MLPH:c.705G>C as a variant explaining a second canine dilution allele. Although relatively rare overall, this d 2 allele is segregating in at least three dog breeds, Chow Chows, Sloughis and Thai Ridgebacks. © 2018 Stichting International Foundation for Animal Genetics.

Global spread and genetic variants of the two CYP9M10 haplotype forms associated with insecticide resistance in Culex quinquefasciatus Say.

PubMed

Itokawa, K; Komagata, O; Kasai, S; Kawada, H; Mwatele, C; Dida, G O; Njenga, S M; Mwandawiro, C; Tomita, T

2013-09-01

Insecticide resistance develops as a genetic factor (allele) conferring lower susceptibility to insecticides proliferates within a target insect population under strong positive selection. Intriguingly, a resistance allele pre-existing in a population often bears a series of further adaptive allelic variants through new mutations. This phenomenon occasionally results in replacement of the predominating resistance allele by fitter new derivatives, and consequently, development of greater resistance at the population level. The overexpression of the cytochrome P450 gene CYP9M10 is associated with pyrethroid resistance in the southern house mosquito Culex quinquefasciatus. Previously, we have found two genealogically related overexpressing CYP9M10 haplotypes, which differ in gene copy number (duplicated and non-duplicated). The duplicated haplotype was derived from the non-duplicated overproducer probably recently. In the present study, we investigated allelic series of CYP9M10 involved in three C. quinquefasciatus laboratory colonies recently collected from three different localities. Duplicated and non-duplicated overproducing haplotypes coexisted in African and Asian colonies indicating a global distribution of both haplotype lineages. The duplicated haplotypes both in the Asian and African colonies were associated with higher expression levels and stronger resistance than non-duplicated overproducing haplotypes. There were slight variation in expression level among the non-duplicated overproducing haplotypes. The nucleotide sequences in coding and upstream regions among members of this group also showed a little diversity. Non-duplicated overproducing haplotypes with relatively higher expression were genealogically closer to the duplicated haplotypes than the other non-duplicated overproducing haplotypes, suggesting multiple cis-acting mutations before duplication.

ABCC6 Gene Analysis in 20 Japanese Patients with Angioid Streaks Revealing Four Frequent and Two Novel Variants and Pseudodominant Inheritance

PubMed Central

Negishi, Yuya; Mizobuchi, Kei; Urashima, Mitsuyoshi; Nakano, Tadashi

2017-01-01

Purpose To report the spectrum of ABCC6 variants in Japanese patients with angioid streaks (AS). Patients and Methods This was a single-center cohort study. The medical records of 20 patients with AS from 18 unrelated Japanese families were retrospectively reviewed. Screening of the ABCC6 gene (exons 1 to 31) was performed using PCR-based Sanger sequencing. Results Eight ABCC6 variants were identified as candidate disease-causing variants. These eight variants included five known variants (p.Q378X, p.R419Q, p.V848CfsX83, p.R1114C, and p.R1357W), one previously reported variant (p.N428S) of unknown significance, and two novel variants (c.1939C>T [p.H647Y] and c.3374C>T [p.S1125F]); the three latter variants were determined to be variants of significance. The following four variants were frequently identified: p.V848CfsX83 (14/40 alleles, 35.0%), p.Q378X (7/40 alleles, 17.5%), p.R1357W (6/40 alleles, 15.0%), and p.R419Q (4/40 alleles, 10.0%). The ABCC6 variants were identified in compound heterozygous or homozygous states in 13 of 18 probands. Two families showed a pseudodominant inheritance pattern. Pseudoxanthoma elasticum was seen in 15 of 17 patients (88.2%) who underwent dermatological examination. Conclusions We identified disease-causing ABCC6 variants that were in homozygous or compound heterozygous states in 13 of 18 families (72.2%). Our results indicated that ABCC6 variants play a significant role in patients with AS in the Japanese population. PMID:28912966

Complement factor H gene (CFH) polymorphisms C-257T, G257A and haplotypes are associated with protection against severe dengue phenotype, possible related with high CFH expression

PubMed Central

Pastor, André F.; Moura, Laís Rodrigues; Neto, José W.D.; Nascimento, Eduardo J.M.; Calzavara-Silva, Carlos E.; Gomes, Ana Lisa V.; da Silva, Ana Maria; Cordeiro, Marli T.; Braga-Neto, Ulisses; Crovella, Sergio; Gil, Laura H.V.G.; Marques, Ernesto T.A.; Acioli-Santos, Bartolomeu

2013-01-01

Four genetic polymorphisms located at the promoter (C-257T) and coding regions of CFH gene (exon 2 G257A, exon 14 A2089G and exon 19 G2881T) were investigated in 121 dengue patients (DENV-3) in order to assess the relationship between allele/haplotypes variants and clinical outcomes. A statistical value was found between the CFH-257T allele (TT/TC genotypes) and reduced susceptibility to severe dengue (SD). Statistical associations indicate that individuals bearing a T allele presented significantly higher protein levels in plasma. The –257T variant is located within a NF-κB binding site, suggesting that this variant might have effect on the ability of the CFH gene to respond to signals via the NF-κB pathway. The G257A allelic variant showed significant protection against severe dengue. When CFH haplotypes effect was considered, the ancestral CG/CG promoter-exon 2 SNP genotype showed significant risk to SD either in a general comparison (ancestral × all variant genotypes), as well as in individual genotypes comparison (ancestral × each variant genotype), where the most prevalent effect was observed in the CG/CG × CA/TG comparison. These findings support the involvement of –257T, 257A allele variants and haplotypes on severe dengue phenotype protection, related with high basal CFH expression. PMID:23747994

Molecular outcomes, clinical consequences, and genetic diagnosis of Oculocutaneous Albinism in Pakistani population.

PubMed

Shahzad, Mohsin; Yousaf, Sairah; Waryah, Yar M; Gul, Hadia; Kausar, Tasleem; Tariq, Nabeela; Mahmood, Umair; Ali, Muhammad; Khan, Muzammil A; Waryah, Ali M; Shaikh, Rehan S; Riazuddin, Saima; Ahmed, Zubair M

2017-03-07

Nonsyndromic oculocutaneous Albinism (nsOCA) is clinically characterized by the loss of pigmentation in the skin, hair, and iris. OCA is amongst the most common causes of vision impairment in children. To date, pathogenic variants in six genes have been identified in individuals with nsOCA. Here, we determined the identities, frequencies, and clinical consequences of OCA alleles in 94 previously unreported Pakistani families. Combination of Sanger and Exome sequencing revealed 38 alleles, including 22 novel variants, segregating with nsOCA phenotype in 80 families. Variants of TYR and OCA2 genes were the most common cause of nsOCA, occurring in 43 and 30 families, respectively. Twenty-two novel variants include nine missense, four splice site, two non-sense, one insertion and six gross deletions. In vitro studies revealed retention of OCA proteins harboring novel missense alleles in the endoplasmic reticulum (ER) of transfected cells. Exon-trapping assays with constructs containing splice site alleles revealed errors in splicing. As eight alleles account for approximately 56% (95% CI: 46.52-65.24%) of nsOCA cases, primarily enrolled from Punjab province of Pakistan, hierarchical strategies for variant detection would be feasible and cost-efficient genetic tests for OCA in families with similar origin. Thus, we developed Tetra-primer ARMS assays for rapid, reliable, reproducible and economical screening of most of these common alleles.

Detection of new HLA-DPB1 alleles generated by interallelic gene conversion using PCR amplification of DPB1 second exon sequences from sperm

DOE Office of Scientific and Technical Information (OSTI.GOV)

Erlich, H.; Zangenberg, G.; Bugawan, T.

The rate at which allelic diversity at the HLA class I and class II loci evolves has been the subject of considerable controversy as have the mechanisms which generate new alleles. The patchwork pattern of polymorphism, particularly within the second exon of the HLA-DPB1 locus where the polymorphic sequence motifs are localized to 6 discrete regions, is consistent with the hypothesis that much of the allelic sequence variation may have been generated by segmental exchange (gene conversion). To measure the rate of new DPB1 variant generation, we have developed a strategy in which DPB1 second exon sequences are amplified frommore » pools of FACS-sorted sperm (n=50) from a heterozygous sperm donor. Pools of sperm from these heterozygous individuals are amplified with an allele-specific primer for one allele and analyzed with sequence-specific oligonucleotide probes (SSOP) complementary to the other allele. This screening procedure, which is capable of detecting a single variant molecule in a pool of parental alleles, allows the identification of new variants that have been generated by recombination and/or gene conversion between the two parental alleles. To control for potential PCR artifacts, the same screening procedure was carried out with mixtures of sperm from DPB1 *0301/*0301 and DPB1 *0401/ 0401 individuals. Pools containing putative new variants DPB1 alleles were analyzed further by cloning into M13 and sequencing the M13 clones. Our current estimate is that about 1/10,000 sperm from these heterozygous individuals represents a new DPB1 allele generated by micro-gene conversion within the second exon.« less

svviz: a read viewer for validating structural variants.

PubMed

Spies, Noah; Zook, Justin M; Salit, Marc; Sidow, Arend

2015-12-15

Visualizing read alignments is the most effective way to validate candidate structural variants (SVs) with existing data. We present svviz, a sequencing read visualizer for SVs that sorts and displays only reads relevant to a candidate SV. svviz works by searching input bam(s) for potentially relevant reads, realigning them against the inferred sequence of the putative variant allele as well as the reference allele and identifying reads that match one allele better than the other. Separate views of the two alleles are then displayed in a scrollable web browser view, enabling a more intuitive visualization of each allele, compared with the single reference genome-based view common to most current read browsers. The browser view facilitates examining the evidence for or against a putative variant, estimating zygosity, visualizing affected genomic annotations and manual refinement of breakpoints. svviz supports data from most modern sequencing platforms. svviz is implemented in python and freely available from http://svviz.github.io/. Published by Oxford University Press 2015. This work is written by US Government employees and is in the public domain in the US.

Prevalence of melanocortin receptor 4 (MC4R) V103I gene variant and its association with obesity among the Kampar Health Clinic cohort, Perak, Malaysia.

PubMed

Chua, H N; Fan, S H; Say, Y H

2012-04-01

This study investigated the prevalence of the Melanocortin receptor 4 (MC4R) V1031 gene variant and its association with obesity among a cohort of 254 patients (101 males; 118 obese) attending the Kampar Health Clinic. Genotyping revealed the mutated I allele frequency of 0.02, no homozygous mutated (II), and similar distribution of V and I alleles across BMI groups, genders and ethnic groups. No significant difference was found for the means of anthropometric measurements between alleles. Prevalence of this gene variant among the Malaysian cohort was similar with previous populations (2-4% of mutated allele carrier), but was not associated with obesity.

The effect of wild card designations and rare alleles in forensic DNA database searches.

PubMed

Tvedebrink, Torben; Bright, Jo-Anne; Buckleton, John S; Curran, James M; Morling, Niels

2015-05-01

Forensic DNA databases are powerful tools used for the identification of persons of interest in criminal investigations. Typically, they consist of two parts: (1) a database containing DNA profiles of known individuals and (2) a database of DNA profiles associated with crime scenes. The risk of adventitious or chance matches between crimes and innocent people increases as the number of profiles within a database grows and more data is shared between various forensic DNA databases, e.g. from different jurisdictions. The DNA profiles obtained from crime scenes are often partial because crime samples may be compromised in quantity or quality. When an individual's profile cannot be resolved from a DNA mixture, ambiguity is introduced. A wild card, F, may be used in place of an allele that has dropped out or when an ambiguous profile is resolved from a DNA mixture. Variant alleles that do not correspond to any marker in the allelic ladder or appear above or below the extent of the allelic ladder range are assigned the allele designation R for rare allele. R alleles are position specific with respect to the observed/unambiguous allele. The F and R designations are made when the exact genotype has not been determined. The F and R designation are treated as wild cards for searching, which results in increased chance of adventitious matches. We investigated the probability of adventitious matches given these two types of wild cards. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Serotonin transporter promoter polymorphism and monoamine oxidase type A VNTR allelic variants together influence alcohol binge drinking risk in young women.

PubMed

Herman, Aryeh I; Kaiss, Kristi M; Ma, Rui; Philbeck, John W; Hasan, Asfar; Dasti, Humza; DePetrillo, Paolo B

2005-02-05

The short allelic variant of the serotonin transporter protein promoter polymorphism (5HTTLPR) appears to influence binge drinking in college students. Both monoamine oxidase type A (MAOA) and the serotonin transporter protein are involved in the processing of serotonin, and allelic variants are both associated with differences in the efficiency of expression. We hypothesized that a significant gene x gene interaction would further stratify the risk of binge drinking in this population. Participants were college students (n = 412) who completed the College Alcohol Study, used to measure binge drinking behaviors. Genomic DNA was extracted from saliva for PCR based genotyping. The risk function for binge drinking was modeled using logistic regression, with final model fit P < 0.0005. This model was valid only for Caucasian females (n = 223), but the power to detect sex and ethnic effects was small. Young Caucasian women carrying higher expression MAOA VNTR alleles homozygous for the short allelic variant of the 5HTTLPR demonstrated the highest rate of binge drinking by self-report, odds ratio (genotype odds: population odds) and 95% confidence intervals, 3.11 (1.14-18.10). Individuals carrying higher expression MAOA VNTR alleles carrying at least one long 5HTTLPR allelic variant had the lowest risk of binge drinking 0.46 (0.28-0.71). These results support the hypothesis that binge drinking behavior in young adulthood may be influenced by neurobiological differences in serotonergic function conferred by functional polymorphisms in genes involved in serotonin processing. (c) 2004 Wiley-Liss, Inc.

Functional and Structural Consequence of Rare Exonic Single Nucleotide Polymorphisms: One Story, Two Tales

PubMed Central

Gu, Wanjun; Gurguis, Christopher I.; Zhou, Jin J.; Zhu, Yihua; Ko, Eun-A.; Ko, Jae-Hong; Wang, Ting; Zhou, Tong

2015-01-01

Genetic variation arising from single nucleotide polymorphisms (SNPs) is ubiquitously found among human populations. While disease-causing variants are known in some cases, identifying functional or causative variants for most human diseases remains a challenging task. Rare SNPs, rather than common ones, are thought to be more important in the pathology of most human diseases. We propose that rare SNPs should be divided into two categories dependent on whether the minor alleles are derived or ancestral. Derived alleles are less likely to have been purified by evolutionary processes and may be more likely to induce deleterious effects. We therefore hypothesized that the rare SNPs with derived minor alleles would be more important for human diseases and predicted that these variants would have larger functional or structural consequences relative to the rare variants for which the minor alleles are ancestral. We systematically investigated the consequences of the exonic SNPs on protein function, mRNA structure, and translation. We found that the functional and structural consequences are more significant for the rare exonic variants for which the minor alleles are derived. However, this pattern is reversed when the minor alleles are ancestral. Thus, the rare exonic SNPs with derived minor alleles are more likely to be deleterious. Age estimation of rare SNPs confirms that these potentially deleterious SNPs are recently evolved in the human population. These results have important implications for understanding the function of genetic variations in human exonic regions and for prioritizing functional SNPs in genome-wide association studies of human diseases. PMID:26454016

267 Spanish Exomes Reveal Population-Specific Differences in Disease-Related Genetic Variation

PubMed Central

Dopazo, Joaquín; Amadoz, Alicia; Bleda, Marta; Garcia-Alonso, Luz; Alemán, Alejandro; García-García, Francisco; Rodriguez, Juan A.; Daub, Josephine T.; Muntané, Gerard; Rueda, Antonio; Vela-Boza, Alicia; López-Domingo, Francisco J.; Florido, Javier P.; Arce, Pablo; Ruiz-Ferrer, Macarena; Méndez-Vidal, Cristina; Arnold, Todd E.; Spleiss, Olivia; Alvarez-Tejado, Miguel; Navarro, Arcadi; Bhattacharya, Shomi S.; Borrego, Salud; Santoyo-López, Javier; Antiñolo, Guillermo

2016-01-01

Recent results from large-scale genomic projects suggest that allele frequencies, which are highly relevant for medical purposes, differ considerably across different populations. The need for a detailed catalog of local variability motivated the whole-exome sequencing of 267 unrelated individuals, representative of the healthy Spanish population. Like in other studies, a considerable number of rare variants were found (almost one-third of the described variants). There were also relevant differences in allelic frequencies in polymorphic variants, including ∼10,000 polymorphisms private to the Spanish population. The allelic frequencies of variants conferring susceptibility to complex diseases (including cancer, schizophrenia, Alzheimer disease, type 2 diabetes, and other pathologies) were overall similar to those of other populations. However, the trend is the opposite for variants linked to Mendelian and rare diseases (including several retinal degenerative dystrophies and cardiomyopathies) that show marked frequency differences between populations. Interestingly, a correspondence between differences in allelic frequencies and disease prevalence was found, highlighting the relevance of frequency differences in disease risk. These differences are also observed in variants that disrupt known drug binding sites, suggesting an important role for local variability in population-specific drug resistances or adverse effects. We have made the Spanish population variant server web page that contains population frequency information for the complete list of 170,888 variant positions we found publicly available (http://spv.babelomics.org/), We show that it if fundamental to determine population-specific variant frequencies to distinguish real disease associations from population-specific polymorphisms. PMID:26764160

Effect of six type II diabetes susceptibility loci and an FTO variant on obesity in Pakistani subjects

PubMed Central

Shabana; Ullah Shahid, Saleem; Wah Li, Ka; Acharya, Jayshree; Cooper, Jackie A; Hasnain, Shahida; Humphries, Stephen E

2016-01-01

The aim of the current study was to analyze the effect of six type II diabetes GWAS loci rs3923113 (GRB14), rs16861329 (ST6GAL1), rs1802295 (VPS26A), rs7178572 (HMG20A), rs2028299 (AP3S2) and rs4812829 (HNF4A), and an FTO polymorphism (rs9939609) on obesity. The probable mechanism of action of these SNPs was analyzed by studying their association with various biochemical and anthropometric parameters. A total of 475 subjects (obese=250, controls=225) were genotyped by TaqMan assay and their lipid profile was determined. Allele/genotype frequencies and an unweighted/weighted gene score were calculated. The effect of the gene score on anthropometric and biochemical parameters was analyzed. The minor allele frequencies of all variants were comparable to that reported in the original studies and were associated with obesity in these Pakistani subjects. Subjects with 9 risk alleles differ from those with <3 and overall there is no significant effect (P-value for trend 0.26). None of the SNPs were associated with any of the serum lipid traits. We are the first to report the association of these T2D SNPs with obesity. In the Pakistani population the reported effect of six SNPs for obesity is similar to that reported for T2D and having a combination of risk alleles on obesity can be considerable. The mechanism of this effect is unclear, but appears not to be mediated by changing serum lipid chemistry. PMID:26395551

Identification of a novel CHEK2 variant and assessment of its contribution to the risk of breast cancer in French Canadian women.

PubMed

Novak, David J; Chen, Long Qi; Ghadirian, Parviz; Hamel, Nancy; Zhang, Phil; Rossiny, Vanessa; Cardinal, Guy; Robidoux, André; Tonin, Patricia N; Rousseau, Francois; Narod, Steven A; Foulkes, William D

2008-08-15

BRCA1 and BRCA2 account for the majority of the known familial breast cancer risk, however, the impact of other cancer susceptibility genes largely remains to be elucidated. Checkpoint Kinase 2 (CHEK2) is an important signal transducer of cellular responses to DNA damage, whose defects have been associated with an increase in breast cancer risk. Previous studies have identified low penetrance CHEK2 alleles such as 1100delC and I157T, as well as variants such as S428F in the Ashkenazi Jewish population and IVS2 + 1G>A in the Polish population. No founder allele has been specifically identified in the French Canadian population. The 14 coding exons of CHEK2 were fully sequenced for variant alleles in a panel of 25 affected French Canadian women and 25 healthy controls. Two variants were identified of which one novel variant was further screened for in an additional panel of 667 breast cancer patients and 6548 healthy controls. Additional genotyping was conducted using allele specific PCR and a restriction digest assay. Significance of amino acid substitutions were deduced by employing comparative analysis techniques. Two variants were identified: the previously reported silent substitution 252A>G (E84E) and the novel missense variant, 1217G>A (R406H). No significant difference in allele distribution between French Canadian women with breast cancer and healthy controls was observed (3/692, 0.43% vs. 22/6573, 0.33%, respectively, P = 0.73). The novel CHEK2 missense variant identified in this study, R406H, is unlikely to contribute to breast cancer risk in French Canadian women.

Identification of a null allele of cytochrome P450 3A7: CYP3A7 polymorphism in a Korean population.

PubMed

Lee, Sang Seop; Jung, Hyun-Ju; Park, Jung Soon; Cha, In-June; Cho, Doo-Yeoun; Shin, Jae-Gook

2010-01-01

Cytochrome P450 3A7 (CYP3A7) is expressed in the human fetal liver and plays a role in the metabolism of hormones, drugs, and toxic compounds. Genetic variants of CYP3A7 are associated with serum estrone level, bone density, and hepatic CYP3A activity in adults. We analyzed the genetic variations of CYP3A7 in a Korean population. From direct sequencing of all exons and flanking regions of the CYP3A7 gene in 48 Koreans, we found five genetic variants, including three novel variants. One variant, a thymidine insertion in exon 2 (4011insT), causes premature termination of CYP3A7 translation, which may result in a null phenotype. The novel variant was assigned to the CYP3A7*3 allele by the CYP allele nomenclature committee. For further screen of this novel variant in other ethnic populations, we used pyrosequencing to analyze an additional 185 Koreans, 100 African Americans, 100 Caucasians, and 159 Vietnamese for the presence of this variant. The variant was not found in any other individuals, except for one Korean subject. The frequencies of two known functional alleles, CYP3A7*2 and CYP3A7*1C, were 26 and 0%, respectively, in Koreans. The frequencies of the functional CYP3A7 polymorphisms in Koreans were significantly different from those in Caucasians and African Americans. This is the first report of a null-type allele of the CYP3A7 gene. It also provides population-level genetic data on CYP3A7 in Koreans to reveal the wide ethnic variation in CYP3A7 polymorphism.

Identification of a novel CHEK2 variant and assessment of its contribution to the risk of breast cancer in French Canadian women

PubMed Central

Novak, David J; Chen, Long Qi; Ghadirian, Parviz; Hamel, Nancy; Zhang, Phil; Rossiny, Vanessa; Cardinal, Guy; Robidoux, André; Tonin, Patricia N; Rousseau, Francois; Narod, Steven A; Foulkes, William D

2008-01-01

Background BRCA1 and BRCA2 account for the majority of the known familial breast cancer risk, however, the impact of other cancer susceptibility genes largely remains to be elucidated. Checkpoint Kinase 2 (CHEK2) is an important signal transducer of cellular responses to DNA damage, whose defects have been associated with an increase in breast cancer risk. Previous studies have identified low penetrance CHEK2 alleles such as 1100delC and I157T, as well as variants such as S428F in the Ashkenazi Jewish population and IVS2 + 1G>A in the Polish population. No founder allele has been specifically identified in the French Canadian population. Methods The 14 coding exons of CHEK2 were fully sequenced for variant alleles in a panel of 25 affected French Canadian women and 25 healthy controls. Two variants were identified of which one novel variant was further screened for in an additional panel of 667 breast cancer patients and 6548 healthy controls. Additional genotyping was conducted using allele specific PCR and a restriction digest assay. Significance of amino acid substitutions were deduced by employing comparative analysis techniques. Results Two variants were identified: the previously reported silent substitution 252A>G (E84E) and the novel missense variant, 1217G>A (R406H). No significant difference in allele distribution between French Canadian women with breast cancer and healthy controls was observed (3/692, 0.43% vs. 22/6573, 0.33%, respectively, P = 0.73). Conclusion The novel CHEK2 missense variant identified in this study, R406H, is unlikely to contribute to breast cancer risk in French Canadian women. PMID:18706089

Many amino acid substitution variants identified in DNA repair genes during human population screenings are predicted to impact protein function

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xi, T; Jones, I M; Mohrenweiser, H W

2003-11-03

Over 520 different amino acid substitution variants have been previously identified in the systematic screening of 91 human DNA repair genes for sequence variation. Two algorithms were employed to predict the impact of these amino acid substitutions on protein activity. Sorting Intolerant From Tolerant (SIFT) classified 226 of 508 variants (44%) as ''Intolerant''. Polymorphism Phenotyping (PolyPhen) classed 165 of 489 amino acid substitutions (34%) as ''Probably or Possibly Damaging''. Another 9-15% of the variants were classed as ''Potentially Intolerant or Damaging''. The results from the two algorithms are highly associated, with concordance in predicted impact observed for {approx}62% of themore » variants. Twenty one to thirty one percent of the variant proteins are predicted to exhibit reduced activity by both algorithms. These variants occur at slightly lower individual allele frequency than do the variants classified as ''Tolerant'' or ''Benign''. Both algorithms correctly predicted the impact of 26 functionally characterized amino acid substitutions in the APE1 protein on biochemical activity, with one exception. It is concluded that a substantial fraction of the missense variants observed in the general human population are functionally relevant. These variants are expected to be the molecular genetic and biochemical basis for the associations of reduced DNA repair capacity phenotypes with elevated cancer risk.« less

Toll-Like Receptor-3 and Geographic Atrophy in Age-Related Macular Degeneration

PubMed Central

Yang, Zhenglin; Stratton, Charity; Francis, Peter J.; Kleinman, Mark E.; Tan, Perciliz L.; Gibbs, Daniel; Tong, Zongzhong; Chen, Haoyu; Constantine, Ryan; Yang, Xian; Chen, Yuhong; Zeng, Jiexi; Davey, Lisa; Ma, Xiang; Hau, Vincent S.; Wang, Chi; Harmon, Jennifer; Buehler, Jeanette; Pearson, Erik; Patel, Shrena; Kaminoh, Yuuki; Watkins, Scott; Luo, Ling; Zabriskie, Norman A.; Bernstein, Paul S.; Cho, Wongil; Schwager, Andrea; Hinton, David R; Klein, Michael L; Hamon, Sara C.; Simmons, Emily; Yu, Beifeng; Campochiaro, Betsy; Sunness, Janet S.; Campochiaro, Peter; Jorde, Lynn; Parmigiani, Giovanni; Zack, Donald J.; Katsanis, Nicholas; Ambati, Jayakrishna; Zhang, Kang

2008-01-01

BACKGROUND Age-related macular degeneration (AMD) is the most common cause of irreversible visual impairment in the developed world. Advanced AMD is comprised of geographic atrophy (GA) and choroidal neovascularization (CNV). Specific genetic variants that predispose for GA are largely unknown. METHODS We tested (i) for association between the functional toll-like receptor-3 (TLR3) variant rs3775291 (L412F) and AMD in European Americans and (ii) the effect of TLR3 L and F variants on the viability of human retinal pigment epithelium (RPE) cells in vitro and on RPE cell apoptosis in wildtype and Tlr3−/− mice. RESULTS The F variant (or T allele at single nucleotide polymorphism at rs3775291) was associated with protection against GA (P=0.005); this association was replicated in two independent GA case-control series (P=5.43×10−4 and P=0.002, respectively. We observed no association between TLR3 variants and CNV. The rs377291 variant is probably critical to the function of TLR3, because a prototypic TLR3 ligand induced cell death and apoptosis in human RPE cells with the LL genotype to a greater extent than it did RPE cells with the LF genotype. Moreover, the ligand induced more RPE cell death and apoptosis in wild-type than in Tlr3−/− mice. CONCLUSIONS The TLR3 412F variant confers protection against GA, probably by suppressing RPE cell death. Given that double stranded RNA can activate TLR3-mediated apoptosis, our results suggest a possible role for viral dsRNA transcripts in the development of GA and raise awareness of potential toxicity induced by short interfering RNA (siRNA) therapeutics in the eye. PMID:18753640

Complement factor H gene (CFH) polymorphisms C-257T, G257A and haplotypes are associated with protection against severe dengue phenotype, possible related with high CFH expression.

PubMed

Pastor, André F; Rodrigues Moura, Laís; Neto, José W D; Nascimento, Eduardo J M; Calzavara-Silva, Carlos E; Gomes, Ana Lisa V; Silva, Ana Maria da; Cordeiro, Marli T; Braga-Neto, Ulisses; Crovella, Sergio; Gil, Laura H V G; Marques, Ernesto T A; Acioli-Santos, Bartolomeu

2013-09-01

Four genetic polymorphisms located at the promoter (C-257T) and coding regions of CFH gene (exon 2 G257A, exon 14 A2089G and exon 19 G2881T) were investigated in 121 dengue patients (DENV-3) in order to assess the relationship between allele/haplotypes variants and clinical outcomes. A statistical value was found between the CFH-257T allele (TT/TC genotypes) and reduced susceptibility to severe dengue (SD). Statistical associations indicate that individuals bearing a T allele presented significantly higher protein levels in plasma. The -257T variant is located within a NF-κB binding site, suggesting that this variant might have effect on the ability of the CFH gene to respond to signals via the NF-κB pathway. The G257A allelic variant showed significant protection against severe dengue. When CFH haplotypes effect was considered, the ancestral CG/CG promoter-exon 2 SNP genotype showed significant risk to SD either in a general comparison (ancestral × all variant genotypes), as well as in individual genotypes comparison (ancestral × each variant genotype), where the most prevalent effect was observed in the CG/CG × CA/TG comparison. These findings support the involvement of -257T, 257A allele variants and haplotypes on severe dengue phenotype protection, related with high basal CFH expression. Copyright © 2013 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

New insights into the history of the C-14010 lactase persistence variant in Eastern and Southern Africa.

PubMed

Macholdt, Enrico; Slatkin, Montgomery; Pakendorf, Brigitte; Stoneking, Mark

2015-04-01

Lactase persistence (LP), the ability to digest lactose into adulthood, is strongly associated with the cultural traits of pastoralism and milk-drinking among human populations, and several different genetic variants are known that confer LP. Recent studies of LP variants in Southern African populations, with a focus on Khoisan-speaking groups, found high frequencies of an LP variant (the C-14010 allele) that also occurs in Eastern Africa, and concluded that the C-14010 allele was brought to Southern Africa via a migration of pastoralists from Eastern Africa. However, this conclusion was based on indirect evidence; to date no study has jointly analyzed data on the C-14010 allele from both Southern African Khoisan-speaking groups and Eastern Africa. Here, we combine and analyze published data on the C-14010 allele in Southern and Eastern African populations, consisting of haplotypes with the C-14010 allele and four closely-linked short tandem repeat loci. Our results provide direct evidence for the previously-hypothesized Eastern African origin of the C-14010 allele in Southern African Khoisan-speaking groups. In addition, we find evidence for a separate introduction of the C-14010 allele into the Bantu-speaking Xhosa. The estimated selection intensity on the C-14010 allele in Eastern Africa is lower than that in Southern Africa, which suggests that in Eastern Africa the dietary changes conferring the fitness advantage associated with LP occurred some time after the origin of the C-14010 allele. Conversely, in Southern Africa the fitness advantage was present when the allele was introduced, as would be expected if pastoralism was introduced concomitantly. © 2014 Wiley Periodicals, Inc.

Complex Analysis of Urate Transporters SLC2A9, SLC22A12 and Functional Characterization of Non-Synonymous Allelic Variants of GLUT9 in the Czech Population: No Evidence of Effect on Hyperuricemia and Gout

PubMed Central

Hurba, Olha; Mancikova, Andrea; Krylov, Vladimir; Pavlikova, Marketa; Pavelka, Karel; Stibůrková, Blanka

2014-01-01

Objective Using European descent Czech populations, we performed a study of SLC2A9 and SLC22A12 genes previously identified as being associated with serum uric acid concentrations and gout. This is the first study of the impact of non-synonymous allelic variants on the function of GLUT9 except for patients suffering from renal hypouricemia type 2. Methods The cohort consisted of 250 individuals (150 controls, 54 nonspecific hyperuricemics and 46 primary gout and/or hyperuricemia subjects). We analyzed 13 exons of SLC2A9 (GLUT9 variant 1 and GLUT9 variant 2) and 10 exons of SLC22A12 by PCR amplification and sequenced directly. Allelic variants were prepared and their urate uptake and subcellular localization were studied by Xenopus oocytes expression system. The functional studies were analyzed using the non-parametric Wilcoxon and Kruskall-Wallis tests; the association study used the Fisher exact test and linear regression approach. Results We identified a total of 52 sequence variants (12 unpublished). Eight non-synonymous allelic variants were found only in SLC2A9: rs6820230, rs2276961, rs144196049, rs112404957, rs73225891, rs16890979, rs3733591 and rs2280205. None of these variants showed any significant difference in the expression of GLUT9 and in urate transport. In the association study, eight variants showed a possible association with hyperuricemia. However, seven of these were in introns and the one exon located variant, rs7932775, did not show a statistically significant association with serum uric acid concentration. Conclusion Our results did not confirm any effect of SLC22A12 and SLC2A9 variants on serum uric acid concentration. Our complex approach using association analysis together with functional and immunohistochemical characterization of non-synonymous allelic variants did not show any influence on expression, subcellular localization and urate uptake of GLUT9. PMID:25268603

Effect of common NAT2 variant alleles in the acetylation of the major clonazepam metabolite, 7-aminoclonazepam.

PubMed

Olivera, M; Martínez, C; Gervasini, G; Carrillo, J A; Ramos, S; Benítez, J; García-Martin, E; Agúndez, J A G

2007-01-01

We investigated the role of NAT2 on clonazepam acetylation, using transiently expressed human NAT2 alleles. The NAT25*B and the NAT2*6A variant alleles cause a 20 and 22-fold reduction in the Vmax, respectively. We conclude that NAT2 is responsible for 7-aminoclonazepam acetylation and that NAT2 gene polymorphisms impair such metabolic pathway.

The insulin-sensitivity sulphonylurea receptor variant is associated with thyrotoxic paralysis.

PubMed

Rolim, Ana Luiza R; Lindsey, Susan C; Kunii, Ilda S; Crispim, Felipe; Moisés, Regina Célia M S; Maciel, Rui M B; Dias-da-Silva, Magnus R

2014-10-01

Thyrotoxicosis is the most common cause of the acquired flaccid muscle paralysis in adults called thyrotoxic periodic paralysis (TPP) and is characterised by transient hypokalaemia and hypophosphataemia under high thyroid hormone levels that is frequently precipitated by carbohydrate load. The sulphonylurea receptor 1 (SUR1 (ABCC8)) is an essential regulatory subunit of the β-cell ATP-sensitive K(+) channel that controls insulin secretion after feeding. Additionally, the SUR1 Ala1369Ser variant appears to be associated with insulin sensitivity. We examined the ABCC8 gene at the single nucleotide level using PCR-restriction fragment length polymorphism (RFLP) analysis to determine its allelic variant frequency and calculated the frequency of the Ala1369Ser C-allele variant in a cohort of 36 Brazilian TPP patients in comparison with 32 controls presenting with thyrotoxicosis without paralysis (TWP). We verified that the frequency of the alanine 1369 C-allele was significantly higher in TPP patients than in TWP patients (61.1 vs 34.4%, odds ratio (OR)=3.42, P=0.039) and was significantly more common than the minor allele frequency observed in the general population from the 1000 Genomes database (61.1 vs 29.0%, OR=4.87, P<0.005). Additionally, the C-allele frequency was similar between TWP patients and the general population (34.4 vs 29%, OR=1.42, P=0.325). We have demonstrated that SUR1 alanine 1369 variant is associated with allelic susceptibility to TPP. We suggest that the hyperinsulinaemia that is observed in TPP may be linked to the ATP-sensitive K(+)/SUR1 alanine variant and, therefore, contribute to the major feedforward precipitating factors in the pathophysiology of TPP. © 2014 Society for Endocrinology.

Biochemical polymorphisms in Spanish Avileña-Negra Iberica cattle.

PubMed

Arranz, J J; Bayón, Y; Medjugorac, I; Primitivo, F

1994-01-12

Thirteen biochemical blood polymorphisms were analysed in a population of 149 Spanish Avileña-Negra Ibérica cattle. The study revealed variation at the following nine loci: HBB, CA, NP, CP, AMY1, ALB, GC, TF and PTF2. The following systems were monomorphic: CAT, DIA1, MDH1 and ME1. Using polyacrylamide-gel electrophoresis, a slow, migrating pair of bands was found in the GC protein system. This pattern is probably controlled by the GC(C) allele, described in only a few cases in cattle. Furthermore, starch-gel electrophoresis allowed the detection of a variant with intermediate mobility between the ALB(A) and the ALB(B) alleles at the albumin locus. A variant with a similar electrophoretic pattern has occasionally been reported in cattle. However, utilizing IEF under denaturing conditions, such a variant could not be differentiated from the ALB(A) allele and thus its significance is not clear. ZUSAMMENFASSUNG: Biochemischer Polymorphismus in spanischen Avileña-Negra Iberica Rindern Insgesamt 13 biochemische Systeme wurden in einer Population von 149 spanischen Avilena-Negra-Iberika-Rindern hinsichtlich Polymorphismus analysiert. Es zeigten sich Varianten bei folgenden Loci: HBB, CA, NP, CP, AMY1, ANB, GC, TF und BTF2, während CAT, DEA, MDH1 und ME1 monomorph sind. Bei stärke Gel-Elektrophorese wurde im Albumin-Locus eine Variante mit intermediärer Mobilität zwischen ALB(A) und ÄLB(B) Allel entdeckt. Eine solche Variante wurde bisher nur sehr selten bei Rindern beobachtet. Darüber hinaus wurde bei Polyacrylamid-Gel-Elektrophorese ein langsam wanderndes Paar von Bändern im GC-Proteinsystem gefunden. Dieses Muster ist wahrscheinlich von dem selten vorkommenden GC(C) -Allel verursacht. RESUMEN: Se analizaron trece polimorfismos bioquímicos sanguíneos en una población de 149 animales de la raza Avileña-Negra Ibérica de ganado vacuno. El estudio reveló la existencia de variación en los nueve loci siguientes: HBB, CA, NP, CP, AMY1, ALB, GC, TF y PTF2. Fueron monomórficos los sistemas siguientes: CAT, DIA1, MDH1 y ME1. Utilizando eletroforesis en gel de poliacrilamida se encontró un par de bandas de migración lenta en el sistema de la proteína GC. Este patrón probablemente está controlado por el infrecuente alelo GC(C) , descrito en unos pocos casos en el ganado vacuno. Además, la electroforesis en gel de almidón permitió detectar en el locus de la albúmina una banda con movilidad intermedia entre los alelos ALB(A) y ALB(B) . Una variante con un patrón electroforético similar ha sido descrita en muy pocas ocasiones en el ganado vacuno. Sin embargo, la utilización de IEF en condiciones desnaturalizantes no permitió diferenciar esta variante del alelo ALB(A) y, por lo tanto, el significado de la misma no está claro. 1994 Blackwell Verlag GmbH.

Identification of low-frequency TRAF3IP2 coding variants in psoriatic arthritis patients and functional characterization

PubMed Central

2012-01-01

Introduction In recent genome-wide association studies for psoriatic arthritis (PsA) and psoriasis vulgaris, common coding variants in the TRAF3IP2 gene were identified to contribute to susceptibility to both disease entities. The risk allele of p.Asp10Asn (rs33980500) proved to be most significantly associated and to encode a mutant protein with an almost completely disrupted binding property to TRAF6, supporting its impact as a main disease-causing variant and modulator of IL-17 signaling. Methods To identify further variants, exons 2-4 encoding both known TNF-receptor-associated factor (TRAF) binding domains were sequenced in 871 PsA patients. Seven missense variants and one three-base-pair insertion were identified in 0.06% to 1.02% of alleles. Five of these variants were also present in 931 control individuals at comparable frequency. Constructs containing full-length wild-type or mutant TRAF3IP2 were generated and used to analyze functionally all variants for TRAF6-binding in a mammalian two-hybrid assay. Results None of the newly found alleles, though, encoded proteins with different binding properties to TRAF6, or to the cytoplasmic tail of the IL-17-receptor α-chain, suggesting that they do not contribute to susceptibility. Conclusions Thus, the TRAF3IP2-variant p.Asp10Asn is the only susceptibility allele with functional impact on TRAF6 binding, at least in the German population. PMID:22513239

TPMT Genetic Variations in Populations of the Russian Federation

PubMed Central

Samochatova, Elena V; Chupova, Natalia V; Rudneva, Anastassia; Makarova, Olga; Nasedkina, Tatyana V; Fedorova, Olga E; Glotov, Andrei S; Kozhekbaeva, Zh.; Maiorova, Olga A; Roumyantsev, Alexander G; Krynetski, Eugene Y; Krynetskaia, Natalia F; Evans, William E; Ribeiro, Raul C

2009-01-01

Background Polymorphisms that reduce the activity of thiopurine S-methyltransferase (TPMT) cause adverse reactions to conventional doses of thiopurines, routinely used for antileukemic and immunosuppressive treatment. There are more than 20 variant alleles of TPMT that cause decreased enzymatic activity. We studied the most common variant alleles of TPMT and their frequency distribution in a large cohort of multiracial residents in the Russian Federation and compared their frequencies in children with and without malignancy to determine whether TPMT gene abnormality is associated with hematologic malignancy. Procedure The TPMT biochip was used to detect 6 TPMT single nucleotide polymorphisms (SNPs) corresponding to 7 TPMT-deficiency alleles (TPMT*2, TPMT*3A, TPMT*3B, TPMT*3C, TPMT*3D, TPMT*7, and TPMT*8). We analyzed allele frequencies in the whole cohort, the childhood cancer group, and the non-cancer group. We also characterized disease features and outcome according to the presence of TPMT SNPs in children with acute lymphoblastic leukemia (ALL). Results Fifty-five (5.5%) study participants overall had heterozygous TPMT genotypes (1 variant and 1 wild-type allele): TPMT*1/*3A (n=45; 4.5%), TPMT*1/*3C (n=8; 0.8%), and TPMT*1/*2 (n=2; 0.2%). TPMT SNPs were more frequent in children with hematologic malignancy than in other participants (7.5% vs. 4.0%, P = 0.02). We found no significant association between TPMT SNPs and ALL treatment outcome (median follow-up, 31.3 months). Conclusions TPMT*3A is the most prevalent variant allele in the Russian Federation. The estimated frequency of variant alleles in the study cohort (5.5%) was similar to that observed in the White populations in the U.S. and Eastern Europe. PMID:19034904

The functional spectrum of low-frequency coding variation.

PubMed

Marth, Gabor T; Yu, Fuli; Indap, Amit R; Garimella, Kiran; Gravel, Simon; Leong, Wen Fung; Tyler-Smith, Chris; Bainbridge, Matthew; Blackwell, Tom; Zheng-Bradley, Xiangqun; Chen, Yuan; Challis, Danny; Clarke, Laura; Ball, Edward V; Cibulskis, Kristian; Cooper, David N; Fulton, Bob; Hartl, Chris; Koboldt, Dan; Muzny, Donna; Smith, Richard; Sougnez, Carrie; Stewart, Chip; Ward, Alistair; Yu, Jin; Xue, Yali; Altshuler, David; Bustamante, Carlos D; Clark, Andrew G; Daly, Mark; DePristo, Mark; Flicek, Paul; Gabriel, Stacey; Mardis, Elaine; Palotie, Aarno; Gibbs, Richard

2011-09-14

Rare coding variants constitute an important class of human genetic variation, but are underrepresented in current databases that are based on small population samples. Recent studies show that variants altering amino acid sequence and protein function are enriched at low variant allele frequency, 2 to 5%, but because of insufficient sample size it is not clear if the same trend holds for rare variants below 1% allele frequency. The 1000 Genomes Exon Pilot Project has collected deep-coverage exon-capture data in roughly 1,000 human genes, for nearly 700 samples. Although medical whole-exome projects are currently afoot, this is still the deepest reported sampling of a large number of human genes with next-generation technologies. According to the goals of the 1000 Genomes Project, we created effective informatics pipelines to process and analyze the data, and discovered 12,758 exonic SNPs, 70% of them novel, and 74% below 1% allele frequency in the seven population samples we examined. Our analysis confirms that coding variants below 1% allele frequency show increased population-specificity and are enriched for functional variants. This study represents a large step toward detecting and interpreting low frequency coding variation, clearly lays out technical steps for effective analysis of DNA capture data, and articulates functional and population properties of this important class of genetic variation.

267 Spanish Exomes Reveal Population-Specific Differences in Disease-Related Genetic Variation.

PubMed

Dopazo, Joaquín; Amadoz, Alicia; Bleda, Marta; Garcia-Alonso, Luz; Alemán, Alejandro; García-García, Francisco; Rodriguez, Juan A; Daub, Josephine T; Muntané, Gerard; Rueda, Antonio; Vela-Boza, Alicia; López-Domingo, Francisco J; Florido, Javier P; Arce, Pablo; Ruiz-Ferrer, Macarena; Méndez-Vidal, Cristina; Arnold, Todd E; Spleiss, Olivia; Alvarez-Tejado, Miguel; Navarro, Arcadi; Bhattacharya, Shomi S; Borrego, Salud; Santoyo-López, Javier; Antiñolo, Guillermo

2016-05-01

Recent results from large-scale genomic projects suggest that allele frequencies, which are highly relevant for medical purposes, differ considerably across different populations. The need for a detailed catalog of local variability motivated the whole-exome sequencing of 267 unrelated individuals, representative of the healthy Spanish population. Like in other studies, a considerable number of rare variants were found (almost one-third of the described variants). There were also relevant differences in allelic frequencies in polymorphic variants, including ∼10,000 polymorphisms private to the Spanish population. The allelic frequencies of variants conferring susceptibility to complex diseases (including cancer, schizophrenia, Alzheimer disease, type 2 diabetes, and other pathologies) were overall similar to those of other populations. However, the trend is the opposite for variants linked to Mendelian and rare diseases (including several retinal degenerative dystrophies and cardiomyopathies) that show marked frequency differences between populations. Interestingly, a correspondence between differences in allelic frequencies and disease prevalence was found, highlighting the relevance of frequency differences in disease risk. These differences are also observed in variants that disrupt known drug binding sites, suggesting an important role for local variability in population-specific drug resistances or adverse effects. We have made the Spanish population variant server web page that contains population frequency information for the complete list of 170,888 variant positions we found publicly available (http://spv.babelomics.org/), We show that it if fundamental to determine population-specific variant frequencies to distinguish real disease associations from population-specific polymorphisms. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Cis-Regulatory Variants Affect CHRNA5 mRNA Expression in Populations of African and European Ancestry

PubMed Central

Wang, Jen-Chyong; Spiegel, Noah; Bertelsen, Sarah; Le, Nhung; McKenna, Nicholas; Budde, John P.; Harari, Oscar; Kapoor, Manav; Brooks, Andrew; Hancock, Dana; Tischfield, Jay; Foroud, Tatiana; Bierut, Laura J.; Steinbach, Joe Henry; Edenberg, Howard J.; Traynor, Bryan J.; Goate, Alison M.

2013-01-01

Variants within the gene cluster encoding α3, α5, and β4 nicotinic receptor subunits are major risk factors for substance dependence. The strongest impact on risk is associated with variation in the CHRNA5 gene, where at least two mechanisms are at work: amino acid variation and altered mRNA expression levels. The risk allele of the non-synonymous variant (rs16969968; D398N) primarily occurs on the haplotype containing the low mRNA expression allele. In populations of European ancestry, there are approximately 50 highly correlated variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster and the adjacent PSMA4 gene region that are associated with CHRNA5 mRNA levels. It is not clear which of these variants contribute to the changes in CHRNA5 transcript level. Because populations of African ancestry have reduced linkage disequilibrium among variants spanning this gene cluster, eQTL mapping in subjects of African ancestry could potentially aid in defining the functional variants that affect CHRNA5 mRNA levels. We performed quantitative allele specific gene expression using frontal cortices derived from 49 subjects of African ancestry and 111 subjects of European ancestry. This method measures allele-specific transcript levels in the same individual, which eliminates other biological variation that occurs when comparing expression levels between different samples. This analysis confirmed that substance dependence associated variants have a direct cis-regulatory effect on CHRNA5 transcript levels in human frontal cortices of African and European ancestry and identified 10 highly correlated variants, located in a 9 kb region, that are potential functional variants modifying CHRNA5 mRNA expression levels. PMID:24303001

NKX2-3 and IRGM variants are associated with disease susceptibility to IBD in Eastern European patients

PubMed Central

Meggyesi, Nora; Kiss, Lajos S; Koszarska, Magdalena; Bortlik, Martin; Duricova, Dana; Lakatos, Laszlo; Molnar, Tamas; Leniček, Martin; Vítek, Libor; Altorjay, Istvan; Papp, Maria; Tulassay, Zsolt; Miheller, Pal; Papp, Janos; Tordai, Attila; Andrikovics, Hajnalka; Lukas, Milan; Lakatos, Peter Laszlo

2010-01-01

AIM: To investigate variants of immunity-related GTPase family M (IRGM) and NKX2-3 genes and genotype-phenotype in Eastern European patients with inflammatory bowel disease (IBD). METHODS: We analyzed 1707 Hungarian and Czech subjects with Crohn’s disease (CD) (n = 810, age: 37.1 ± 12.6 years, duration: 10.7 ± 8.4 years) and ulcerative colitis (UC) (n = 428, age: 43.7 ± 15.0 years, duration: 12.6 ± 9.9 years), as well as 469 healthy controls. IRGM rs13361189, NKX2-3 rs10883365 and ECM1 rs13294 polymorphisms were tested by LightCycler allele discrimination. Detailed clinical phenotypes were determined by reviewing the medical charts. RESULTS: NKX2-3 rs10883365 variant allele was associated with increased risk for CD (P = 0.009, OR = 1.24, 95% CI = 1.06-1.48) and UC (P = 0.001, OR = 1.36, 95% CI = 1.13-1.63), whereas variant IRGM allele increased risk for CD (P = 0.029, OR = 1.36, 95% CI = 1.03-1.79). In contrast, ECM1 rs13294 was not associated with either CD or UC. In CD, the variant IRGM allele was associated with a colon-only location (P = 0.02, OR = 1.62, 95% CI = 1.07-2.44), whereas in UC, the ECM1 variant was associated with cutaneous manifestations (P = 0.002, OR = 3.36, 95% CI = 1.48-7.63). Variant alleles did not predict resistance to steroids or azathioprine, efficacy of infliximab, or need for surgery. CONCLUSION: NKX2-3 and IRGM are susceptibility loci for IBD in Eastern European patients. Further studies are needed to confirm the reported phenotype-genotype associations. PMID:21049557

A clinical and molecular characterisation of CRB1-associated maculopathy.

PubMed

Khan, Kamron N; Robson, Anthony; Mahroo, Omar A R; Arno, Gavin; Inglehearn, Chris F; Armengol, Monica; Waseem, Naushin; Holder, Graham E; Carss, Keren J; Raymond, Lucy F; Webster, Andrew R; Moore, Anthony T; McKibbin, Martin; van Genderen, Maria M; Poulter, James A; Michaelides, Michel

2018-05-01

To date, over 150 disease-associated variants in CRB1 have been described, resulting in a range of retinal disease phenotypes including Leber congenital amaurosis and retinitis pigmentosa. Despite this, no genotype-phenotype correlations are currently recognised. We performed a retrospective review of electronic patient records to identify patients with macular dystrophy due to bi-allelic variants in CRB1. In total, seven unrelated individuals were identified. The median age at presentation was 21 years, with a median acuity of 0.55 decimalised Snellen units (IQR = 0.43). The follow-up period ranged from 0 to 19 years (median = 2.0 years), with a median final decimalised Snellen acuity of 0.65 (IQR = 0.70). Fundoscopy revealed only a subtly altered foveal reflex, which evolved into a bull's-eye pattern of outer retinal atrophy. Optical coherence tomography identified structural changes-intraretinal cysts in the early stages of disease, and later outer retinal atrophy. Genetic testing revealed that one rare allele (c.498_506del, p.(Ile167_Gly169del)) was present in all patients, with one patient being homozygous for the variant and six being heterozygous. In trans with this, one variant recurred twice (p.(Cys896Ter)), while the four remaining alleles were each observed once (p.(Pro1381Thr), p.(Ser478ProfsTer24), p.(Cys195Phe) and p.(Arg764Cys)). These findings show that the rare CRB1 variant, c.498_506del, is strongly associated with localised retinal dysfunction. The clinical findings are much milder than those observed with bi-allelic, loss-of-function variants in CRB1, suggesting this in-frame deletion acts as a hypomorphic allele. This is the most prevalent disease-causing CRB1 variant identified in the non-Asian population to date.

Lupus Risk Variant Increases pSTAT1 Binding and Decreases ETS1 Expression

PubMed Central

Lu, Xiaoming; Zoller, Erin E.; Weirauch, Matthew T.; Wu, Zhiguo; Namjou, Bahram; Williams, Adrienne H.; Ziegler, Julie T.; Comeau, Mary E.; Marion, Miranda C.; Glenn, Stuart B.; Adler, Adam; Shen, Nan; Nath, Swapan K.; Stevens, Anne M.; Freedman, Barry I.; Tsao, Betty P.; Jacob, Chaim O.; Kamen, Diane L.; Brown, Elizabeth E.; Gilkeson, Gary S.; Alarcón, Graciela S.; Reveille, John D.; Anaya, Juan-Manuel; James, Judith A.; Sivils, Kathy L.; Criswell, Lindsey A.; Vilá, Luis M.; Alarcón-Riquelme, Marta E.; Petri, Michelle; Scofield, R. Hal; Kimberly, Robert P.; Ramsey-Goldman, Rosalind; Joo, Young Bin; Choi, Jeongim; Bae, Sang-Cheol; Boackle, Susan A.; Graham, Deborah Cunninghame; Vyse, Timothy J.; Guthridge, Joel M.; Gaffney, Patrick M.; Langefeld, Carl D.; Kelly, Jennifer A.; Greis, Kenneth D.; Kaufman, Kenneth M.; Harley, John B.; Kottyan, Leah C.

2015-01-01

Genetic variants at chromosomal region 11q23.3, near the gene ETS1, have been associated with systemic lupus erythematosus (SLE), or lupus, in independent cohorts of Asian ancestry. Several recent studies have implicated ETS1 as a critical driver of immune cell function and differentiation, and mice deficient in ETS1 develop an SLE-like autoimmunity. We performed a fine-mapping study of 14,551 subjects from multi-ancestral cohorts by starting with genotyped variants and imputing to all common variants spanning ETS1. By constructing genetic models via frequentist and Bayesian association methods, we identified 16 variants that are statistically likely to be causal. We functionally assessed each of these variants on the basis of their likelihood of affecting transcription factor binding, miRNA binding, or chromatin state. Of the four variants that we experimentally examined, only rs6590330 differentially binds lysate from B cells. Using mass spectrometry, we found more binding of the transcription factor signal transducer and activator of transcription 1 (STAT1) to DNA near the risk allele of rs6590330 than near the non-risk allele. Immunoblot analysis and chromatin immunoprecipitation of pSTAT1 in B cells heterozygous for rs6590330 confirmed that the risk allele increased binding to the active form of STAT1. Analysis with expression quantitative trait loci indicated that the risk allele of rs6590330 is associated with decreased ETS1 expression in Han Chinese, but not other ancestral cohorts. We propose a model in which the risk allele of rs6590330 is associated with decreased ETS1 expression and increases SLE risk by enhancing the binding of pSTAT1. PMID:25865496

A false positive newborn screening result due to a complex allele carrying two frequent CF-causing variants.

PubMed

Bergougnoux, Anne; Boureau-Wirth, Amandine; Rouzier, Cécile; Altieri, Jean-Pierre; Verneau, Fanny; Larrieu, Lise; Koenig, Michel; Claustres, Mireille; Raynal, Caroline

2016-05-01

The detection of two frequent CFTR disease-causing variations in the context of a newborn screening program (NBS) usually leads to the diagnosis of cystic fibrosis (CF) and a relevant genetic counseling in the family. In the present study, CF-causing variants p.Phe508del (F508del) and c.3140-26A>G (3272-26A>G) were identified on a neonate with positive ImmunoReactive Trypsinogen test by the Elucigene™ CF30 kit. The CF diagnosis initially suggested, despite three inconclusive Sweat Chloride Tests (SCT), was finally ruled out after the familial segregation study combined with a negative SCT. Haplotype studies, based on the comparison of 80 p.Phe508del haplotypes, suggested a probable de novo occurrence of c.3140-26A>G on the p.Phe508del ancestral allele in this family. This false positive case emphasizes the importance of SCT in the NBS strategy. Moreover, it raises the need for familial segregation studies in CF and in overall molecular diagnosis strategy of autosomal recessive diseases. Copyright © 2016 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

FTO genetic variants, dietary intake and body mass index: insights from 177,330 individuals.

PubMed

Qi, Qibin; Kilpeläinen, Tuomas O; Downer, Mary K; Tanaka, Toshiko; Smith, Caren E; Sluijs, Ivonne; Sonestedt, Emily; Chu, Audrey Y; Renström, Frida; Lin, Xiaochen; Ängquist, Lars H; Huang, Jinyan; Liu, Zhonghua; Li, Yanping; Asif Ali, Muhammad; Xu, Min; Ahluwalia, Tarunveer Singh; Boer, Jolanda M A; Chen, Peng; Daimon, Makoto; Eriksson, Johan; Perola, Markus; Friedlander, Yechiel; Gao, Yu-Tang; Heppe, Denise H M; Holloway, John W; Houston, Denise K; Kanoni, Stavroula; Kim, Yu-Mi; Laaksonen, Maarit A; Jääskeläinen, Tiina; Lee, Nanette R; Lehtimäki, Terho; Lemaitre, Rozenn N; Lu, Wei; Luben, Robert N; Manichaikul, Ani; Männistö, Satu; Marques-Vidal, Pedro; Monda, Keri L; Ngwa, Julius S; Perusse, Louis; van Rooij, Frank J A; Xiang, Yong-Bing; Wen, Wanqing; Wojczynski, Mary K; Zhu, Jingwen; Borecki, Ingrid B; Bouchard, Claude; Cai, Qiuyin; Cooper, Cyrus; Dedoussis, George V; Deloukas, Panos; Ferrucci, Luigi; Forouhi, Nita G; Hansen, Torben; Christiansen, Lene; Hofman, Albert; Johansson, Ingegerd; Jørgensen, Torben; Karasawa, Shigeru; Khaw, Kay-Tee; Kim, Mi-Kyung; Kristiansson, Kati; Li, Huaixing; Lin, Xu; Liu, Yongmei; Lohman, Kurt K; Long, Jirong; Mikkilä, Vera; Mozaffarian, Dariush; North, Kari; Pedersen, Oluf; Raitakari, Olli; Rissanen, Harri; Tuomilehto, Jaakko; van der Schouw, Yvonne T; Uitterlinden, André G; Zillikens, M Carola; Franco, Oscar H; Shyong Tai, E; Ou Shu, Xiao; Siscovick, David S; Toft, Ulla; Verschuren, W M Monique; Vollenweider, Peter; Wareham, Nicholas J; Witteman, Jacqueline C M; Zheng, Wei; Ridker, Paul M; Kang, Jae H; Liang, Liming; Jensen, Majken K; Curhan, Gary C; Pasquale, Louis R; Hunter, David J; Mohlke, Karen L; Uusitupa, Matti; Cupples, L Adrienne; Rankinen, Tuomo; Orho-Melander, Marju; Wang, Tao; Chasman, Daniel I; Franks, Paul W; Sørensen, Thorkild I A; Hu, Frank B; Loos, Ruth J F; Nettleton, Jennifer A; Qi, Lu

2014-12-20

FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177,330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m(2), P = 1.9 × 10(-105)), and all participants (0.30 [0.30, 0.35] kg/m(2), P = 3.6 × 10(-107)). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10(-16)), and relative weak associations with lower total energy intake (-6.4 [-10.1, -2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10(-9)) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Haplotype block structure study of the CFTR gene. Most variants are associated with the M470 allele in several European populations.

PubMed

Pompei, Fiorenza; Ciminelli, Bianca Maria; Bombieri, Cristina; Ciccacci, Cinzia; Koudova, Monika; Giorgi, Silvia; Belpinati, Francesca; Begnini, Angela; Cerny, Milos; Des Georges, Marie; Claustres, Mireille; Ferec, Claude; Macek, Milan; Modiano, Guido; Pignatti, Pier Franco

2006-01-01

An average of about 1700 CFTR (cystic fibrosis transmembrane conductance regulator) alleles from normal individuals from different European populations were extensively screened for DNA sequence variation. A total of 80 variants were observed: 61 coding SNSs (results already published), 13 noncoding SNSs, three STRs, two short deletions, and one nucleotide insertion. Eight DNA variants were classified as non-CF causing due to their high frequency of occurrence. Through this survey the CFTR has become the most exhaustively studied gene for its coding sequence variability and, though to a lesser extent, for its noncoding sequence variability as well. Interestingly, most variation was associated with the M470 allele, while the V470 allele showed an 'extended haplotype homozygosity' (EHH). These findings make us suggest a role for selection acting either on the M470V itself or through an hitchhiking mechanism involving a second site. The possible ancient origin of the V allele in an 'out of Africa' time frame is discussed.

Mapping rare and common causal alleles for complex human diseases

PubMed Central

Raychaudhuri, Soumya

2011-01-01

Advances in genotyping and sequencing technologies have revolutionized the genetics of complex disease by locating rare and common variants that influence an individual’s risk for diseases, such as diabetes, cancers, and psychiatric disorders. However, to capitalize on this data for prevention and therapies requires the identification of causal alleles and a mechanistic understanding for how these variants contribute to the disease. After discussing the strategies currently used to map variants for complex diseases, this Primer explores how variants may be prioritized for follow-up functional studies and the challenges and approaches for assessing the contributions of rare and common variants to disease phenotypes. PMID:21962507

Systematic Functional Interrogation of Rare Cancer Variants Identifies Oncogenic Alleles | Office of Cancer Genomics

Cancer.gov

Cancer genome characterization efforts now provide an initial view of the somatic alterations in primary tumors. However, most point mutations occur at low frequency, and the function of these alleles remains undefined. We have developed a scalable systematic approach to interrogate the function of cancer-associated gene variants. We subjected 474 mutant alleles curated from 5,338 tumors to pooled in vivo tumor formation assays and gene expression profiling. We identified 12 transforming alleles, including two in genes (PIK3CB, POT1) that have not been shown to be tumorigenic.

Variability and genetics of spacer DNA sequences between the ribosomal-RNA genes of hexaploid wheat (Triticum aestivum).

PubMed

May, C E; Appels, R

1987-09-01

Using restriction enzyme digests of genomic DNA extracted from the leaves of 25 hexaploid wheat (Triticum aestivum L. em. Thell.) cultivars and their hybrids, restriction fragment length polymorphisms of the spacer DNA which separates the ribosomal-RNA genes have been examined. (From one to three thousand of these genes are borne on chromosomes 1B and 6B of hexaploid wheat). The data show that there are three distinct alleles of the 1B locus, designated Nor-B1a, Nor-B1b, and Nor-B1c, and at least five allelic variants of the 6B locus, designated Nor-B2a, Nor-B2b, Nor-B2c, Nor-B2d, and Nor-B2e. A further, previously reported allele on 6B has been named Nor-B2f. Chromosome 5D has only one allelic variant, Nor-D3. Whereas the major spacer variants of the 1B alleles apparently differ by the loss or gain of one or two of the 133 bp sub-repeat units within the spacer DNA, the 6B allelic variants show major differences in their compositions and lengths. This may be related to the greater number of rDNA repeat units at this locus. The practical implications of these differences and their application to wheat breeding are discussed.

Meta-analyses of the association of HLA-DRB1 alleles with rheumatoid arthritis among Arabs.

PubMed

Bizzari, Sami; Nair, Pratibha; Al Ali, Mahmoud Taleb; Hamzeh, Abdul Rezzak

2017-07-01

Various studies incorporating Arab populations have reported on specific associations between HLA-DRB1 variants and rheumatoid arthritis (RA). We sought to provide an overview on the association of HLA-DRB1 with RA in Arabs using meta-analysis tools. Data on allele counts and frequencies were compiled from the relevant literature (published before 16 February 2016) and the associations of 13 -DRB1 variants with RA were assessed; relationships were defined in terms of odds ratios (ORs) with a 95% confidence interval. Based on a collection of six studies, risk conferring or protective allele associations were derived from allele counts in 475 RA patients and 1213 controls. Two HLA-DRB1 alleles (-DRB1*04, *10) significantly conferred an increased risk for RA (OR > 2; P < 0.0001). Conversely, four alleles (-DRB1*03, *07, *11 and *13) significantly conferred a protective effect against RA (OR < 1; P < 0.05). No significant associations with RA were found for seven -DRB1 variants (-DRB1*01, *08, *09, *12, *14, *15 and *16). With increased statistical power and effect size over individual studies, we present a more robust profile on the association of HLA-DRB1 variants with RA in the Arab ethnicity, and contribute to the global geo-ethnic picture in this context. © 2016 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

Pooled Resequencing of 122 Ulcerative Colitis Genes in a Large Dutch Cohort Suggests Population-Specific Associations of Rare Variants in MUC2.

PubMed

Visschedijk, Marijn C; Alberts, Rudi; Mucha, Soren; Deelen, Patrick; de Jong, Dirk J; Pierik, Marieke; Spekhorst, Lieke M; Imhann, Floris; van der Meulen-de Jong, Andrea E; van der Woude, C Janneke; van Bodegraven, Adriaan A; Oldenburg, Bas; Löwenberg, Mark; Dijkstra, Gerard; Ellinghaus, David; Schreiber, Stefan; Wijmenga, Cisca; Rivas, Manuel A; Franke, Andre; van Diemen, Cleo C; Weersma, Rinse K

2016-01-01

Genome-wide association studies have revealed several common genetic risk variants for ulcerative colitis (UC). However, little is known about the contribution of rare, large effect genetic variants to UC susceptibility. In this study, we performed a deep targeted re-sequencing of 122 genes in Dutch UC patients in order to investigate the contribution of rare variants to the genetic susceptibility to UC. The selection of genes consists of 111 established human UC susceptibility genes and 11 genes that lead to spontaneous colitis when knocked-out in mice. In addition, we sequenced the promoter regions of 45 genes where known variants exert cis-eQTL-effects. Targeted pooled re-sequencing was performed on DNA of 790 Dutch UC cases. The Genome of the Netherlands project provided sequence data of 500 healthy controls. After quality control and prioritization based on allele frequency and pathogenicity probability, follow-up genotyping of 171 rare variants was performed on 1021 Dutch UC cases and 1166 Dutch controls. Single-variant association and gene-based analyses identified an association of rare variants in the MUC2 gene with UC. The associated variants in the Dutch population could not be replicated in a German replication cohort (1026 UC cases, 3532 controls). In conclusion, this study has identified a putative role for MUC2 on UC susceptibility in the Dutch population and suggests a population-specific contribution of rare variants to UC.

Detecting very low allele fraction variants using targeted DNA sequencing and a novel molecular barcode-aware variant caller.

PubMed

Xu, Chang; Nezami Ranjbar, Mohammad R; Wu, Zhong; DiCarlo, John; Wang, Yexun

2017-01-03

Detection of DNA mutations at very low allele fractions with high accuracy will significantly improve the effectiveness of precision medicine for cancer patients. To achieve this goal through next generation sequencing, researchers need a detection method that 1) captures rare mutation-containing DNA fragments efficiently in the mix of abundant wild-type DNA; 2) sequences the DNA library extensively to deep coverage; and 3) distinguishes low level true variants from amplification and sequencing errors with high accuracy. Targeted enrichment using PCR primers provides researchers with a convenient way to achieve deep sequencing for a small, yet most relevant region using benchtop sequencers. Molecular barcoding (or indexing) provides a unique solution for reducing sequencing artifacts analytically. Although different molecular barcoding schemes have been reported in recent literature, most variant calling has been done on limited targets, using simple custom scripts. The analytical performance of barcode-aware variant calling can be significantly improved by incorporating advanced statistical models. We present here a highly efficient, simple and scalable enrichment protocol that integrates molecular barcodes in multiplex PCR amplification. In addition, we developed smCounter, an open source, generic, barcode-aware variant caller based on a Bayesian probabilistic model. smCounter was optimized and benchmarked on two independent read sets with SNVs and indels at 5 and 1% allele fractions. Variants were called with very good sensitivity and specificity within coding regions. We demonstrated that we can accurately detect somatic mutations with allele fractions as low as 1% in coding regions using our enrichment protocol and variant caller.

Imputation-Based Genomic Coverage Assessments of Current Human Genotyping Arrays

PubMed Central

Nelson, Sarah C.; Doheny, Kimberly F.; Pugh, Elizabeth W.; Romm, Jane M.; Ling, Hua; Laurie, Cecelia A.; Browning, Sharon R.; Weir, Bruce S.; Laurie, Cathy C.

2013-01-01

Microarray single-nucleotide polymorphism genotyping, combined with imputation of untyped variants, has been widely adopted as an efficient means to interrogate variation across the human genome. “Genomic coverage” is the total proportion of genomic variation captured by an array, either by direct observation or through an indirect means such as linkage disequilibrium or imputation. We have performed imputation-based genomic coverage assessments of eight current genotyping arrays that assay from ~0.3 to ~5 million variants. Coverage was determined separately in each of the four continental ancestry groups in the 1000 Genomes Project phase 1 release. We used the subset of 1000 Genomes variants present on each array to impute the remaining variants and assessed coverage based on correlation between imputed and observed allelic dosages. More than 75% of common variants (minor allele frequency > 0.05) are covered by all arrays in all groups except for African ancestry, and up to ~90% in all ancestries for the highest density arrays. In contrast, less than 40% of less common variants (0.01 < minor allele frequency < 0.05) are covered by low density arrays in all ancestries and 50–80% in high density arrays, depending on ancestry. We also calculated genome-wide power to detect variant-trait association in a case-control design, across varying sample sizes, effect sizes, and minor allele frequency ranges, and compare these array-based power estimates with a hypothetical array that would type all variants in 1000 Genomes. These imputation-based genomic coverage and power analyses are intended as a practical guide to researchers planning genetic studies. PMID:23979933

Genomic constitution of an H-2:Tla variant leukemia.

PubMed

Shen, F W; Chaganti, R S; Doucette, L A; Litman, G W; Steinmetz, M; Hood, L; Boyse, E A

1984-10-01

A TL+ leukemia of a (B6 X A)F1 hybrid mouse (H-2b/H-2a) was previously subjected to immunoselection against H-2a by passage in (B6 X A.SW)F1 mice (H-2b/H-2s). A variant leukemia line was obtained that serologically lacked not only the H-2a phenotype but also the TL phenotype determined by the linked cis Tlaa allele of strain A. The H-2b phenotype and the TL phenotype of the Tlab allele of the B6 strain, which is expressed only by leukemia cells, were retained by the variant. Southern blotting with an H-2 cDNA probe that identifies restriction fragment polymorphisms distinguishing alleles of the H-2 and Tla regions of the B6 and A strains indicates that both the H-2a and Tlaa alleles are missing from the genome of this H-2a:Tlaa negative variant. Since the variant has two apparently unaltered chromosomes 17, where the H-2:Tla complex is situated, and since the intensity of bands in Southern blotting is suggestive of H-2b homozygosity, it is considered that loss of the H-2a:Tlaa haplotype by the variant was accompanied by duplication of the H-2b:Tlab haplotype. The implied change from heterozygosity to homozygosity that the variant has undergone with respect to H-2:Tla was not paralleled by a similar change at the three other loci tested, since the variant retained heterozygosity for Pep-3 (chromosome 1), Gpi-1 (chromosome 7), and Es-1 (chromosome 8).

Effects of a common variant in the CD38 gene on social processing in an oxytocin challenge study: possible links to autism.

PubMed

Sauer, Carina; Montag, Christian; Wörner, Christiane; Kirsch, Peter; Reuter, Martin

2012-05-01

The intranasal application of oxytocin (OT) has been shown to influence behavioral and neural correlates of social processing. These effects are probably mediated by genetic variations within the OT system. One potential candidate could be the CD38 gene, which codes for a transmembrane protein engaged in OT secretion processes. A common variation in this gene (rs3796863) was recently found to be associated with autism spectrum disorders (ASD). Using an imaging genetics approach, we studied differential effects of an intranasal OT application on neural processing of social stimuli in 55 healthy young men depending on their CD38 gene variant in a double-blind placebo-controlled crossover design. Genotype had a significant influence on both behavioral and neuronal measures of social processing. Homozygotic risk allele carriers showed slower reaction times (RT) and higher activation of left fusiform gyrus during visual processing of social stimuli. Under OT activation differences between genotypes were more evident (though not statistically significantly increased) and RT were accelerated in homozygotic risk allele carriers. According to our data, rs3796863 mainly influences fusiform gyrus activation, an area which has been widely discussed in ASD research. OT seems to modulate this effect by enhancing activation differences between allele groups, which suggests an interaction between genetic makeup and OT availability on fusiform gyrus activation. These results support recent approaches to apply OT as a pharmacological treatment of ASD symptoms.

Characterization of the c.(-203)A>G variant in the glucocerebrosidase gene and its association with phenotype in Gaucher disease.

PubMed

Alfonso, Pilar; Pampín, Sandra; García-Rodríguez, Beatriz; Tejedor, Teresa; Domínguez, Carmen; Rodríguez-Rey, Jose C; Giraldo, Pilar; Pocoví, Miguel

2011-01-30

Gaucher disease (GD) is a rare autosomal recessive disorder caused mainly by mutations in the glucocerebrosidase (GBA) gene. Great phenotypic variability has been observed among patients with the same genotype, suggesting other factors, such as polymorphic variants, might influence GD phenotypes. We previously reported the c.(-203)A>G (g.1256A>G) variant in exon 1 of the GBA gene in Spanish GD patients. We analyzed the frequency and transcriptional activity of the promoter carrying the G-allele using restriction isotyping, electrophoretic mobility shift assay, cell culture, transfection, and luciferase assays. We found the variant is present at a similar frequency to the control group. In our patients, the G-allele was always found in combination with another mutation in the same allele, and patients carrying the c.(-203)A>G variant showed a more severe GD phenotype. The promoter containing the G-allele showed a 35% reduction in promoter activity when transfected into HepG2 cells. The c.(-203)A>G variant seems to be a polymorphism resulting in a decrease in activity of the GBA promoter. The change, per se, is not enough to elicit a GD phenotype, but it may produce a more severe phenotype in GD patients when combined with an already defective GBA protein. Copyright © 2010 Elsevier B.V. All rights reserved.

Selection and explosive growth alter genetic architecture and hamper the detection of causal rare variants

PubMed Central

Zaitlen, Noah A.; Ye, Chun Jimmie; Witte, John S.

2016-01-01

The role of rare alleles in complex phenotypes has been hotly debated, but most rare variant association tests (RVATs) do not account for the evolutionary forces that affect genetic architecture. Here, we use simulation and numerical algorithms to show that explosive population growth, as experienced by human populations, can dramatically increase the impact of very rare alleles on trait variance. We then assess the ability of RVATs to detect causal loci using simulations and human RNA-seq data. Surprisingly, we find that statistical performance is worst for phenotypes in which genetic variance is due mainly to rare alleles, and explosive population growth decreases power. Although many studies have attempted to identify causal rare variants, few have reported novel associations. This has sometimes been interpreted to mean that rare variants make negligible contributions to complex trait heritability. Our work shows that RVATs are not robust to realistic human evolutionary forces, so general conclusions about the impact of rare variants on complex traits may be premature. PMID:27197206

A low-frequency inactivating AKT2 variant enriched in the Finnish population is associated with fasting insulin levels and type 2 diabetes risk

PubMed Central

Grarup, Niels; Rivas, Manuel A; Mahajan, Anubha; Locke, Adam E; Cingolani, Pablo; Pers, Tune H; Viñuela, Ana; Brown, Andrew A; Wu, Ying; Flannick, Jason; Fuchsberger, Christian; Gamazon, Eric R; Gaulton, Kyle J; Im, Hae Kyung; Teslovich, Tanya M; Blackwell, Thomas W; Bork-Jensen, Jette; Burtt, Noël P; Chen, Yuhui; Green, Todd; Hartl, Christopher; Kang, Hyun Min; Kumar, Ashish; Ladenvall, Claes; Ma, Clement; Moutsianas, Loukas; Pearson, Richard D; Perry, John R B; Rayner, N William; Robertson, Neil R; Scott, Laura J; van de Bunt, Martijn; Eriksson, Johan G; Jula, Antti; Koskinen, Seppo; Lehtimäki, Terho; Palotie, Aarno; Raitakari, Olli T; Jacobs, Suzanne BR; Wessel, Jennifer; Chu, Audrey Y; Scott, Robert A; Goodarzi, Mark O; Blancher, Christine; Buck, Gemma; Buck, David; Chines, Peter S; Gabriel, Stacey; Gjesing, Anette P; Groves, Christopher J; Hollensted, Mette; Huyghe, Jeroen R; Jackson, Anne U; Jun, Goo; Justesen, Johanne Marie; Mangino, Massimo; Murphy, Jacquelyn; Neville, Matt; Onofrio, Robert; Small, Kerrin S; Stringham, Heather M; Trakalo, Joseph; Banks, Eric; Carey, Jason; Carneiro, Mauricio O; DePristo, Mark; Farjoun, Yossi; Fennell, Timothy; Goldstein, Jacqueline I; Grant, George; de Angelis, Martin Hrabé; Maguire, Jared; Neale, Benjamin M; Poplin, Ryan; Purcell, Shaun; Schwarzmayr, Thomas; Shakir, Khalid; Smith, Joshua D; Strom, Tim M; Wieland, Thomas; Lindstrom, Jaana; Brandslund, Ivan; Christensen, Cramer; Surdulescu, Gabriela L; Lakka, Timo A; Doney, Alex S F; Nilsson, Peter; Wareham, Nicholas J; Langenberg, Claudia; Varga, Tibor V; Franks, Paul W; Rolandsson, Olov; Rosengren, Anders H; Farook, Vidya S; Thameem, Farook; Puppala, Sobha; Kumar, Satish; Lehman, Donna M; Jenkinson, Christopher P; Curran, Joanne E; Hale, Daniel Esten; Fowler, Sharon P; Arya, Rector; DeFronzo, Ralph A; Abboud, Hanna E; Syvänen, Ann-Christine; Hicks, Pamela J; Palmer, Nicholette D; Ng, Maggie C Y; Bowden, Donald W; Freedman, Barry I; Esko, Tõnu; Mägi, Reedik; Milani, Lili; Mihailov, Evelin; Metspalu, Andres; Narisu, Narisu; Kinnunen, Leena; Bonnycastle, Lori L; Swift, Amy; Pasko, Dorota; Wood, Andrew R; Fadista, João; Pollin, Toni I; Barzilai, Nir; Atzmon, Gil; Glaser, Benjamin; Thorand, Barbara; Strauch, Konstantin; Peters, Annette; Roden, Michael; Müller-Nurasyid, Martina; Liang, Liming; Kriebel, Jennifer; Illig, Thomas; Grallert, Harald; Gieger, Christian; Meisinger, Christa; Lannfelt, Lars; Musani, Solomon K; Griswold, Michael; Taylor, Herman A; Wilson, Gregory; Correa, Adolfo; Oksa, Heikki; Scott, William R; Afzal, Uzma; Tan, Sian-Tsung; Loh, Marie; Chambers, John C; Sehmi, Jobanpreet; Kooner, Jaspal Singh; Lehne, Benjamin; Cho, Yoon Shin; Lee, Jong-Young; Han, Bok-Ghee; Käräjämäki, Annemari; Qi, Qibin; Qi, Lu; Huang, Jinyan; Hu, Frank B; Melander, Olle; Orho-Melander, Marju; Below, Jennifer E; Aguilar, David; Wong, Tien Yin; Liu, Jianjun; Khor, Chiea-Chuen; Chia, Kee Seng; Lim, Wei Yen; Cheng, Ching-Yu; Chan, Edmund; Tai, E Shyong; Aung, Tin; Linneberg, Allan; Isomaa, Bo; Meitinger, Thomas; Tuomi, Tiinamaija; Hakaste, Liisa; Kravic, Jasmina; Jørgensen, Marit E; Lauritzen, Torsten; Deloukas, Panos; Stirrups, Kathleen E; Owen, Katharine R; Farmer, Andrew J; Frayling, Timothy M; O'Rahilly, Stephen P; Walker, Mark; Levy, Jonathan C; Hodgkiss, Dylan; Hattersley, Andrew T; Kuulasmaa, Teemu; Stančáková, Alena; Barroso, Inês; Bharadwaj, Dwaipayan; Chan, Juliana; Chandak, Giriraj R; Daly, Mark J; Donnelly, Peter J; Ebrahim, Shah B; Elliott, Paul; Fingerlin, Tasha; Froguel, Philippe; Hu, Cheng; Jia, Weiping; Ma, Ronald C W; McVean, Gilean; Park, Taesung; Prabhakaran, Dorairaj; Sandhu, Manjinder; Scott, James; Sladek, Rob; Tandon, Nikhil; Teo, Yik Ying; Zeggini, Eleftheria; Watanabe, Richard M; Koistinen, Heikki A; Kesaniemi, Y Antero; Uusitupa, Matti; Spector, Timothy D; Salomaa, Veikko; Rauramaa, Rainer; Palmer, Colin N A; Prokopenko, Inga; Morris, Andrew D; Bergman, Richard N; Collins, Francis S; Lind, Lars; Ingelsson, Erik; Tuomilehto, Jaakko; Karpe, Fredrik; Groop, Leif; Jørgensen, Torben; Hansen, Torben; Pedersen, Oluf; Kuusisto, Johanna; Abecasis, Gonçalo; Bell, Graeme I; Blangero, John; Cox, Nancy J; Duggirala, Ravindranath; Seielstad, Mark; Wilson, James G; Dupuis, Josee; Ripatti, Samuli; Hanis, Craig L; Florez, Jose C; Mohlke, Karen L; Meigs, James B; Laakso, Markku; Morris, Andrew P; Boehnke, Michael; Altshuler, David; McCarthy, Mark I; Gloyn, Anna L; Lindgren, Cecilia M

2017-01-01

To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting insulin, a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in fasting plasma insulin (FI) levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-hour insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio=1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2. PMID:28341696

Finding missing heritability in less significant Loci and allelic heterogeneity: genetic variation in human height.

PubMed

Zhang, Ge; Karns, Rebekah; Sun, Guangyun; Indugula, Subba Rao; Cheng, Hong; Havas-Augustin, Dubravka; Novokmet, Natalija; Durakovic, Zijad; Missoni, Sasa; Chakraborty, Ranajit; Rudan, Pavao; Deka, Ranjan

2012-01-01

Genome-wide association studies (GWAS) have identified many common variants associated with complex traits in human populations. Thus far, most reported variants have relatively small effects and explain only a small proportion of phenotypic variance, leading to the issues of 'missing' heritability and its explanation. Using height as an example, we examined two possible sources of missing heritability: first, variants with smaller effects whose associations with height failed to reach genome-wide significance and second, allelic heterogeneity due to the effects of multiple variants at a single locus. Using a novel analytical approach we examined allelic heterogeneity of height-associated loci selected from SNPs of different significance levels based on the summary data of the GIANT (stage 1) studies. In a sample of 1,304 individuals collected from an island population of the Adriatic coast of Croatia, we assessed the extent of height variance explained by incorporating the effects of less significant height loci and multiple effective SNPs at the same loci. Our results indicate that approximately half of the 118 loci that achieved stringent genome-wide significance (p-value<5×10(-8)) showed evidence of allelic heterogeneity. Additionally, including less significant loci (i.e., p-value<5×10(-4)) and accounting for effects of allelic heterogeneity substantially improved the variance explained in height.

Association between sequence variants in panicle development genes and the number of spikelets per panicle in rice.

PubMed

Jang, Su; Lee, Yunjoo; Lee, Gileung; Seo, Jeonghwan; Lee, Dongryung; Yu, Yoye; Chin, Joong Hyoun; Koh, Hee-Jong

2018-01-15

Balancing panicle-related traits such as panicle length and the numbers of primary and secondary branches per panicle, is key to improving the number of spikelets per panicle in rice. Identifying genetic information contributes to a broader understanding of the roles of gene and provides candidate alleles for use as DNA markers. Discovering relations between panicle-related traits and sequence variants allows opportunity for molecular application in rice breeding to improve the number of spikelets per panicle. In total, 142 polymorphic sites, which constructed 58 haplotypes, were detected in coding regions of ten panicle development gene and 35 sequence variants in six genes were significantly associated with panicle-related traits. Rice cultivars were clustered according to their sequence variant profiles. One of the four resultant clusters, which contained only indica and tong-il varieties, exhibited the largest average number of favorable alleles and highest average number of spikelets per panicle, suggesting that the favorable allele combination found in this cluster was beneficial in increasing the number of spikelets per panicle. Favorable alleles identified in this study can be used to develop functional markers for rice breeding programs. Furthermore, stacking several favorable alleles has the potential to substantially improve the number of spikelets per panicle in rice.

A phylogenetic framework facilitates Y-STR variant discovery and classification via massively parallel sequencing.

PubMed

Huszar, Tunde I; Jobling, Mark A; Wetton, Jon H

2018-04-12

Short tandem repeats on the male-specific region of the Y chromosome (Y-STRs) are permanently linked as haplotypes, and therefore Y-STR sequence diversity can be considered within the robust framework of a phylogeny of haplogroups defined by single nucleotide polymorphisms (SNPs). Here we use massively parallel sequencing (MPS) to analyse the 23 Y-STRs in Promega's prototype PowerSeq™ Auto/Mito/Y System kit (containing the markers of the PowerPlex® Y23 [PPY23] System) in a set of 100 diverse Y chromosomes whose phylogenetic relationships are known from previous megabase-scale resequencing. Including allele duplications and alleles resulting from likely somatic mutation, we characterised 2311 alleles, demonstrating 99.83% concordance with capillary electrophoresis (CE) data on the same sample set. The set contains 267 distinct sequence-based alleles (an increase of 58% compared to the 169 detectable by CE), including 60 novel Y-STR variants phased with their flanking sequences which have not been reported previously to our knowledge. Variation includes 46 distinct alleles containing non-reference variants of SNPs/indels in both repeat and flanking regions, and 145 distinct alleles containing repeat pattern variants (RPV). For DYS385a,b, DYS481 and DYS390 we observed repeat count variation in short flanking segments previously considered invariable, and suggest new MPS-based structural designations based on these. We considered the observed variation in the context of the Y phylogeny: several specific haplogroup associations were observed for SNPs and indels, reflecting the low mutation rates of such variant types; however, RPVs showed less phylogenetic coherence and more recurrence, reflecting their relatively high mutation rates. In conclusion, our study reveals considerable additional diversity at the Y-STRs of the PPY23 set via MPS analysis, demonstrates high concordance with CE data, facilitates nomenclature standardisation, and places Y-STR sequence variants in their phylogenetic context. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Differences in N-linked glycosylation between human surfactant protein-B variants of the C or T allele at the single-nucleotide polymorphism at position 1580: implications for disease.

PubMed Central

Wang, Guirong; Christensen, Neil D; Wigdahl, Brian; Guttentag, Susan H; Floros, Joanna

2003-01-01

Human surfactant protein-B (SP-B), a hydrophobic protein, is essential for normal lung function. SP-B is expressed and secreted by specific lung cell types, i.e. alveolar type II and Clara cells, of the respiratory epithelium. The SP-B precursor (42 kDa) undergoes post-translational processing to generate an 8 kDa mature SP-B. A single-nucleotide polymorphism (SNP) at nucleotide 1580 (C/T) in exon 4 of SP-B that changes amino acid 131 from threonine to isoleucine (Thr131-->Ile) is associated with several pulmonary diseases. The Thr131-->Ile substitution can eliminate a potential N-linked glycosylation site, Asn129-Gln-Thr131, which is present in the SP-B variant of the C allele (ACT/Thr) but not in that of the T allele (ATT/Ile). To determine whether the C allele SP-B variant is indeed glycosylated at Asn(129)-Gln-Thr131, we first generated stably transfected Chinese hamster ovary cell lines that expressed each version of SP-B, and developed specific SP-B polyclonal anti-peptide antibodies. Using both the stably transfected cell lines and fetal lung explants, we observed that the C allele variant is indeed glycosylated at the Asn129-Gln-Thr131 site, whereas the T allele variant, which served as a control, is not. In addition, we also confirmed that both SP-B variants contain another N-linked glycosylation site, Asn311-Ser-Ser313. Given its association with several pulmonary diseases, this finding provides useful information for future studies in disease systems associated with this SNP. Further, we speculate that, given the fact that this SNP is found frequently in the general population, N-linked glycosylation at residue Asn129 interferes with SP-B processing, secretion and folding under certain disease conditions. PMID:12356334

Frequency of interleukin 28B rs12979860 C>T variants in Filipino patients chronically infected with hepatitis B virus.

PubMed

Baclig, Michael O; Reyes, Karen G; Mapua, Cynthia A; Gopez-Cervantes, Juliet; Natividad, Filipinas F

2015-03-01

Hepatitis B virus (HBV) is one of the most prevalent viral infections worldwide. Nearly 400 million individuals are chronic carriers of HBV. The aim of the present study was to determine the frequency of human interleukin 28B (IL28B) variants among treatment naive Filipino patients clinically diagnosed with chronic hepatitis B (CHB), and to compare the IL28B frequency distribution with various ethnic populations. Fifty-seven CHB patients and 43 normal controls were enrolled in this study. Real-time PCR was performed using the TaqMan genotyping assay for IL28B rs12979860. The allelic frequencies among normal controls were 0.94 and 0.06 for the IL28B rs12979860 C and T alleles, respectively. Eighty-eight percent were identified as homozygous for the IL28B C/C genotype and 12% were identified as heterozygous for the IL28B C/T genotype. Among CHB patients, the allelic frequencies were 0.90 for the IL28B C allele and 0.10 for the IL28B T allele. No IL28B T/T genotype was observed between the two groups. No significant difference in the distribution of IL28B genotypes was observed between normal controls and CHB patients. Allelic frequencies of IL28B among Filipinos were similar with other Asian populations but significantly different from Caucasians. The frequency of rs12979860 C>T variants among Filipino CHB patients has not yet been reported. These data provided new insight into the geographical frequency distribution of IL28B variants. Further studies are needed to determine the possible association between IL28B variants and response to pegylated-interferon-α plus ribavirin combination therapy among Filipino patients chronically infected with HBV.

Rare key functional domain missense substitutions in MRE11A, RAD50, and NBN contribute to breast cancer susceptibility: results from a Breast Cancer Family Registry case-control mutation-screening study

PubMed Central

2014-01-01

Introduction The MRE11A-RAD50-Nibrin (MRN) complex plays several critical roles related to repair of DNA double-strand breaks. Inherited mutations in the three components predispose to genetic instability disorders and the MRN genes have been implicated in breast cancer susceptibility, but the underlying data are not entirely convincing. Here, we address two related questions: (1) are some rare MRN variants intermediate-risk breast cancer susceptibility alleles, and if so (2) do the MRN genes follow a BRCA1/BRCA2 pattern wherein most susceptibility alleles are protein-truncating variants, or do they follow an ATM/CHEK2 pattern wherein half or more of the susceptibility alleles are missense substitutions? Methods Using high-resolution melt curve analysis followed by Sanger sequencing, we mutation screened the coding exons and proximal splice junction regions of the MRN genes in 1,313 early-onset breast cancer cases and 1,123 population controls. Rare variants in the three genes were pooled using bioinformatics methods similar to those previously applied to ATM, BRCA1, BRCA2, and CHEK2, and then assessed by logistic regression. Results Re-analysis of our ATM, BRCA1, and BRCA2 mutation screening data revealed that these genes do not harbor pathogenic alleles (other than modest-risk SNPs) with minor allele frequencies >0.1% in Caucasian Americans, African Americans, or East Asians. Limiting our MRN analyses to variants with allele frequencies of <0.1% and combining protein-truncating variants, likely spliceogenic variants, and key functional domain rare missense substitutions, we found significant evidence that the MRN genes are indeed intermediate-risk breast cancer susceptibility genes (odds ratio (OR) = 2.88, P = 0.0090). Key domain missense substitutions were more frequent than the truncating variants (24 versus 12 observations) and conferred a slightly higher OR (3.07 versus 2.61) with a lower P value (0.029 versus 0.14). Conclusions These data establish that MRE11A, RAD50, and NBN are intermediate-risk breast cancer susceptibility genes. Like ATM and CHEK2, their spectrum of pathogenic variants includes a relatively high proportion of missense substitutions. However, the data neither establish whether variants in each of the three genes are best evaluated under the same analysis model nor achieve clinically actionable classification of individual variants observed in this study. PMID:24894818

Linkage Disequilibrium and Inversion-Typing of the Drosophila melanogaster Genome Reference Panel

PubMed Central

Houle, David; Márquez, Eladio J.

2015-01-01

We calculated the linkage disequilibrium between all pairs of variants in the Drosophila Genome Reference Panel with minor allele count ≥5. We used r2 ≥ 0.5 as the cutoff for a highly correlated SNP. We make available the list of all highly correlated SNPs for use in association studies. Seventy-six percent of variant SNPs are highly correlated with at least one other SNP, and the mean number of highly correlated SNPs per variant over the whole genome is 83.9. Disequilibrium between distant SNPs is also common when minor allele frequency (MAF) is low: 37% of SNPs with MAF < 0.1 are highly correlated with SNPs more than 100 kb distant. Although SNPs within regions with polymorphic inversions are highly correlated with somewhat larger numbers of SNPs, and these correlated SNPs are on average farther away, the probability that a SNP in such regions is highly correlated with at least one other SNP is very similar to SNPs outside inversions. Previous karyotyping of the DGRP lines has been inconsistent, and we used LD and genotype to investigate these discrepancies. When previous studies agreed on inversion karyotype, our analysis was almost perfectly concordant with those assignments. In discordant cases, and for inversion heterozygotes, our results suggest errors in two previous analyses or discordance between genotype and karyotype. Heterozygosities of chromosome arms are, in many cases, surprisingly highly correlated, suggesting strong epsistatic selection during the inbreeding and maintenance of the DGRP lines. PMID:26068573

Linkage Disequilibrium and Inversion-Typing of the Drosophila melanogaster Genome Reference Panel.

PubMed

Houle, David; Márquez, Eladio J

2015-06-10

We calculated the linkage disequilibrium between all pairs of variants in the Drosophila Genome Reference Panel with minor allele count ≥5. We used r(2) ≥ 0.5 as the cutoff for a highly correlated SNP. We make available the list of all highly correlated SNPs for use in association studies. Seventy-six percent of variant SNPs are highly correlated with at least one other SNP, and the mean number of highly correlated SNPs per variant over the whole genome is 83.9. Disequilibrium between distant SNPs is also common when minor allele frequency (MAF) is low: 37% of SNPs with MAF < 0.1 are highly correlated with SNPs more than 100 kb distant. Although SNPs within regions with polymorphic inversions are highly correlated with somewhat larger numbers of SNPs, and these correlated SNPs are on average farther away, the probability that a SNP in such regions is highly correlated with at least one other SNP is very similar to SNPs outside inversions. Previous karyotyping of the DGRP lines has been inconsistent, and we used LD and genotype to investigate these discrepancies. When previous studies agreed on inversion karyotype, our analysis was almost perfectly concordant with those assignments. In discordant cases, and for inversion heterozygotes, our results suggest errors in two previous analyses or discordance between genotype and karyotype. Heterozygosities of chromosome arms are, in many cases, surprisingly highly correlated, suggesting strong epsistatic selection during the inbreeding and maintenance of the DGRP lines. Copyright © 2015 Houle and Márquez.

Mutation intolerant genes and targets of FMRP are enriched for nonsynonymous alleles in schizophrenia.

PubMed

Leonenko, Ganna; Richards, Alexander L; Walters, James T; Pocklington, Andrew; Chambert, Kimberly; Al Eissa, Mariam M; Sharp, Sally I; O'Brien, Niamh L; Curtis, David; Bass, Nicholas J; McQuillin, Andrew; Hultman, Christina; Moran, Jennifer L; McCarroll, Steven A; Sklar, Pamela; Neale, Benjamin M; Holmans, Peter A; Owen, Michael J; Sullivan, Patrick F; O'Donovan, Michael C

2017-10-01

Risk of schizophrenia is conferred by alleles occurring across the full spectrum of frequencies from common SNPs of weak effect through to ultra rare alleles, some of which may be moderately to highly penetrant. Previous studies have suggested that some of the risk of schizophrenia is attributable to uncommon alleles represented on Illumina exome arrays. Here, we present the largest study of exomic variation in schizophrenia to date, using samples from the United Kingdom and Sweden (10,011 schizophrenia cases and 13,791 controls). Single variants, genes, and gene sets were analyzed for association with schizophrenia. No single variant or gene reached genome-wide significance. Among candidate gene sets, we found significant enrichment for rare alleles (minor allele frequency [MAF] < 0.001) in genes intolerant of loss-of-function (LoF) variation and in genes whose messenger RNAs bind to fragile X mental retardation protein (FMRP). We further delineate the genetic architecture of schizophrenia by excluding a role for uncommon exomic variants (0.01 ≤ MAF ≥ 0.001) that confer a relatively large effect (odds ratio [OR] > 4). We also show risk alleles within this frequency range exist, but confer smaller effects and should be identified by larger studies. © 2017 Wiley Periodicals, Inc.

Some mutations of exon-7 in cytochrome P450 gene 3A4 and their effect on 6beta-hydroxylation of cortisol.

PubMed

Shchepotina, E G; Vavilin, V A; Goreva, O B; Lyakhovich, V V

2006-06-01

Analysis of variants of exon 7 sequences in cytochrome P450 gene 3A4 in a sample of Caucasoid persons was carried out. The effect of these variants on activity of CYP3A was assessed by the level of cortisol 6beta-hydroxylation. Alleles CYP3A4*5 and *17 were not detected: probably, these mutations are rare and consequently they have little effect on the character of polymorphic distribution of CYP3A4 activity in this population. The incidence of CYP3A4*2 was 5.26%. The 6betaOH-cortisol/cortisol ratio in an individual with CYP3A4*2/*2 genotype was 7.408, which corresponded to "slow metabolizer" phenotype in this sample.

Heterogenous Distribution of MTHFR Gene Variants among Mestizos and Diverse Amerindian Groups from Mexico

PubMed Central

Contreras-Cubas, Cecilia; Sánchez-Hernández, Beatríz E.; García-Ortiz, Humberto; Martínez-Hernández, Angélica; Barajas-Olmos, Francisco; Cid, Miguel; Mendoza-Caamal, Elvia C.; Centeno-Cruz, Federico; Ortiz-Cruz, Gabriela; Jiménez-López, José Concepción; Córdova, Emilio J.; Salas-Bautista, Eva Gabriela; Saldaña-Alvarez, Yolanda; Fernández-López, Juan Carlos; Mutchinick, Osvaldo M.

2016-01-01

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism. Folate deficiency has been related to several conditions, including neural tube defects (NTDs) and cardiovascular diseases. Hence, MTHFR genetic variants have been studied worldwide, particularly the C677T and A1298C. We genotyped the C677T and A1298C MTHFR polymorphisms in Mexican Amerindians (MAs), from the largest sample included in a genetic study (n = 2026, from 62 ethnic groups), and in a geographically-matched Mexican Mestizo population (MEZ, n = 638). The 677T allele was most frequent in Mexican individuals, particularly in MAs. The frequency of this allele in both MAs and MEZs was clearly enriched in the South region of the country, followed by the Central East and South East regions. In contrast, the frequency of the 1298C risk allele in Mexicans was one of the lowest in the world. Both in MAs and MEZs the variants 677T and 1298C displayed opposite allele frequency gradients from southern to northern Mexico. Our findings suggest that in Mestizos the 677T allele was derived from Amerindians while the 1298C allele was a European contribution. Some subgroups showed an allele frequency distribution that highlighted their genetic diversity. Notably, the distribution of the frequency of the 677T allele was consistent with that of the high incidence of NTDs reported in MEZ. PMID:27649570

DNA repair genes polymorphisms and genetic susceptibility to Philadelphia-negative myeloproliferative neoplasms in a Portuguese population: The role of base excision repair genes polymorphisms.

PubMed

Azevedo, Ana P; Silva, Susana N; De Lima, João P; Reichert, Alice; Lima, Fernando; Júnior, Esmeraldina; Rueff, José

2017-06-01

The role of base excision repair (BER) genes in Philadelphia-negative (PN)-myeloproliferative neoplasms (MPNs) susceptibility was evaluated by genotyping eight polymorphisms [apurinic/apyrimidinic endodeoxyribonuclease 1, mutY DNA glycosylase, earlier mutY homolog ( E. coli ) (MUTYH), 8-oxoguanine DNA glycosylase 1, poly (ADP-ribose) polymerase (PARP) 1, PARP4 and X-ray repair cross-complementing 1 (XRCC1)] in a case-control study involving 133 Caucasian Portuguese patients. The results did not reveal a correlation between individual BER polymorphisms and PN-MPNs when considered as a whole. However, stratification for essential thrombocythaemia revealed i) borderline effect/tendency to increased risk when carrying at least one variant allele for XRCC1_399 single-nucleotide polymorphism (SNP); ii) decreased risk for Janus kinase 2-positive patients carrying at least one variant allele for XRCC1_399 SNP; and iii) decreased risk in females carrying at least one variant allele for MUTYH SNP. Combination of alleles demonstrated an increased risk to PN-MPNs for one specific haplogroup. These findings may provide evidence for gene variants in susceptibility to MPNs. Indeed, common variants in DNA repair genes may hamper the capacity to repair DNA, thus increasing cancer susceptibility.

DNA repair genes polymorphisms and genetic susceptibility to Philadelphia-negative myeloproliferative neoplasms in a Portuguese population: The role of base excision repair genes polymorphisms

PubMed Central

Azevedo, Ana P.; Silva, Susana N.; De Lima, João P.; Reichert, Alice; Lima, Fernando; Júnior, Esmeraldina; Rueff, José

2017-01-01

The role of base excision repair (BER) genes in Philadelphia-negative (PN)-myeloproliferative neoplasms (MPNs) susceptibility was evaluated by genotyping eight polymorphisms [apurinic/apyrimidinic endodeoxyribonuclease 1, mutY DNA glycosylase, earlier mutY homolog (E. coli) (MUTYH), 8-oxoguanine DNA glycosylase 1, poly (ADP-ribose) polymerase (PARP) 1, PARP4 and X-ray repair cross-complementing 1 (XRCC1)] in a case-control study involving 133 Caucasian Portuguese patients. The results did not reveal a correlation between individual BER polymorphisms and PN-MPNs when considered as a whole. However, stratification for essential thrombocythaemia revealed i) borderline effect/tendency to increased risk when carrying at least one variant allele for XRCC1_399 single-nucleotide polymorphism (SNP); ii) decreased risk for Janus kinase 2-positive patients carrying at least one variant allele for XRCC1_399 SNP; and iii) decreased risk in females carrying at least one variant allele for MUTYH SNP. Combination of alleles demonstrated an increased risk to PN-MPNs for one specific haplogroup. These findings may provide evidence for gene variants in susceptibility to MPNs. Indeed, common variants in DNA repair genes may hamper the capacity to repair DNA, thus increasing cancer susceptibility. PMID:28599464

Response to DNA damage of CHEK2 missense mutations in familial breast cancer

PubMed Central

Roeb, Wendy; Higgins, Jake; King, Mary-Claire

2012-01-01

Comprehensive sequencing of tumor suppressor genes to evaluate inherited predisposition to cancer yields many individually rare missense alleles of unknown functional and clinical consequence. To address this problem for CHEK2 missense alleles, we developed a yeast-based assay to assess in vivo CHEK2-mediated response to DNA damage. Of 25 germline CHEK2 missense alleles detected in familial breast cancer patients, 12 alleles had complete loss of DNA damage response, 8 had partial loss and 5 exhibited a DNA damage response equivalent to that mediated by wild-type CHEK2. Variants exhibiting reduced response to DNA damage were found in all domains of the CHEK2 protein. Assay results were in agreement with epidemiologic assessments of breast cancer risk for those variants sufficiently common for case–control studies to have been undertaken. Assay results were largely concordant with consensus predictions of in silico tools, particularly for damaging alleles in the kinase domain. However, of the 25 variants, 6 were not consistently classifiable by in silico tools. An in vivo assay of cellular response to DNA damage by mutant CHEK2 alleles may complement and extend epidemiologic and genetic assessment of their clinical consequences. PMID:22419737

Response to DNA damage of CHEK2 missense mutations in familial breast cancer.

PubMed

Roeb, Wendy; Higgins, Jake; King, Mary-Claire

2012-06-15

Comprehensive sequencing of tumor suppressor genes to evaluate inherited predisposition to cancer yields many individually rare missense alleles of unknown functional and clinical consequence. To address this problem for CHEK2 missense alleles, we developed a yeast-based assay to assess in vivo CHEK2-mediated response to DNA damage. Of 25 germline CHEK2 missense alleles detected in familial breast cancer patients, 12 alleles had complete loss of DNA damage response, 8 had partial loss and 5 exhibited a DNA damage response equivalent to that mediated by wild-type CHEK2. Variants exhibiting reduced response to DNA damage were found in all domains of the CHEK2 protein. Assay results were in agreement with epidemiologic assessments of breast cancer risk for those variants sufficiently common for case-control studies to have been undertaken. Assay results were largely concordant with consensus predictions of in silico tools, particularly for damaging alleles in the kinase domain. However, of the 25 variants, 6 were not consistently classifiable by in silico tools. An in vivo assay of cellular response to DNA damage by mutant CHEK2 alleles may complement and extend epidemiologic and genetic assessment of their clinical consequences.

Molecular characterization of both alleles in an unusual Tay-Sachs disease BI variant

DOE Office of Scientific and Technical Information (OSTI.GOV)

Coulter-Mackie, M.B.

1994-06-01

In a recent report, the authors described an exon 6 mutation in a Tay-Sachs B1 variant patient, first reported by Gordon et al. (1988), who displayed a typical B1 variant biochemical phenotype - i.e., (a) significant levels of hexosaminidase A (Hex A) activity in an assay with a neutral synthetic substrate, 4-methylumbelliferyl-[beta]-N-acetylglucosamide, and (b) <2% of control Hex A in a test on the sulfated substrate, 4-methylumbelliferyl-[beta]-N-acetylglucosamide-6-sulfate. The patient was found to carry a double mutation (G[sub 574][yields]C [val[sub 192][yields]leu] and G[sub 598][yields]A [val[sub 200][yields]met]) inherited from her mother. Only the 574 mutation produced a deleterious effect on Hex Amore » activity in transfected COS0-1 cells, producing a B1 variant biochemical phenotype. The paternal allele apparently caused decreased abundance of mRNA, since no candidate paternal mutations were found in cloned reverse transcription-PCR (RT-PCR) products in the reported study. The biochemical phenotype of the original patient and the properties of the cDNA carrying the G[sub 574] [yields] C mutation in transient expression studies were compatible with a B1 variant mutation. The possibility remained that there might be some contribution from the paternal allele to the patient's phenotype. However, the paternal allele produces relatively low yields of a largely mis-spliced mRNA whose product would not be functional. Therefore, the G[sub 574] [yields] C (val[yields]leu) mutation in the maternal allele is clearly confirmed as a B1 variant mutation with all the ramifications for the substrate binding site and/or catalytic center that this implies.« less

A Recurrent De Novo Variant in NACC1 Causes a Syndrome Characterized by Infantile Epilepsy, Cataracts, and Profound Developmental Delay.

PubMed

Schoch, Kelly; Meng, Linyan; Szelinger, Szabolcs; Bearden, David R; Stray-Pedersen, Asbjorg; Busk, Oyvind L; Stong, Nicholas; Liston, Eriskay; Cohn, Ronald D; Scaglia, Fernando; Rosenfeld, Jill A; Tarpinian, Jennifer; Skraban, Cara M; Deardorff, Matthew A; Friedman, Jeremy N; Akdemir, Zeynep Coban; Walley, Nicole; Mikati, Mohamad A; Kranz, Peter G; Jasien, Joan; McConkie-Rosell, Allyn; McDonald, Marie; Wechsler, Stephanie Burns; Freemark, Michael; Kansagra, Sujay; Freedman, Sharon; Bali, Deeksha; Millan, Francisca; Bale, Sherri; Nelson, Stanley F; Lee, Hane; Dorrani, Naghmeh; Goldstein, David B; Xiao, Rui; Yang, Yaping; Posey, Jennifer E; Martinez-Agosto, Julian A; Lupski, James R; Wangler, Michael F; Shashi, Vandana

2017-02-02

Whole-exome sequencing (WES) has increasingly enabled new pathogenic gene variant identification for undiagnosed neurodevelopmental disorders and provided insights into both gene function and disease biology. Here, we describe seven children with a neurodevelopmental disorder characterized by microcephaly, profound developmental delays and/or intellectual disability, cataracts, severe epilepsy including infantile spasms, irritability, failure to thrive, and stereotypic hand movements. Brain imaging in these individuals reveals delay in myelination and cerebral atrophy. We observe an identical recurrent de novo heterozygous c.892C>T (p.Arg298Trp) variant in the nucleus accumbens associated 1 (NACC1) gene in seven affected individuals. One of the seven individuals is mosaic for this variant. NACC1 encodes a transcriptional repressor implicated in gene expression and has not previously been associated with germline disorders. The probability of finding the same missense NACC1 variant by chance in 7 out of 17,228 individuals who underwent WES for diagnoses of neurodevelopmental phenotypes is extremely small and achieves genome-wide significance (p = 1.25 × 10 -14 ). Selective constraint against missense variants in NACC1 makes this excess of an identical missense variant in all seven individuals more remarkable. Our findings are consistent with a germline recurrent mutational hotspot associated with an allele-specific neurodevelopmental phenotype in NACC1. Copyright © 2017 American Society of Human Genetics. All rights reserved.

Geographical gradient of the eIF4E alleles conferring resistance to potyviruses in pea (Pisum) germplasm.

PubMed

Konečná, Eva; Šafářová, Dana; Navrátil, Milan; Hanáček, Pavel; Coyne, Clarice; Flavell, Andrew; Vishnyakova, Margarita; Ambrose, Mike; Redden, Robert; Smýkal, Petr

2014-01-01

The eukaryotic translation initiation factor 4E was shown to be involved in resistance against several potyviruses in plants, including pea. We combined our knowledge of pea germplasm diversity with that of the eIF4E gene to identify novel genetic diversity. Germplasm of 2803 pea accessions was screened for eIF4E intron 3 length polymorphism, resulting in the detection of four eIF4E(A-B-C-S) variants, whose distribution was geographically structured. The eIF4E(A) variant conferring resistance to the P1 PSbMV pathotype was found in 53 accessions (1.9%), of which 15 were landraces from India, Afghanistan, Nepal, and 7 were from Ethiopia. A newly discovered variant, eIF4E(B), was present in 328 accessions (11.7%) from Ethiopia (29%), Afghanistan (23%), India (20%), Israel (25%) and China (39%). The eIF4E(C) variant was detected in 91 accessions (3.2% of total) from India (20%), Afghanistan (33%), the Iberian Peninsula (22%) and the Balkans (9.3%). The eIF4E(S) variant for susceptibility predominated as the wild type. Sequencing of 73 samples, identified 34 alleles at the whole gene, 26 at cDNA and 19 protein variants, respectively. Fifteen alleles were virologically tested and 9 alleles (eIF4E(A-1-2-3-4-5-6-7), eIF4E(B-1), eIF4E(C-2)) conferred resistance to the P1 PSbMV pathotype. This work identified novel eIF4E alleles within geographically structured pea germplasm and indicated their independent evolution from the susceptible eIF4E(S1) allele. Despite high variation present in wild Pisum accessions, none of them possessed resistance alleles, supporting a hypothesis of distinct mode of evolution of resistance in wild as opposed to crop species. The Highlands of Central Asia, the northern regions of the Indian subcontinent, Eastern Africa and China were identified as important centers of pea diversity that correspond with the diversity of the pathogen. The series of alleles identified in this study provides the basis to study the co-evolution of potyviruses and the pea host.

Geographical Gradient of the eIF4E Alleles Conferring Resistance to Potyviruses in Pea (Pisum) Germplasm

PubMed Central

Konečná, Eva; Šafářová, Dana; Navrátil, Milan; Hanáček, Pavel; Coyne, Clarice; Flavell, Andrew; Vishnyakova, Margarita; Ambrose, Mike; Redden, Robert; Smýkal, Petr

2014-01-01

Background The eukaryotic translation initiation factor 4E was shown to be involved in resistance against several potyviruses in plants, including pea. We combined our knowledge of pea germplasm diversity with that of the eIF4E gene to identify novel genetic diversity. Methodology/Principal findings Germplasm of 2803 pea accessions was screened for eIF4E intron 3 length polymorphism, resulting in the detection of four eIF4EA-B-C-S variants, whose distribution was geographically structured. The eIF4EA variant conferring resistance to the P1 PSbMV pathotype was found in 53 accessions (1.9%), of which 15 were landraces from India, Afghanistan, Nepal, and 7 were from Ethiopia. A newly discovered variant, eIF4EB, was present in 328 accessions (11.7%) from Ethiopia (29%), Afghanistan (23%), India (20%), Israel (25%) and China (39%). The eIF4EC variant was detected in 91 accessions (3.2% of total) from India (20%), Afghanistan (33%), the Iberian Peninsula (22%) and the Balkans (9.3%). The eIF4ES variant for susceptibility predominated as the wild type. Sequencing of 73 samples, identified 34 alleles at the whole gene, 26 at cDNA and 19 protein variants, respectively. Fifteen alleles were virologically tested and 9 alleles (eIF4EA-1-2-3-4-5-6-7, eIF4EB-1, eIF4EC-2) conferred resistance to the P1 PSbMV pathotype. Conclusions/Significance This work identified novel eIF4E alleles within geographically structured pea germplasm and indicated their independent evolution from the susceptible eIF4ES1 allele. Despite high variation present in wild Pisum accessions, none of them possessed resistance alleles, supporting a hypothesis of distinct mode of evolution of resistance in wild as opposed to crop species. The Highlands of Central Asia, the northern regions of the Indian subcontinent, Eastern Africa and China were identified as important centers of pea diversity that correspond with the diversity of the pathogen. The series of alleles identified in this study provides the basis to study the co-evolution of potyviruses and the pea host. PMID:24609094

Variants in glucose- and circadian rhythm-related genes affect the response of energy expenditure to weight-loss diets: the POUNDS LOST Trial.

PubMed

Mirzaei, Khadijeh; Xu, Min; Qi, Qibin; de Jonge, Lilian; Bray, George A; Sacks, Frank; Qi, Lu

2014-02-01

Circadian rhythm has been shown to be related to glucose metabolism and risk of diabetes, probably through effects on energy balance. Recent genome-wide association studies identified variants in circadian rhythm-related genes (CRY2 and MTNR1B) associated with glucose homeostasis. We tested whether CRY2 and MTNR1B genotypes affected changes in measures of energy expenditure in response to a weight-loss diet intervention in a 2-y randomized clinical trial, the POUNDS (Preventing Overweight Using Novel Dietary Strategies) LOST Trial. The variants CRY2 rs11605924 (n = 721) and MTNR1B rs10830963 (n = 722) were genotyped in overweight or obese adults who were randomly assigned to 1 of 4 weight-loss diets that differed in their proportions of macronutrients. Respiratory quotient (RQ) and resting metabolic rate (RMR) were measured. By 2 y of diet intervention, the A allele of CRY2 rs11605924 was significantly associated with a greater reduction in RQ (P = 0.03) and a greater increase in RMR and RMR/kg (both P = 0.04). The G allele of MTNR1B rs10830963 was significantly associated with a greater increase in RQ (P = 0.01) but was not related to changes in RMR and RMR/kg. In addition, we found significant gene-diet fat interactions for both CRY2 (P-interaction = 0.02) and MTNR1B (P-interaction < 0.001) in relation to 2-y changes in RQ. Our data indicate that variants in the circadian-related genes CRY2 and MTNR1B may affect long-term changes in energy expenditure, and dietary fat intake may modify the genetic effects. This trial was registered at www.clinicaltrials.gov as NCT00072995.

Loss-of-function DNA sequence variant in the CLCNKA chloride channel implicates the cardio-renal axis in interindividual heart failure risk variation.

PubMed

Cappola, Thomas P; Matkovich, Scot J; Wang, Wei; van Booven, Derek; Li, Mingyao; Wang, Xuexia; Qu, Liming; Sweitzer, Nancy K; Fang, James C; Reilly, Muredach P; Hakonarson, Hakon; Nerbonne, Jeanne M; Dorn, Gerald W

2011-02-08

Common heart failure has a strong undefined heritable component. Two recent independent cardiovascular SNP array studies identified a common SNP at 1p36 in intron 2 of the HSPB7 gene as being associated with heart failure. HSPB7 resequencing identified other risk alleles but no functional gene variants. Here, we further show no effect of the HSPB7 SNP on cardiac HSPB7 mRNA levels or splicing, suggesting that the SNP marks the position of a functional variant in another gene. Accordingly, we used massively parallel platforms to resequence all coding exons of the adjacent CLCNKA gene, which encodes the K(a) renal chloride channel (ClC-K(a)). Of 51 exonic CLCNKA variants identified, one SNP (rs10927887, encoding Arg83Gly) was common, in linkage disequilibrium with the heart failure risk SNP in HSPB7, and associated with heart failure in two independent Caucasian referral populations (n = 2,606 and 1,168; combined P = 2.25 × 10(-6)). Individual genotyping of rs10927887 in the two study populations and a third independent heart failure cohort (combined n = 5,489) revealed an additive allele effect on heart failure risk that is independent of age, sex, and prior hypertension (odds ratio = 1.27 per allele copy; P = 8.3 × 10(-7)). Functional characterization of recombinant wild-type Arg83 and variant Gly83 ClC-K(a) chloride channel currents revealed ≈ 50% loss-of-function of the variant channel. These findings identify a common, functionally significant genetic risk factor for Caucasian heart failure. The variant CLCNKA risk allele, telegraphed by linked variants in the adjacent HSPB7 gene, uncovers a previously overlooked genetic mechanism affecting the cardio-renal axis.

Genomic constitution of an H-2:Tla variant leukemia.

PubMed Central

Shen, F W; Chaganti, R S; Doucette, L A; Litman, G W; Steinmetz, M; Hood, L; Boyse, E A

1984-01-01

A TL+ leukemia of a (B6 X A)F1 hybrid mouse (H-2b/H-2a) was previously subjected to immunoselection against H-2a by passage in (B6 X A.SW)F1 mice (H-2b/H-2s). A variant leukemia line was obtained that serologically lacked not only the H-2a phenotype but also the TL phenotype determined by the linked cis Tlaa allele of strain A. The H-2b phenotype and the TL phenotype of the Tlab allele of the B6 strain, which is expressed only by leukemia cells, were retained by the variant. Southern blotting with an H-2 cDNA probe that identifies restriction fragment polymorphisms distinguishing alleles of the H-2 and Tla regions of the B6 and A strains indicates that both the H-2a and Tlaa alleles are missing from the genome of this H-2a:Tlaa negative variant. Since the variant has two apparently unaltered chromosomes 17, where the H-2:Tla complex is situated, and since the intensity of bands in Southern blotting is suggestive of H-2b homozygosity, it is considered that loss of the H-2a:Tlaa haplotype by the variant was accompanied by duplication of the H-2b:Tlab haplotype. The implied change from heterozygosity to homozygosity that the variant has undergone with respect to H-2:Tla was not paralleled by a similar change at the three other loci tested, since the variant retained heterozygosity for Pep-3 (chromosome 1), Gpi-1 (chromosome 7), and Es-1 (chromosome 8). Images PMID:6593710

Systematic RH genotyping and variant identification in French donors of African origin

PubMed Central

Kappler-Gratias, Sandrine; Auxerre, Carine; Dubeaux, Isabelle; Beolet, Marylise; Ripaux, Maryline; Le Pennec, Pierre-Yves; Pham, Bach-Nga

2014-01-01

Background RH molecular analysis has enabled the documentation of numerous variants of RHD and RHCE alleles, especially in individuals of African origin. The aim of the present study was to determine the type and frequency of D and/or RhCE variants among blood donors of African origin in France, by performing a systematic RH molecular analysis, in order to evaluate the implications for blood transfusion of patients of African origin. Materials and methods Samples from 316 African blood donors, whose origin was established by their Fy(a−b−) phenotype, were first analysed using the RHD and RHCE BeadChips Kit (BioArray Solutions, Immucor, Warren, NJ, USA). Sequencing was performed when necessary. Results RHD molecular analysis showed that 26.2% of donors had a variant RHD allele. It allowed the prediction of a partial D in 11% of cases. RHCE molecular analysis showed that 14.2% of donors had a variant RHCE allele or RH [RN or (C)ces] haplotype. A rare Rh phenotype associated with the loss of a high-prevalence antigen or partial RhCE antigens were predicted from RHCE molecular analysis in 1 (0.3%) and 17 (5%) cases, respectively. Discussion Systematic RHD and RHCE molecular analysis performed in blood donors of African origin provides transfusion-relevant information for individuals of African origin because of the frequency of variant RH alleles. RH molecular analysis may improve transfusion therapy of patients by allowing better donor and recipient matching, based not only on phenotypically matched red blood cell units, but also on units that are genetically matched with regards to RhCE variants. PMID:23867180

QuASAR-MPRA: accurate allele-specific analysis for massively parallel reporter assays.

PubMed

Kalita, Cynthia A; Moyerbrailean, Gregory A; Brown, Christopher; Wen, Xiaoquan; Luca, Francesca; Pique-Regi, Roger

2018-03-01

The majority of the human genome is composed of non-coding regions containing regulatory elements such as enhancers, which are crucial for controlling gene expression. Many variants associated with complex traits are in these regions, and may disrupt gene regulatory sequences. Consequently, it is important to not only identify true enhancers but also to test if a variant within an enhancer affects gene regulation. Recently, allele-specific analysis in high-throughput reporter assays, such as massively parallel reporter assays (MPRAs), have been used to functionally validate non-coding variants. However, we are still missing high-quality and robust data analysis tools for these datasets. We have further developed our method for allele-specific analysis QuASAR (quantitative allele-specific analysis of reads) to analyze allele-specific signals in barcoded read counts data from MPRA. Using this approach, we can take into account the uncertainty on the original plasmid proportions, over-dispersion, and sequencing errors. The provided allelic skew estimate and its standard error also simplifies meta-analysis of replicate experiments. Additionally, we show that a beta-binomial distribution better models the variability present in the allelic imbalance of these synthetic reporters and results in a test that is statistically well calibrated under the null. Applying this approach to the MPRA data, we found 602 SNPs with significant (false discovery rate 10%) allele-specific regulatory function in LCLs. We also show that we can combine MPRA with QuASAR estimates to validate existing experimental and computational annotations of regulatory variants. Our study shows that with appropriate data analysis tools, we can improve the power to detect allelic effects in high-throughput reporter assays. http://github.com/piquelab/QuASAR/tree/master/mpra. fluca@wayne.edu or rpique@wayne.edu. Supplementary data are available online at Bioinformatics. © The Author (2017). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Genetic analysis of the Yavapai Native Americans from West-Central Arizona using the Illumina MiSeq FGx™ forensic genomics system.

PubMed

Wendt, Frank R; Churchill, Jennifer D; Novroski, Nicole M M; King, Jonathan L; Ng, Jillian; Oldt, Robert F; McCulloh, Kelly L; Weise, Jessica A; Smith, David Glenn; Kanthaswamy, Sreetharan; Budowle, Bruce

2016-09-01

Forensically-relevant genetic markers were typed for sixty-two Yavapai Native Americans using the ForenSeq™ DNA Signature Prep Kit.These data are invaluable to the human identity community due to the greater genetic differentiation among Native American tribes than among other subdivisions within major populations of the United States. Autosomal, X-chromosomal, and Y-chromosomal short tandem repeat (STR) and identity-informative (iSNPs), ancestry-informative (aSNPs), and phenotype-informative (pSNPs) single nucleotide polymorphism (SNP) allele frequencies are reported. Sequence-based allelic variants were observed in 13 autosomal, 3 X, and 3 Y STRs. These observations increased observed and expected heterozygosities for autosomal STRs by 0.081±0.068 and 0.073±0.063, respectively, and decreased single-locus random match probabilities by 0.051±0.043 for 13 autosomal STRs. The autosomal random match probabilities (RMPs) were 2.37×10-26 and 2.81×10-29 for length-based and sequence-based alleles, respectively. There were 22 and 25 unique Y-STR haplotypes among 26 males, generating haplotype diversities of 0.95 and 0.96, for length-based and sequencebased alleles, respectively. Of the 26 haplotypes generated, 17 were assigned to haplogroup Q, three to haplogroup R1b, two each to haplogroups E1b1b and L, and one each to haplogroups R1a and I1. Male and female sequence-based X-STR random match probabilities were 3.28×10-7 and 1.22×10-6, respectively. The average observed and expected heterozygosities for 94 iSNPs were 0.39±0.12 and 0.39±0.13, respectively, and the combined iSNP RMP was 1.08×10-32. The combined STR and iSNP RMPs were 2.55×10-58 and 3.02×10-61 for length-based and sequence-based STR alleles, respectively. Ancestry and phenotypic SNP information, performed using the ForenSeq™ Universal Analysis Software, predicted black hair, brown eyes, and some probability of East Asian ancestry for all but one sample that clustered between European and Admixed American ancestry on a principal components analysis. These data serve as the first population assessment using the ForenSeq™ panel and highlight the value of employing sequence-based alleles for forensic DNA typing to increase heterozygosity, which is beneficial for identity testing in populations with reduced genetic diversity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

NaV channel variants in patients with painful and nonpainful peripheral neuropathy

PubMed Central

Wadhawan, Samir; Pant, Saumya; Golhar, Ryan; Kirov, Stefan; Thompson, John; Jacobsen, Leslie; Qureshi, Irfan; Ajroud-Driss, Senda; Freeman, Roy; Simpson, David M.; Smith, A. Gordon; Hoke, Ahmet

2017-01-01

Objective: To examine the incidence of nonsynonymous missense variants in SCN9A (NaV1.7), SCN10A (NaV1.8), and SCN11A (NaV1.9) in patients with painful and nonpainful peripheral neuropathy. Methods: Next-generation sequencing was performed on 457 patient DNA samples provided by the Peripheral Neuropathy Research Registry (PNRR). The patient diagnosis was as follows: 278 idiopathic peripheral neuropathy (67% painful and 33% nonpainful) and 179 diabetic distal polyneuropathy (77% painful and 23% nonpainful). Results: We identified 36 (SCN9A), 31 (SCN10A), and 15 (SCN11A) nonsynonymous missense variants, with 47.7% of patients carrying a low-frequency (minor allele frequency <5%) missense variant in at least 1 gene. The incidence of previously reported gain-of-function missense variants was low (≤3%), and these were detected in patients with and without pain. There were no significant differences in missense variant allele frequencies of any gene, or SCN9A haplotype frequencies, between PNRR patients with painful or nonpainful peripheral neuropathy. PNRR patient SCN9A and SCN11A missense variant allele frequencies were not significantly different from the Exome Variant Server, European American (EVS-EA) reference population. For SCN10A, there was a significant increase in the alternate allele frequency of the common variant p.V1073A and low-frequency variant pS509P in PNRR patients compared with EVS-EA and the 1000 Genomes European reference populations. Conclusions: These results suggest that identification of a genetically defined subpopulation for testing of NaV1.7 inhibitors in patients with peripheral neuropathy is unlikely and that additional factors, beyond expression of previously reported disease “mutations,” are more important for the development of painful neuropathy than previously discussed. PMID:29264398

Tracking human migrations by the analysis of the distribution of HLA alleles, lineages and haplotypes in closed and open populations

PubMed Central

Vina, Marcelo A. Fernandez; Hollenbach, Jill A.; Lyke, Kirsten E.; Sztein, Marcelo B.; Maiers, Martin; Klitz, William; Cano, Pedro; Mack, Steven; Single, Richard; Brautbar, Chaim; Israel, Shosahna; Raimondi, Eduardo; Khoriaty, Evelyne; Inati, Adlette; Andreani, Marco; Testi, Manuela; Moraes, Maria Elisa; Thomson, Glenys; Stastny, Peter; Cao, Kai

2012-01-01

The human leucocyte antigen (HLA) system shows extensive variation in the number and function of loci and the number of alleles present at any one locus. Allele distribution has been analysed in many populations through the course of several decades, and the implementation of molecular typing has significantly increased the level of diversity revealing that many serotypes have multiple functional variants. While the degree of diversity in many populations is equivalent and may result from functional polymorphism(s) in peptide presentation, homogeneous and heterogeneous populations present contrasting numbers of alleles and lineages at the loci with high-density expression products. In spite of these differences, the homozygosity levels are comparable in almost all of them. The balanced distribution of HLA alleles is consistent with overdominant selection. The genetic distances between outbred populations correlate with their geographical locations; the formal genetic distance measurements are larger than expected between inbred populations in the same region. The latter present many unique alleles grouped in a few lineages consistent with limited founder polymorphism in which any novel allele may have been positively selected to enlarge the communal peptide-binding repertoire of a given population. On the other hand, it has been observed that some alleles are found in multiple populations with distinctive haplotypic associations suggesting that convergent evolution events may have taken place as well. It appears that the HLA system has been under strong selection, probably owing to its fundamental role in varying immune responses. Therefore, allelic diversity in HLA should be analysed in conjunction with other genetic markers to accurately track the migrations of modern humans. PMID:22312049

Evaluation of ATG5 polymorphisms in Italian patients with systemic lupus erythematosus: contribution to disease susceptibility and clinical phenotypes.

PubMed

Ciccacci, C; Perricone, C; Alessandri, C; Latini, A; Politi, C; Delunardo, F; Pierdominici, M; Conti, F; Novelli, G; Ortona, E; Borgiani, P

2018-01-01

Systemic lupus erythematosus (SLE) is a common heterogeneous autoimmune disease that is caused by the involvement both of genetic and environmental factors. There is evidence that autophagy is involved in several aspects of SLE pathogenesis. In particular, polymorphisms in the ATG5 gene have been observed to be associated with disease susceptibility. Our aim was to verify if ATG5 polymorphisms are involved in the susceptibility to disease and its clinical phenotypes in an Italian cohort of SLE patients. This study involved 315 SLE patients and 265 healthy controls. Three polymorphisms in the ATG5 gene (rs573775, rs6568431 and rs2245214) were investigated by allelic discrimination assay. A case-control association study, a genotype/phenotype correlation analysis and a haplotype study were performed. Moreover, an expression study was conducted in peripheral blood mononuclear cells from 15 SLE patients to verify a possible effect of the three SNPs on the expression of ATG5. Among the three investigated SNPs, only the rs573775 SNP was significantly associated with disease susceptibility with the variant allele conferring a higher risk of developing SLE (OR = 1.50, p = 0.018 and OR = 1.48, p = 0.007 at the genotypic and allelic level, respectively). The variant allele of rs6568431 SNP was more present in patients with anemia (OR = 1.86, p = 0.009) and renal involvement (OR = 1.63, p = 0.06), while the variant allele of rs2245214 SNP was significantly associated with a higher risk of producing anti-DNA autoantibodies (OR = 1.66, p = 0.04). Carriers of the rs6568431 variant allele showed higher messenger RNA levels compared to the carriers of the wild-type allele, suggesting also a potential variant allele dose-dependent effect on gene expression. In conclusion, our study confirms a role for ATG5 polymorphisms both in disease susceptibility and in the modulation of clinical phenotypes in an Italian SLE cohort. These results further suggest that genetic variations in autophagy genes could play a role in autoimmune diseases susceptibility and are worth further investigation.

Coronary heart disease-associated variation in TCF21 disrupts a miR-224 binding site and miRNA-mediated regulation.

PubMed

Miller, Clint L; Haas, Ulrike; Diaz, Roxanne; Leeper, Nicholas J; Kundu, Ramendra K; Patlolla, Bhagat; Assimes, Themistocles L; Kaiser, Frank J; Perisic, Ljubica; Hedin, Ulf; Maegdefessel, Lars; Schunkert, Heribert; Erdmann, Jeanette; Quertermous, Thomas; Sczakiel, Georg

2014-03-01

Genome-wide association studies (GWAS) have identified chromosomal loci that affect risk of coronary heart disease (CHD) independent of classical risk factors. One such association signal has been identified at 6q23.2 in both Caucasians and East Asians. The lead CHD-associated polymorphism in this region, rs12190287, resides in the 3' untranslated region (3'-UTR) of TCF21, a basic-helix-loop-helix transcription factor, and is predicted to alter the seed binding sequence for miR-224. Allelic imbalance studies in circulating leukocytes and human coronary artery smooth muscle cells (HCASMC) showed significant imbalance of the TCF21 transcript that correlated with genotype at rs12190287, consistent with this variant contributing to allele-specific expression differences. 3' UTR reporter gene transfection studies in HCASMC showed that the disease-associated C allele has reduced expression compared to the protective G allele. Kinetic analyses in vitro revealed faster RNA-RNA complex formation and greater binding of miR-224 with the TCF21 C allelic transcript. In addition, in vitro probing with Pb2+ and RNase T1 revealed structural differences between the TCF21 variants in proximity of the rs12190287 variant, which are predicted to provide greater access to the C allele for miR-224 binding. miR-224 and TCF21 expression levels were anti-correlated in HCASMC, and miR-224 modulates the transcriptional response of TCF21 to transforming growth factor-β (TGF-β) and platelet derived growth factor (PDGF) signaling in an allele-specific manner. Lastly, miR-224 and TCF21 were localized in human coronary artery lesions and anti-correlated during atherosclerosis. Together, these data suggest that miR-224 interaction with the TCF21 transcript contributes to allelic imbalance of this gene, thus partly explaining the genetic risk for coronary heart disease associated at 6q23.2. These studies implicating rs12190287 in the miRNA-dependent regulation of TCF21, in conjunction with previous studies showing that this variant modulates transcriptional regulation through activator protein 1 (AP-1), suggests a unique bimodal level of complexity previously unreported for disease-associated variants.

Allele-specific Characterization of Alanine: Glyoxylate Aminotransferase Variants Associated with Primary Hyperoxaluria

PubMed Central

Lage, Melissa D.; Pittman, Adrianne M. C.; Roncador, Alessandro; Cellini, Barbara; Tucker, Chandra L.

2014-01-01

Primary Hyperoxaluria Type 1 (PH1) is a rare autosomal recessive kidney stone disease caused by deficiency of the peroxisomal enzyme alanine: glyoxylate aminotransferase (AGT), which is involved in glyoxylate detoxification. Over 75 different missense mutations in AGT have been found associated with PH1. While some of the mutations have been found to affect enzyme activity, stability, and/or localization, approximately half of these mutations are completely uncharacterized. In this study, we sought to systematically characterize AGT missense mutations associated with PH1. To facilitate analysis, we used two high-throughput yeast-based assays: one that assesses AGT specific activity, and one that assesses protein stability. Approximately 30% of PH1-associated missense mutations are found in conjunction with a minor allele polymorphic variant, which can interact to elicit complex effects on protein stability and trafficking. To better understand this allele interaction, we functionally characterized each of 34 mutants on both the major (wild-type) and minor allele backgrounds, identifying mutations that synergize with the minor allele. We classify these mutants into four distinct categories depending on activity/stability results in the different alleles. Twelve mutants were found to display reduced activity in combination with the minor allele, compared with the major allele background. When mapped on the AGT dimer structure, these mutants reveal localized regions of the protein that appear particularly sensitive to interactions with the minor allele variant. While the majority of the deleterious effects on activity in the minor allele can be attributed to synergistic interaction affecting protein stability, we identify one mutation, E274D, that appears to specifically affect activity when in combination with the minor allele. PMID:24718375

A variant in the sonic hedgehog regulatory sequence (ZRS) is associated with triphalangeal thumb and deregulates expression in the developing limb

PubMed Central

Furniss, Dominic; Lettice, Laura A.; Taylor, Indira B.; Critchley, Paul S.; Giele, Henk; Hill, Robert E.; Wilkie, Andrew O.M.

2008-01-01

A locus for triphalangeal thumb, variably associated with pre-axial polydactyly, was previously identified in the zone of polarizing activity regulatory sequence (ZRS), a long range limb-specific enhancer of the Sonic Hedgehog (SHH) gene at human chromosome 7q36.3. Here, we demonstrate that a 295T>C variant in the human ZRS, previously thought to represent a neutral polymorphism, acts as a dominant allele with reduced penetrance. We found this variant in three independently ascertained probands from southern England with triphalangeal thumb, demonstrated significant linkage of the phenotype to the variant (LOD = 4.1), and identified a shared microsatellite haplotype around the ZRS, suggesting that the probands share a common ancestor. An individual homozygous for the 295C allele presented with isolated bilateral triphalangeal thumb resembling the heterozygous phenotype, suggesting that the variant is largely dominant to the wild-type allele. As a functional test of the pathogenicity of the 295C allele, we utilized a mutated ZRS construct to demonstrate that it can drive ectopic anterior expression of a reporter gene in the developing mouse forelimb. We conclude that the 295T>C variant is in fact pathogenic and, in southern England, appears to be the most common cause of triphalangeal thumb. Depending on the dispersal of the founding mutation, it may play a wider role in the aetiology of this disorder. PMID:18463159

The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share.

PubMed

Kottyan, Leah C; Zoller, Erin E; Bene, Jessica; Lu, Xiaoming; Kelly, Jennifer A; Rupert, Andrew M; Lessard, Christopher J; Vaughn, Samuel E; Marion, Miranda; Weirauch, Matthew T; Namjou, Bahram; Adler, Adam; Rasmussen, Astrid; Glenn, Stuart; Montgomery, Courtney G; Hirschfield, Gideon M; Xie, Gang; Coltescu, Catalina; Amos, Chris; Li, He; Ice, John A; Nath, Swapan K; Mariette, Xavier; Bowman, Simon; Rischmueller, Maureen; Lester, Sue; Brun, Johan G; Gøransson, Lasse G; Harboe, Erna; Omdal, Roald; Cunninghame-Graham, Deborah S; Vyse, Tim; Miceli-Richard, Corinne; Brennan, Michael T; Lessard, James A; Wahren-Herlenius, Marie; Kvarnström, Marika; Illei, Gabor G; Witte, Torsten; Jonsson, Roland; Eriksson, Per; Nordmark, Gunnel; Ng, Wan-Fai; Anaya, Juan-Manuel; Rhodus, Nelson L; Segal, Barbara M; Merrill, Joan T; James, Judith A; Guthridge, Joel M; Scofield, R Hal; Alarcon-Riquelme, Marta; Bae, Sang-Cheol; Boackle, Susan A; Criswell, Lindsey A; Gilkeson, Gary; Kamen, Diane L; Jacob, Chaim O; Kimberly, Robert; Brown, Elizabeth; Edberg, Jeffrey; Alarcón, Graciela S; Reveille, John D; Vilá, Luis M; Petri, Michelle; Ramsey-Goldman, Rosalind; Freedman, Barry I; Niewold, Timothy; Stevens, Anne M; Tsao, Betty P; Ying, Jun; Mayes, Maureen D; Gorlova, Olga Y; Wakeland, Ward; Radstake, Timothy; Martin, Ezequiel; Martin, Javier; Siminovitch, Katherine; Moser Sivils, Kathy L; Gaffney, Patrick M; Langefeld, Carl D; Harley, John B; Kaufman, Kenneth M

2015-01-15

Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5-TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5-TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10(-49); OR = 1.38-1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3 (P-valuesEU = 10(-27)-10(-32), OR = 1.7-1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credible set of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögren's syndrome and systemic sclerosis whereas only the IRF5-TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3. Published by Oxford University Press 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.

The IRF5–TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share

PubMed Central

Kottyan, Leah C.; Zoller, Erin E.; Bene, Jessica; Lu, Xiaoming; Kelly, Jennifer A.; Rupert, Andrew M.; Lessard, Christopher J.; Vaughn, Samuel E.; Marion, Miranda; Weirauch, Matthew T.; Namjou, Bahram; Adler, Adam; Rasmussen, Astrid; Glenn, Stuart; Montgomery, Courtney G.; Hirschfield, Gideon M.; Xie, Gang; Coltescu, Catalina; Amos, Chris; Li, He; Ice, John A.; Nath, Swapan K.; Mariette, Xavier; Bowman, Simon; Rischmueller, Maureen; Lester, Sue; Brun, Johan G.; Gøransson, Lasse G.; Harboe, Erna; Omdal, Roald; Cunninghame-Graham, Deborah S.; Vyse, Tim; Miceli-Richard, Corinne; Brennan, Michael T.; Lessard, James A.; Wahren-Herlenius, Marie; Kvarnström, Marika; Illei, Gabor G.; Witte, Torsten; Jonsson, Roland; Eriksson, Per; Nordmark, Gunnel; Ng, Wan-Fai; Anaya, Juan-Manuel; Rhodus, Nelson L.; Segal, Barbara M.; Merrill, Joan T.; James, Judith A.; Guthridge, Joel M.; Hal Scofield, R.; Alarcon-Riquelme, Marta; Bae, Sang-Cheol; Boackle, Susan A.; Criswell, Lindsey A.; Gilkeson, Gary; Kamen, Diane L.; Jacob, Chaim O.; Kimberly, Robert; Brown, Elizabeth; Edberg, Jeffrey; Alarcón, Graciela S.; Reveille, John D.; Vilá, Luis M.; Petri, Michelle; Ramsey-Goldman, Rosalind; Freedman, Barry I.; Niewold, Timothy; Stevens, Anne M.; Tsao, Betty P.; Ying, Jun; Mayes, Maureen D.; Gorlova, Olga Y.; Wakeland, Ward; Radstake, Timothy; Martin, Ezequiel; Martin, Javier; Siminovitch, Katherine; Moser Sivils, Kathy L.; Gaffney, Patrick M.; Langefeld, Carl D.; Harley, John B.; Kaufman, Kenneth M.

2015-01-01

Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5–TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5–TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10−49; OR = 1.38–1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3 (P-valuesEU = 10−27–10−32, OR = 1.7–1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credible set of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögren's syndrome and systemic sclerosis whereas only the IRF5–TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5–TNPO3. PMID:25205108

Structural comparisons of two allelic variants of human placental alkaline phosphatase.

PubMed

Millán, J L; Stigbrand, T; Jörnvall, H

1985-01-01

A simple immunosorbent purification scheme based on monoclonal antibodies has been devised for human placental alkaline phosphatase. The two most common allelic variants, S and F, have similar amino acid compositions with identical N-terminal amino acid sequences through the first 13 residues. Both variants have identical lectin binding properties towards concanavalin A, lentil-lectin, wheat germ agglutinin, phytohemagglutinin and soybean agglutinin, and identical carbohydrate contents as revealed by methylation analysis. CNBr fragments of the variants demonstrate identical high performance liquid chromatography patterns. The carbohydrate containing fragment is different from the 32P-labeled active site fragment and the N-terminal fragment.

A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk.

PubMed

Manning, Alisa; Highland, Heather M; Gasser, Jessica; Sim, Xueling; Tukiainen, Taru; Fontanillas, Pierre; Grarup, Niels; Rivas, Manuel A; Mahajan, Anubha; Locke, Adam E; Cingolani, Pablo; Pers, Tune H; Viñuela, Ana; Brown, Andrew A; Wu, Ying; Flannick, Jason; Fuchsberger, Christian; Gamazon, Eric R; Gaulton, Kyle J; Im, Hae Kyung; Teslovich, Tanya M; Blackwell, Thomas W; Bork-Jensen, Jette; Burtt, Noël P; Chen, Yuhui; Green, Todd; Hartl, Christopher; Kang, Hyun Min; Kumar, Ashish; Ladenvall, Claes; Ma, Clement; Moutsianas, Loukas; Pearson, Richard D; Perry, John R B; Rayner, N William; Robertson, Neil R; Scott, Laura J; van de Bunt, Martijn; Eriksson, Johan G; Jula, Antti; Koskinen, Seppo; Lehtimäki, Terho; Palotie, Aarno; Raitakari, Olli T; Jacobs, Suzanne B R; Wessel, Jennifer; Chu, Audrey Y; Scott, Robert A; Goodarzi, Mark O; Blancher, Christine; Buck, Gemma; Buck, David; Chines, Peter S; Gabriel, Stacey; Gjesing, Anette P; Groves, Christopher J; Hollensted, Mette; Huyghe, Jeroen R; Jackson, Anne U; Jun, Goo; Justesen, Johanne Marie; Mangino, Massimo; Murphy, Jacquelyn; Neville, Matt; Onofrio, Robert; Small, Kerrin S; Stringham, Heather M; Trakalo, Joseph; Banks, Eric; Carey, Jason; Carneiro, Mauricio O; DePristo, Mark; Farjoun, Yossi; Fennell, Timothy; Goldstein, Jacqueline I; Grant, George; Hrabé de Angelis, Martin; Maguire, Jared; Neale, Benjamin M; Poplin, Ryan; Purcell, Shaun; Schwarzmayr, Thomas; Shakir, Khalid; Smith, Joshua D; Strom, Tim M; Wieland, Thomas; Lindstrom, Jaana; Brandslund, Ivan; Christensen, Cramer; Surdulescu, Gabriela L; Lakka, Timo A; Doney, Alex S F; Nilsson, Peter; Wareham, Nicholas J; Langenberg, Claudia; Varga, Tibor V; Franks, Paul W; Rolandsson, Olov; Rosengren, Anders H; Farook, Vidya S; Thameem, Farook; Puppala, Sobha; Kumar, Satish; Lehman, Donna M; Jenkinson, Christopher P; Curran, Joanne E; Hale, Daniel Esten; Fowler, Sharon P; Arya, Rector; DeFronzo, Ralph A; Abboud, Hanna E; Syvänen, Ann-Christine; Hicks, Pamela J; Palmer, Nicholette D; Ng, Maggie C Y; Bowden, Donald W; Freedman, Barry I; Esko, Tõnu; Mägi, Reedik; Milani, Lili; Mihailov, Evelin; Metspalu, Andres; Narisu, Narisu; Kinnunen, Leena; Bonnycastle, Lori L; Swift, Amy; Pasko, Dorota; Wood, Andrew R; Fadista, João; Pollin, Toni I; Barzilai, Nir; Atzmon, Gil; Glaser, Benjamin; Thorand, Barbara; Strauch, Konstantin; Peters, Annette; Roden, Michael; Müller-Nurasyid, Martina; Liang, Liming; Kriebel, Jennifer; Illig, Thomas; Grallert, Harald; Gieger, Christian; Meisinger, Christa; Lannfelt, Lars; Musani, Solomon K; Griswold, Michael; Taylor, Herman A; Wilson, Gregory; Correa, Adolfo; Oksa, Heikki; Scott, William R; Afzal, Uzma; Tan, Sian-Tsung; Loh, Marie; Chambers, John C; Sehmi, Jobanpreet; Kooner, Jaspal Singh; Lehne, Benjamin; Cho, Yoon Shin; Lee, Jong-Young; Han, Bok-Ghee; Käräjämäki, Annemari; Qi, Qibin; Qi, Lu; Huang, Jinyan; Hu, Frank B; Melander, Olle; Orho-Melander, Marju; Below, Jennifer E; Aguilar, David; Wong, Tien Yin; Liu, Jianjun; Khor, Chiea-Chuen; Chia, Kee Seng; Lim, Wei Yen; Cheng, Ching-Yu; Chan, Edmund; Tai, E Shyong; Aung, Tin; Linneberg, Allan; Isomaa, Bo; Meitinger, Thomas; Tuomi, Tiinamaija; Hakaste, Liisa; Kravic, Jasmina; Jørgensen, Marit E; Lauritzen, Torsten; Deloukas, Panos; Stirrups, Kathleen E; Owen, Katharine R; Farmer, Andrew J; Frayling, Timothy M; O'Rahilly, Stephen P; Walker, Mark; Levy, Jonathan C; Hodgkiss, Dylan; Hattersley, Andrew T; Kuulasmaa, Teemu; Stančáková, Alena; Barroso, Inês; Bharadwaj, Dwaipayan; Chan, Juliana; Chandak, Giriraj R; Daly, Mark J; Donnelly, Peter J; Ebrahim, Shah B; Elliott, Paul; Fingerlin, Tasha; Froguel, Philippe; Hu, Cheng; Jia, Weiping; Ma, Ronald C W; McVean, Gilean; Park, Taesung; Prabhakaran, Dorairaj; Sandhu, Manjinder; Scott, James; Sladek, Rob; Tandon, Nikhil; Teo, Yik Ying; Zeggini, Eleftheria; Watanabe, Richard M; Koistinen, Heikki A; Kesaniemi, Y Antero; Uusitupa, Matti; Spector, Timothy D; Salomaa, Veikko; Rauramaa, Rainer; Palmer, Colin N A; Prokopenko, Inga; Morris, Andrew D; Bergman, Richard N; Collins, Francis S; Lind, Lars; Ingelsson, Erik; Tuomilehto, Jaakko; Karpe, Fredrik; Groop, Leif; Jørgensen, Torben; Hansen, Torben; Pedersen, Oluf; Kuusisto, Johanna; Abecasis, Gonçalo; Bell, Graeme I; Blangero, John; Cox, Nancy J; Duggirala, Ravindranath; Seielstad, Mark; Wilson, James G; Dupuis, Josee; Ripatti, Samuli; Hanis, Craig L; Florez, Jose C; Mohlke, Karen L; Meigs, James B; Laakso, Markku; Morris, Andrew P; Boehnke, Michael; Altshuler, David; McCarthy, Mark I; Gloyn, Anna L; Lindgren, Cecilia M

2017-07-01

To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2 . © 2017 by the American Diabetes Association.

Lack of association of rs3798220 with small apolipoprotein(a) isoforms and high lipoprotein(a) levels in East and Southeast Asians.

PubMed

Khalifa, Mahmoud; Noureen, Asma; Ertelthalner, Kathrin; Bandegi, Ahmad Reza; Delport, Rhena; Firdaus, Wance J J; Geethanjali, Finney S; Luthra, Kalpana; Makemaharn, Orawan; Pang, Richard W C; Salem, Abdel-Halim; Sasaki, Jun; Schiefenhoevel, Wulf; Lingenhel, Arno; Kronenberg, Florian; Utermann, Gerd; Schmidt, Konrad

2015-10-01

The variant allele of rs3798220 in the apolipoprotein(a) gene (LPA) is used to assess the risk for coronary artery disease (CAD) in Europeans, where it is associated with short alleles of the Kringle IV-2 (KIV-2) copy number variation (CNV) and high lipoprotein(a) (Lp(a)) concentrations. No association of rs3798220 with CAD was detected in a GWAS of East Asians. Our study investigated the association of rs3798220 with Lp(a) concentrations and KIV-2 CNV size in non-European populations to explain the missing association of the variant with CAD in Asians. We screened three populations from Africa and seven from Asia by TaqMan Assay for rs3798220 and determined KIV-2 CNV sizes of LPA alleles by pulsed-field gel electrophoresis (PFGE). Additionally, CAD cases from India were analysed. To investigate the phylogenetic origin of rs3798220, 40 LPA alleles from Chinese individuals were separated by PFGE and haplotyped for further SNPs. The variant was not found in Africans. Allele frequencies in East and Southeast Asians ranged from 2.9% to 11.6%, and were very low (0.15%) in CAD cases and controls from India. The variant was neither associated with short KIV-2 CNV alleles nor elevated Lp(a) concentrations in Asians. Our study shows that rs3798220 is no marker for short KIV-2 CNV alleles and high Lp(a) in East and Southeast Asians, although the haplotype background is shared with Europeans. It appears unlikely that this SNP confers atherogenic potential on its own. Furthermore, this SNP does not explain Lp(a) attributed risk for CAD in Asian Indians. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Warfarin sensitivity genotyping: a review of the literature and summary of patient experience.

PubMed

Moyer, Thomas P; O'Kane, Dennis J; Baudhuin, Linnea M; Wiley, Carmen L; Fortini, Alexandre; Fisher, Pamela K; Dupras, Denise M; Chaudhry, Rajeev; Thapa, Prabin; Zinsmeister, Alan R; Heit, John A

2009-12-01

The antithrombotic benefits of warfarin are countered by a narrow therapeutic index that contributes to excessive bleeding or cerebrovascular clotting and stroke in some patients. This article reviews the current literature describing warfarin sensitivity genotyping and compares the results of that review to the findings of our study in 189 patients at Mayo Clinic conducted between June 2001 and April 2003. For the review of the literature, we identified relevant peer-reviewed articles by searching the Web of Knowledge using key word warfarin-related adverse event. For the 189 Mayo Clinic patients initiating warfarin therapy to achieve a target international normalized ratio (INR) in the range of 2.0 to 3.5, we analyzed the CYP2C9 (cytochrome P450 2C9) and VKORC1 (vitamin K epoxide reductase complex, subunit 1) genetic loci to study the relationship among the initial warfarin dose, steady-state dose, time to achieve steady-state dose, variations in INR, and allelic variance. Results were compared with those previously reported in the literature for 637 patients. The relationships between allelic variants and warfarin sensitivity found in our study of Mayo Clinic patients are fundamentally the same as in those reported by others. The Mayo Clinic population is predominantly white and shows considerable allelic variability in CYP2C9 and VKORC1. Certain of these alleles are associated with increased sensitivity to warfarin. Polymorphisms in CYP2C9 and VKORC1 have a considerable effect on warfarin dose in white people. A correlation between steady-state warfarin dose and allelic variants of CYP2C9 and VKORC1 has been demonstrated by many previous reports and is reconfirmed in this report. The allelic variants found to most affect warfarin sensitivity are CYP2C9*1*1-VKORC1BB (less warfarin sensitivity than typical); CYP2C9*1*1-VKORC1AA (considerable variance in INR throughout initiation); CYP2C9*1*2-VKORC1AB (more sensitivity to warfarin than typical); CYP2C9*1*3-VKORC1AB (much more sensitivity to warfarin than typical); CYP2C9*1*2-VKORC1AB (much more sensitivity to warfarin than typical); CYP2C9*1*3-VKORC1AA (much more sensitivity to warfarin than typical); and CYP2C9*2*2-VKORC1AB (much more sensitivity to warfarin than typical). Although we were unable to show an association between allelic variants and initial warfarin dose or dose escalation, an association was seen between allelic variant and steady-state warfarin dose. White people show considerable variance in CYP2C9 allele types, whereas people of Asian or African descent infrequently carry CYP2C9 allelic variants. The VKORC1AA allele associated with high warfarin sensitivity predominates in those of Asian descent, whereas white people and those of African descent show diversity, carrying either the VKORC1BB, an allele associated with low warfarin sensitivity, or VKORC1AB or VKORC1AA, alleles associated with moderate and high warfarin sensitivity, respectively.

Allelic variants of hereditary prions: The bimodularity principle.

PubMed

Tikhodeyev, Oleg N; Tarasov, Oleg V; Bondarev, Stanislav A

2017-01-02

Modern biology requires modern genetic concepts equally valid for all discovered mechanisms of inheritance, either "canonical" (mediated by DNA sequences) or epigenetic. Applying basic genetic terms such as "gene" and "allele" to protein hereditary factors is one of the necessary steps toward these concepts. The basic idea that different variants of the same prion protein can be considered as alleles has been previously proposed by Chernoff and Tuite. In this paper, the notion of prion allele is further developed. We propose the idea that any prion allele is a bimodular hereditary system that depends on a certain DNA sequence (DNA determinant) and a certain epigenetic mark (epigenetic determinant). Alteration of any of these 2 determinants may lead to establishment of a new prion allele. The bimodularity principle is valid not only for hereditary prions; it seems to be universal for any epigenetic hereditary factor.

Analysis of monoamine oxidase A (MAOA) promoter polymorphism in Finnish male alcoholics.

PubMed

Saito, Takuya; Lachman, Herbert M; Diaz, Libna; Hallikainen, Tero; Kauhanen, Jussi; Salonen, Jukka T; Ryynänen, Olli-Pekka; Karvonen, Matti K; Syvälahti, Erkka; Pohjalainen, Tiina; Hietala, Jarmo; Tiihonen, Jari

2002-03-15

Alterations in monoamine oxidase A (MAOA) expression and enzyme activity may be associated with alcoholism and impulsive behavior. Therefore, functional polymorphisms in the MAOA gene would be good candidates to consider in the interindividual differences that exist in the susceptibility to alcoholism. One variant that has been considered as a candidate in alcoholism is a repeat polymorphism in the MAOA gene promoter. We analyzed a cohort of Finnish males with either type 1 or type 2 alcoholism, as well as controls, for differences in the distribution of MAOA promoter alleles. Based on other studies, we postulated that type 2 alcoholism, which is associated with antisocial behavior, but not type 1 alcoholism, would be correlated with the inheritance of the low promoter activity allele. However, we failed to find a difference in allele distribution in type 1 and type 2 alcoholics. In addition, there was no difference in the allele distribution when each group of alcoholics was compared with controls. However, when both groups of alcoholics were pooled and compared with controls, the difference in allele distribution reached a trend towards significance. Our results suggest a minimal association between the MAOA low activity promoter alleles and alcoholism, regardless of the presence or absence of antisocial behavior. Interestingly, approximately 3% of type 2 alcoholics were found to be heterozygous for the MAOA promoter polymorphism. Since MAOA is X-linked, the heterozygotes are probable cases of Klinefelter's syndrome (47,XXY) suggesting that X-chromosome aneuploidy may increase the risk for developing type 2 alcoholism.

Selection and explosive growth alter genetic architecture and hamper the detection of causal rare variants.

PubMed

Uricchio, Lawrence H; Zaitlen, Noah A; Ye, Chun Jimmie; Witte, John S; Hernandez, Ryan D

2016-07-01

The role of rare alleles in complex phenotypes has been hotly debated, but most rare variant association tests (RVATs) do not account for the evolutionary forces that affect genetic architecture. Here, we use simulation and numerical algorithms to show that explosive population growth, as experienced by human populations, can dramatically increase the impact of very rare alleles on trait variance. We then assess the ability of RVATs to detect causal loci using simulations and human RNA-seq data. Surprisingly, we find that statistical performance is worst for phenotypes in which genetic variance is due mainly to rare alleles, and explosive population growth decreases power. Although many studies have attempted to identify causal rare variants, few have reported novel associations. This has sometimes been interpreted to mean that rare variants make negligible contributions to complex trait heritability. Our work shows that RVATs are not robust to realistic human evolutionary forces, so general conclusions about the impact of rare variants on complex traits may be premature. © 2016 Uricchio et al.; Published by Cold Spring Harbor Laboratory Press.

Variant ribosomal RNA alleles are conserved and exhibit tissue-specific expression

PubMed Central

Parks, Matthew M.; Kurylo, Chad M.; Dass, Randall A.; Bojmar, Linda; Lyden, David; Vincent, C. Theresa; Blanchard, Scott C.

2018-01-01

The ribosome, the integration point for protein synthesis in the cell, is conventionally considered a homogeneous molecular assembly that only passively contributes to gene expression. Yet, epigenetic features of the ribosomal DNA (rDNA) operon and changes in the ribosome’s molecular composition have been associated with disease phenotypes, suggesting that the ribosome itself may possess inherent regulatory capacity. Analyzing whole-genome sequencing data from the 1000 Genomes Project and the Mouse Genomes Project, we find that rDNA copy number varies widely across individuals, and we identify pervasive intra- and interindividual nucleotide variation in the 5S, 5.8S, 18S, and 28S ribosomal RNA (rRNA) genes of both human and mouse. Conserved rRNA sequence heterogeneities map to functional centers of the assembled ribosome, variant rRNA alleles exhibit tissue-specific expression, and ribosomes bearing variant rRNA alleles are present in the actively translating ribosome pool. These findings provide a critical framework for exploring the possibility that the expression of genomically encoded variant rRNA alleles gives rise to physically and functionally heterogeneous ribosomes that contribute to mammalian physiology and human disease. PMID:29503865

The influence of Glu-1 and Glu-3 loci on dough rheology and bread-making properties in wheat (Triticum aestivum L.) doubled haploid lines.

PubMed

Langner, Monika; Krystkowiak, Karolina; Salmanowicz, Bolesław P; Adamski, Tadeusz; Krajewski, Paweł; Kaczmarek, Zygmunt; Surma, Maria

2017-12-01

The major determinants of wheat quality are Glu-1 and Glu-3 glutenin loci and environmental factors. Additive effects of alleles at the Glu-1 and Glu-3 loci, as well as their interactions, were evaluated for dough rheology and baking properties in four groups of wheat doubled haploid lines differing in high- and low-molecular-weight glutenin composition. Flour quality, Reomixer (Reologica Instruments, Lund, Sweden), dough extension, Farinograph (Brabender GmbH, Duisburg, Germany) and baking parameters were determined. Groups of lines with the alleles Glu-A3b and Glu-B3d were characterized by higher values of dough and baking parameters compared to those with the Glu-A3e and Glu-B3a alleles. Effects of interactions between allelic variants at the Glu-1 and Glu-3 loci on Reomixer parameters, dough extension tests and baking parameters were significant, although additive effects of individual alleles were not always significant. The allelic variants at Glu-B3 had a much greater effect on dough rheological parameters than the variants at Glu-A3 or Glu-D3 loci. The effect of allelic variations at the Glu-D3 loci on rheological parameters and bread-making quality was non-significant, whereas their interactions with a majority of alleles at the other Glu-1 × Glu-3 loci were significant. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

Genetic characteristic of swamp buffalo (Bubalus bubalis) from Pampangan, South Sumatra based on blood protein profile

NASA Astrophysics Data System (ADS)

Windusari, Yuanita; Hanum, Laila; Wahyudi, Rizki

2017-11-01

Swamp buffalo (Bubalus bubalis) is an endemic species and one of the genetic wealth of South Sumatra with a distribution area in the district of Pampangan (OganIlir and OganOganIlir). Suspected inbreeding causes decreased phenotypic properties. Inbreeding among various swamp buffalo is certainly not only lower the qualities but also genotypes and phenotypes. It is of interest to determine kinship variants swamp buffaloes from Pampangan through the analysis of a blood protein profile. Blood protein profile of four variants swamps buffalo was studied by using five electrophoresis system i.e. pre-albumin (Palb), albumin (Alb), ceruloplasmin (Cp), transferrin (Tf) and transferrin post (Ptf). In this paper, it is obtained that there was no significant differences among the four variants of the buffaloes were used as a sample. Prealbumin has two alleles (Palb1 and Palb2), albumin has three alleles (Alba, AlbB, AlbC), ceruloplasmin has one allele (BPA), post-transferrin has one allele (PTFA) with an allele frequency 1.0000 at any time transferrin has two alleles (TFA and TFB) with the allele frequency of 0.7500 and 1.0000. Characteristics prealbumin (Palb), albumin (Alb), ceruloplasmin (Cp), and post-transferrin (P-tf) is monomorphic, while transferrin is polymorphic average heterozygosity values all loci (H) 0.1286. Based on average heterozygosity, the swamp buffalo (Bubalusbubalis) from Pampangan has low genetic variation and closest genetic relationship.

rs6295 [C]-Allele Protects Against Depressive Mood in Elderly Endurance Athletes.

PubMed

Haslacher, Helmuth; Michlmayr, Matthias; Batmyagmar, Delgerdalai; Perkmann, Thomas; Ponocny-Seliger, Elisabeth; Scheichenberger, Vanessa; Scherzer, Thomas M; Nistler, Sonja; Pilger, Alexander; Dal-Bianco, Peter; Lehrner, Johann; Pezawas, Lukas; Wagner, Oswald F; Winker, Robert

2015-12-01

A single nucleotide variant within the promoter of the 5-hydroxytryptamine1A (5HT1A) receptor, rs6295, is part of a binding site for the transcription factor. We aimed to ascertain whether the rs6295 mediates the effect of exercise on depressive mood in elderly endurance athletes. We prospectively enrolled 55 elderly athletes (marathon runners/bicyclists) and 58 controls. In a controlled, univariate model, an interaction between the [C]-allele and physical activity indicated that only among athletes, the variant resulting in an imperfect NUDR binding site was associated with a lower depression score. Hence, athletes presented with a significantly lower relative risk of achieving a suspicious depression score among carriers of at least one [C]-allele. Our results suggest that the positive effect of physical exercise on depressive mood might be mediated by the 5HT1A receptor and the extent of this protective effect seems to be enhanced by the [C]-allele of the rs6295 variant.

Nomenclature for alleles of the thiopurine methyltransferase gene

PubMed Central

Appell, Malin L.; Berg, Jonathan; Duley, John; Evans, William E.; Kennedy, Martin A.; Lennard, Lynne; Marinaki, Tony; McLeod, Howard L.; Relling, Mary V.; Schaeffeler, Elke; Schwab, Matthias; Weinshilboum, Richard; Yeoh, Allen E.J.; McDonagh, Ellen M.; Hebert, Joan M.; Klein, Teri E.; Coulthard, Sally A.

2013-01-01

The drug-metabolizing enzyme thiopurine methyltransferase (TPMT) has become one of the best examples of pharmacogenomics to be translated into routine clinical practice. TPMT metabolizes the thiopurines 6-mercaptopurine, 6-thioguanine, and azathioprine, drugs that are widely used for treatment of acute leukemias, inflammatory bowel diseases, and other disorders of immune regulation. Since the discovery of genetic polymorphisms in the TPMT gene, many sequence variants that cause a decreased enzyme activity have been identified and characterized. Increasingly, to optimize dose, pretreatment determination of TPMT status before commencing thiopurine therapy is now routine in many countries. Novel TPMT sequence variants are currently numbered sequentially using PubMed as a source of information; however, this has caused some problems as exemplified by two instances in which authors’ articles appeared on PubMed at the same time, resulting in the same allele numbers given to different polymorphisms. Hence, there is an urgent need to establish an order and consensus to the numbering of known and novel TPMT sequence variants. To address this problem, a TPMT nomenclature committee was formed in 2010, to define the nomenclature and numbering of novel variants for the TPMT gene. A website (http://www.imh.liu.se/tpmtalleles) serves as a platform for this work. Researchers are encouraged to submit novel TPMT alleles to the committee for designation and reservation of unique allele numbers. The committee has decided to renumber two alleles: nucleotide position 106 (G > A) from TPMT*24 to TPMT*30 and position 611 (T > C, rs79901429) from TPMT*28 to TPMT*31. Nomenclature for all other known alleles remains unchanged. PMID:23407052

The Arg59Trp variant in ANGPTL8 (Betatrophin) is associated with total and HDL-cholesterol in American Indians and Mexican Americans and differentially affects cleavage of ANGPTL3

PubMed Central

Hanson, Robert L.; Leti, Fatjon; Tsinajinnie, Darwin; Kobes, Sayuko; Puppala, Sobha; Curran, Joanne E.; Almasy, Laura; Lehman, Donna M.; Blangero, John; Duggirala, Ravindranath; DiStefano, Johanna K.

2016-01-01

We previously identified a locus linked to total cholesterol (TC) concentration in Pima Indians on chromosome 19p. To characterize this locus, we genotyped >2000 SNPs in 1838 Pimas and assessed association with log(TC). We observed evidence for association with log(TC) with rs2278426 (3.5% decrease/copy of the T allele; P=5.045 x 10−6) in the ANGPTL8 (angiopoietin-like 8) gene. We replicated this association in 2413 participants of the San Antonio Mexican American Family Study (SAMAFS: 2.0% decrease per copy of the T allele; P=0.005842). In a meta-analysis of the combined data, we found the strongest estimated effect with rs2278426 (P=2.563 x 10−7). The variant T allele at rs2278426 predicts an Arg59Trp substitution and has previously been associated with LDL-C and HDL-C. In Pimas and SAMAFS participants, the T allele of rs2278426 was associated with reduced HDL-C levels (P=0.000741 and 0.00002, respectively), and the combined estimated effect for the two cohorts was −3.8% (P=8.526 x 10−8). ANGPTL8 transcript and protein levels increased in response to both glucose and insulin. The variant allele was associated with increased levels of cleaved ANGPTL3. We conclude that individuals with the variant allele may have lower TC and HDL-C levels due to increased activation of ANGPTL3 by ANGPTL8. PMID:27117576

Demonstration of Protein-Based Human Identification Using the Hair Shaft Proteome

PubMed Central

Leppert, Tami; Anex, Deon S.; Hilmer, Jonathan K.; Matsunami, Nori; Baird, Lisa; Stevens, Jeffery; Parsawar, Krishna; Durbin-Johnson, Blythe P.; Rocke, David M.; Nelson, Chad; Fairbanks, Daniel J.; Wilson, Andrew S.; Rice, Robert H.; Woodward, Scott R.; Bothner, Brian; Hart, Bradley R.; Leppert, Mark

2016-01-01

Human identification from biological material is largely dependent on the ability to characterize genetic polymorphisms in DNA. Unfortunately, DNA can degrade in the environment, sometimes below the level at which it can be amplified by PCR. Protein however is chemically more robust than DNA and can persist for longer periods. Protein also contains genetic variation in the form of single amino acid polymorphisms. These can be used to infer the status of non-synonymous single nucleotide polymorphism alleles. To demonstrate this, we used mass spectrometry-based shotgun proteomics to characterize hair shaft proteins in 66 European-American subjects. A total of 596 single nucleotide polymorphism alleles were correctly imputed in 32 loci from 22 genes of subjects’ DNA and directly validated using Sanger sequencing. Estimates of the probability of resulting individual non-synonymous single nucleotide polymorphism allelic profiles in the European population, using the product rule, resulted in a maximum power of discrimination of 1 in 12,500. Imputed non-synonymous single nucleotide polymorphism profiles from European–American subjects were considerably less frequent in the African population (maximum likelihood ratio = 11,000). The converse was true for hair shafts collected from an additional 10 subjects with African ancestry, where some profiles were more frequent in the African population. Genetically variant peptides were also identified in hair shaft datasets from six archaeological skeletal remains (up to 260 years old). This study demonstrates that quantifiable measures of identity discrimination and biogeographic background can be obtained from detecting genetically variant peptides in hair shaft protein, including hair from bioarchaeological contexts. PMID:27603779

Variant Profiling of Candidate Genes in Pancreatic Ductal Adenocarcinoma.

PubMed

Huang, Jiaqi; Löhr, Johannes-Matthias; Nilsson, Magnus; Segersvärd, Ralf; Matsson, Hans; Verbeke, Caroline; Heuchel, Rainer; Kere, Juha; Iafrate, A John; Zheng, Zongli; Ye, Weimin

2015-11-01

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis. Variant profiling is crucial for developing personalized treatment and elucidating the etiology of this disease. Patients with PDAC undergoing surgery from 2007 to 2012 (n = 73) were followed from diagnosis until death or the end of the study. We applied an anchored multiplex PCR (AMP)-based next-generation sequencing (NGS) method to a panel of 65 selected genes and assessed analytical performance by sequencing a quantitative multiplex DNA reference standard. In clinical PDAC samples, detection of low-level KRAS (Kirsten rat sarcoma viral oncogene homolog) mutations was validated by allele-specific PCR and digital PCR. We compared overall survival of patients according to KRAS mutation status by log-rank test and applied logistic regression to evaluate the association between smoking and tumor variant types. The AMP-based NGS method could detect variants with allele frequencies as low as 1% given sufficient sequencing depth (>1500×). Low-frequency KRAS G12 mutations (allele frequency 1%-5%) were all confirmed by allele-specific PCR and digital PCR. The most prevalent genetic alterations were in KRAS (78% of patients), TP53 (tumor protein p53) (25%), and SMAD4 (SMAD family member 4) (8%). Overall survival in T3-stage PDAC patients differed among KRAS mutation subtypes (P = 0.019). Transversion variants were more common in ever-smokers than in never-smokers (odds ratio 5.7; 95% CI 1.2-27.8). The AMP-based NGS method is applicable for profiling tumor variants. Using this approach, we demonstrated that in PDAC patients, KRAS mutant subtype G12V is associated with poorer survival, and that transversion variants are more common among smokers. © 2015 American Association for Clinical Chemistry.

In vitro metabolism of phenytoin in 36 CYP2C9 variants found in the Chinese population.

PubMed

Chen, Lian-Guo; Wang, Zhe; Zhu, Yuan; Xiong, Jian-Hua; Sun, Li-Rong; Dai, Da-Peng; Cai, Jian-Ping; Hu, Guo-Xin

2016-06-25

Cytochrome P450 2C9 (CYP2C9) is an important member of the cytochrome P450 enzyme superfamily, with 57 CYP2C9 allelic variants being previously reported. Recently, we identified 22 novel alleles (*36 -*56 and N418T) in the Han Chinese population. This study aims to assess the catalytic activities of wild-type (CYP2C9*1) and 36 CYP2C9 allelic variants found in the Chinese population toward phenytoin (PHT) in vitro. Insect microsomes expressing CYP2C9*1 and 36 CYP2C9 variants were incubated with 1-200 μM phenytoin for 30 min at 37 °C. Then, these products were extracted and the signal detection was performed by HPLC-MS/MS. The intrinsic clearance (Vmax/Km) values of all variants, with the exception of CYP2C9*2, CYP2C9*11, CYP2C9*23, CYP2C9*29, CYP2C9*34, CYP2C9*38, CYP2C9*44, CYP2C9*46 and CYP2C9*48, were significantly different from CYP2C9*1. CYP2C9*27, *40, *41, *47, *49, *51, *53, *54, *56 and N418T variant exhibited markedly larger values than CYP2C9*1 (>152.8%), whereas 17 variants exhibited smaller values (from 48.6% to 99.9%) due to larger Km and/or smaller Vmax values than CYP2C9*1. The findings suggest that more attention should be paid on subjects carrying these infrequent CYP2C9 alleles when administering phenytoin in clinic. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Melanocortin-1 Receptor Polymorphisms and Risk of Melanoma: Is the Association Explained Solely by Pigmentation Phenotype?

PubMed Central

Palmer, James S.; Duffy, David L.; Box, Neil F.; Aitken, Joanne F.; O'Gorman, Louise E.; Green, Adele C.; Hayward, Nicholas K.; Martin, Nicholas G.; Sturm, Richard A.

2000-01-01

Summary Risk of cutaneous malignant melanoma (CMM) is increased in sun-exposed whites, particularly those with a pale complexion. This study was designed to investigate the relationship of the melanocortin-1 receptor (MC1R) genotype to CMM risk, controlled for pigmentation phenotype. We report the occurrence of five common MC1R variants in an Australian population-based sample of 460 individuals with familial and sporadic CMM and 399 control individuals—and their relationship to such other risk factors as skin, hair, and eye color; freckling; and nevus count. There was a strong relationship between MC1R variants and hair color and skin type. Moreover, MC1R variants were found in 72% of the individuals with CMM, whereas only 56% of the control individuals carried at least one variant (P<.001), a finding independent of strength of family history of melanoma. Three active alleles (Arg151Cys, Arg160Trp, and Asp294His), previously associated with red hair, doubled CMM risk for each additional allele carried (odds ratio 2.0; 95% confidence interval 1.6–2.6). No such independent association could be demonstrated with the Val60Leu and Asp84Glu variants. Among pale-skinned individuals alone, this association between CMM and MC1R variants was absent, but it persisted among those reporting a medium or olive/dark complexion. We conclude that the effect that MC1R variant alleles have on CMM is partly mediated via determination of pigmentation phenotype and that these alleles may also negate the protection normally afforded by darker skin coloring in some members of this white population. PMID:10631149

Fc gamma receptor IIIb polymorphism and systemic lupus erythematosus: association with disease susceptibility and identification of a novel FCGR3B*01 variant.

PubMed

Santos, V C; Grecco, M; Pereira, K M C; Terzian, C C N; Andrade, L E C; Silva, N P

2016-10-01

The objective of this study was to evaluate the association between Fc gamma receptor IIIb polymorphism and susceptibility to systemic lupus erythematosus and clinical traits of the disease. Genomic DNA was obtained from 303 consecutive systemic lupus erythematosus patients and 300 healthy blood donors from the southeastern region of Brazil. The polymorphic region of the FCGR3B gene was sequenced and the alleles FCGR3B*01, FCGR3B*02 and FCGR3B*03 were analyzed. The FCGR3B*01 allele was more frequent in systemic lupus erythematosus patients (43.1%) while the FCGR3B*02 allele prevailed among controls (63.7%) (P = 0.001). The FCGR3B*03 allele was found equally in both groups. The FCGR3B*01/*01 (20.7%) and FCGR3B*01/*02 (41.1%) genotypes were more frequent among systemic lupus erythematosus patients (P = 0.028 and P = 0.012, respectively) while the FCGR3B*02/*02 genotype was more frequent in controls (45.5%) (P < 0.001). One variant of the FCGR3B*01 allele previously described in Germany was found in only one control. A new variant of the FCGR3B*01 allele with two substitutions (A227G/G277A) was found in one control. Three variants of the FCGR3B*02 allele previously described in African-Americans, Brazilians, Chinese and Japanese were found in ten 10 patients and two controls. In addition, several single nucleotide polymorphisms at non-polymorphic positions were identified in both patients and controls. Susceptibility to systemic lupus erythematosus was associated with the FCGR3B*01 allele, as well as with the FCGR3B*01/*01 and FCGR3B*01/*02 genotypes. No association was found between FCGR3B genotypes and clinical manifestations, disease severity or the presence of autoantibodies. © The Author(s) 2016.

Alpha-synuclein mRNA isoform formation and translation affected by polymorphism in the human SNCA 3'UTR.

PubMed

Barrie, Elizabeth S; Lee, Sung-Ha; Frater, John T; Kataki, Maria; Scharre, Douglas W; Sadee, Wolfgang

2018-05-06

Multiple variants in SNCA, encoding alpha-synuclein, a main component of Lewy bodies, are implicated in Parkinson's disease. We searched for cis-acting SNCA variants using allelic mRNA ratios in human brain tissues. In a SNCA 3'UTR (2,520 bp) luciferase reporter gene assay, translation in SH-SY5Y cells in the presence of the rs17016074 G/A alleles was measured. To assess clinical impact, we queried neurocognitive genome-wide association studies. Allelic ratios deviated up to twofold, measured at a marker SNP in the middle of a long 3' untranslated region (3'UTR), but not at a marker at its start, suggesting regulation of 3'UTR processing. 3'UTR SNP rs17016074 G/A, minor allele frequency (MAF) <1% in Caucasians, 13% in Africans, strongly associates with large allelic mRNA expression imbalance (AEI), resulting in reduced expression of long 3'UTR isoforms. A second 3'UTR SNP (rs356165) associates with moderate AEI and enhances SNCA mRNA expression. The rs17016074 A allele reduces overall 3'UTR expression in luciferase reporter gene assays but supports more efficient translation, resolving previous contradictory results. We failed to detect significant genome-wide associations for rs17016074, possibly a result of low MAF in Caucasians or its absence from most genotyping panels. In the "Genome Wide Association Study of Yoruba in Nigeria," rs356165 was associated with reduced memory performance. Here, we identify two cis-acting regulatory variants affecting SNCA mRNA expression, measured by allelic ratios in the 3'UTR. The rs17016074 minor A allele is associated with higher expression of luciferase protein activity. Resolving the genetic influence of SNCA polymorphisms requires study of the interactions between multiple regulatory variants with distinct frequencies among populations. © 2018 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

Natural gene expression variation studies in yeast.

PubMed

Thompson, Dawn A; Cubillos, Francisco A

2017-01-01

The rise of sequence information across different yeast species and strains is driving an increasing number of studies in the emerging field of genomics to associate polymorphic variants, mRNA abundance and phenotypic differences between individuals. Here, we gathered evidence from recent studies covering several layers that define the genotype-phenotype gap, such as mRNA abundance, allele-specific expression and translation efficiency to demonstrate how genetic variants co-evolve and define an individual's genome. Moreover, we exposed several antecedents where inter- and intra-specific studies led to opposite conclusions, probably owing to genetic divergence. Future studies in this area will benefit from the access to a massive array of well-annotated genomes and new sequencing technologies, which will allow the fine breakdown of the complex layers that delineate the genotype-phenotype map. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Protective effect of the APOE-e3 allele in Alzheimer's disease

PubMed Central

de-Almada, B.V.P.; de-Almeida, L.D.; Camporez, D.; de-Moraes, M.V.D.; Morelato, R.L.; Perrone, A.M.S.; Belcavello, L.; Louro, I.D.; de-Paula, F.

2011-01-01

Although several alleles of susceptibility to Alzheimer's disease (AD) have been studied in the last decades, few polymorphisms have been considered as risk factors for the disease. Among them, the APOE-e4 allele appears to be the major genetic risk factor for the onset of the disease. However, it is important to confirm the potential susceptibility of these genetic variants in different populations in order to establish a genetic profile for the disease in specific communities. This study analyzed the APOE polymorphisms regarding susceptibility to AD in a sample of 264 individuals (primarily Caucasians; 82 cases and 182 controls) in the population from Vitória, ES, Brazil, by PCR restriction fragment length polymorphism (PCR-RFLP) methods. The patients were selected according to clinical criteria for probable AD. Whereas the e4 allele showed statistically significant positive association with susceptibility to AD (OR = 3.01, 95%CI = 1.96-4.61; P < 0.0001), the e2 allele did not. The results of the e4 allele confirm the role of this polymorphism as a risk factor for AD in the sample studied as observed in other populations. Although the e3 allele has been considered neutral in several studies, our results suggest that it acts as a protective factor against AD in the population studied (OR = 0.46, 95%CI = 0.30-0.67; P < 0.0001). This study may provide a new insight into the role of the APOE-e3 allele in the etiology of AD and might help to estabilish a profile of risk for AD in the population from Vitória, ES. PMID:22068907

Genetic polymorphisms in warfarin and tacrolimus-related genes VKORC1, CYP2C9 and CYP3A5 in the Greek-Cypriot population

PubMed Central

2014-01-01

Background Two variants in the gene encoding the cytochrome P450 2C9 enzyme (CYP2C9) are considered the most significant genetic risk factors associated with bleeding after warfarin prescription. A variant in the vitamin K epoxide reductase (VKORC1) has been also associated by several studies with warfarin response. Another variant in the P450 3A5 enzyme (CYP3A5) gene is known to affect the metabolism of many drugs, including tacrolimus. Findings We conducted a population genetic study in 148 unrelated healthy Greek-Cypriot volunteers (through PCR-RFLP assays), in order to determine the frequencies of the above pharmacogenetics variants and to compare allele frequencies with those in other major ethnic groups. The allele frequencies of CYP2C9*2, CYP2C9*3 and CYP3A5*3 were found to be 0.162, 0.112 and 0.943 respectively, whereas VKORC1 - 1639A was 0.534. The latter frequency differs significantly when compared with Caucasians, Asians and Africans (p < 0.001) and is still significant when compared with the geographically and culturally closely related to Greek-Cypriots, Hellenes of Greece (p = 0.01). Interestingly ~18% of our population are carriers of four or three risk alleles regarding warfarin sensitivity, therefore they have a high predisposition for bleeding after taking high or even normal warfarin doses. Conclusions Our data show no significant difference in the frequency of CYP2C9 and CYP3A5 allelic variants when compared to the Caucasian population, but differ significantly when compared with Africans and Asians (p < 0.001). Also, the frequency of variant VKORC1 - 1639A differs between Greek-Cypriots and every other population we compared. Finally, about 1/5 Greek-Cypriots carry three or four risk alleles and ~50% of them carry at least two independent risk alleles regarding warfarin sensitivity, a potentially high risk for over-anticoagulation. PMID:24593903

Poisson Approximation-Based Score Test for Detecting Association of Rare Variants.

PubMed

Fang, Hongyan; Zhang, Hong; Yang, Yaning

2016-07-01

Genome-wide association study (GWAS) has achieved great success in identifying genetic variants, but the nature of GWAS has determined its inherent limitations. Under the common disease rare variants (CDRV) hypothesis, the traditional association analysis methods commonly used in GWAS for common variants do not have enough power for detecting rare variants with a limited sample size. As a solution to this problem, pooling rare variants by their functions provides an efficient way for identifying susceptible genes. Rare variant typically have low frequencies of minor alleles, and the distribution of the total number of minor alleles of the rare variants can be approximated by a Poisson distribution. Based on this fact, we propose a new test method, the Poisson Approximation-based Score Test (PAST), for association analysis of rare variants. Two testing methods, namely, ePAST and mPAST, are proposed based on different strategies of pooling rare variants. Simulation results and application to the CRESCENDO cohort data show that our methods are more powerful than the existing methods. © 2016 John Wiley & Sons Ltd/University College London.

Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170.

PubMed

Dunning, Alison M; Michailidou, Kyriaki; Kuchenbaecker, Karoline B; Thompson, Deborah; French, Juliet D; Beesley, Jonathan; Healey, Catherine S; Kar, Siddhartha; Pooley, Karen A; Lopez-Knowles, Elena; Dicks, Ed; Barrowdale, Daniel; Sinnott-Armstrong, Nicholas A; Sallari, Richard C; Hillman, Kristine M; Kaufmann, Susanne; Sivakumaran, Haran; Moradi Marjaneh, Mahdi; Lee, Jason S; Hills, Margaret; Jarosz, Monika; Drury, Suzie; Canisius, Sander; Bolla, Manjeet K; Dennis, Joe; Wang, Qin; Hopper, John L; Southey, Melissa C; Broeks, Annegien; Schmidt, Marjanka K; Lophatananon, Artitaya; Muir, Kenneth; Beckmann, Matthias W; Fasching, Peter A; Dos-Santos-Silva, Isabel; Peto, Julian; Sawyer, Elinor J; Tomlinson, Ian; Burwinkel, Barbara; Marme, Frederik; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E; Flyger, Henrik; González-Neira, Anna; Perez, Jose I A; Anton-Culver, Hoda; Eunjung, Lee; Arndt, Volker; Brenner, Hermann; Meindl, Alfons; Schmutzler, Rita K; Brauch, Hiltrud; Hamann, Ute; Aittomäki, Kristiina; Blomqvist, Carl; Ito, Hidemi; Matsuo, Keitaro; Bogdanova, Natasha; Dörk, Thilo; Lindblom, Annika; Margolin, Sara; Kosma, Veli-Matti; Mannermaa, Arto; Tseng, Chiu-Chen; Wu, Anna H; Lambrechts, Diether; Wildiers, Hans; Chang-Claude, Jenny; Rudolph, Anja; Peterlongo, Paolo; Radice, Paolo; Olson, Janet E; Giles, Graham G; Milne, Roger L; Haiman, Christopher A; Henderson, Brian E; Goldberg, Mark S; Teo, Soo H; Yip, Cheng Har; Nord, Silje; Borresen-Dale, Anne-Lise; Kristensen, Vessela; Long, Jirong; Zheng, Wei; Pylkäs, Katri; Winqvist, Robert; Andrulis, Irene L; Knight, Julia A; Devilee, Peter; Seynaeve, Caroline; Figueroa, Jonine; Sherman, Mark E; Czene, Kamila; Darabi, Hatef; Hollestelle, Antoinette; van den Ouweland, Ans M W; Humphreys, Keith; Gao, Yu-Tang; Shu, Xiao-Ou; Cox, Angela; Cross, Simon S; Blot, William; Cai, Qiuyin; Ghoussaini, Maya; Perkins, Barbara J; Shah, Mitul; Choi, Ji-Yeob; Kang, Daehee; Lee, Soo Chin; Hartman, Mikael; Kabisch, Maria; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Brennan, Paul; Sangrajrang, Suleeporn; Ambrosone, Christine B; Toland, Amanda E; Shen, Chen-Yang; Wu, Pei-Ei; Orr, Nick; Swerdlow, Anthony; McGuffog, Lesley; Healey, Sue; Lee, Andrew; Kapuscinski, Miroslav; John, Esther M; Terry, Mary Beth; Daly, Mary B; Goldgar, David E; Buys, Saundra S; Janavicius, Ramunas; Tihomirova, Laima; Tung, Nadine; Dorfling, Cecilia M; van Rensburg, Elizabeth J; Neuhausen, Susan L; Ejlertsen, Bent; Hansen, Thomas V O; Osorio, Ana; Benitez, Javier; Rando, Rachel; Weitzel, Jeffrey N; Bonanni, Bernardo; Peissel, Bernard; Manoukian, Siranoush; Papi, Laura; Ottini, Laura; Konstantopoulou, Irene; Apostolou, Paraskevi; Garber, Judy; Rashid, Muhammad Usman; Frost, Debra; Izatt, Louise; Ellis, Steve; Godwin, Andrew K; Arnold, Norbert; Niederacher, Dieter; Rhiem, Kerstin; Bogdanova-Markov, Nadja; Sagne, Charlotte; Stoppa-Lyonnet, Dominique; Damiola, Francesca; Sinilnikova, Olga M; Mazoyer, Sylvie; Isaacs, Claudine; Claes, Kathleen B M; De Leeneer, Kim; de la Hoya, Miguel; Caldes, Trinidad; Nevanlinna, Heli; Khan, Sofia; Mensenkamp, Arjen R; Hooning, Maartje J; Rookus, Matti A; Kwong, Ava; Olah, Edith; Diez, Orland; Brunet, Joan; Pujana, Miquel Angel; Gronwald, Jacek; Huzarski, Tomasz; Barkardottir, Rosa B; Laframboise, Rachel; Soucy, Penny; Montagna, Marco; Agata, Simona; Teixeira, Manuel R; Park, Sue Kyung; Lindor, Noralane; Couch, Fergus J; Tischkowitz, Marc; Foretova, Lenka; Vijai, Joseph; Offit, Kenneth; Singer, Christian F; Rappaport, Christine; Phelan, Catherine M; Greene, Mark H; Mai, Phuong L; Rennert, Gad; Imyanitov, Evgeny N; Hulick, Peter J; Phillips, Kelly-Anne; Piedmonte, Marion; Mulligan, Anna Marie; Glendon, Gord; Bojesen, Anders; Thomassen, Mads; Caligo, Maria A; Yoon, Sook-Yee; Friedman, Eitan; Laitman, Yael; Borg, Ake; von Wachenfeldt, Anna; Ehrencrona, Hans; Rantala, Johanna; Olopade, Olufunmilayo I; Ganz, Patricia A; Nussbaum, Robert L; Gayther, Simon A; Nathanson, Katherine L; Domchek, Susan M; Arun, Banu K; Mitchell, Gillian; Karlan, Beth Y; Lester, Jenny; Maskarinec, Gertraud; Woolcott, Christy; Scott, Christopher; Stone, Jennifer; Apicella, Carmel; Tamimi, Rulla; Luben, Robert; Khaw, Kay-Tee; Helland, Åslaug; Haakensen, Vilde; Dowsett, Mitch; Pharoah, Paul D P; Simard, Jacques; Hall, Per; García-Closas, Montserrat; Vachon, Celine; Chenevix-Trench, Georgia; Antoniou, Antonis C; Easton, Douglas F; Edwards, Stacey L

2016-04-01

We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.

Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170

PubMed Central

Dunning, Alison M; Michailidou, Kyriaki; Kuchenbaecker, Karoline B; Thompson, Deborah; French, Juliet D; Beesley, Jonathan; Healey, Catherine S; Kar, Siddhartha; Pooley, Karen A; Lopez-Knowles, Elena; Dicks, Ed; Barrowdale, Daniel; Sinnott-Armstrong, Nicholas A; Sallari, Richard C; Hillman, Kristine M; Kaufmann, Susanne; Sivakumaran, Haran; Marjaneh, Mahdi Moradi; Lee, Jason S; Hills, Margaret; Jarosz, Monika; Drury, Suzie; Canisius, Sander; Bolla, Manjeet K; Dennis, Joe; Wang, Qin; Hopper, John L; Southey, Melissa C; Broeks, Annegien; Schmidt, Marjanka K; Lophatananon, Artitaya; Muir, Kenneth; Beckmann, Matthias W; Fasching, Peter A; dos-Santos-Silva, Isabel; Peto, Julian; Sawyer, Elinor J; Tomlinson, Ian; Burwinkel, Barbara; Marme, Frederik; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E; Flyger, Henrik; González-Neira, Anna; Perez, Jose I A; Anton-Culver, Hoda; Eunjung, Lee; Arndt, Volker; Brenner, Hermann; Meindl, Alfons; Schmutzler, Rita K; Brauch, Hiltrud; Hamann, Ute; Aittomäki, Kristiina; Blomqvist, Carl; Ito, Hidemi; Matsuo, Keitaro; Bogdanova, Natasha; Dörk, Thilo; Lindblom, Annika; Margolin, Sara; Kosma, Veli-Matti; Mannermaa, Arto; Tseng, Chiu-chen; Wu, Anna H; Lambrechts, Diether; Wildiers, Hans; Chang-Claude, Jenny; Rudolph, Anja; Peterlongo, Paolo; Radice, Paolo; Olson, Janet E; Giles, Graham G; Milne, Roger L; Haiman, Christopher A; Henderson, Brian E; Goldberg, Mark S; Teo, Soo H; Yip, Cheng Har; Nord, Silje; Borresen-Dale, Anne-Lise; Kristensen, Vessela; Long, Jirong; Zheng, Wei; Pylkäs, Katri; Winqvist, Robert; Andrulis, Irene L; Knight, Julia A; Devilee, Peter; Seynaeve, Caroline; Figueroa, Jonine; Sherman, Mark E; Czene, Kamila; Darabi, Hatef; Hollestelle, Antoinette; van den Ouweland, Ans M W; Humphreys, Keith; Gao, Yu-Tang; Shu, Xiao-Ou; Cox, Angela; Cross, Simon S; Blot, William; Cai, Qiuyin; Ghoussaini, Maya; Perkins, Barbara J; Shah, Mitul; Choi, Ji-Yeob; Kang, Daehee; Lee, Soo Chin; Hartman, Mikael; Kabisch, Maria; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Brennan, Paul; Sangrajrang, Suleeporn; Ambrosone, Christine B; Toland, Amanda E; Shen, Chen-Yang; Wu, Pei-Ei; Orr, Nick; Swerdlow, Anthony; McGuffog, Lesley; Healey, Sue; Lee, Andrew; Kapuscinski, Miroslav; John, Esther M; Terry, Mary Beth; Daly, Mary B; Goldgar, David E; Buys, Saundra S; Janavicius, Ramunas; Tihomirova, Laima; Tung, Nadine; Dorfling, Cecilia M; van Rensburg, Elizabeth J; Neuhausen, Susan L; Ejlertsen, Bent; Hansen, Thomas V O; Osorio, Ana; Benitez, Javier; Rando, Rachel; Weitzel, Jeffrey N; Bonanni, Bernardo; Peissel, Bernard; Manoukian, Siranoush; Papi, Laura; Ottini, Laura; Konstantopoulou, Irene; Apostolou, Paraskevi; Garber, Judy; Rashid, Muhammad Usman; Frost, Debra; Izatt, Louise; Ellis, Steve; Godwin, Andrew K; Arnold, Norbert; Niederacher, Dieter; Rhiem, Kerstin; Bogdanova-Markov, Nadja; Sagne, Charlotte; Stoppa-Lyonnet, Dominique; Damiola, Francesca; Sinilnikova, Olga M; Mazoyer, Sylvie; Isaacs, Claudine; Claes, Kathleen B M; De Leeneer, Kim; de la Hoya, Miguel; Caldes, Trinidad; Nevanlinna, Heli; Khan, Sofia; Mensenkamp, Arjen R; Hooning, Maartje J; Rookus, Matti A; Kwong, Ava; Olah, Edith; Diez, Orland; Brunet, Joan; Pujana, Miquel Angel; Gronwald, Jacek; Huzarski, Tomasz; Barkardottir, Rosa B; Laframboise, Rachel; Soucy, Penny; Montagna, Marco; Agata, Simona; Teixeira, Manuel R; Park, Sue Kyung; Lindor, Noralane; Couch, Fergus J; Tischkowitz, Marc; Foretova, Lenka; Vijai, Joseph; Offit, Kenneth; Singer, Christian F; Rappaport, Christine; Phelan, Catherine M; Greene, Mark H; Mai, Phuong L; Rennert, Gad; Imyanitov, Evgeny N; Hulick, Peter J; Phillips, Kelly-Anne; Piedmonte, Marion; Mulligan, Anna Marie; Glendon, Gord; Bojesen, Anders; Thomassen, Mads; Caligo, Maria A; Yoon, Sook-Yee; Friedman, Eitan; Laitman, Yael; Borg, Ake; von Wachenfeldt, Anna; Ehrencrona, Hans; Rantala, Johanna; Olopade, Olufunmilayo I; Ganz, Patricia A; Nussbaum, Robert L; Gayther, Simon A; Nathanson, Katherine L; Domchek, Susan M; Arun, Banu K; Mitchell, Gillian; Karlan, Beth Y; Lester, Jenny; Maskarinec, Gertraud; Woolcott, Christy; Scott, Christopher; Stone, Jennifer; Apicella, Carmel; Tamimi, Rulla; Luben, Robert; Khaw, Kay-Tee; Helland, Åslaug; Haakensen, Vilde; Dowsett, Mitch; Pharoah, Paul D P; Simard, Jacques; Hall, Per; García-Closas, Montserrat; Vachon, Celine; Chenevix-Trench, Georgia; Antoniou, Antonis C; Easton, Douglas F; Edwards, Stacey L

2016-01-01

We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER+ or ER−) and human ERBB2 (HER2+ or HER2−) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER− tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression. PMID:26928228

Differences among allelic variants of human glutathione transferase A2-2 in the activation of azathioprine.

PubMed

Zhang, Wei; Modén, Olof; Mannervik, Bengt

2010-07-30

Azathioprine has been clinically used for decades in connection with organ transplantation, autoimmune disease, and treatment of cancer. Toxic side-reactions are common and have been linked to the liberation of excessively high concentrations of 6-mercaptopurine and corresponding toxic metabolites. An allelic variant of thiopurine methyltransferase with low activity is associated with elevated concentrations of 6-mercaptopurine. However, other genetic markers remain to be identified in order to fully account for adverse reactions and efficacy failure. In the present study, we studied the five known allelic variants of human glutathione transferase A2-2 (GST A2-2) (EC 2.5.1.18), abundantly expressed in liver and efficiently catalyzing the bioactivation of azathioprine to release 6-mercaptopurine. All five variants exhibited high activity with azathioprine, but allelic variant E of GST A2-2 displayed a 3-4-fold elevated catalytic efficiency compared to the other variants. High GST activity can lead to overproduction of 6-mercaptopurine, and the nature of the multiple forms of GSTs in a patient will obviously affect the metabolism of azathioprine. In addition to GST A2-2, the polymorphic GST M1-1 is also highly active with azathioprine. Considering our findings, it appears that the genotypic and phenotypic variations in the GST complement may influence the presentation of adverse reactions in patients treated with azathioprine. Clinical trials will be required to clarify the impact of the GST expression in comparison with the established biomarker thiopurine methyltransferase as predictors of adverse reactions. (c) 2010 Elsevier Ireland Ltd. All rights reserved.

The risk variant in ODZ4 for bipolar disorder impacts on amygdala activation during reward processing.

PubMed

Heinrich, Angela; Lourdusamy, Anbarasu; Tzschoppe, Jelka; Vollstädt-Klein, Sabine; Bühler, Mira; Steiner, Sabina; Bach, Christiane; Poustka, Luise; Banaschewski, Tobias; Barker, Gareth; Büchel, Christian; Conrod, Patricia; Garavan, Hugh; Gallinat, Jürgen; Heinz, Andreas; Ittermann, Bernd; Loth, Eva; Mann, Karl; Martinot, Jean-Luc; Paus, Tomáš; Pausova, Zdenka; Smolka, Michael; Ströhle, Andreas; Struve, Maren; Witt, Stephanie; Flor, Herta; Schumann, Gunter; Rietschel, Marcella; Nees, Frauke

2013-06-01

Bipolar disorder is a severe mood disorder, which normally begins during adolescence or early adulthood and has a heritability of up to 80%. The largest genome-wide association analysis of bipolar disorder recently identified a new genome-wide associated variant in OZD4 (rs12576775). The aim of the present study was to further elucidate the role of this risk variant in the disease process using an imaging genetics approach. As increased amygdala and striatal responses during the processing of reward and emotion are characteristic for bipolar disorder patients, it was tested whether the risk variant has an influence on this endophenotype in healthy adolescents. We examined the impact of the risk variant rs12576775 on functional magnetic resonance imaging data in an adolescent sample (N = 485). Differential activation between carriers of the risk allele (G-allele) and homozygous A-allele carriers in the amygdala and the striatum during a modification of the monetary incentive delay task (examining reward) and a face task (examining emotion) was analyzed. Carriers of the risk allele showed an increased blood oxygen level-dependent response in the amygdala during reward sensitivity (p = 0.05) and reward expectation (p < 0.05) but not during the face task. No significant group differences were found in the striatum during both reward and emotion processing. Our results indicate that the ODZ4 risk variant influences reward processing in the amygdala. Alterations in the processing of emotion may have different underlying mechanisms and need to be further examined. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Maternal variant in the upstream of FOXP3 gene on the X chromosome is associated with recurrent infertility in Japanese Black cattle.

PubMed

Arishima, Taichi; Sasaki, Shinji; Isobe, Tomohiro; Ikebata, Yoshihisa; Shimbara, Shinichi; Ikeda, Shogo; Kawashima, Keisuke; Suzuki, Yutaka; Watanabe, Manabu; Sugano, Sumio; Mizoshita, Kazunori; Sugimoto, Yoshikazu

2017-12-06

Repeat breeding, which is defined as cattle failure to conceive after three or more inseminations in the absence of clinical abnormalities, is a substantial problem in cattle breeding. To identify maternal genetic variants of repeat breeding in Japanese Black cattle, we selected 29 repeat-breeding heifers that failed to conceive following embryo transfer (ET) and conducted a genome-wide association study (GWAS) using the traits. We found that a single-nucleotide polymorphism (SNP; g.92,377,635A > G) in the upstream region of the FOXP3 gene on the X chromosome was highly associated with repeat breeding and failure to conceive following ET (P = 1.51 × 10 -14 ). FOXP3 is a master gene for differentiation of regulatory T (T reg ) cells that function in pregnancy maintenance. Reporter assay results revealed that the activity of the FOXP3 promoter was lower in reporter constructs with the risk-allele than in those with the non-risk-allele by approximately 0.68 fold. These findings suggest that the variant in the upstream region of FOXP3 with the risk-allele decreased FOXP3 transcription, which in turn, could reduce the number of maternal T reg cells and lead to infertility. The frequency of the risk-allele in repeat-breeding heifers is more than that in cows, suggesting that the risk-allele could be associated with infertility in repeat-breeding heifers. This GWAS identified a maternal variant in the upstream region of FOXP3 that was associated with infertility in repeat-breeding Japanese Black cattle that failed to conceive using ET. The variant affected the level of FOXP3 mRNA expression. Thus, the results suggest that the risk-allele could serve as a useful marker to reduce and eliminate animals with inferior fertility in Japanese Black cattle.

High-resolution genetic mapping of allelic variants associated with cell wall chemistry in Populus

DOE PAGES

Muchero, Wellington; Guo, Jianjun; Difazio, Stephen P.; ...

2015-01-23

We report the identification of six genetic loci and the allelic-variants associated with Populus cell wall phenotypes determined independently using pyrolysis Molecular Beam Mass Spectrometry (pyMBMS), saccharification assay and wet chemistry in two partially overlapping populations of P. trichocarpa genotypes sampled from multiple environments in the Pacific Northwest of North America. All 6 variants co-located with a quantitative trait locus (QTL) hotspot on chromosome XIV for lignin content, syringyl to guaiacyl (S/G) ratio, 5- and 6- carbon sugars identified in an interspecific P. trichocarpa x P. deltoides pseudo-backcross mapping pedigree. Genomic intervals containing an amino acid transporter, a MYB transcriptionmore » factor, an angustifolia CtBP transcription factor, a copper transport protein ATOX1-related, a Ca 2+ transporting ATPase and a protein kinase were identified within 5 QTL regions. Each interval contained single nucleotide polymorphisms (SNPs) that were significantly associated to cell-wall phenotypes, with associations exceeding the chromosome-wise Bonferroni-adjusted p-values in at least one environment. cDNA sequencing for allelic variants of 3 of the 6 genes identified polymorphisms leading to premature stop codons in the MYB transcription factor and protein kinase. On the other hand, variants of the Angustifolia CtBP transcription factor exhibited a polyglutamine (PolyQ) length polymorphism. Results from transient protoplast assays suggested that each of the polymorphisms conferred allelic differences in activation of cellulose, hemicelluloses and lignin pathway marker genes, with truncated and short PolyQ alleles exhibiting significantly reduced marker gene activation. Genes identified in this study represent novel targets for reducing cell wall recalcitrance for lignocellulosic biofuels production using plant biomass.« less

Picosecond-resolved FRET on non-amplified DNA for identifying individuals genetically susceptible to type-1 diabetes

NASA Astrophysics Data System (ADS)

Nardo, Luca; Tosi, Giovanna; Bondani, Maria; Accolla, Roberto; Andreoni, Alessandra

2012-06-01

By tens-of-picosecond resolved fluorescence detection we study Förster resonance energy transfer between a donor and a black-hole-quencher bound at the 5'- and 3'-positions of an oligonucleotide probe matching the highly polymorphic region between codons 51 and 58 of the human leukocyte antigen DQB1 0201 allele, conferring susceptibility to type-1 diabetes. The probe is annealed with non-amplified genomic DNAs carrying either the 0201 sequence or other DQB1 allelic variants. We detect the longest-lived donor fluorescence in the case of hybridization with the 0201 allele and definitely faster and distinct decays for the other allelic variants, some of which are single-nucleotide polymorphic.

Gamma-aminobutyric acid A receptor, α-2 (GABRA2) variants as individual markers for alcoholism: a meta-analysis.

PubMed

Zintzaras, Elias

2012-08-01

The available evidence from the genetic association studies (GAS) published to date on the association between variants in the GABRA2 gene and alcoholism has produced inconclusive results. To interpret these results, a meticulous meta-analysis of all available studies was carried out. The PubMed database and the HuGE Navigator were searched for published GAS-related variants in the GABRA2 gene with susceptibility to alcoholism. Then, the GAS were synthesized to decrease the uncertainty of estimated genetic risk effects. The risk effects were estimated on the basis of the odds ratio (OR) of the allele contrast and the generalized odds ratio (OR(G)), a model-free approach. Cumulative and recursive cumulative meta-analyses (CMA) were also carried out to investigate the trend and stability of effect sizes as evidence accumulates. Fourteen variants investigated in eight studies were analyzed. Significant associations were derived for four variants either for the allele contrast or for the OR(G). In particular, the variants rs279858 and rs279845 showed marginal significance for OR(G): OR(G)=1.27 (1.01-1.60) and OR(G)=1.49 (1.02-2.19), respectively. Also, the variants rs567926 and rs279844 showed significance for the allele contrast: OR=1.24 (1.06-1.46) and OR=1.23 (1.08-1.43), respectively; the ORG produced similar results. The variant rs279858 produced a large heterogeneity between studies. CMA showed a trend of an association only for the variant rs567926. Recursive CMA indicated that more evidence is needed to conclude on the status of significance of all variants. There is evidence that variants in the GABRA2 gene are associated with alcoholism. However, the present findings should be interpreted with caution.

PTGER4 modulating variants in Crohn's disease.

PubMed

Prager, Matthias; Büttner, Janine; Büning, Carsten

2014-08-01

Variants modulating expression of the prostaglandin receptor 4 (PTGER4) have been reported to be associated with Cohn's disease (CD), but the clinical impact remains to be elucidated. We analyzed these variants in a large German inflammatory bowel disease (IBD) cohort and searched for a potential phenotype association. The variants rs4495224 and rs7720838 were studied in adult German IBD patients (CD, n = 475; ulcerative colitis (UC), n = 293) and healthy controls (HC, n = 467). Data were correlated to results from NOD2 genotyping and to clinical characteristics. We found a significant association for the rs7720838 variant with overrepresentation of the T allele to CD (p = 0.0058; OR 0.7703, 95 % CI 0.641-0.926) but not to UC. Furthermore, logistic regression analysis revealed that the presence of the T allele was associated with stricturing disease behavior in CD patients (p = 0.03; OR 1.84, 95 % CI 1.07-3.16). Interestingly, the chance for developing stricturing disease behavior was enhanced if mutant alleles in both rs7720838 and NOD2 were present (OR 2.87, 95 % CI 1.42-5.81; p = 0.003). No overall association to CD or UC was found for the rs4495224 variant. The PTGER4 modulating variant rs7720838 increases susceptibility for CD and might resemble a risk factor for stricturing disease behavior.

al mena: a comprehensive resource of human genetic variants integrating genomes and exomes from Arab, Middle Eastern and North African populations.

PubMed

Koshy, Remya; Ranawat, Anop; Scaria, Vinod

2017-10-01

Middle East and North Africa (MENA) encompass very unique populations, with a rich history and encompasses characteristic ethnic, linguistic and genetic diversity. The genetic diversity of MENA region has been largely unknown. The recent availability of whole-exome and whole-genome sequences from the region has made it possible to collect population-specific allele frequencies. The integration of data sets from this region would provide insights into the landscape of genetic variants in this region. We integrated genetic variants from multiple data sets systematically, available from this region to create a compendium of over 26 million genetic variations. The variants were systematically annotated and their allele frequencies in the data sets were computed and available as a web interface which enables quick query. As a proof of principle for application of the compendium for genetic epidemiology, we analyzed the allele frequencies for variants in transglutaminase 1 (TGM1) gene, associated with autosomal recessive lamellar ichthyosis. Our analysis revealed that the carrier frequency of selected variants differed widely with significant interethnic differences. To the best of our knowledge, al mena is the first and most comprehensive repertoire of genetic variations from the Arab, Middle Eastern and North African region. We hope al mena would accelerate Precision Medicine in the region.

Lynch syndrome associated with two MLH1 promoter variants and allelic imbalance of MLH1 expression.

PubMed

Hesson, Luke B; Packham, Deborah; Kwok, Chau-To; Nunez, Andrea C; Ng, Benedict; Schmidt, Christa; Fields, Michael; Wong, Jason W H; Sloane, Mathew A; Ward, Robyn L

2015-06-01

Lynch syndrome is a hereditary cancer syndrome caused by a constitutional mutation in one of the mismatch repair genes. The implementation of predictive testing and targeted preventative surveillance is hindered by the frequent finding of sequence variants of uncertain significance in these genes. We aimed to determine the pathogenicity of previously reported variants (c.-28A>G and c.-7C>T) within the MLH1 5'untranslated region (UTR) in two individuals from unrelated suspected Lynch syndrome families. We investigated whether these variants were associated with other pathogenic alterations using targeted high-throughput sequencing of the MLH1 locus. We also determined their relationship to gene expression and epigenetic alterations at the promoter. Sequencing revealed that the c.-28A>G and c.-7C>T variants were the only potentially pathogenic alterations within the MLH1 gene. In both individuals, the levels of transcription from the variant allele were reduced to 50% compared with the wild-type allele. Partial loss of expression occurred in the absence of constitutional epigenetic alterations within the MLH1 promoter. We propose that these variants may be pathogenic due to constitutional partial loss of MLH1 expression, and that this may be associated with intermediate penetrance of a Lynch syndrome phenotype. Our findings provide further evidence of the potential importance of noncoding variants in the MLH1 5'UTR in the pathogenesis of Lynch syndrome. © 2015 The Authors. **Human Mutation published by Wiley Periodicals, Inc.

Lynch Syndrome Associated with Two MLH1 Promoter Variants and Allelic Imbalance of MLH1 Expression

PubMed Central

Hesson, Luke B; Packham, Deborah; Kwok, Chau-To; Nunez, Andrea C; Ng, Benedict; Schmidt, Christa; Fields, Michael; Wong, Jason WH; Sloane, Mathew A; Ward, Robyn L

2015-01-01

Lynch syndrome is a hereditary cancer syndrome caused by a constitutional mutation in one of the mismatch repair genes. The implementation of predictive testing and targeted preventative surveillance is hindered by the frequent finding of sequence variants of uncertain significance in these genes. We aimed to determine the pathogenicity of previously reported variants (c.-28A>G and c.-7C>T) within the MLH1 5′untranslated region (UTR) in two individuals from unrelated suspected Lynch syndrome families. We investigated whether these variants were associated with other pathogenic alterations using targeted high-throughput sequencing of the MLH1 locus. We also determined their relationship to gene expression and epigenetic alterations at the promoter. Sequencing revealed that the c.-28A>G and c.-7C>T variants were the only potentially pathogenic alterations within the MLH1 gene. In both individuals, the levels of transcription from the variant allele were reduced to 50% compared with the wild-type allele. Partial loss of expression occurred in the absence of constitutional epigenetic alterations within the MLH1 promoter. We propose that these variants may be pathogenic due to constitutional partial loss of MLH1 expression, and that this may be associated with intermediate penetrance of a Lynch syndrome phenotype. Our findings provide further evidence of the potential importance of noncoding variants in the MLH1 5′UTR in the pathogenesis of Lynch syndrome. PMID:25762362

Temperature Sensitivity Conferred by ligA Alleles from Psychrophilic Bacteria upon Substitution in Mesophilic Bacteria and a Yeast Species

PubMed Central

Pankowski, Jarosław A.; Puckett, Stephanie M.

2016-01-01

We have assembled a collection of 13 psychrophilic ligA alleles that can serve as genetic elements for engineering mesophiles to a temperature-sensitive (TS) phenotype. When these ligA alleles were substituted into Francisella novicida, they conferred a TS phenotype with restrictive temperatures between 33 and 39°C. When the F. novicida ligA hybrid strains were plated above their restrictive temperatures, eight of them generated temperature-resistant variants. For two alleles, the mutations that led to temperature resistance clustered near the 5′ end of the gene, and the mutations increased the predicted strength of the ribosome binding site at least 3-fold. Four F. novicida ligA hybrid strains generated no temperature-resistant variants at a detectable level. These results suggest that multiple mutations are needed to create temperature-resistant variants of these ligA gene products. One ligA allele was isolated from a Colwellia species that has a maximal growth temperature of 12°C, and this allele supported growth of F. novicida only as a hybrid between the psychrophilic and the F. novicida ligA genes. However, the full psychrophilic gene alone supported the growth of Salmonella enterica, imparting a restrictive temperature of 27°C. We also tested two ligA alleles from two Pseudoalteromonas strains for their ability to support the viability of a Saccharomyces cerevisiae strain that lacked its essential gene, CDC9, encoding an ATP-dependent DNA ligase. In both cases, the psychrophilic bacterial alleles supported yeast viability and their expression generated TS phenotypes. This collection of ligA alleles should be useful in engineering bacteria, and possibly eukaryotic microbes, to predictable TS phenotypes. PMID:26773080

Candidate Cancer Allele cDNA Collection | Office of Cancer Genomics

Cancer.gov

CTD2 researchers at the Broad Institute/DFCI have developed a collection of plasmids including mutant alleles found in sequencing studies of cancer. It includes somatic variants found in lung adenocarcinoma and across other cancer types. The clones enable researchers to characterize the function of the cancer variants in a high throughput experiments. These plasmids are collectively called the “Broad Target Accelerator Plasmid Collections”.

Using high-resolution variant frequencies to empower clinical genome interpretation.

PubMed

Whiffin, Nicola; Minikel, Eric; Walsh, Roddy; O'Donnell-Luria, Anne H; Karczewski, Konrad; Ing, Alexander Y; Barton, Paul J R; Funke, Birgit; Cook, Stuart A; MacArthur, Daniel; Ware, James S

2017-10-01

PurposeWhole-exome and whole-genome sequencing have transformed the discovery of genetic variants that cause human Mendelian disease, but discriminating pathogenic from benign variants remains a daunting challenge. Rarity is recognized as a necessary, although not sufficient, criterion for pathogenicity, but frequency cutoffs used in Mendelian analysis are often arbitrary and overly lenient. Recent very large reference datasets, such as the Exome Aggregation Consortium (ExAC), provide an unprecedented opportunity to obtain robust frequency estimates even for very rare variants.MethodsWe present a statistical framework for the frequency-based filtering of candidate disease-causing variants, accounting for disease prevalence, genetic and allelic heterogeneity, inheritance mode, penetrance, and sampling variance in reference datasets.ResultsUsing the example of cardiomyopathy, we show that our approach reduces by two-thirds the number of candidate variants under consideration in the average exome, without removing true pathogenic variants (false-positive rate<0.001).ConclusionWe outline a statistically robust framework for assessing whether a variant is "too common" to be causative for a Mendelian disorder of interest. We present precomputed allele frequency cutoffs for all variants in the ExAC dataset.

GENETIC VARIANTS, IMMUNE FUNCTION AND RISK OF PRE-ECLAMPSIA AMONG AMERICAN INDIANS

PubMed Central

Best, Lyle G.; Nadeau, Melanie; Davis, Kylie; Lamb, Felicia; Bercier, Shellee; Anderson, Cindy M.

2011-01-01

Objective To determine the prevalence in an American Indian population of genetic variants with putative effects on immune function and determine if they are associated with pre-eclampsia. Methods In a study of 66 cases and 130 matched controls, six single nucleotide polymorphisms (SNP) with either previously demonstrated or postulated modulating effects on the immune system were genotyped. Allele frequencies and various genetic models were evaluated by conditional logistic regression in both univariate and multiply adjusted models. Results Although most genetic variants lacked evidence of association with pre-eclampsia, the minor allele of the CRP related, rs1205 SNP in a dominant model with adjustment for age at delivery, nulliparity and body mass index, exhibited an odds ratio of 0.259 (95% CI of 0.08 – 0.81, p=0.020) in relation to severe pre-eclampsia (48 cases). The allelic prevalence of this variant was 46.1% in this population. Conclusion Of the six SNPs related to immune function in this study, a functional variant in the 3'UTR of the CRP gene was shown to be associated with severe pre-eclampsia in an American Indian population. PMID:22004660

Association between allelic variants of the human glucocorticoid receptor gene and autoimmune diseases: A systematic review and meta-analysis.

PubMed

Herrera, Cristian; Marcos, Miguel; Carbonell, Cristina; Mirón-Canelo, José Antonio; Espinosa, Gerard; Cervera, Ricard; Chamorro, Antonio-Javier

2018-05-01

The human glucocorticoid receptor gene (NR3C1) is considered to play a role in the differences and sensitivities of the glucocorticoid response in individuals with autoimmune diseases. The objective of this study was to examine by means of a systematic review previous findings regarding allelic variants of NR3C1 in relation to the risk of developing systemic autoimmune diseases. Studies that analysed the genotype distribution of NR3C1 allelic variants among patients with systemic autoimmune diseases were retrieved. A meta-analysis was conducted with a random effects model. Odds ratios (ORs) and their confidence intervals (CIs) were calculated. In addition, sub-analysis by ethnicity, sensitivity analysis and tests for heterogeneity of the results were performed. Eleven studies met the inclusion criteria for meta-analysis. We found no evidence that the analysed NR3C1 polymorphisms, rs6198, rs56149945, and rs6189/rs6190, modulate the risk of developing a systemic autoimmune disease. Nonetheless, a protective role for the minor allele of rs41423247 was found among Caucasians (OR=0.78; 95% CI: 0.65, 0.92; P=0.004). A subgroup analysis according to underlying diseases revealed no significant association either for Behçet's disease or rheumatoid arthritis, while correlations between NR3C1 polymorphisms and disease activity or response to glucocorticoids could not be evaluated due to insufficient data. There is no clear evidence that the analysed NR3C1 allelic variants confer a risk for developing systemic autoimmune diseases although the minor G allele of rs41423247 may be protective among Caucasians. Copyright © 2018 Elsevier B.V. All rights reserved.

Caprine PrP variants harboring Asp-146, His-154 and Gln-211 alleles display reduced convertibility upon interaction with pathogenic murine prion protein in scrapie infected cells.

PubMed

Kanata, Eirini; Arsenakis, Minas; Sklaviadis, Theodoros

2016-09-02

Scrapie, the prion disease of sheep and goats, is a devastating malady of small ruminants. Due to its infectious nature, epidemic outbreaks may occur in flocks/herds consisting of highly susceptible animals. Field studies identified scrapie-protective caprine PrP variants, harboring specific single amino acid changes (Met-142, Arg-143, Asp-146, Ser-146, His-154, Gln-211 and Lys-222). Their effects are under further evaluation, and aim to determine the most protective allele. We assessed some of these variants (Asp-146, His-154, Gln-211 and Lys-222), after their exogenous expression as murine-caprine chimeras in a scrapie- infected murine cell line. We report that exogenously expressed PrPs undergo conformational conversion upon interaction with the endogenous pathological murine prion protein (PrP SC ), which results in the detection of goat-specific and partially PK-resistant moieties. These moieties display a PK-resistance pattern distinct from the one detected in natural goat scrapie cases. Within this cellular model, distinct conformational conversion potentials were assigned to the tested variants. Molecules carrying the Asp-146, His-154 and Gln-211 alleles showed significantly lower conversion levels compared to wild type, confirming their protective effects against scrapie. Although we utilized a heterologous conversion system, this is to our knowledge, the first study of caprine PrP variants in a cellular context of scrapie, that confirms the protective effects of some of the studied alleles.

Germline MC1R status influences somatic mutation burden in melanoma.

PubMed

Robles-Espinoza, Carla Daniela; Roberts, Nicola D; Chen, Shuyang; Leacy, Finbarr P; Alexandrov, Ludmil B; Pornputtapong, Natapol; Halaban, Ruth; Krauthammer, Michael; Cui, Rutao; Timothy Bishop, D; Adams, David J

2016-07-12

The major genetic determinants of cutaneous melanoma risk in the general population are disruptive variants (R alleles) in the melanocortin 1 receptor (MC1R) gene. These alleles are also linked to red hair, freckling, and sun sensitivity, all of which are known melanoma phenotypic risk factors. Here we report that in melanomas and for somatic C>T mutations, a signature linked to sun exposure, the expected single-nucleotide variant count associated with the presence of an R allele is estimated to be 42% (95% CI, 15-76%) higher than that among persons without an R allele. This figure is comparable to the expected mutational burden associated with an additional 21 years of age. We also find significant and similar enrichment of non-C>T mutation classes supporting a role for additional mutagenic processes in melanoma development in individuals carrying R alleles.

Allelic variants of hereditary prions: The bimodularity principle

PubMed Central

Tikhodeyev, Oleg N.; Tarasov, Oleg V.; Bondarev, Stanislav A.

2017-01-01

ABSTRACT Modern biology requires modern genetic concepts equally valid for all discovered mechanisms of inheritance, either “canonical” (mediated by DNA sequences) or epigenetic. Applying basic genetic terms such as “gene” and “allele” to protein hereditary factors is one of the necessary steps toward these concepts. The basic idea that different variants of the same prion protein can be considered as alleles has been previously proposed by Chernoff and Tuite. In this paper, the notion of prion allele is further developed. We propose the idea that any prion allele is a bimodular hereditary system that depends on a certain DNA sequence (DNA determinant) and a certain epigenetic mark (epigenetic determinant). Alteration of any of these 2 determinants may lead to establishment of a new prion allele. The bimodularity principle is valid not only for hereditary prions; it seems to be universal for any epigenetic hereditary factor. PMID:28281926

Rare genetic variants and the risk of cancer.

PubMed

Bodmer, Walter; Tomlinson, Ian

2010-06-01

There are good reasons to expect that common genetic variants do not explain all of the inherited risk of the common cancers, not least of these being the relatively low proportion of familial relative risk that common cancer SNPs currently explain. One promising source of the unexplained risk is rare, low-penetrance genetic variants, a class that ranges from low-frequency polymorphisms (allele frequency < 5%) through subpolymorphic variants (frequency 0.1-1.0%) to very low frequency or 'private' variants with frequencies of 0.1% or less. Examples of rare cancer variants include breast cancer susceptibility loci CHEK2, BRIP1 and PALB2. There are considerable challenges associated with the discovery and testing of rare predisposition alleles, many of which are illustrated by the issues associated with variants of unknown significance in the Mendelian cancer predisposition genes. However, whilst cost constraints remain, the technological barriers to rare variant discovery and large-scale genotyping no longer exist. If each individual carries many disease-causing rare variants, the so-called missing heritability of cancer might largely be explained. Whether or not rare variants do end up filling the heritability gap, it is imperative to look for them along side common variants.

Proposal for the nomenclature of human plasminogen (PLG) polymorphism.

PubMed

Skoda, U; Bertrams, J; Dykes, D; Eiberg, H; Hobart, M; Hummel, K; Kühnl, P; Mauff, G; Nakamura, S; Nishimukai, H

1986-01-01

Since its discovery, human plasminogen (PLG) polymorphism has received widespread acceptance in population genetics and forensic haematology. Due to the large number of variant alleles described, a PLG reference typing and Plasminogen Symposium was held, at which a nomenclature proposal was inaugurated. The technology of comparing PLG variants was based on isoelectric focusing and subsequent detection by caseinolytic overlay and 'Western' blotting. Typing results permitted comparison of so far described variant designations and resulted in a new nomenclature proposal for PLG polymorphism. It is recommended that the two most common alleles found in all investigated races be called: PLG*A (previously also PLG*1) and PLG*B (previously also PLG*2), the known variants with acidic pI: PLG*A1 to *A3, intermediate variants: PLG*M1 to *M5, PLG*M5 being functionally inactive, and basic variants: PLG*B1 to *B3. For future classification of newly discovered variants, samples should be compared at any of the laboratories participating in the reference typing.

Association of obesity susceptibility gene variants with metabolic syndrome and related traits in 1,443 Czech adolescents.

PubMed

Dušátková, L; Zamrazilová, H; Sedláčková, B; Včelák, J; Hlavatý, P; Aldhoon Hainerová, I; Korenková, V; Bradnová, O; Bendlová, B; Kunešová, M; Hainer, V

2013-01-01

Genome-wide association studies have revealed several gene variants associated with obesity; however, only a few studies have further investigated their association with metabolic syndrome. We performed a study of eleven variants in/near genes TMEM18, SH2B1, KCTD15, PCSK1, BDNF, SEC16B, MC4R, and FTO in Czech adolescents and analysed their association with obesity, metabolic syndrome and related traits. Genotyping was performed in 1,443 adolescents aged 13.0-17.9 years. Anthropometric parameters, biochemical parameters and blood pressure were assessed. Metabolic syndrome was defined according to the International Diabetes Federation. The FTO rs9939609 variant was associated with overweight/obesity (OR 1.40, 95% CI 1.21-1.63, P < 0.001). The minor allele of TMEM18 rs7561317 was related to underweight (OR 1.78, 95% CI 1.14-2.79, P = 0.015). BDNF rs925946 and MC4R rs17782313 were associated with metabolic syndrome (OR 1.53, 95% CI 1.14-2.04, P = 0.005; 1.51, 95% CI 1.12-2.04, P = 0.009). The PCSK1 rs6235 variant was negatively related to increased blood glucose (OR 0.69, 95% CI 0.49-0.97, P = 0.040). In conclusion, the FTO variant was associated with overweight/obesity in Czech adolescents. Moreover, MC4R and BDNF variants increased the risk of metabolic syndrome, probably through their effect on abdominal obesity. The PCSK1 variant may have a protective role in the development of type 2 diabetes.

The BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity.

PubMed

Colombo, Mara; Lòpez-Perolio, Irene; Meeks, Huong D; Caleca, Laura; Parsons, Michael T; Li, Hongyan; De Vecchi, Giovanna; Tudini, Emma; Foglia, Claudia; Mondini, Patrizia; Manoukian, Siranoush; Behar, Raquel; Garcia, Encarna B Gómez; Meindl, Alfons; Montagna, Marco; Niederacher, Dieter; Schmidt, Ane Y; Varesco, Liliana; Wappenschmidt, Barbara; Bolla, Manjeet K; Dennis, Joe; Michailidou, Kyriaki; Wang, Qin; Aittomäki, Kristiina; Andrulis, Irene L; Anton-Culver, Hoda; Arndt, Volker; Beckmann, Matthias W; Beeghly-Fadel, Alicia; Benitez, Javier; Boeckx, Bram; Bogdanova, Natalia V; Bojesen, Stig E; Bonanni, Bernardo; Brauch, Hiltrud; Brenner, Hermann; Burwinkel, Barbara; Chang-Claude, Jenny; Conroy, Don M; Couch, Fergus J; Cox, Angela; Cross, Simon S; Czene, Kamila; Devilee, Peter; Dörk, Thilo; Eriksson, Mikael; Fasching, Peter A; Figueroa, Jonine; Fletcher, Olivia; Flyger, Henrik; Gabrielson, Marike; García-Closas, Montserrat; Giles, Graham G; González-Neira, Anna; Guénel, Pascal; Haiman, Christopher A; Hall, Per; Hamann, Ute; Hartman, Mikael; Hauke, Jan; Hollestelle, Antoinette; Hopper, John L; Jakubowska, Anna; Jung, Audrey; Kosma, Veli-Matti; Lambrechts, Diether; Le Marchand, Loid; Lindblom, Annika; Lubinski, Jan; Mannermaa, Arto; Margolin, Sara; Miao, Hui; Milne, Roger L; Neuhausen, Susan L; Nevanlinna, Heli; Olson, Janet E; Peterlongo, Paolo; Peto, Julian; Pylkäs, Katri; Sawyer, Elinor J; Schmidt, Marjanka K; Schmutzler, Rita K; Schneeweiss, Andreas; Schoemaker, Minouk J; See, Mee Hoong; Southey, Melissa C; Swerdlow, Anthony; Teo, Soo H; Toland, Amanda E; Tomlinson, Ian; Truong, Thérèse; van Asperen, Christi J; van den Ouweland, Ans M W; van der Kolk, Lizet E; Winqvist, Robert; Yannoukakos, Drakoulis; Zheng, Wei; Dunning, Alison M; Easton, Douglas F; Henderson, Alex; Hogervorst, Frans B L; Izatt, Louise; Offitt, Kenneth; Side, Lucy E; van Rensburg, Elizabeth J; Embrace, Study; Hebon, Study; McGuffog, Lesley; Antoniou, Antonis C; Chenevix-Trench, Georgia; Spurdle, Amanda B; Goldgar, David E; Hoya, Miguel de la; Radice, Paolo

2018-05-01

Although the spliceogenic nature of the BRCA2 c.68-7T > A variant has been demonstrated, its association with cancer risk remains controversial. In this study, we accurately quantified by real-time PCR and digital PCR (dPCR), the BRCA2 isoforms retaining or missing exon 3. In addition, the combined odds ratio for causality of the variant was estimated using genetic and clinical data, and its associated cancer risk was estimated by case-control analysis in 83,636 individuals. Co-occurrence in trans with pathogenic BRCA2 variants was assessed in 5,382 families. Exon 3 exclusion rate was 4.5-fold higher in variant carriers (13%) than controls (3%), indicating an exclusion rate for the c.68-7T > A allele of approximately 20%. The posterior probability of pathogenicity was 7.44 × 10 -115 . There was neither evidence for increased risk of breast cancer (OR 1.03; 95% CI 0.86-1.24) nor for a deleterious effect of the variant when co-occurring with pathogenic variants. Our data provide for the first time robust evidence of the nonpathogenicity of the BRCA2 c.68-7T > A. Genetic and quantitative transcript analyses together inform the threshold for the ratio between functional and altered BRCA2 isoforms compatible with normal cell function. These findings might be exploited to assess the relevance for cancer risk of other BRCA2 spliceogenic variants. © 2018 The Authors. Human Mutation published by Wiley Periodicals, Inc.

Biallelic germline and somatic mutations in malignant mesothelioma: multiple mutations in transcription regulators including mSWI/SNF genes.

PubMed

Yoshikawa, Yoshie; Sato, Ayuko; Tsujimura, Tohru; Otsuki, Taiichiro; Fukuoka, Kazuya; Hasegawa, Seiki; Nakano, Takashi; Hashimoto-Tamaoki, Tomoko

2015-02-01

We detected low levels of acetylation for histone H3 tail lysines in malignant mesothelioma (MM) cell lines resistant to histone deacetylase inhibitors. To identify the possible genetic causes related to the low histone acetylation levels, whole-exome sequencing was conducted with MM cell lines established from eight patients. A mono-allelic variant of BRD1 was common to two MM cell lines with very low acetylation levels. We identified 318 homozygous protein-damaging variants/mutations (18-78 variants/mutations per patient); annotation analysis showed enrichment of the molecules associated with mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complexes and co-activators that facilitate initiation of transcription. In seven of the patients, we detected a combination of variants in histone modifiers or transcription factors/co-factors, in addition to variants in mSWI/SNF. Direct sequencing showed that homozygous mutations in SMARCA4, PBRM1 and ARID2 were somatic. In one patient, homozygous germline variants were observed for SMARCC1 and SETD2 in chr3p22.1-3p14.2. These exhibited extended germline homozygosity and were in regions containing somatic mutations, leading to a loss of BAP1 and PBRM1 expression in MM cell line. Most protein-damaging variants were heterozygous in normal tissues. Heterozygous germline variants were often converted into hemizygous variants by mono-allelic deletion, and were rarely homozygous because of acquired uniparental disomy. Our findings imply that MM might develop through the somatic inactivation of mSWI/SNF complex subunits and/or histone modifiers, including BAP1, in subjects that have rare germline variants of these transcription regulators and/or transcription factors/co-factors, and in regions prone to mono-allelic deletion during oncogenesis. © 2014 UICC.

Sex-specific allelic transmission bias suggests sexual conflict at MC1R.

PubMed

Ducret, Valérie; Gaigher, Arnaud; Simon, Céline; Goudet, Jérôme; Roulin, Alexandre

2016-09-01

Sexual conflict arises when selection in one sex causes the displacement of the other sex from its phenotypic optimum, leading to an inevitable tension within the genome - called intralocus sexual conflict. Although the autosomal melanocortin-1-receptor gene (MC1R) can generate colour variation in sexually dichromatic species, most previous studies have not considered the possibility that MC1R may be subject to sexual conflict. In the barn owl (Tyto alba), the allele MC1RWHITE is associated with whitish plumage coloration, typical of males, and the allele MC1RRUFOUS is associated with dark rufous coloration, typical of females, although each sex can express any phenotype. Because each colour variant is adapted to specific environmental conditions, the allele MC1RWHITE may be more strongly selected in males and the allele MC1RRUFOUS in females. We therefore investigated whether MC1R genotypes are in excess or deficit in male and female fledglings compared with the expected Hardy-Weinberg proportions. Our results show an overall deficit of 7.5% in the proportion of heterozygotes in males and of 12.9% in females. In males, interannual variation in assortative pairing with respect to MC1R explained the year-specific deviations from Hardy-Weinberg proportions, whereas in females, the deficit was better explained by the interannual variation in the probability of inheriting the MC1RWHITE or MC1RRUFOUS allele. Additionally, we observed that sons inherit the MC1RRUFOUS allele from their fathers on average slightly less often than expected under the first Mendelian law. Transmission ratio distortion may be adaptive in this sexually dichromatic species if males and females are, respectively, selected to display white and rufous plumages. © 2016 John Wiley & Sons Ltd.

Allelic polymorphism in the T cell receptor and its impact on immune responses.

PubMed

Gras, Stephanie; Chen, Zhenjun; Miles, John J; Liu, Yu Chih; Bell, Melissa J; Sullivan, Lucy C; Kjer-Nielsen, Lars; Brennan, Rebekah M; Burrows, Jacqueline M; Neller, Michelle A; Khanna, Rajiv; Purcell, Anthony W; Brooks, Andrew G; McCluskey, James; Rossjohn, Jamie; Burrows, Scott R

2010-07-05

In comparison to human leukocyte antigen (HLA) polymorphism, the impact of allelic sequence variation within T cell receptor (TCR) loci is much less understood. Particular TCR loci have been associated with autoimmunity, but the molecular basis for this phenomenon is undefined. We examined the T cell response to an HLA-B*3501-restricted epitope (HPVGEADYFEY) from Epstein-Barr virus (EBV), which is frequently dominated by a TRBV9*01(+) public TCR (TK3). However, the common allelic variant TRBV9*02, which differs by a single amino acid near the CDR2beta loop (Gln55-->His55), was never used in this response. The structure of the TK3 TCR, its allelic variant, and a nonnaturally occurring mutant (Gln55-->Ala55) in complex with HLA-B*3501(HPVGEADYFEY) revealed that the Gln55-->His55 polymorphism affected the charge complementarity at the TCR-peptide-MHC interface, resulting in reduced functional recognition of the cognate and naturally occurring variants of this EBV peptide. Thus, polymorphism in the TCR loci may contribute toward variability in immune responses and the outcome of infection.

Mining the human phenome using allelic scores that index biological intermediates.

PubMed

Evans, David M; Brion, Marie Jo A; Paternoster, Lavinia; Kemp, John P; McMahon, George; Munafò, Marcus; Whitfield, John B; Medland, Sarah E; Montgomery, Grant W; Timpson, Nicholas J; St Pourcain, Beate; Lawlor, Debbie A; Martin, Nicholas G; Dehghan, Abbas; Hirschhorn, Joel; Smith, George Davey

2013-10-01

It is common practice in genome-wide association studies (GWAS) to focus on the relationship between disease risk and genetic variants one marker at a time. When relevant genes are identified it is often possible to implicate biological intermediates and pathways likely to be involved in disease aetiology. However, single genetic variants typically explain small amounts of disease risk. Our idea is to construct allelic scores that explain greater proportions of the variance in biological intermediates, and subsequently use these scores to data mine GWAS. To investigate the approach's properties, we indexed three biological intermediates where the results of large GWAS meta-analyses were available: body mass index, C-reactive protein and low density lipoprotein levels. We generated allelic scores in the Avon Longitudinal Study of Parents and Children, and in publicly available data from the first Wellcome Trust Case Control Consortium. We compared the explanatory ability of allelic scores in terms of their capacity to proxy for the intermediate of interest, and the extent to which they associated with disease. We found that allelic scores derived from known variants and allelic scores derived from hundreds of thousands of genetic markers explained significant portions of the variance in biological intermediates of interest, and many of these scores showed expected correlations with disease. Genome-wide allelic scores however tended to lack specificity suggesting that they should be used with caution and perhaps only to proxy biological intermediates for which there are no known individual variants. Power calculations confirm the feasibility of extending our strategy to the analysis of tens of thousands of molecular phenotypes in large genome-wide meta-analyses. We conclude that our method represents a simple way in which potentially tens of thousands of molecular phenotypes could be screened for causal relationships with disease without having to expensively measure these variables in individual disease collections.

Transcriptome sequencing of Eucalyptus camaldulensis seedlings subjected to water stress reveals functional single nucleotide polymorphisms and genes under selection

PubMed Central

2012-01-01

Background Water stress limits plant survival and production in many parts of the world. Identification of genes and alleles responding to water stress conditions is important in breeding plants better adapted to drought. Currently there are no studies examining the transcriptome wide gene and allelic expression patterns under water stress conditions. We used RNA sequencing (RNA-seq) to identify the candidate genes and alleles and to explore the evolutionary signatures of selection. Results We studied the effect of water stress on gene expression in Eucalyptus camaldulensis seedlings derived from three natural populations. We used reference-guided transcriptome mapping to study gene expression. Several genes showed differential expression between control and stress conditions. Gene ontology (GO) enrichment tests revealed up-regulation of 140 stress-related gene categories and down-regulation of 35 metabolic and cell wall organisation gene categories. More than 190,000 single nucleotide polymorphisms (SNPs) were detected and 2737 of these showed differential allelic expression. Allelic expression of 52% of these variants was correlated with differential gene expression. Signatures of selection patterns were studied by estimating the proportion of nonsynonymous to synonymous substitution rates (Ka/Ks). The average Ka/Ks ratio among the 13,719 genes was 0.39 indicating that most of the genes are under purifying selection. Among the positively selected genes (Ka/Ks > 1.5) apoptosis and cell death categories were enriched. Of the 287 positively selected genes, ninety genes showed differential expression and 27 SNPs from 17 positively selected genes showed differential allelic expression between treatments. Conclusions Correlation of allelic expression of several SNPs with total gene expression indicates that these variants may be the cis-acting variants or in linkage disequilibrium with such variants. Enrichment of apoptosis and cell death gene categories among the positively selected genes reveals the past selection pressures experienced by the populations used in this study. PMID:22853646

Polymorphisms of the thiopurine S-methyltransferase gene among the Libyan population

PubMed Central

Zeglam, Hamza Ben; Benhamer, Abdrazak; Aboud, Adel; Rtemi, Haitem; Mattardi, Meftah; Saleh, Saleh Suleiman; Bashein, Abdullah; Enattah, Nabil

2015-01-01

Background Thiopurine S-methyltransferase (TPMT) is a cytosolic enzyme that catalyses the S-methylation of 6-mercaptopurine and azathioprine. Low activity phenotypes are correlated with polymorphism in the TPMT gene. Patients with low or undetectable TMPT activity could develop severe myelosuppression when they are treated with standard doses of thiopurine drugs. Since ethnic differences in the TPMT gene polymorphism have been demonstrated worldwide, assessing it in the Libyan population is worthwhile. Methods We investigated TPMT gene polymorphism in a total of 246 Libyan healthy adult blood donors from three different Libyan regions (Tripoli, Yefren, and Tawargha) and 50 children with acute lymphoblastic leukaemia (ALL). We used polymerase chain reaction restriction length polymorphism (PCR-RFLP) and allele-specific PCR-based assays to analyse the TPMT gene for the variants *2 c.238 G>C, *3A (c.460 G>A and c.719 A>G), *3B (c.460 G>A), and *3C (c.719 A>G). Results Our results show that the TPMT variants associated with low enzymatic activity were detected in 3.25% (8 in 246) of adult Libyan individuals and the frequency of total mutant alleles was 1.63%. Heterozygous genotypes were TPMT*3A in three subjects (0.61%) and TPMT*3C in five subjects (1.02%). No TPMT*2 and TPMT*3B allelic variants and no homozygous or compound heterozygous mutant alleles were detected. The normal allele (wild-type) was found in 98.4% of the adult individuals studied. No mutant alleles were detected among the 50 children who had ALL. Conclusions We report on the presence of the TPMT*3C and *3A mutant alleles in the Libyan population. Therefore, monitoring the patients to be treated with doses of thiopurine drugs for TPMT variants is worthwhile to avoid the development of severe myelosuppression. PMID:25819542

Genetic variants of cell cycle pathway genes predict disease-free survival of hepatocellular carcinoma.

PubMed

Liu, Shun; Yang, Tian-Bo; Nan, Yue-Li; Li, An-Hua; Pan, Dong-Xiang; Xu, Yang; Li, Shu; Li, Ting; Zeng, Xiao-Yun; Qiu, Xiao-Qiang

2017-07-01

Disruption of the cell cycle pathway has previously been related to development of human cancers. However, associations between genetic variants of cell cycle pathway genes and prognosis of hepatocellular carcinoma (HCC) remain largely unknown. In this study, we evaluated the associations between 24 potential functional single nucleotide polymorphisms (SNPs) of 16 main cell cycle pathway genes and disease-free survival (DFS) of 271 HCC patients who had undergone radical surgery resection. We identified two SNPs, i.e., SMAD3 rs11556090 A>G and RBL2 rs3929G>C, that were independently predictive of DFS in an additive genetic model with false-positive report probability (FPRP) <0.2. The SMAD3 rs11556090G allele was associated with a poorer DFS, compared with the A allele [hazard ratio (HR) = 1.46, 95% confidential interval (95% CI) = 1.13-1.89, P = 0.004]; while the RBL2 rs3929 C allele was associated with a superior DFS, compared with the G allele (HR = 0.74, 95% CI = 0.57-0.96, P = 0.023). Additionally, patients with an increasing number of unfavorable genotypes (NUGs) of these loci had a significant shorter DFS (P trend  = 0.0001). Further analysis using receiver operating characteristic (ROC) curves showed that the model including the NUGs and known prognostic clinical variables demonstrated a significant improvement in predicting the 1-year DFS (P = 0.011). Moreover, the RBL2 rs3929 C allele was significantly associated with increased mRNA expression levels of RBL2 in liver tissue (P = 1.8 × 10 -7 ) and the whole blood (P = 3.9 × 10 -14 ). Our data demonstrated an independent or a joint effect of SMAD3 rs11556090 and RBL2 rs3929 in the cell cycle pathway on DFS of HCC, which need to be validated by large cohort and biological studies. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

The role of functionally defective rare germline variants of sialic acid acetylesterase in autoimmune Addison's disease

PubMed Central

Gan, Earn H; MacArthur, Katie; Mitchell, Anna L; Pearce, Simon H S

2012-01-01

Background Autoimmune Addison's disease (AAD) is a rare condition with a complex genetic basis. A panel of rare and functionally defective genetic variants in the sialic acid acetylesterase (SIAE) gene has recently been implicated in several common autoimmune conditions. We performed a case–control study to determine whether these rare variants are associated with a rarer condition, AAD. Method We analysed nine SIAE gene variants (W48X, M89V, C196F, C226G, R230W, T312M, Y349C, F404S and R479C) in a United Kingdom cohort of 378 AAD subjects and 387 healthy controls. All samples were genotyped using Sequenom iPlex chemistry to characterise primer extension products. Results A heterozygous rare allele at codon 312 (312*M) was found in one AAD patient (0.13%) but was not detected in the healthy controls. The commoner, functionally recessive variant at codon 89 (89*V) was found to be homozygous in two AAD patients but was only found in the heterozygous state in controls. Taking into account all nine alleles examined, 4/378 (1.06%) AAD patients and 1/387 (0.25%) healthy controls carried the defective SIAE alleles, with a calculated odds ratio of 4.13 (95% CI 0.44–97.45, two-tailed P value 0.212, NS). Conclusion We demonstrated the presence of 89*V homozygotes and the 312*M rare allele in the AAD cohort, but overall, our analysis does not support a role for rare variants in SIAE in the pathogenesis of AAD. However, the relatively small collection of AAD patients limits the power to exclude a small effect. PMID:23011869

Variation resources at UC Santa Cruz.

PubMed

Thomas, Daryl J; Trumbower, Heather; Kern, Andrew D; Rhead, Brooke L; Kuhn, Robert M; Haussler, David; Kent, W James

2007-01-01

The variation resources within the University of California Santa Cruz Genome Browser include polymorphism data drawn from public collections and analyses of these data, along with their display in the context of other genomic annotations. Primary data from dbSNP is included for many organisms, with added information including genomic alleles and orthologous alleles for closely related organisms. Display filtering and coloring is available by variant type, functional class or other annotations. Annotation of potential errors is highlighted and a genomic alignment of the variant's flanking sequence is displayed. HapMap allele frequencies and linkage disequilibrium (LD) are available for each HapMap population, along with non-human primate alleles. The browsing and analysis tools, downloadable data files and links to documentation and other information can be found at http://genome.ucsc.edu/.

[Allelic variants of apolipoproteins B and CII genes in patients with ischemic heart disease and in healthy persons from the Moscow population].

PubMed

Pogoda, T V; Nikonova, A L; Kolosova, T V; Liudvikova, E K; Perova, N V; Limborskaia, S A

1995-07-01

Allelic frequencies of a microsatellite of the apolipoprotein CII gene (APOCII) and a minisatellite of the apolipoprotein B gene (APOB) were studied using polymerase chain reaction (PCR). The study was conducted on a random sample of male Moscow inhabitants and a sample of patients with coronary heart disease (CHD) from the same population. Fourteen variants of the APOB minisatellite (the 82% heterozygosity level) and 13 alleles of the APOCII microsatellite (the 85% heterozygosity level) were found. CHD patients significantly differed from the control group in the distributions of alleles in these loci: APOB 32, APOB 46, APOB 48, and APOB 50 as well as APOCII 17 and APOCII 29 were found more frequently. A relationship was found between the distributions of APOB and APOCII in the CHD patients. The CHD patients with alleles APOCII 21 and APOCII 30 very often had the allele APOB 32; and patients with the genotype APOB 34, 36 had the allele APOCII 29 even more often than affected individuals in general. Individuals of the control group with the allele APOCII 30 exhibited hypertriglyceridemia without increased levels of total cholesterol and apolipoprotein B in plasma.

A Clinical and Molecular Survey of 62 Cystic Fibrosis Patients from Umbria (Central Italy) Disclosing a High Frequency (2.4%) of the 2184insA Allele: Implications for Screening.

PubMed

Prontera, Paolo; Isidori, Ilenia; Mencarini, Valeria; Pennoni, Guido; Mencarelli, Amedea; Stangoni, Gabriela; Di Cara, Giuseppe; Verrotti, Alberto

2016-01-01

Genetic testing strategies and counseling in cystic fibrosis (CF) can be problematic due to its extreme allelic heterogeneity and the difficult clinical interpretation of rare variants. Since in a previous survey of Italian CF patients, Umbria (a small region with about 900,000 inhabitants) was excluded due to the low number of chromosomes tested (<50), we have performed a comprehensive retrospective clinical and molecular survey of 62 CF patients coming from this region. We have summarized all the genotypic and phenotypic data in a table, and we interviewed the older patients in order to obtain a comprehensive overview of their conditions. We found that the c.2052_2053insA (2184insA) variant, a class I mutation with high frequency in Eastern Europe but very rare in Italy, is the fourth most frequent allele in Umbria. The 2184insA variant was not included in the first-level regional screening, and we therefore suggest the implementation of this variant in the future. © 2016 S. Karger AG, Basel.

A SNP in the HTT promoter alters NF-κB binding and is a bidirectional genetic modifier of Huntington disease.

PubMed

Bečanović, Kristina; Nørremølle, Anne; Neal, Scott J; Kay, Chris; Collins, Jennifer A; Arenillas, David; Lilja, Tobias; Gaudenzi, Giulia; Manoharan, Shiana; Doty, Crystal N; Beck, Jessalyn; Lahiri, Nayana; Portales-Casamar, Elodie; Warby, Simon C; Connolly, Colúm; De Souza, Rebecca A G; Tabrizi, Sarah J; Hermanson, Ola; Langbehn, Douglas R; Hayden, Michael R; Wasserman, Wyeth W; Leavitt, Blair R

2015-06-01

Cis-regulatory variants that alter gene expression can modify disease expressivity, but none have previously been identified in Huntington disease (HD). Here we provide in vivo evidence in HD patients that cis-regulatory variants in the HTT promoter are bidirectional modifiers of HD age of onset. HTT promoter analysis identified a NF-κB binding site that regulates HTT promoter transcriptional activity. A non-coding SNP, rs13102260:G > A, in this binding site impaired NF-κB binding and reduced HTT transcriptional activity and HTT protein expression. The presence of the rs13102260 minor (A) variant on the HD disease allele was associated with delayed age of onset in familial cases, whereas the presence of the rs13102260 (A) variant on the wild-type HTT allele was associated with earlier age of onset in HD patients in an extreme case-based cohort. Our findings suggest a previously unknown mechanism linking allele-specific effects of rs13102260 on HTT expression to HD age of onset and have implications for HTT silencing treatments that are currently in development.

The QTN program and the alleles that matter for evolution: all that's gold does not glitter.

PubMed

Rockman, Matthew V

2012-01-01

The search for the alleles that matter, the quantitative trait nucleotides (QTNs) that underlie heritable variation within populations and divergence among them, is a popular pursuit. But what is the question to which QTNs are the answer? Although their pursuit is often invoked as a means of addressing the molecular basis of phenotypic evolution or of estimating the roles of evolutionary forces, the QTNs that are accessible to experimentalists, QTNs of relatively large effect, may be uninformative about these issues if large-effect variants are unrepresentative of the alleles that matter. Although 20th century evolutionary biology generally viewed large-effect variants as atypical, the field has recently undergone a quiet realignment toward a view of readily discoverable large-effect alleles as the primary molecular substrates for evolution. I argue that neither theory nor data justify this realignment. Models and experimental findings covering broad swaths of evolutionary phenomena suggest that evolution often acts via large numbers of small-effect polygenes, individually undetectable. Moreover, these small-effect variants are different in kind, at the molecular level, from the large-effect alleles accessible to experimentalists. Although discoverable QTNs address some fundamental evolutionary questions, they are essentially misleading about many others. © 2011 The Author(s). Evolution © 2011 The Society for the Study of Evolution.

Genotype-phenotype correlations of low frequency variants in the complement system in renal disease and age-related macular degeneration.

PubMed

Geerlings, M J; Volokhina, E B; de Jong, E K; van de Kar, N; Pauper, M; Hoyng, C B; van den Heuvel, L P; den Hollander, A I

2018-06-11

Genetic alterations in the complement system have been linked to a variety of diseases, including atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G), and age-related macular degeneration (AMD). We performed sequence analysis of the complement genes CFH, CFI, and C3 in 866 aHUS/C3G and 697 AMD patients. In total we identified 505 low frequency alleles, representing 121 unique variants, of which 51 are novel. CFH contained the largest number of unique low frequency variants (n=64; 53%), followed by C3 (n=32; 26%) and CFI (n=25; 21%). A substantial number of variants were found in both patients groups (n=48; 40%), while 41 (34%) variants were found only in aHUS/C3G and 32 (26%) variants were AMD-specific. Genotype-phenotype correlations between the disease groups identified a higher frequency of protein-altering alleles in SCR20 of Factor H (FH), and in the serine protease domain of Factor I (FI) in aHUS/C3G patients. In AMD a higher frequency of protein-altering alleles was observed in SCR3, SCR5 and SCR7 of FH, the SRCR domain of FI, and in the MG3 domain of C3. In conclusion, we observed a substantial overlap of variants between aHUS/C3G and AMD, however, there is a distinct clustering of variants within specific domains. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Demonstration of protein-based human identification using the hair shaft proteome [Protein-based human identification: A proof of concept using the hair shaft proteome

DOE PAGES

Parker, Glendon J.; Leppert, Tami; Anex, Deon S.; ...

2016-09-07

Human identification from biological material is largely dependent on the ability to characterize genetic polymorphisms in DNA. Unfortunately, DNA can degrade in the environment, sometimes below the level at which it can be amplified by PCR. Protein however is chemically more robust than DNA and can persist for longer periods. Protein also contains genetic variation in the form of single amino acid polymorphisms. These can be used to infer the status of non-synonymous single nucleotide polymorphism alleles. To demonstrate this, we used mass spectrometry-based shotgun proteomics to characterize hair shaft proteins in 66 European-American subjects. A total of 596 singlemore » nucleotide polymorphism alleles were correctly imputed in 32 loci from 22 genes of subjects’ DNA and directly validated using Sanger sequencing. Estimates of the probability of resulting individual non-synonymous single nucleotide polymorphism allelic profiles in the European population, using the product rule, resulted in a maximum power of discrimination of 1 in 12,500. Imputed non-synonymous single nucleotide polymorphism profiles from European–American subjects were considerably less frequent in the African population (maximum likelihood ratio = 11,000). The converse was true for hair shafts collected from an additional 10 subjects with African ancestry, where some profiles were more frequent in the African population. Genetically variant peptides were also identified in hair shaft datasets from six archaeological skeletal remains (up to 260 years old). Furthermore, this study demonstrates that quantifiable measures of identity discrimination and biogeographic background can be obtained from detecting genetically variant peptides in hair shaft protein, including hair from bioarchaeological contexts.« less

Demonstration of protein-based human identification using the hair shaft proteome [Protein-based human identification: A proof of concept using the hair shaft proteome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Parker, Glendon J.; Leppert, Tami; Anex, Deon S.

Human identification from biological material is largely dependent on the ability to characterize genetic polymorphisms in DNA. Unfortunately, DNA can degrade in the environment, sometimes below the level at which it can be amplified by PCR. Protein however is chemically more robust than DNA and can persist for longer periods. Protein also contains genetic variation in the form of single amino acid polymorphisms. These can be used to infer the status of non-synonymous single nucleotide polymorphism alleles. To demonstrate this, we used mass spectrometry-based shotgun proteomics to characterize hair shaft proteins in 66 European-American subjects. A total of 596 singlemore » nucleotide polymorphism alleles were correctly imputed in 32 loci from 22 genes of subjects’ DNA and directly validated using Sanger sequencing. Estimates of the probability of resulting individual non-synonymous single nucleotide polymorphism allelic profiles in the European population, using the product rule, resulted in a maximum power of discrimination of 1 in 12,500. Imputed non-synonymous single nucleotide polymorphism profiles from European–American subjects were considerably less frequent in the African population (maximum likelihood ratio = 11,000). The converse was true for hair shafts collected from an additional 10 subjects with African ancestry, where some profiles were more frequent in the African population. Genetically variant peptides were also identified in hair shaft datasets from six archaeological skeletal remains (up to 260 years old). Furthermore, this study demonstrates that quantifiable measures of identity discrimination and biogeographic background can be obtained from detecting genetically variant peptides in hair shaft protein, including hair from bioarchaeological contexts.« less

RS 10767664 gene variant in Brain Derived Neurotrophic Factor (BDNF) affect metabolic changes and insulin resistance after a standard hypocaloric diet.

PubMed

de Luis, Daniel Antonio; Fernández Ovalle, H; Izaola, O; Primo, D; Aller, Rocío

2018-02-01

Role of BDNF variants on change in body weight and cardiovascular risk factors after weight loss remains unclear in obese patients. Our aim was to analyze the effects of rs10767664 BDNF gene polymorphism on body weight, cardiovascular risk factors and serum adipokine levels after a standard hypocaloric diet in obese subjects. A Caucasian population of 80 obese patients was analyzed before and after 3months on a standard hypocaloric diet. Fifty patients (62.5%) had the genotype AA and 30 (37.5%) subjects had the next genotypes; AT (25 patients, 31.3%) or TT (5 study subjects, 6.3%) (second group). In non T allele carriers, the decreases in weight-3.4±2.9kg (T allele group -1.7±2.0kg:p=0.01), BMI -1.5±0.2kg (T allele group -1.2±0.5kg:p=0.02), fat mass-2.3±1.1kg (T allele group -1.7±0.9kg:p=0.009), waist circumference-3.8±2.4cm (T allele group -2.1±3.1cm:p=0.008), triglycerides -13.2±7.5mg/dl (T allele group +2.8±1.2mg/dl:p=0.02), insulin -2.1±1.9mUI/L (T allele group -0.3±1.0mUI/L:p=0.01), HOMA-IR -0.9±0.4 (T allele group -0.1±0.8:p=0.01) and leptin -10.1±9.5ng/dl (T allele group -3.1±0.2ng/dl:p=0.01) were higher than T allele carriers. rs10767664 variant of BDNF gene modify anthropometric and biochemical changes after weight loss with a hypocaloric diet. Copyright © 2017 Elsevier Inc. All rights reserved.

A novel FY*A allele with the 265T and 298A SNPs formerly associated exclusively with the FY*B allele and weak Fy(b) antigen expression: implication for genotyping interpretative algorithms.

PubMed

Lopez, G H; Condon, J A; Wilson, B; Martin, J R; Liew, Y-W; Flower, R L; Hyland, C A

2015-01-01

An Australian Caucasian blood donor consistently presented a serology profile for the Duffy blood group as Fy(a+b+) with Fy(a) antigen expression weaker than other examples of Fy(a+b+) red cells. Molecular typing studies were performed to investigate the reason for the observed serology profile. Blood group genotyping was performed using a commercial SNP microarray platform. Sanger sequencing was performed using primer sets to amplify across exons 1 and 2 of the FY gene and using allele-specific primers. The propositus was genotyped as FY*A/B, FY*X heterozygote that predicted the Fy(a+b+(w) ) phenotype. Sequencing identified the 265T and 298A variants on the FY*A allele. This link between FY*A allele and 265T was confirmed by allele-specific PCR. The reduced Fy(a) antigen reactivity is attributed to a FY*A allele-carrying 265T and 298A variants previously defined in combination only with the FY*B allele and associated with weak Fy(b) antigen expression. This novel allele should be considered in genotyping interpretative algorithms for generating a predicted phenotype. © 2014 International Society of Blood Transfusion.

The Contribution of GWAS Loci in Familial Dyslipidemias

PubMed Central

Söderlund, Sanni; Surakka, Ida; Matikainen, Niina; Pirinen, Matti; Pajukanta, Päivi; Service, Susan K.; Laurila, Pirkka-Pekka; Ehnholm, Christian; Salomaa, Veikko; Wilson, Richard K.; Palotie, Aarno; Freimer, Nelson B.; Taskinen, Marja-Riitta; Ripatti, Samuli

2016-01-01

Familial combined hyperlipidemia (FCH) is a complex and common familial dyslipidemia characterized by elevated total cholesterol and/or triglyceride levels with over five-fold risk of coronary heart disease. The genetic architecture and contribution of rare Mendelian and common variants to FCH susceptibility is unknown. In 53 Finnish FCH families, we genotyped and imputed nine million variants in 715 family members with DNA available. We studied the enrichment of variants previously implicated with monogenic dyslipidemias and/or lipid levels in the general population by comparing allele frequencies between the FCH families and population samples. We also constructed weighted polygenic scores using 212 lipid-associated SNPs and estimated the relative contributions of Mendelian variants and polygenic scores to the risk of FCH in the families. We identified, across the whole allele frequency spectrum, an enrichment of variants known to elevate, and a deficiency of variants known to lower LDL-C and/or TG levels among both probands and affected FCH individuals. The score based on TG associated SNPs was particularly high among affected individuals compared to non-affected family members. Out of 234 affected FCH individuals across the families, seven (3%) carried Mendelian variants and 83 (35%) showed high accumulation of either known LDL-C or TG elevating variants by having either polygenic score over the 90th percentile in the population. The positive predictive value of high score was much higher for affected FCH individuals than for similar sporadic cases in the population. FCH is highly polygenic, supporting the hypothesis that variants across the whole allele frequency spectrum contribute to this complex familial trait. Polygenic SNP panels improve identification of individuals affected with FCH, but their clinical utility remains to be defined. PMID:27227539

High prevalence of the c.74A>C SPINK1 variant in miniature and standard Schnauzers.

PubMed

Furrow, E; Armstrong, P J; Patterson, E E

2012-01-01

Variants in the serine protease inhibitor Kazal type 1 (SPINK1) gene have been associated with pancreatitis in Miniature Schnauzers. Replication of the association in an independent population is necessary to determine if genetic screening for SPINK1 variants should be considered in clinical practice. An association between the SPINK1 exonic variant c.74A > C and pancreatitis exists in Miniature Schnauzers. In addition, the variant is absent or rare in Standard Schnauzers, a related breed that is not reported to have an increased risk for pancreatitis. Case-control study. Seventeen Miniature Schnauzers with pancreatitis (cases), 60 mature Miniature Schnauzers with no substantial history of gastrointestinal signs in their lifetime (controls), and 31 Standard Schnauzers of unknown pancreatitis status. A PCR-RFLP assay was used to genotype dogs for the c.74A > C SPINK1 variant. Allele and genotype frequencies were reported for Schnauzers and compared between case and control Miniature Schnauzers. The c.74A > C variant was the major allele in both Schnauzer breeds with a frequency of 0.77 in Miniatures and 0.55 in Standards. The allele and genotype frequencies were similar between Miniature Schnauzers with and without a history of pancreatitis and did not impart an increased risk for pancreatitis. Genotyping a larger population of the Miniature Schnauzer breed than a previous study, along with a Standard Schnauzer cohort, demonstrated that the SPINK1 c.74A > C variant is a common polymorphism in the Schnauzer lineage. Furthermore, we were unable to confirm a relationship between the variant and clinically detectable pancreatitis in Miniature Schnauzers. Copyright © 2012 by the American College of Veterinary Internal Medicine.

A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma

PubMed Central

Yokoyama, Satoru; Woods, Susan L.; Boyle, Glen M.; Aoude, Lauren G.; MacGregor, Stuart; Zismann, Victoria; Gartside, Michael; Cust, Anne E.; Haq, Rizwan; Harland, Mark; Taylor, John C.; Duffy, David L.; Holohan, Kelly; Dutton-Regester, Ken; Palmer, Jane M.; Bonazzi, Vanessa; Stark, Mitchell S.; Symmons, Judith; Law, Matthew H.; Schmidt, Christopher; Lanagan, Cathy; O’Connor, Linda; Holland, Elizabeth A.; Schmid, Helen; Maskiell, Judith A.; Jetann, Jodie; Ferguson, Megan; Jenkins, Mark A.; Kefford, Richard F.; Giles, Graham G.; Armstrong, Bruce K.; Aitken, Joanne F.; Hopper, John L.; Whiteman, David C.; Pharoah, Paul D.; Easton, Douglas F.; Dunning, Alison M.; Newton-Bishop, Julia A.; Montgomery, Grant W.; Martin, Nicholas G.; Mann, Graham J.; Bishop, D. Timothy; Tsao, Hensin; Trent, Jeffrey M.; Fisher, David E.; Hayward, Nicholas K.; Brown, Kevin M.

2012-01-01

So far, two familial melanoma genes have been identified, accounting for a minority of genetic risk in families. Mutations in CDKN2A account for approximately 40% of familial cases1, and predisposing mutations in CDK4 have been reported in a very small number of melanoma kindreds2. To identify other familial melanoma genes, here we conducted whole-genome sequencing of probands from several melanoma families, identifying one individual carrying a novel germline variant (coding DNA sequence c.G1075A; protein sequence p.E318K; rs149617956) in the melanoma-lineage-specific oncogene microphthalmia-associated transcription factor (MITF). Although the variant co-segregated with melanoma in some but not all cases in the family, linkage analysis of 31 families subsequently identified to carry the variant generated a log odds ratio (lod) score of 2.7 under a dominant model, indicating E318K as a possible intermediate risk variant. Consistent with this, the E318K variant was significantly associated with melanoma in a large Australian case–control sample. Likewise, it was similarly associated in an independent case–control sample from the United Kingdom. In the Australian sample, the variant allele was significantly over-represented in cases with a family history of melanoma, multiple primary melanomas, or both. The variant allele was also associated with increased naevus count and non-blue eye colour. Functional analysis of E318K showed that MITF encoded by the variant allele had impaired sumoylation and differentially regulated several MITF targets. These data indicate that MITF is a melanoma-predisposition gene and highlight the utility of whole-genome sequencing to identify novel rare variants associated with disease susceptibility. PMID:22080950

An Evaluation of Different Target Enrichment Methods in Pooled Sequencing Designs for Complex Disease Association Studies

PubMed Central

Day-Williams, Aaron G.; McLay, Kirsten; Drury, Eleanor; Edkins, Sarah; Coffey, Alison J.; Palotie, Aarno; Zeggini, Eleftheria

2011-01-01

Pooled sequencing can be a cost-effective approach to disease variant discovery, but its applicability in association studies remains unclear. We compare sequence enrichment methods coupled to next-generation sequencing in non-indexed pools of 1, 2, 10, 20 and 50 individuals and assess their ability to discover variants and to estimate their allele frequencies. We find that pooled resequencing is most usefully applied as a variant discovery tool due to limitations in estimating allele frequency with high enough accuracy for association studies, and that in-solution hybrid-capture performs best among the enrichment methods examined regardless of pool size. PMID:22069447

Heme Oxygenase 1 and 2 Common Genetic Variants and Risk for Essential Tremor

PubMed Central

Ayuso, Pedro; Agúndez, José A.G.; Alonso-Navarro, Hortensia; Martínez, Carmen; Benito-León, Julián; Ortega-Cubero, Sara; Lorenzo-Betancor, Oswaldo; Pastor, Pau; López-Alburquerque, Tomás; García-Martín, Elena; Jiménez-Jiménez, Félix J.

2015-01-01

Abstract Several reports suggested a role of heme oxygenase genes 1 and 2 (HMOX1 and HMOX2) in modifying the risk to develop Parkinson disease (PD). Because essential tremor (ET) and PD share phenotypical and, probably, etiologic factors of the similarities, we analyzed whether such genes are related with the risk to develop ET. We analyzed the distribution of allelic and genotype frequencies of the HMOX1 rs2071746, HMOX1 rs2071747, HMOX2 rs2270363, and HMOX2 rs1051308 single nucleotide polymorphisms, as well as the presence of copy number variations of these genes in 202 subjects with familial ET and 747 healthy controls. Allelic frequencies of rs2071746T and rs1051308G were significantly lower in ET patients than in controls. None of the studied polymorphisms influenced the disease onset. The present study suggests a weak association between HMOX1 rs2071746 and HMOX2 rs1051308 polymorphisms and the risk to develop ET in the Spanish population. PMID:26091465

Heme Oxygenase 1 and 2 Common Genetic Variants and Risk for Essential Tremor.

PubMed

Ayuso, Pedro; Agúndez, José A G; Alonso-Navarro, Hortensia; Martínez, Carmen; Benito-León, Julián; Ortega-Cubero, Sara; Lorenzo-Betancor, Oswaldo; Pastor, Pau; López-Alburquerque, Tomás; García-Martín, Elena; Jiménez-Jiménez, Félix J

2015-06-01

Several reports suggested a role of heme oxygenase genes 1 and 2 (HMOX1 and HMOX2) in modifying the risk to develop Parkinson disease (PD). Because essential tremor (ET) and PD share phenotypical and, probably, etiologic factors of the similarities, we analyzed whether such genes are related with the risk to develop ET. We analyzed the distribution of allelic and genotype frequencies of the HMOX1 rs2071746, HMOX1 rs2071747, HMOX2 rs2270363, and HMOX2 rs1051308 single nucleotide polymorphisms, as well as the presence of copy number variations of these genes in 202 subjects with familial ET and 747 healthy controls. Allelic frequencies of rs2071746T and rs1051308G were significantly lower in ET patients than in controls. None of the studied polymorphisms influenced the disease onset. The present study suggests a weak association between HMOX1 rs2071746 and HMOX2 rs1051308 polymorphisms and the risk to develop ET in the Spanish population.

APOL1–Mediated Cell Injury Involves Disruption of Conserved Trafficking Processes

PubMed Central

Kruzel-Davila, Etty; Shemer, Revital; Ofir, Ayala; Bavli-Kertselli, Ira; Darlyuk-Saadon, Ilona; Oren-Giladi, Pazit; Wasser, Walter G.; Magen, Daniella; Zaknoun, Eid; Schuldiner, Maya; Salzberg, Adi; Kornitzer, Daniel; Marelja, Zvonimir; Simons, Matias

2017-01-01

APOL1 harbors C–terminal sequence variants (G1 and G2), which account for much of the increased risk for kidney disease in sub–Saharan African ancestry populations. Expression of the risk variants has also been shown to cause injury to podocytes and other cell types, but the underlying mechanisms are not understood. We used Drosophila melanogaster and Saccharomyces cerevisiae to help clarify these mechanisms. Ubiquitous expression of the human APOL1 G1 and G2 disease risk alleles caused near-complete lethality in D. melanogaster, with no effect of the G0 nonrisk APOL1 allele, corresponding to the pattern of human disease risk. We also observed a congruent pattern of cellular damage with tissue-specific expression of APOL1. In particular, expression of APOL1 risk variants in D. melanogaster nephrocytes caused cell-autonomous accumulation of the endocytic tracer atrial natriuretic factor-red fluorescent protein at early stages and nephrocyte loss at later stages. We also observed differential toxicity of the APOL1 risk variants compared with the APOL1 nonrisk variants in S. cerevisiae, including impairment of vacuole acidification. Yeast strains defective in endosomal trafficking or organelle acidification but not those defective in autophagy displayed augmented APOL1 toxicity with all isoforms. This pattern of differential injury by the APOL1 risk alleles compared with the nonrisk alleles across evolutionarily divergent species is consistent with an impairment of conserved core intracellular endosomal trafficking processes. This finding should facilitate the identification of cell injury pathways and corresponding therapeutic targets of interest in these amenable experimental platforms. PMID:27864431

Relationship between polymorphisms of nucleotide excision repair genes and oral cancer risk in Taiwan: evidence for modification of smoking habit.

PubMed

Bau, Da-Tian; Tsai, Ming-Hsui; Huang, Chih-Yang; Lee, Cheng-Chun; Tseng, Hsien-Chang; Lo, Yen-Li; Tsai, Yuhsin; Tsai, Fuu-Jen

2007-12-31

Inherited polymorphisms in DNA repair genes may be associated with differences in the repair capacity and contribute to individual's susceptibility to smoking-related cancers. Both XPA and XPD encode proteins that are part of the nucleotide excision repair (NER) pathway. In a hospital-based case-control study, we have investigated the influence of XPA A-23G and XPD Lys751Gln polymorphisms on oral cancer risk in a Taiwanese population. In total, 154 patients with oral cancer, and 105 age-matched controls recruited from the Chinese Medical Hospital in Central Taiwan were genotyped. No significant association was found between the heterozygous variant allele (AG), the homozygous variant allele (AA) at XPA A-23G, the heterozygous variant allele (AC), the homozygous variant allele (CC) at XPD Lys751Gln, and oral cancer risk. There was no significant joint effect of XPA A-23G and XPD Lys751Gln on oral cancer risk either. Since XPA and XPD are both NER genes, which are very important in removing tobacco-induced DNA adducts, further stratified analyses of both genotype and smoking habit were performed. We found a synergistic effect of variant genotypes of both XPA and XPD, and smoking status on oral cancer risk. Our results suggest that the genetic polymorphisms are modified by environmental carcinogen exposure status, and combined analyses of both genotype and personal habit record are a better access to know the development of oral cancer and useful for primary prevention and early intervention.

Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene

PubMed Central

Sosnay, Patrick R; Siklosi, Karen R; Van Goor, Fredrick; Kaniecki, Kyle; Yu, Haihui; Sharma, Neeraj; Ramalho, Anabela S; Amaral, Margarida D; Dorfman, Ruslan; Zielenski, Julian; Masica, David L; Karchin, Rachel; Millen, Linda; Thomas, Philip J; Patrinos, George P; Corey, Mary; Lewis, Michelle H; Rommens, Johanna M; Castellani, Carlo; Penland, Christopher M; Cutting, Garry R

2013-01-01

Allelic heterogeneity in disease-causing genes presents a substantial challenge to the translation of genomic variation to clinical practice. Few of the almost 2,000 variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene have empirical evidence that they cause cystic fibrosis. To address this gap, we collected both genotype and phenotype data for 39,696 cystic fibrosis patients in registries and clinics in North America and Europe. Among these patients, 159 CFTR variants had an allele frequency of ≥0.01%. These variants were evaluated for both clinical severity and functional consequence with 127 (80%) meeting both clinical and functional criteria consistent with disease. Assessment of disease penetrance in 2,188 fathers of cystic fibrosis patients enabled assignment of 12 of the remaining 32 variants as neutral while the other 20 variants remained indeterminate. This study illustrates that sourcing data directly from well-phenotyped subjects can address the gap in our ability to interpret clinically-relevant genomic variation. PMID:23974870

Variants in glucose- and circadian rhythm–related genes affect the response of energy expenditure to weight-loss diets: the POUNDS LOST Trial123

PubMed Central

Mirzaei, Khadijeh; Xu, Min; Qi, Qibin; de Jonge, Lilian; Bray, George A; Sacks, Frank; Qi, Lu

2014-01-01

Background: Circadian rhythm has been shown to be related to glucose metabolism and risk of diabetes, probably through effects on energy balance. Recent genome-wide association studies identified variants in circadian rhythm–related genes (CRY2 and MTNR1B) associated with glucose homeostasis. Objective: We tested whether CRY2 and MTNR1B genotypes affected changes in measures of energy expenditure in response to a weight-loss diet intervention in a 2-y randomized clinical trial, the POUNDS (Preventing Overweight Using Novel Dietary Strategies) LOST Trial. Design: The variants CRY2 rs11605924 (n = 721) and MTNR1B rs10830963 (n = 722) were genotyped in overweight or obese adults who were randomly assigned to 1 of 4 weight-loss diets that differed in their proportions of macronutrients. Respiratory quotient (RQ) and resting metabolic rate (RMR) were measured. Results: By 2 y of diet intervention, the A allele of CRY2 rs11605924 was significantly associated with a greater reduction in RQ (P = 0.03) and a greater increase in RMR and RMR/kg (both P = 0.04). The G allele of MTNR1B rs10830963 was significantly associated with a greater increase in RQ (P = 0.01) but was not related to changes in RMR and RMR/kg. In addition, we found significant gene-diet fat interactions for both CRY2 (P-interaction = 0.02) and MTNR1B (P-interaction < 0.001) in relation to 2-y changes in RQ. Conclusions: Our data indicate that variants in the circadian-related genes CRY2 and MTNR1B may affect long-term changes in energy expenditure, and dietary fat intake may modify the genetic effects. This trial was registered at www.clinicaltrials.gov as NCT00072995. PMID:24335056

Burden of Common Complex Disease Variants in the Exomes of Two Healthy Centenarian Brothers.

PubMed

Tindale, Lauren C; Zeng, Andy; Bretherick, Karla L; Leach, Stephen; Thiessen, Nina; Brooks-Wilson, Angela R

2015-01-01

It is not understood whether long-term good health is promoted by the absence of disease risk variants, the presence of protective variants, or both. We characterized the exomes of two exceptionally healthy centenarian brothers aged 106 and 109 years who had never been diagnosed with cancer, cardiovascular disease, diabetes, Alzheimer's disease, or major pulmonary disease. The aim of this study was to gain insight into whether exceptional health and longevity are a result of carrying fewer disease-associated variants than typical individuals. We compared the number of disease-associated alleles, and the proportion of alleles predicted to be functionally damaging, between the centenarian brothers and published population data. Mitochondrial sequence reads were extracted from the exome data in order to analyze mitochondrial variants. The brothers carry a similar number of common disease-associated variants and predicted damaging variants compared to reference groups. They did not carry any high-penetrance clinically actionable variants. They carry mitochondrial haplogroup T, and one brother has a single heteroplasmic variant. Although our small sample size does not allow for definitive conclusions, a healthy aging and longevity phenotype is not necessarily due to a decreased burden of common disease-associated variants. Instead, it may be rare 'positive' variants that play a role in this desirable phenotype. © 2015 S. Karger AG, Basel.

A genetic variant in the LDLR promoter is responsible for part of the LDL-cholesterol variability in primary hypercholesterolemia

PubMed Central

2014-01-01

Background GWAS have consistently revealed that LDLR locus variability influences LDL-cholesterol in general population. Severe LDLR mutations are responsible for familial hypercholesterolemia (FH). However, most primary hypercholesterolemias are polygenic diseases. Although Cis-regulatory regions might be the cause of LDL-cholesterol variability; an extensive analysis of the LDLR distal promoter has not yet been performed. We hypothesized that genetic variants in this region are responsible for the LDLR association with LDL-cholesterol found in GWAS. Methods Four-hundred seventy-seven unrelated subjects with polygenic hypercholesterolemia (PH) and without causative FH-mutations and 525 normolipemic subjects were selected. A 3103 pb from LDLR (-625 to +2468) was sequenced in 125 subjects with PH. All subjects were genotyped for 4 SNPs (rs17242346, rs17242739, rs17248720 and rs17249120) predicted to be potentially involved in transcription regulation by in silico analysis. EMSA and luciferase assays were carried out for the rs17248720 variant. Multivariable linear regression analysis using LDL-cholesterol levels as the dependent variable were done in order to find out the variables that were independently associated with LDL-cholesterol. Results The sequencing of the 125 PH subjects did not show variants with minor allele frequency ≥ 10%. The T-allele from g.3131C > T (rs17248720) had frequencies of 9% (PH) and 16.4% (normolipemic), p < 0.00001. Studies of this variant with EMSA and luciferase assays showed a higher affinity for transcription factors and an increase of 2.5 times in LDLR transcriptional activity (T-allele vs C-allele). At multivariate analysis, this polymorphism with the lipoprotein(a) and age explained ≈ 10% of LDL-cholesterol variability. Conclusion Our results suggest that the T-allele at the g.3131 T > C SNP is associated with LDL-cholesterol levels, and explains part of the LDL-cholesterol variability. As a plausible cause, the T-allele produces an increase in LDLR transcriptional activity and lower LDL-cholesterol levels. PMID:24708769

Rapid and cost-effective method for the detection of the c.533G>A mutation in the HEXA gene.

PubMed

Ribeiro, Diogo; Duarte, Ana Joana; Amaral, Olga

2011-03-01

Tay-Sachs disease is a rare autosomal recessive neurodegenerative disorder that results from mutations in the HEXA gene, leading to β-hexosaminidase A (HexA) α subunit deficiency. An unusual variant of Tay-Sachs disease is known as the B1 variant. Previous studies indicated that, in northern Portugal, this is not only the most common variant but also one of the most prevalent lysosomal storage diseases. Additionally, this variant might also show a higher prevalence in populations of Portuguese and Spanish ancestry. A single mutation is invariably present in at least one of the alleles of B1 variant patients, HEXA mutation c.533G >A. To implement a method for c.533G >A testing in individuals and populations, we have optimized two distinct mutation analysis techniques, one based on restriction fragment length polymorphism analysis and the other based on allelic discrimination. We present the comparison of both methods and their advantages. Mutation screening by allelic discrimination proved to be particularly useful for the studying of large samples of individuals. It is time saving and highly reproducible, and under the conditions used, its cost is lower than the cost of polymerase chain reaction-based restriction fragment length polymorphism analysis.

A Variable Polyglutamine Repeat Affects Subcellular Localization and Regulatory Activity of a Populus ANGUSTIFOLIA Protein.

PubMed

Bryan, Anthony C; Zhang, Jin; Guo, Jianjun; Ranjan, Priya; Singan, Vasanth; Barry, Kerrie; Schmutz, Jeremy; Weighill, Deborah; Jacobson, Daniel; Jawdy, Sara; Tuskan, Gerald A; Chen, Jin-Gui; Muchero, Wellington

2018-06-08

Polyglutamine (polyQ) stretches have been reported to occur in proteins across many organisms including animals, fungi and plants. Expansion of these repeats has attracted much attention due their associations with numerous human diseases including Huntington's and other neurological maladies. This suggests that the relative length of polyQ stretches is an important modulator of their function. Here, we report the identification of a Populus C-terminus binding protein (CtBP) ANGUSTIFOLIA ( PtAN1 ) which contains a polyQ stretch whose functional relevance had not been established. Analysis of 917 resequenced Populus trichocarpa genotypes revealed three allelic variants at this locus encoding 11-, 13- and 15-glutamine residues. Transient expression assays using Populus leaf mesophyll protoplasts revealed that the 11Q variant exhibited strong nuclear localization whereas the 15Q variant was only found in the cytosol, with the 13Q variant exhibiting localization in both subcellular compartments. We assessed functional implications by evaluating expression changes of putative PtAN1 targets in response to overexpression of the three allelic variants and observed allele-specific differences in expression levels of putative targets. Our results provide evidence that variation in polyQ length modulates PtAN1 function by altering subcellular localization. Copyright © 2018, G3: Genes, Genomes, Genetics.

Sherpas share genetic variations with Tibetans for high-altitude adaptation.

PubMed

Bhandari, Sushil; Zhang, Xiaoming; Cui, Chaoying; Yangla; Liu, Lan; Ouzhuluobu; Baimakangzhuo; Gonggalanzi; Bai, Caijuan; Bianba; Peng, Yi; Zhang, Hui; Xiang, Kun; Shi, Hong; Liu, Shiming; Gengdeng; Wu, Tianyi; Qi, Xuebin; Su, Bing

2017-01-01

Sherpas, a highlander population living in Khumbu region of Nepal, are well known for their superior climbing ability in Himalayas. However, the genetic basis of their adaptation to high-altitude environments remains elusive. We collected DNA samples of 582 Sherpas from Nepal and Tibetan Autonomous Region of China, and we measured their hemoglobin levels and degrees of blood oxygen saturation. We genotyped 29 EPAS1 SNPs, two EGLN1 SNPs and the TED polymorphism (3.4 kb deletion) in Sherpas. We also performed genetic association analysis among these sequence variants with phenotypic data. We found similar allele frequencies on the tested 32 variants of these genes in Sherpas and Tibetans. Sherpa individuals carrying the derived alleles of EPAS1 (rs113305133, rs116611511 and rs12467821), EGLN1 (rs186996510 and rs12097901) and TED have lower hemoglobin levels when compared with those wild-type allele carriers. Most of the EPAS1 variants showing significant association with hemoglobin levels in Tibetans were replicated in Sherpas. The shared sequence variants and hemoglobin trait between Sherpas and Tibetans indicate a shared genetic basis for high-altitude adaptation, consistent with the proposal that Sherpas are in fact a recently derived population from Tibetans and they inherited adaptive variants for high-altitude adaptation from their Tibetan ancestors.

Effect of FTO rs9939609 variant on insulin resistance in obese female adolescents.

PubMed

Iskandar, Kristy; Patria, Suryono Yudha; Huriyati, Emy; Luglio, Harry Freitag; Julia, Madarina; Susilowati, Rina

2018-05-15

FTO rs9939609 variant has been shown to be associated with insulin resistance in Caucasian children. However, studies in Asia show inconsistent findings. We investigated the association between FTO rs9939609 polymorphisms and insulin resistance in obese female adolescents in Indonesia, a genetically distinct group within Asia. A total of 78 obese female adolescents participated in this study. The risk allele (A) frequency of FTO rs9939609 variant in Indonesian obese female adolescence was 44.2%. The frequency of insulin resistance was higher in the subjects with AA (54.6%) or AT (59.6%) than the subject with TT genotype (50%), but did not statistically different (p = 0.81 and p = 0.47, respectively). The insulin resistance rate was also higher in the risk allele (A) than the non-risk allele (T) subjects (0.58 vs. 0.55), but did not statistically different (p = 0.75). There was no association between FTO rs9939609 variant and body mass index, fasting glucose level, fasting insulin level, homeostatic model assessment of insulin resistance, and waist circumference (p > 0.05). In conclusion, FTO rs9939609 variant may not be associated with insulin resistance in Indonesian obese female adolescents. A multicenter study with a larger sample size is needed to clarify these findings.

Transporter TAP1-637G and Immunoproteasome PSMB9-60H Variants Influence the Risk of Developing Vitiligo in the Saudi Population

PubMed Central

Elhawary, Nasser Attia; Bogari, Neda; Jiffri, Essam Hussien; Rashad, Mona; Fatani, Abdulhamid; Tayeb, Mohammed

2014-01-01

We evaluated whether TAP1-rs1135216 (p.637D>G) and PSMB9-rs17587 (p.60R>H) were significantly associated with the risk and severity of vitiligo among Saudi patients. One hundred seventy-two subjects were genotyped for the TAP1-rs1135216 and PSMB9-rs17587 variants using endonuclease digestions of amplified genomic DNA. The TAP1-rs1135216 and PSMB9-rs17587 mutant alleles were strongly associated with vitiligo, with odds ratios showing five fold and two fold risks (P < 0.0001 and P = 0.007, resp.). In TAP1-rs1135216, the 637G mutant allele was more frequent in cases (74%) than in healthy controls. In cases, the 60H mutant allele PSMB9-rs17587 was less frequent (42%) than the wild-type 60R allele (58%). Vitiligo vulgaris was the most common type of disease, associated with the DG (55%) and GG (46%) genotypes for rs1135216 and with the RH genotype (59%) for rs17587. The heterozygous 637DG and 60RH genotypes were each linked with active phenotypes in 64% of cases. In conclusion, the TAP1-rs1135216 and PSMB9-rs17587 variants are significantly associated with vitiligo, and even one copy of these mutant alleles can influence the risk among Saudis. Vitiligo vulgaris is associated with genotypes containing the mutant G and H alleles. PMID:25548428

Combination of PNPLA3 and TLL1 polymorphism can predict advanced fibrosis in Japanese patients with nonalcoholic fatty liver disease.

PubMed

Seko, Yuya; Yamaguchi, Kanji; Mizuno, Naoki; Okuda, Keiichiro; Takemura, Masashi; Taketani, Hiroyoshi; Hara, Tasuku; Umemura, Atsushi; Nishikawa, Taichiro; Moriguchi, Michihisa; Yasui, Kohichiroh; Kamaguchi, Mai; Nishioji, Kenichi; Mochizuki, Naomi; Kobayashi, Masao; Mori, Kojiroh; Tanaka, Saiyu; Matsuura, Kentaro; Tanaka, Yasuhito; Itoh, Yoshito

2018-03-01

Hepatic fibrosis is an independent risk factor for mortality and liver-related events in patients with nonalcoholic fatty liver disease (NAFLD). PNPLA3 rs738409 has been associated with fibrosis in viral and non-viral hepatitis. TLL1 rs17047200 also has been associated with developing hepatocellular carcinoma probably via hepatic fibrogenesis. We estimated the impact of these genetic polymorphisms on hepatic fibrosis in Japanese patients with NAFLD. We analyzed the association between these genetic variants and the backgrounds of 817 individuals who received health checkups (health check cohort) from 2012 to 2014. Then, we investigated the relationship between genetic variants and liver histology in 258 consecutive patients with biopsy-proven NAFLD in Japan (NAFLD cohort) from 2012 to 2017 (UMIN000027399). The prevalence of PNPLA3 CG/GG in the NAFLD cohort was higher than that in the health check cohort (p < 0.001). The prevalence of patients with advanced fibrosis (stages 3-4) was higher for PNPLA3 genotype CG/GG than CC (p = 0.048) and for TLL1 genotype AT/TT than AA (p = 0.044). The high-risk group which had at least two risk alleles of these variants was more likely to have advanced fibrosis (p = 0.004). Multivariate analysis identified body mass index [odds ratio (OR) 1.123, serum AST (OR 1.037, p = 0.004], serum albumin (OR 0.247, p = 0.032), and genetic high risk (OR 2.632, p = 0.026) as predictors of advanced fibrosis. In Japanese patients with NAFLD, individuals with risk alleles of PNPLA3 and TLL1 may have a risk of advanced fibrosis.

Natural selection on marine carnivores elaborated a diverse family of classical MHC class I genes exhibiting haplotypic gene content variation and allelic polymorphism

PubMed Central

Norman, Paul J.; Parham, Peter

2012-01-01

Pinnipeds, marine carnivores, diverged from terrestrial carnivores ~45 million years ago, before their adaptation to marine environments. This lifestyle change exposed pinnipeds to different microbiota and pathogens, with probable impact on their MHC class I genes. Investigating this question, genomic sequences were determined for 71 MHC class I variants: 27 from harbor seal and 44 from gray seal. These variants form three MHC class I gene lineages, one comprising a pseudogene. The second, a candidate nonclassical MHC class I gene, comprises a nonpolymorphic transcribed gene related to dog DLA-79 and giant panda Aime-1906. The third is the diversity lineage, which includes 62 of the 71 seal MHC class I variants. All are transcribed, and they minimally represent six harbor and 12 gray seal MHC class I genes. Besides species-specific differences in gene number, seal MHC class I haplotypes exhibit gene content variation and allelic polymorphism. Patterns of sequence variation, and of positions for positively selected sites, indicate the diversity lineage genes are the seals’ classical MHC class I genes. Evidence that expansion of diversity lineage genes began before gray and harbor seals diverged is the presence in both species of two distinctive sublineages of diversity lineage genes. Pointing to further expansion following the divergence are the presence of species-specific genes and greater MHC class I diversity in gray seals than harbor seals. The elaboration of a complex variable family of classical MHC class I genes in pinnipeds contrasts with the single, highly polymorphic classical MHC class I gene of dog and giant panda, terrestrial carnivores. PMID:23001684

The effect of rare alleles on estimated genomic relationships from whole genome sequence data.

PubMed

Eynard, Sonia E; Windig, Jack J; Leroy, Grégoire; van Binsbergen, Rianne; Calus, Mario P L

2015-03-12

Relationships between individuals and inbreeding coefficients are commonly used for breeding decisions, but may be affected by the type of data used for their estimation. The proportion of variants with low Minor Allele Frequency (MAF) is larger in whole genome sequence (WGS) data compared to Single Nucleotide Polymorphism (SNP) chips. Therefore, WGS data provide true relationships between individuals and may influence breeding decisions and prioritisation for conservation of genetic diversity in livestock. This study identifies differences between relationships and inbreeding coefficients estimated using pedigree, SNP or WGS data for 118 Holstein bulls from the 1000 Bull genomes project. To determine the impact of rare alleles on the estimates we compared three scenarios of MAF restrictions: variants with a MAF higher than 5%, variants with a MAF higher than 1% and variants with a MAF between 1% and 5%. We observed significant differences between estimated relationships and, although less significantly, inbreeding coefficients from pedigree, SNP or WGS data, and between MAF restriction scenarios. Computed correlations between pedigree and genomic relationships, within groups with similar relationships, ranged from negative to moderate for both estimated relationships and inbreeding coefficients, but were high between estimates from SNP and WGS (0.49 to 0.99). Estimated relationships from genomic information exhibited higher variation than from pedigree. Inbreeding coefficients analysis showed that more complete pedigree records lead to higher correlation between inbreeding coefficients from pedigree and genomic data. Finally, estimates and correlations between additive genetic (A) and genomic (G) relationship matrices were lower, and variances of the relationships were larger when accounting for allele frequencies than without accounting for allele frequencies. Using pedigree data or genomic information, and including or excluding variants with a MAF below 5% showed significant differences in relationship and inbreeding coefficient estimates. Estimated relationships and inbreeding coefficients are the basis for selection decisions. Therefore, it can be expected that using WGS instead of SNP can affect selection decision. Inclusion of rare variants will give access to the variation they carry, which is of interest for conservation of genetic diversity.

Preferential association of a functional variant in complement receptor 2 with antibodies to double-stranded DNA

PubMed Central

Zhao, Jian; Giles, Brendan M; Taylor, Rhonda L; Yette, Gabriel A; Lough, Kara M; Ng, Han Leng; Abraham, Lawrence J; Wu, Hui; Kelly, Jennifer A; Glenn, Stuart B; Adler, Adam J; Williams, Adrienne H; Comeau, Mary E; Ziegler, Julie T; Marion, Miranda; Alarcón-Riquelme, Marta E; Alarcón, Graciela S; Anaya, Juan-Manuel; Bae, Sang-Cheol; Kim, Dam; Lee, Hye-Soon; Criswell, Lindsey A; Freedman, Barry I; Gilkeson, Gary S; Guthridge, Joel M; Jacob, Chaim O; James, Judith A; Kamen, Diane L; Merrill, Joan T; Sivils, Kathy Moser; Niewold, Timothy B; Petri, Michelle A; Ramsey-Goldman, Rosalind; Reveille, John D; Scofield, R Hal; Stevens, Anne M; Vilá, Luis M; Vyse, Timothy J; Kaufman, Kenneth M; Harley, John B; Langefeld, Carl D; Gaffney, Patrick M; Brown, Elizabeth E; Edberg, Jeffrey C; Kimberly, Robert P; Ulgiati, Daniela; Tsao, Betty P; Boackle, Susan A

2016-01-01

Objectives Systemic lupus erythematosus (SLE; OMIM 152700) is characterised by the production of antibodies to nuclear antigens. We previously identified variants in complement receptor 2 (CR2/CD21) that were associated with decreased risk of SLE. This study aimed to identify the causal variant for this association. Methods Genotyped and imputed genetic variants spanning CR2 were assessed for association with SLE in 15 750 case-control subjects from four ancestral groups. Allele-specific functional effects of associated variants were determined using quantitative real-time PCR, quantitative flow cytometry, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP)-PCR. Results The strongest association signal was detected at rs1876453 in intron 1 of CR2 (pmeta=4.2×10−4, OR 0.85), specifically when subjects were stratified based on the presence of dsDNA autoantibodies (case-control pmeta=7.6×10−7, OR 0.71; case-only pmeta=1.9×10−4, OR 0.75). Although allele-specific effects on B cell CR2 mRNA or protein levels were not identified, levels of complement receptor 1 (CR1/CD35) mRNA and protein were significantly higher on B cells of subjects harbouring the minor allele (p=0.0248 and p=0.0006, respectively). The minor allele altered the formation of several DNA protein complexes by EMSA, including one containing CCCTC-binding factor (CTCF), an effect that was confirmed by ChIP-PCR. Conclusions These data suggest that rs1876453 in CR2 has long-range effects on gene regulation that decrease susceptibility to lupus. Since the minor allele at rs1876453 is preferentially associated with reduced risk of the highly specific dsDNA autoantibodies that are present in preclinical, active and severe lupus, understanding its mechanisms will have important therapeutic implications. PMID:25180293

The controversial p.Met34Thr variant in GJB2 gene: Two siblings, one genotype, two phenotypes.

PubMed

Lameiras, Ana Rita; Gonçalves, Ana Cláudia; Santos, Ricardo; O'Neill, Assunção; Reis, Luís Roque Dos; Matos, Tiago Daniel; Fialho, Graça; Caria, Helena; Escada, Pedro

2015-08-01

Recent advances in molecular genetics have increased the identification of genes and mutations responsible for inherited forms of hearing loss (HL), enabling early detection of these cases. Approximately, 60% of early-onset HL cases are due to genetic causes, of which 70% are non-syndromic. Of these, 75-80% are inherited in an autosomal recessive pattern (DFNB). Mutations in GJB2 gene, coding for connexin 26 (Cx26), are the major cause of autosomal recessive hereditary HL, but some GJB2 mutations are yet of unclear or controversial significance. The aim of the present study was to identify the etiology of hearing loss, and correlate genotype-phenotype, in two Portuguese siblings with profound and moderate non-syndromic sensorineural bilateral HL. The affected subjects and their parents underwent audiological and genetic study. Molecular analysis of GJB2 gene was performed, searching for mutations in the coding region and receptor splicing site by automated sequencing. The onset and the degree of HL were different in the two affected subjects. However, the same GJB2 genotype [p.Met34Thr]+[p.Arg184Pro] was identified in both siblings. The c.551G>C (p.Arg184Pro) and c.101T>C (p.Met34Thr) missense variants were inherited from the father and mother, respectively, both heterozygous carriers of these variants. The clinical and genetic data here presented suggest that the non-syndromic sensorineural HL of these two Portuguese siblings might be due to the presence of p.Met34Thr and p.Arg184Pro variants in compound heterozygosity. If so, p.Met34Thr variant could have function as a hypomorphic allele that may cause HL depending on the opposing GJB2 allele. The observed phenotypic variability may not, however, be solely explained by variable expression of this genotype. A putative modifier gene or mutations in another HL-associated gene could probably be contributing to the severe HL in one of the siblings. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

PREVALENCE OF CELIAC DISEASE PREDISPOSING GENOTYPES, INCLUDING HLA-DQ2.2 VARIANT, IN BRAZILIAN CHILDREN.

PubMed

Selleski, Nicole; Almeida, Lucas Malta; Almeida, Fernanda Coutinho de; Pratesi, Claudia Beatriz; Nóbrega, Yanna Karla de Medeiros; Gandolfi, Lenora

2018-01-01

Celiac disease is an autoimmune enteropathy triggered by the ingestion of gluten in genetically susceptible individuals. Almost all celiac patients carry immune recognition genes coding for HLA-DQ2.5 and DQ8 heterodimers. Over the last few years, great importance has been given to HLA-DQ2.2 as probable predisposing variant, although controversies still exist regarding its relevance. The aim of our study was to determine the possible existence of an association between HLA-DQ2.2 and celiac disease in Brazilian children by analyzing the prevalence of the predisposing variants for celiac disease in a representative group of children of a population in which this determination is still missing. HLA-DQ typing was performed in samples from a group of celiac (n=100) and non-celiac children (n=110). All samples were tested for the presence of the following variants: DQA1*05-DQB1*02 (DQ2.5), DQA1*03-DQB1*03:02 (DQ8) and DQA1*02:01-DQB1*02:02 (DQ2.2). Fisher`s exact test was used for statistical analysis. In the group of 100 celiac children, 78 (78%) were positive for DQ2, 13 (13 %) were DQ2/DQ8 and 6 (6%) were DQ8 positives. The HLA-DQ pattern in the 110 non-celiac children was as follows: positive for DQ2 in 33 (29.9%) samples, in 2 (1.8 %) was positive for DQ2/DQ8 and in 15 (13.6%) was positive for DQ8. We found significant differences between the distribution of some but not all of the analyzed alleles when comparing celiac and non-celiac children. The genotyping of celiac disease HLA-DQ predisposing alleles showed similarities with HLA-DQ patterns found in both European and non-European populations, which may be a reflection of the miscegenation, which gave origin to the current Brazilian population. No significant association was found between DQ2.2 variant and celiac disease in the studied population.

Difference between age-related macular degeneration and polypoidal choroidal vasculopathy in the hereditary contribution of the A69S variant of the age-related maculopathy susceptibility 2 gene (ARMS2).

PubMed

Yanagisawa, Suiho; Kondo, Naoshi; Miki, Akiko; Matsumiya, Wataru; Kusuhara, Sentaro; Tsukahara, Yasutomo; Honda, Shigeru; Negi, Akira

2011-01-01

To investigate whether the A69S variant of the age-related maculopathy susceptibility 2 gene (ARMS2) has a different hereditary contribution in neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV). We initially conducted a comparative genetic analysis of neovascular AMD and PCV, genotyping the ARMS2 A69S variant in 181 subjects with neovascular AMD, 198 subjects with PCV, and 203 controls in a Japanese population. Genotyping was conducted using TaqMan technology. Results were then integrated into a meta-analysis of previous studies representing an assessment of the association between the ARMS2 A69S variant and neovascular AMD and/or PCV, comprising a total of 3,828 subjects of Asian descent. The Q-statistic test was used to assess between-study heterogeneity. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using a fixed effects model. The genetic effect of the A69S variant was stronger in neovascular AMD (allelic summary OR=3.09 [95% CI, 2.71-3.51], fixed effects p<0.001) than in PCV (allelic summary OR=2.13 [95% CI, 1.91-2.38], fixed effects p<0.001). The pooled risk allele frequency was significantly higher in neovascular AMD (64.7%) than in PCV (55.6%). The population attributable risks for the variant allele were estimated to be 43.9% (95% CI, 39.0%-48.4%) and 29.7% (95% CI, 25.4%-34.0%) for neovascular AMD and PCV, respectively. No significant between-study heterogeneity was observed in any statistical analysis in this meta-analysis. Our meta-analysis provides substantial evidence that the ARMS2 A69S variant confers a significantly higher risk of neovascular AMD than PCV. Furthermore, there is compelling evidence that the risk attributable to the A69S variant differs between geographic atrophy and neovascular AMD. Together with defining the molecular basis of susceptibility, understanding the relationships between this genomic region and disease subtypes will yield important insights, elucidating the biologic architecture of this phenotypically heterogeneous disorder.

Association of levels of fasting glucose and insulin with rare variants at the chromosome 11p11.2-MADD locus: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.

PubMed

Cornes, Belinda K; Brody, Jennifer A; Nikpoor, Naghmeh; Morrison, Alanna C; Chu, Huan; Ahn, Byung Soo; Wang, Shuai; Dauriz, Marco; Barzilay, Joshua I; Dupuis, Josée; Florez, Jose C; Coresh, Josef; Gibbs, Richard A; Kao, W H Linda; Liu, Ching-Ti; McKnight, Barbara; Muzny, Donna; Pankow, James S; Reid, Jeffrey G; White, Charles C; Johnson, Andrew D; Wong, Tien Y; Psaty, Bruce M; Boerwinkle, Eric; Rotter, Jerome I; Siscovick, David S; Sladek, Robert; Meigs, James B

2014-06-01

Common variation at the 11p11.2 locus, encompassing MADD, ACP2, NR1H3, MYBPC3, and SPI1, has been associated in genome-wide association studies with fasting glucose and insulin (FI). In the Cohorts for Heart and Aging Research in Genomic Epidemiology Targeted Sequencing Study, we sequenced 5 gene regions at 11p11.2 to identify rare, potentially functional variants influencing fasting glucose or FI levels. Sequencing (mean depth, 38×) across 16.1 kb in 3566 individuals without diabetes mellitus identified 653 variants, 79.9% of which were rare (minor allele frequency <1%) and novel. We analyzed rare variants in 5 gene regions with FI or fasting glucose using the sequence kernel association test. At NR1H3, 53 rare variants were jointly associated with FI (P=2.73×10(-3)); of these, 7 were predicted to have regulatory function and showed association with FI (P=1.28×10(-3)). Conditioning on 2 previously associated variants at MADD (rs7944584, rs10838687) did not attenuate this association, suggesting that there are >2 independent signals at 11p11.2. One predicted regulatory variant, chr11:47227430 (hg18; minor allele frequency=0.00068), contributed 20.6% to the overall sequence kernel association test score at NR1H3, lies in intron 2 of NR1H3, and is a predicted binding site for forkhead box A1 (FOXA1), a transcription factor associated with insulin regulation. In human HepG2 hepatoma cells, the rare chr11:47227430 A allele disrupted FOXA1 binding and reduced FOXA1-dependent transcriptional activity. Sequencing at 11p11.2-NR1H3 identified rare variation associated with FI. One variant, chr11:47227430, seems to be functional, with the rare A allele reducing transcription factor FOXA1 binding and FOXA1-dependent transcriptional activity. © 2014 American Heart Association, Inc.

Polymorphic Variants rs3088442 and rs2292334 in the Organic Cation Transporter 3 (OCT3) Gene and Susceptibility Against Type 2 Diabetes: Role of their Interaction.

PubMed

Mahrooz, Abdolkarim; Alizadeh, Ahad; Hashemi-Soteh, Mohammad Bagher; Ghaffari-Cherati, Maryam; Hosseyni-Talei, Seyyedeh Raheleh

2017-02-01

In this study, we investigated whether two common variants (rs3088442G>A and rs2292334G>A) in the organic cation transporter 3 (OCT3) gene, a high-capacity transporter widely expressed in various tissues, affect susceptibility to type 2 diabetes (T2D) in patients newly diagnosed with T2D. We performed a study with 150 newly diagnosed patients with T2D and 152 controls. The genetic analyses were performed using the restricted fragment length polymorphism (RFLP) after PCR amplification. For the rs3088442G>A variant, A allele carriers had a significantly lower odds ratio (OR) vs. GG homozygotes in the BMI <30 kg/m 2 group (OR = 0.23, p <0.001) compared with the BMI ≥30 kg/m 2 group (OR = 0.67, p = 0.34). When ORs were adjusted for BMI, age, sex, and blood pressure, our findings showed that the overexpression of the A allele of the rs3088442G>A variant was associated with a decreased risk of T2D (OR = 0.016, p <0.001). A Bayesian logistic model revealed that the interaction of two variants studied were significantly associated with a decreased risk of T2D (OR = 0.61, p = 0.03). The present study has identified the protective effect of the variant rs3088442G>A in the 3'-untranslated region of the OCT3 gene in susceptibility to T2D, and that the protective role is maintained in the presence of risky alleles of the variant rs2292334G>A. The association of the A allele of rs3088442G>A with T2D become weaker in obese people than that of non-obese. If confirmed in other populations, the rs3088442G>A variant as a genetic marker may potentially assist in the identification of individuals at an increased risk of T2D. Copyright © 2017 IMSS. Published by Elsevier Inc. All rights reserved.

Association between gene variants and response to buprenorphine maintenance treatment.

PubMed

Gerra, Gilberto; Somaini, Lorenzo; Leonardi, Claudio; Cortese, Elena; Maremmani, Icro; Manfredini, Matteo; Donnini, Claudia

2014-01-30

A variety of studies were addressed to differentiate responders and non-responders to substitution treatment among heroin dependent patients, without conclusive findings. In particular, preliminary pharmacogenetic findings have been reported to predict treatment effectiveness in mental health and substance use disorders. Aim of the present study was to investigate the possible association of buprenorphine (BUP) treatment outcome with gene variants that may affect kappa-opioid receptors and dopamine system function. One hundred and seven heroin addicts (West European, Caucasians) who underwent buprenorphine maintenance treatment were genotyped and classified into two groups (A and B) on the basis of treatment outcome. Non-responders to buprenorphine (group B) have been identified taking into account early drop out, continuous use of heroin, severe behavioral or psychiatric problems, misbehavior and diversion during the 6 months treatment period. No difference was evidenced between responders and non-responders to BUP in the frequency of kappa opioid receptor (OPRK1) 36G>T SNP. The frequency of dopamine transporter (DAT) gene polymorphism (SLC6A3/DAT1), allele 10, was evidently much higher in "non-responder" than in "responder" individuals (64.9% vs. 55.93%) whereas the frequency of the category of other alleles (6, 7 and 11) was higher in responder than in non-responder individuals (11.02% vs. 2.13% respectively). On one hand, the hypothesis that possible gene-related changes in kappa-opioid receptor could consistently affect buprenorphine pharmacological action and clinical effectiveness was not confirmed in our study, at least in relation to the single nucleotide polymorphism 36G>T. On the other hand, the possibility that gene-related dopamine changes could have reduced BUP effectiveness and impaired maintenance treatment outcome was cautiously supported by our findings. DAT1 gene variants such as allele 10, previously reported in association with personality and behavioral problems, would have influenced the effects of BUP-induced dopamine release, modulated through mu and kappa opioid receptors, and probably the related reinforcing capacity of the drug. © 2013 Published by Elsevier Ireland Ltd.

Conserved and Variant Epitopes of Plasmodium vivax Duffy Binding Protein as Targets of Inhibitory Monoclonal Antibodies

PubMed Central

Ntumngia, Francis B.; Schloegel, Jesse; Barnes, Samantha J.; McHenry, Amy M.; Singh, Sanjay; King, Christopher L.

2012-01-01

The Duffy binding protein (DBP) is a vital ligand for Plasmodium vivax blood-stage merozoite invasion, making the molecule an attractive vaccine candidate against vivax malaria. Similar to other blood-stage vaccine candidates, DBP allelic variation eliciting a strain-specific immunity may be a major challenge for development of a broadly effective vaccine against vivax malaria. To understand whether conserved epitopes can be the target of neutralizing anti-DBP inhibition, we generated a set of monoclonal antibodies to DBP and functionally analyzed their reactivity to a panel of allelic variants. Quantitative analysis by enzyme-linked immunosorbent assay (ELISA) determined that some monoclonal antibodies reacted strongly with epitopes conserved on all DBP variants tested, while reactivity of others was allele specific. Qualitative analysis characterized by anti-DBP functional inhibition using an in vitro erythrocyte binding inhibition assay indicated that there was no consistent correlation between the endpoint titers and functional inhibition. Some monoclonal antibodies were broadly inhibitory while inhibition of others varied significantly by target allele. These data demonstrate a potential for vaccine-elicited immunization to target conserved epitopes but optimization of DBP epitope target specificity and immunogenicity may be necessary for protection against diverse P. vivax strains. PMID:22215740

Conserved and variant epitopes of Plasmodium vivax Duffy binding protein as targets of inhibitory monoclonal antibodies.

PubMed

Ntumngia, Francis B; Schloegel, Jesse; Barnes, Samantha J; McHenry, Amy M; Singh, Sanjay; King, Christopher L; Adams, John H

2012-03-01

The Duffy binding protein (DBP) is a vital ligand for Plasmodium vivax blood-stage merozoite invasion, making the molecule an attractive vaccine candidate against vivax malaria. Similar to other blood-stage vaccine candidates, DBP allelic variation eliciting a strain-specific immunity may be a major challenge for development of a broadly effective vaccine against vivax malaria. To understand whether conserved epitopes can be the target of neutralizing anti-DBP inhibition, we generated a set of monoclonal antibodies to DBP and functionally analyzed their reactivity to a panel of allelic variants. Quantitative analysis by enzyme-linked immunosorbent assay (ELISA) determined that some monoclonal antibodies reacted strongly with epitopes conserved on all DBP variants tested, while reactivity of others was allele specific. Qualitative analysis characterized by anti-DBP functional inhibition using an in vitro erythrocyte binding inhibition assay indicated that there was no consistent correlation between the endpoint titers and functional inhibition. Some monoclonal antibodies were broadly inhibitory while inhibition of others varied significantly by target allele. These data demonstrate a potential for vaccine-elicited immunization to target conserved epitopes but optimization of DBP epitope target specificity and immunogenicity may be necessary for protection against diverse P. vivax strains.

Frequency of genetic polymorphisms of PXR gene in the Brazilian population.

PubMed

Moreira, Ricardo P P; Jorge, Alexander A L; Mendonca, Berenice B; Bachega, Tânia A S S

2011-01-01

PXR polymorphisms have been implicated in modulating CYP3A4 and PXR expression, potentially accounting for interindividual differences in drug metabolism. The prevalence of PXR polymorphisms varies among ethnic groups and data on the allelic distribution in the highly mixed Brazilian population is lacking. The aim of this study was to analyze genetic variations in the PXR gene in Brazilians and to compare the results to other ethnic groups. DNA samples from 117 healthy Brazilians underwent PCR amplification and sequencing. Eleven polymorphisms were identified, 3 of which are highly associated with differences in CYP3A4 expression. We also identified 1 new synonymous variant in 1.3% of the alleles. Among the functional polymorphisms, -25913 C>T and -6994T>C occurred at a higher frequency comparedtothe Africanalleles (p < 0.05) but at a lower frequency compared to Caucasian alleles. The 8055 C>T allele was found at a similar frequency to those described in Caucasians and Africans (p > 0.05). We observed that functional variants of the PXR were frequent in our sample of the Brazilian population. Our results suggest that PXR gene variants may be of interest in pharmacogenetic studies involving Brazilians.

Estimated allele substitution effects underlying genomic evaluation models depend on the scaling of allele counts.

PubMed

Bouwman, Aniek C; Hayes, Ben J; Calus, Mario P L

2017-10-30

Genomic evaluation is used to predict direct genomic values (DGV) for selection candidates in breeding programs, but also to estimate allele substitution effects (ASE) of single nucleotide polymorphisms (SNPs). Scaling of allele counts influences the estimated ASE, because scaling of allele counts results in less shrinkage towards the mean for low minor allele frequency (MAF) variants. Scaling may become relevant for estimating ASE as more low MAF variants will be used in genomic evaluations. We show the impact of scaling on estimates of ASE using real data and a theoretical framework, and in terms of power, model fit and predictive performance. In a dairy cattle dataset with 630 K SNP genotypes, the correlation between DGV for stature from a random regression model using centered allele counts (RRc) and centered and scaled allele counts (RRcs) was 0.9988, whereas the overall correlation between ASE using RRc and RRcs was 0.27. The main difference in ASE between both methods was found for SNPs with a MAF lower than 0.01. Both the ratio (ASE from RRcs/ASE from RRc) and the regression coefficient (regression of ASE from RRcs on ASE from RRc) were much higher than 1 for low MAF SNPs. Derived equations showed that scenarios with a high heritability, a large number of individuals and a small number of variants have lower ratios between ASE from RRc and RRcs. We also investigated the optimal scaling parameter [from - 1 (RRcs) to 0 (RRc) in steps of 0.1] in the bovine stature dataset. We found that the log-likelihood was maximized with a scaling parameter of - 0.8, while the mean squared error of prediction was minimized with a scaling parameter of - 1, i.e., RRcs. Large differences in estimated ASE were observed for low MAF SNPs when allele counts were scaled or not scaled because there is less shrinkage towards the mean for scaled allele counts. We derived a theoretical framework that shows that the difference in ASE due to shrinkage is heavily influenced by the power of the data. Increasing the power results in smaller differences in ASE whether allele counts are scaled or not.

ZNF804A variants confer risk for heroin addiction and affect decision making and gray matter volume in heroin abusers.

PubMed

Sun, Yan; Zhao, Li-Yan; Wang, Gui-Bin; Yue, Wei-Hua; He, Yong; Shu, Ni; Lin, Qi-Xiang; Wang, Fan; Li, Jia-Li; Chen, Na; Wang, Hui-Min; Kosten, Thomas R; Feng, Jia-Jia; Wang, Jun; Tang, Yu-De; Liu, Shu-Xue; Deng, Gui-Fa; Diao, Gan-Huan; Tan, Yun-Long; Han, Hong-Bin; Lin, Lu; Shi, Jie

2016-05-01

Drug addiction shares common neurobiological pathways and risk genes with other psychiatric diseases, including psychosis. One of the commonly identified risk genes associated with broad psychosis has been ZNF804A. We sought to test whether psychosis risk variants in ZNF804A increase the risk of heroin addiction by modulating neurocognitive performance and gray matter volume (GMV) in heroin addiction. Using case-control genetic analysis, we compared the distribution of ZNF804A variants (genotype and haplotype) in 1035 heroin abusers and 2887 healthy subjects. We also compared neurocognitive performance (impulsivity, global cognitive ability and decision-making ability) in 224 subjects and GMV in 154 subjects based on the ZNF804A variants. We found significant differences in the distribution of ZNF804A intronic variants (rs1344706 and rs7597593) allele and haplotype frequencies between the heroin and control groups. Decision-making impairment was worse in heroin abusers who carried the ZNF804A risk allele and haplotype. Subjects who carried more risk alleles and haplotypes of ZNF804A had greater GMV in the bilateral insular cortex, right temporal cortex and superior parietal cortex. The interaction between heroin addiction and ZNF804A variants affected GMV in the left sensorimotor cortex. Our findings revealed several ZNF804A variants that were significantly associated with the risk of heroin addiction, and these variants affected decision making and GMV in heroin abusers compared with controls. The precise neural mechanisms that underlie these associations are unknown, which requires future investigations of the effects of ZNF804A on both dopamine neurotransmission and the relative increases in the volume of various brain areas. © 2015 Society for the Study of Addiction.

Massively parallel sequencing of 68 insertion/deletion markers identifies novel microhaplotypes for utility in human identity testing.

PubMed

Wendt, Frank R; Warshauer, David H; Zeng, Xiangpei; Churchill, Jennifer D; Novroski, Nicole M M; Song, Bing; King, Jonathan L; LaRue, Bobby L; Budowle, Bruce

2016-11-01

Short tandem repeat (STR) loci are the traditional markers used for kinship, missing persons, and direct comparison human identity testing. These markers hold considerable value due to their highly polymorphic nature, amplicon size, and ability to be multiplexed. However, many STRs are still too large for use in analysis of highly degraded DNA. Small bi-allelic polymorphisms, such as insertions/deletions (INDELs), may be better suited for analyzing compromised samples, and their allele size differences are amenable to analysis by capillary electrophoresis. The INDEL marker allelic states range in size from 2 to 6 base pairs, enabling small amplicon size. In addition, heterozygote balance may be increased by minimizing preferential amplification of the smaller allele, as is more common with STR markers. Multiplexing a large number of INDELs allows for generating panels with high discrimination power. The Nextera™ Rapid Capture Custom Enrichment Kit (Illumina, Inc., San Diego, CA) and massively parallel sequencing (MPS) on the Illumina MiSeq were used to sequence 68 well-characterized INDELs in four major US population groups. In addition, the STR Allele Identification Tool: Razor (STRait Razor) was used in a novel way to analyze INDEL sequences and detect adjacent single nucleotide polymorphisms (SNPs) and other polymorphisms. This application enabled the discovery of unique allelic variants, which increased the discrimination power and decreased the single-locus random match probabilities (RMPs) of 22 of these well-characterized INDELs which can be considered as microhaplotypes. These findings suggest that additional microhaplotypes containing human identification (HID) INDELs may exist elsewhere in the genome. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Assessment of allelic diversity in intron-containing Mal d 1 genes and their association to apple allergenicity

PubMed Central

Gao, Zhongshan; Weg, Eric W van de; Matos, Catarina I; Arens, Paul; Bolhaar, Suzanne THP; Knulst, Andre C; Li, Yinghui; Hoffmann-Sommergruber, Karin; Gilissen, Luud JWJ

2008-01-01

Background Mal d 1 is a major apple allergen causing food allergic symptoms of the oral allergy syndrome (OAS) in birch-pollen sensitised patients. The Mal d 1 gene family is known to have at least 7 intron-containing and 11 intronless members that have been mapped in clusters on three linkage groups. In this study, the allelic diversity of the seven intron-containing Mal d 1 genes was assessed among a set of apple cultivars by sequencing or indirectly through pedigree genotyping. Protein variant constitutions were subsequently compared with Skin Prick Test (SPT) responses to study the association of deduced protein variants with allergenicity in a set of 14 cultivars. Results From the seven intron-containing Mal d 1 genes investigated, Mal d 1.01 and Mal d 1.02 were highly conserved, as nine out of ten cultivars coded for the same protein variant, while only one cultivar coded for a second variant. Mal d 1.04, Mal d 1.05 and Mal d 1.06 A, B and C were more variable, coding for three to six different protein variants. Comparison of Mal d 1 allelic composition between the high-allergenic cultivar Golden Delicious and the low-allergenic cultivars Santana and Priscilla, which are linked in pedigree, showed an association between the protein variants coded by the Mal d 1.04 and -1.06A genes (both located on linkage group 16) with allergenicity. This association was confirmed in 10 other cultivars. In addition, Mal d 1.06A allele dosage effects associated with the degree of allergenicity based on prick to prick testing. Conversely, no associations were observed for the protein variants coded by the Mal d 1.01 (on linkage group 13), -1.02, -1.06B, -1.06C genes (all on linkage group 16), nor by the Mal d 1.05 gene (on linkage group 6). Conclusion Protein variant compositions of Mal d 1.04 and -1.06A and, in case of Mal d 1.06A, allele doses are associated with the differences in allergenicity among fourteen apple cultivars. This information indicates the involvement of qualitative as well as quantitative factors in allergenicity and warrants further research in the relative importance of quantitative and qualitative aspects of Mal d 1 gene expression on allergenicity. Results from this study have implications for medical diagnostics, immunotherapy, clinical research and breeding schemes for new hypo-allergenic cultivars. PMID:19014530

What can we learn about lipoprotein metabolism and coronary heart disease from studying rare variants?

PubMed

Jeff, Janina M; Peloso, Gina M; Do, Ron

2016-04-01

Rare variant association studies (RVAS) target the class of genetic variation with frequencies less than 1%. Recently, investigators have used exome sequencing in RVAS to identify rare alleles responsible for Mendelian diseases but have experienced greater difficulty discovering such alleles for complex diseases. In this review, we describe what we have learned about lipoprotein metabolism and coronary heart disease through the conduct of RVAS. Rare protein-altering genetic variation can provide important insights that are not as easily attainable from common variant association studies. First, RVAS can facilitate gene discovery by identifying novel rare protein-altering variants in specific genes that are associated with disease. Second, rare variant associations can provide supportive evidence for putative drug targets for novel therapies. Finally, rare variants can uncover new pathways and reveal new biologic mechanisms. The field of human genetics has already made tremendous progress in understanding lipoprotein metabolism and the causes of coronary heart disease in the context of rare variants. As next generation sequencing becomes more cost-effective, RVAS with larger sample sizes will be conducted. This will lead to more novel rare variant discoveries and the translation of genomic data into biological knowledge and clinical insights for cardiovascular disease.

Trans-ethnic meta-regression of genome-wide association studies accounting for ancestry increases power for discovery and improves fine-mapping resolution

PubMed Central

Mägi, Reedik; Horikoshi, Momoko; Sofer, Tamar; Mahajan, Anubha; Kitajima, Hidetoshi; Franceschini, Nora; McCarthy, Mark I.; Morris, Andrew P.

2017-01-01

Abstract Trans-ethnic meta-analysis of genome-wide association studies (GWAS) across diverse populations can increase power to detect complex trait loci when the underlying causal variants are shared between ancestry groups. However, heterogeneity in allelic effects between GWAS at these loci can occur that is correlated with ancestry. Here, a novel approach is presented to detect SNP association and quantify the extent of heterogeneity in allelic effects that is correlated with ancestry. We employ trans-ethnic meta-regression to model allelic effects as a function of axes of genetic variation, derived from a matrix of mean pairwise allele frequency differences between GWAS, and implemented in the MR-MEGA software. Through detailed simulations, we demonstrate increased power to detect association for MR-MEGA over fixed- and random-effects meta-analysis across a range of scenarios of heterogeneity in allelic effects between ethnic groups. We also demonstrate improved fine-mapping resolution, in loci containing a single causal variant, compared to these meta-analysis approaches and PAINTOR, and equivalent performance to MANTRA at reduced computational cost. Application of MR-MEGA to trans-ethnic GWAS of kidney function in 71,461 individuals indicates stronger signals of association than fixed-effects meta-analysis when heterogeneity in allelic effects is correlated with ancestry. Application of MR-MEGA to fine-mapping four type 2 diabetes susceptibility loci in 22,086 cases and 42,539 controls highlights: (i) strong evidence for heterogeneity in allelic effects that is correlated with ancestry only at the index SNP for the association signal at the CDKAL1 locus; and (ii) 99% credible sets with six or fewer variants for five distinct association signals. PMID:28911207

LBH Gene Transcription Regulation by the Interplay of an Enhancer Risk Allele and DNA Methylation in Rheumatoid Arthritis.

PubMed

Hammaker, Deepa; Whitaker, John W; Maeshima, Keisuke; Boyle, David L; Ekwall, Anna-Karin H; Wang, Wei; Firestein, Gary S

2016-11-01

To identify nonobvious therapeutic targets for rheumatoid arthritis (RA), we performed an integrative analysis incorporating multiple "omics" data and the Encyclopedia of DNA Elements (ENCODE) database for potential regulatory regions. This analysis identified the limb bud and heart development (LBH) gene, which has risk alleles associated with RA/celiac disease and lupus, and can regulate cell proliferation in RA. We identified a novel LBH transcription enhancer with an RA risk allele (rs906868 G [Ref]/T) 6 kb upstream of the LBH gene with a differentially methylated locus. The confluence of 3 regulatory elements, rs906868, an RA differentially methylated locus, and a putative enhancer, led us to investigate their effects on LBH regulation in fibroblast-like synoviocytes (FLS). We cloned the 1.4-kb putative enhancer with either the rs906868 Ref allele or single-nucleotide polymorphism (SNP) variant into reporter constructs. The constructs were methylated in vitro and transfected into cultured FLS by nucleofection. We found that both variants increased transcription, thereby confirming the region's enhancer function. Unexpectedly, the transcriptional activity of the Ref risk allele was significantly lower than that of the SNP variant and is consistent with low LBH levels as a risk factor for aggressive FLS behavior. Using RA FLS lines with a homozygous Ref or SNP allele, we confirmed that homozygous Ref lines expressed lower LBH messenger RNA levels than did the SNP lines. Methylation significantly reduced enhancer activity for both alleles, indicating that enhancer function is dependent on its methylation status. This study shows how the interplay between genetics and epigenetics can affect expression of LBH in RA. © 2016, American College of Rheumatology.

A candidate gene for autoimmune myasthenia gravis

PubMed Central

Landouré, Guida; Knight, Melanie A.; Stanescu, Horia; Taye, Addis A.; Shi, Yijun; Diallo, Oumarou; Johnson, Janel O.; Hernandez, Dena; Traynor, Bryan J.; Biesecker, Leslie G.; Elkahloun, Abdel; Rinaldi, Carlo; Vincent, Angela; Willcox, Nick; Kleta, Robert; Fischbeck, Kenneth H.

2012-01-01

Objective: We sought to identify a causative mutation in a previously reported kindred with parental consanguinity and 5 of 10 siblings with adult-onset autoimmune myasthenia gravis. Methods: We performed genome-wide homozygosity mapping, and sequenced all known genes in the one region of extended homozygosity. Quantitative and allele-specific reverse transcriptase PCR (RT-PCR) were performed on a candidate gene to determine the RNA expression level in affected siblings and controls and the relative abundance of the wild-type and mutant alleles in a heterozygote. Results: A region of shared homozygosity at chromosome 13q13.3–13q14.11 was found in 4 affected siblings and 1 unaffected sibling. A homozygous single nucleotide variant was found in the 3′-untranslated region of the ecto-NADH oxidase 1 gene (ENOX1). No other variants likely to be pathogenic were found in genes in this region or elsewhere. The ENOX1 sequence variant was not found in 764 controls. Quantitative RT-PCR showed that expression of ENOX1 decreased to about 20% of normal levels in lymphoblastoid cells from individuals homozygous for the variant and to about 50% in 2 unaffected heterozygotes. Allele-specific RT-PCR showed a 55%–60% reduction in the level of the variant transcript in heterozygous cells due to reduced mRNA stability. Conclusion: These results indicate that this sequence variant in ENOX1 may contribute to the familial autoimmune myasthenia in these patients. PMID:22744667

Misregulation effect of a novel allelic variant in the Z promoter region found in cis with the CYP21A2 p.P482S mutation: implications for 21-hydroxylase deficiency.

PubMed

Fernández, Cecilia S; Bruque, Carlos D; Taboas, Melisa; Buzzalino, Noemí D; Espeche, Lucia D; Pasqualini, Titania; Charreau, Eduardo H; Alba, Liliana G; Ghiringhelli, Pablo D; Dain, Liliana

2015-09-01

The aim of the current study was to search for the presence of genetic variants in the CYP21A2 Z promoter regulatory region in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Screening of the 10 most frequent pseudogene-derived mutations was followed by direct sequencing of the entire coding sequence, the proximal promoter, and a distal regulatory region in DNA samples from patients with at least one non-determined allele. We report three non-classical patients that presented a novel genetic variant-g.15626A>G-within the Z promoter regulatory region. In all the patients, the novel variant was found in cis with the mild, less frequent, p.P482S mutation located in the exon 10 of the CYP21A2 gene. The putative pathogenic implication of the novel variant was assessed by in silico analyses and in vitro assays. Topological analyses showed differences in the curvature and bendability of the DNA region bearing the novel variant. By performing functional studies, a significantly decreased activity of a reporter gene placed downstream from the regulatory region was found by the G transition. Our results may suggest that the activity of an allele bearing the p.P482S mutation may be influenced by the misregulated CYP21A2 transcriptional activity exerted by the Z promoter A>G variation.

Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus

PubMed Central

Mahajan, Anubha; Sim, Xueling; Ng, Hui Jin; Manning, Alisa; Rivas, Manuel A.; Highland, Heather M.; Locke, Adam E.; Grarup, Niels; Im, Hae Kyung; Cingolani, Pablo; Flannick, Jason; Fontanillas, Pierre; Fuchsberger, Christian; Gaulton, Kyle J.; Teslovich, Tanya M.; Rayner, N. William; Robertson, Neil R.; Beer, Nicola L.; Rundle, Jana K.; Bork-Jensen, Jette; Ladenvall, Claes; Blancher, Christine; Buck, David; Buck, Gemma; Burtt, Noël P.; Gabriel, Stacey; Gjesing, Anette P.; Groves, Christopher J.; Hollensted, Mette; Huyghe, Jeroen R.; Jackson, Anne U.; Jun, Goo; Justesen, Johanne Marie; Mangino, Massimo; Murphy, Jacquelyn; Neville, Matt; Onofrio, Robert; Small, Kerrin S.; Stringham, Heather M.; Syvänen, Ann-Christine; Trakalo, Joseph; Abecasis, Goncalo; Bell, Graeme I.; Blangero, John; Cox, Nancy J.; Duggirala, Ravindranath; Hanis, Craig L.; Seielstad, Mark; Wilson, James G.; Christensen, Cramer; Brandslund, Ivan; Rauramaa, Rainer; Surdulescu, Gabriela L.; Doney, Alex S. F.; Lannfelt, Lars; Linneberg, Allan; Isomaa, Bo; Tuomi, Tiinamaija; Jørgensen, Marit E.; Jørgensen, Torben; Kuusisto, Johanna; Uusitupa, Matti; Salomaa, Veikko; Spector, Timothy D.; Morris, Andrew D.; Palmer, Colin N. A.; Collins, Francis S.; Mohlke, Karen L.; Bergman, Richard N.; Ingelsson, Erik; Lind, Lars; Tuomilehto, Jaakko; Hansen, Torben; Watanabe, Richard M.; Prokopenko, Inga; Dupuis, Josee; Karpe, Fredrik; Groop, Leif; Laakso, Markku; Pedersen, Oluf; Florez, Jose C.; Morris, Andrew P.; Altshuler, David; Meigs, James B.; Boehnke, Michael; McCarthy, Mark I.; Lindgren, Cecilia M.; Gloyn, Anna L.

2015-01-01

Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights. PMID:25625282

Identification and functional characterization of G6PC2 coding variants influencing glycemic traits define an effector transcript at the G6PC2-ABCB11 locus.

PubMed

Mahajan, Anubha; Sim, Xueling; Ng, Hui Jin; Manning, Alisa; Rivas, Manuel A; Highland, Heather M; Locke, Adam E; Grarup, Niels; Im, Hae Kyung; Cingolani, Pablo; Flannick, Jason; Fontanillas, Pierre; Fuchsberger, Christian; Gaulton, Kyle J; Teslovich, Tanya M; Rayner, N William; Robertson, Neil R; Beer, Nicola L; Rundle, Jana K; Bork-Jensen, Jette; Ladenvall, Claes; Blancher, Christine; Buck, David; Buck, Gemma; Burtt, Noël P; Gabriel, Stacey; Gjesing, Anette P; Groves, Christopher J; Hollensted, Mette; Huyghe, Jeroen R; Jackson, Anne U; Jun, Goo; Justesen, Johanne Marie; Mangino, Massimo; Murphy, Jacquelyn; Neville, Matt; Onofrio, Robert; Small, Kerrin S; Stringham, Heather M; Syvänen, Ann-Christine; Trakalo, Joseph; Abecasis, Goncalo; Bell, Graeme I; Blangero, John; Cox, Nancy J; Duggirala, Ravindranath; Hanis, Craig L; Seielstad, Mark; Wilson, James G; Christensen, Cramer; Brandslund, Ivan; Rauramaa, Rainer; Surdulescu, Gabriela L; Doney, Alex S F; Lannfelt, Lars; Linneberg, Allan; Isomaa, Bo; Tuomi, Tiinamaija; Jørgensen, Marit E; Jørgensen, Torben; Kuusisto, Johanna; Uusitupa, Matti; Salomaa, Veikko; Spector, Timothy D; Morris, Andrew D; Palmer, Colin N A; Collins, Francis S; Mohlke, Karen L; Bergman, Richard N; Ingelsson, Erik; Lind, Lars; Tuomilehto, Jaakko; Hansen, Torben; Watanabe, Richard M; Prokopenko, Inga; Dupuis, Josee; Karpe, Fredrik; Groop, Leif; Laakso, Markku; Pedersen, Oluf; Florez, Jose C; Morris, Andrew P; Altshuler, David; Meigs, James B; Boehnke, Michael; McCarthy, Mark I; Lindgren, Cecilia M; Gloyn, Anna L

2015-01-01

Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights.

The Oxytocin Receptor Gene (OXTR) in Relation to State Levels of Loneliness in Adolescence: Evidence for Micro-Level Gene-Environment Interactions

PubMed Central

van Roekel, Eeske; Verhagen, Maaike; Scholte, Ron H. J.; Kleinjan, Marloes; Goossens, Luc; Engels, Rutger C. M. E.

2013-01-01

Previous research has shown that the rs53576 variant of the oxytocin receptor gene (OXTR) is associated with trait levels of loneliness, but results are inconsistent. The aim of the present study is to examine micro-level effects of the OXTR rs53576 variant on state levels of loneliness in early adolescents. In addition, gene-environment interactions are examined between this OXTR variant and positive and negative perceptions of company. Data were collected in 278 adolescents (58% girls), by means of the Experience Sampling Method (ESM). Sampling periods consisted of six days with nine assessments per day. A relation was found between the OXTR rs53576 variant and state loneliness, in girls only. Girls carrying an A allele had higher levels of state loneliness than girls carrying the GG genotype. In addition, adolescents with an A allele were more affected by negative perceptions of company than GG carriers, on weekend days only. No significant gene-environment interactions were found with positive company. Adolescents carrying an A allele were more susceptible to negative environments during weekend days than GG carriers. Our findings emphasize the importance of operationalizing the phenotype and the environment accurately. PMID:24223720

The oxytocin receptor gene (OXTR) in relation to state levels of loneliness in adolescence: evidence for micro-level gene-environment interactions.

PubMed

van Roekel, Eeske; Verhagen, Maaike; Scholte, Ron H J; Kleinjan, Marloes; Goossens, Luc; Engels, Rutger C M E

2013-01-01

Previous research has shown that the rs53576 variant of the oxytocin receptor gene (OXTR) is associated with trait levels of loneliness, but results are inconsistent. The aim of the present study is to examine micro-level effects of the OXTR rs53576 variant on state levels of loneliness in early adolescents. In addition, gene-environment interactions are examined between this OXTR variant and positive and negative perceptions of company. Data were collected in 278 adolescents (58% girls), by means of the Experience Sampling Method (ESM). Sampling periods consisted of six days with nine assessments per day. A relation was found between the OXTR rs53576 variant and state loneliness, in girls only. Girls carrying an A allele had higher levels of state loneliness than girls carrying the GG genotype. In addition, adolescents with an A allele were more affected by negative perceptions of company than GG carriers, on weekend days only. No significant gene-environment interactions were found with positive company. Adolescents carrying an A allele were more susceptible to negative environments during weekend days than GG carriers. Our findings emphasize the importance of operationalizing the phenotype and the environment accurately.

Sex determination: balancing selection in the honey bee.

PubMed

Charlesworth, Deborah

2004-07-27

Sequences of alleles of the honey bee's primary sex-determining gene have extremely high diversity, with many amino acid variants, suggesting that different alleles of this gene have been maintained in populations for very long evolutionary times.

A family study of DRD3 rs6280, SLC1A2 rs3794087 and MAPT rs1052553 variants in essential tremor.

PubMed

Jiménez-Jiménez, Félix Javier; García-Martín, Elena; Alonso-Navarro, Hortensia; Lorenzo-Betancor, Oswaldo; Ortega-Cubero, Sara; Pastor, Pau; Calleja, Marisol; Agúndez, José A G

2016-10-01

Despite many data suggesting a role of genetic factors in the risk for essential tremor (ET), the responsible genes have not been identified. We analyzed in ET Spanish families three single nucleotide polymorphisms (SNPs): DRD3 rs6280, SLC1A2 rs3794087, and MAPT rs1052553) previously related to an increased risk for developing the disease. We recruited 45 subjects with ET and 13 subjects without tremor belonging to 11 families who were evaluated because of familial tremor. Diagnosis of probable or definite ET was done according to TRIG criteria. Genotyping of the 3 SNPs was done using TaqMan-based qPCR assays. Data were compared with those of healthy controls of our laboratory. Family-based association testing for disease traits was performed as well. rs6280 and rs3794087 genotype and allelic frequencies did not differ significantly between subjects with ET and healthy controls. However, rs1052553AA genotype and the allele rs1052553A allele were significantly more frequent among ET patients. rs1052553A allele was non-significantly overrepresented in ET patients compared with controls when considering only the more severely affected member of each ET family. Family-based association test for disease traits showed lack of association between ET and the three SNPs studied. Our results showed a lack of association between rs6280 and rs3794087 with the risk for ET, though a marginal increased risk for ET was observed among the rs1052553A allele carriers, which was not confirmed with a family-based association study.

Exome sequencing coupled with mRNA analysis identifies NDUFAF6 as a Leigh gene.

PubMed

Bianciardi, Laura; Imperatore, Valentina; Fernandez-Vizarra, Erika; Lopomo, Angela; Falabella, Micol; Furini, Simone; Galluzzi, Paolo; Grosso, Salvatore; Zeviani, Massimo; Renieri, Alessandra; Mari, Francesca; Frullanti, Elisa

2016-11-01

We report here the case of a young male who started to show verbal fluency disturbance, clumsiness and gait anomalies at the age of 3.5years and presented bilateral striatal necrosis. Clinically, the diagnosis was compatible with Leigh syndrome but the underlying molecular defect remained elusive even after exome analysis using autosomal/X-linked recessive or de novo models. Dosage of respiratory chain activity on fibroblasts, but not in muscle, underlined a deficit in complex I. Re-analysis of heterozygous probably pathogenic variants, inherited from one healthy parent, identified the p.Ala178Pro in NDUFAF6, a complex I assembly factor. RNA analysis showed an almost mono-allelic expression of the mutated allele in blood and fibroblasts and puromycin treatment on cultured fibroblasts did not lead to the rescue of the maternal allele expression, not supporting the involvement of nonsense-mediated RNA decay mechanism. Complementation assay underlined a recovery of complex I activity after transduction of the wild-type gene. Since the second mutation was not detected and promoter methylation analysis resulted normal, we hypothesized a non-exonic event in the maternal allele affecting a regulatory element that, in conjunction with the paternal mutation, leads to the autosomal recessive disorder and the different allele expression in various tissues. This paper confirms NDUFAF6 as a genuine morbid gene and proposes the coupling of exome sequencing with mRNA analysis as a method useful for enhancing the exome sequencing detection rate when the simple application of classical inheritance models fails. Copyright © 2016 Elsevier Inc. All rights reserved.

High Levels of Antibodies to Multiple Domains and Strains of VAR2CSA Correlate with the Absence of Placental Malaria in Cameroonian Women Living in an Area of High Plasmodium falciparum Transmission

PubMed Central

Tutterrow, Yeung L.; Avril, Marion; Singh, Kavita; Long, Carole A.; Leke, Robert J.; Sama, Grace; Salanti, Ali; Smith, Joseph D.; Leke, Rose G. F.

2012-01-01

Placental malaria, caused by sequestration of Plasmodium falciparum-infected erythrocytes in the placenta, is associated with increased risk of maternal morbidity and poor birth outcomes. The parasite antigen VAR2CSA (variant surface antigen 2-chondroitin sulfate A) is expressed on infected erythrocytes and mediates binding to chondroitin sulfate A, initiating inflammation and disrupting homeostasis at the maternal-fetal interface. Although antibodies can prevent sequestration, it is unclear whether parasite clearance is due to antibodies to a single Duffy binding-like (DBL) domain or to an extensive repertoire of antibodies to multiple DBL domains and allelic variants. Accordingly, plasma samples collected longitudinally from pregnant women were screened for naturally acquired antibodies against an extensive panel of VAR2CSA proteins, including 2 to 3 allelic variants for each of 5 different DBL domains. Analyses were performed on plasma samples collected from 3 to 9 months of pregnancy from women living in areas in Cameroon with high and low malaria transmission. The results demonstrate that high antibody levels to multiple VAR2CSA domains, rather than a single domain, were associated with the absence of placental malaria when antibodies were present from early in the second trimester until term. Absence of placental malaria was associated with increasing antibody breadth to different DBL domains and allelic variants in multigravid women. Furthermore, the antibody responses of women in the lower-transmission site had both lower magnitude and lesser breadth than those in the high-transmission site. These data suggest that immunity to placental malaria results from high antibody levels to multiple VAR2CSA domains and allelic variants and that antibody breadth is influenced by malaria transmission intensity. PMID:22331427

Variation in the HFE gene is associated with the development of bleomycin-induced pulmonary toxicity in testicular cancer patients.

PubMed

van der Schoot, Gabriela G F; Westerink, Nico-Derk L; Lubberts, Sjoukje; Nuver, Janine; Zwart, Nynke; Walenkamp, Annemiek M E; Wempe, Johan B; Meijer, Coby; Gietema, Jourik A

2016-05-01

Bleomycin and cisplatin are of key importance in testicular cancer treatment. Known potential serious adverse effects are bleomycin-induced pulmonary toxicity (BIP) and cisplatin-induced renal toxicity. Iron handling may play a role in development of this toxicity. Carriage of allelic variants of the HFE gene induces altered iron metabolism and may contribute to toxicity. We investigated the association between two common allelic variants of the HFE gene, H63D and C282Y, with development of pulmonary and renal toxicity during and after treatment with bleomycin- and cisplatin-containing chemotherapy. In 369 testicular cancer patients treated with bleomycin and cisplatin at the University Medical Center Groningen between 1978 and 2006, H63D and/or C282Y genotypes were determined with an allelic discrimination assay. Data were collected on development of BIP, pulmonary function parameters, renal function, and survival. BIP developed more frequently in patients who were heterozygote (16 in 75, 21%) and homozygote (2 in 4, 50%) for the H63D variant, compared with those who had the HFE wild-type gene (31 in 278, 11%) (p = 0.012). Overall survival, testicular cancer-related survival, and change in renal function were not associated with the H63D variant. We observed an association between presence of one or both H63D alleles and development of BIP in testicular cancer patients treated with bleomycin combination chemotherapy. In patients heterozygote and homozygote for the H63D variant, BIP occurred more frequently compared with wild-type patients. When validated and confirmed, HFE H63D genotyping may be used to identify patients with increased risk for pulmonary bleomycin toxicity. Copyright © 2016 Elsevier Ltd. All rights reserved.

Gene variants in the folate-mediated one-carbon metabolism (FOCM) pathway as risk factors for conotruncal heart defects.

PubMed

Zhu, Huiping; Yang, Wei; Lu, Wei; Etheredge, Analee J; Lammer, Edward J; Finnell, Richard H; Carmichael, Suzan L; Shaw, Gary M

2012-05-01

We evaluated 35 variants among four folate-mediated one-carbon metabolism pathway genes, MTHFD1, SHMT1, MTHFR, and DHFR as risk factors for conotruncal heart defects. Cases with a diagnosis of single gene disorders or chromosomal aneusomies were excluded. Controls were randomly selected from area hospitals in proportion to their contribution to the total population of live-born infants. Odds ratios (OR) and the 95% confidence intervals (CI) were computed for each genotype (homozygous variant or heterozygote, vs. homozygous wildtype) and for increase of each less common allele (log-additive model). Interactions between each variant and three folate intake variables (maternal multivitamin use, maternal dietary folate intake, and combined maternal folate intake) were also evaluated under the log-additive model. In general, we did not identify notable associations. The A allele of MTHFD1 rs11627387 was associated with a 1.7-fold increase in conotruncal defects risk in both Hispanic mothers (OR = 1.7, 95% CI = 1.1-2.5) and Hispanic infants (OR = 1.7, 95% CI = 1.2-2.3). The T allele of MTHFR rs1801133 was associated with a 2.8-fold increase of risk among Hispanic women whose dietary folate intake was ≤ 25th centile. The C allele of MTHFR rs1801131 was associated with a two-fold increase of risk (OR = 2.0, 95% CI = 1.0-3.9) only among those whose dietary folate intake was >25th centile. Our study suggested that MTHFD1 rs11627387 may be associated with risk of conotruncal defects through both maternal and offspring genotype effect among the Hispanics. Maternal functional variants in MTHFR gene may interact with dietary folate intake and modify the conotruncal defects risk in the offspring. Copyright © 2012 Wiley Periodicals, Inc.

A Genetic Variant in Vitamin B12 Metabolic Genes That Reduces the Risk of Congenital Heart Disease in Han Chinese Populations

PubMed Central

Wang, Feng; Peng, Qian-Qian; Hou, Jia; Sun, Shu-Na; Gui, Yong-Hao; Duan, Wen-Yuan; Qiao, Bin; Wang, Hong-Yan

2014-01-01

Background Genome-wide association studies on components of the one-carbon metabolic pathway revealed that human vitamin B12 levels could be significantly influenced by variationsinthefucosyltransferase 2 (FUT2), cubilin (CUBN), and transcobalamin-I (TCN1) genes. An altered vitamin B12 level is an important factor that disturbs the homeostasis of the folate metabolism pathway, which in turn can potentially lead to the development of congenital heart disease (CHD). Therefore, we investigated the association between the variants of vitamin B12-related genes and CHD in Han Chinese populations. Methods and Results Six variants of the vitamin B12-related genes were selected for analysis in two independent case-control studies, with a total of 868 CHD patients and 931 controls. The variant rs11254363 of the CUBN gene was associated with a decreased risk of developing CHD in both the separate and combined case-control studies. Combined samples from the two cohorts had a significant decrease in CHD risk for the G allele (OR = 0.48, P = 1.7×10−5) and AG+GG genotypes (OR = 0.49, P = 4×10−5), compared with the wild-type A allele and AA genotype, respectively. Conclusions Considering the G allele of variant rs11254363 of the CUBN gene was associated with an increased level of circulating vitamin B12. This result suggested that the carriers of the G allele would benefit from the protection offered by the high vitamin B12 concentration during critical heart development stages. This finding shed light on the unexpected role of CUBN in CHD development and highlighted the interplay of diet, genetics, and human birth defects. PMID:24533076

Genetic variants in endotoxin signalling pathway, domestic endotoxin exposure and asthma exacerbations.

PubMed

Kljaic-Bukvic, Blazenka; Blekic, Mario; Aberle, Neda; Curtin, John A; Hankinson, Jenny; Semic-Jusufagic, Aida; Belgrave, Danielle; Simpson, Angela; Custovic, Adnan

2014-10-01

We investigated the interaction between genetic variants in endotoxin signalling pathway and domestic endotoxin exposure in relation to asthma presence, and amongst children with asthma, we explored the association of these genetic variants and endotoxin exposure with hospital admissions due to asthma exacerbations. In a case-control study, we analysed data from 824 children (417 asthmatics, 407 controls; age 5-18 yr). Amongst asthmatics, we extracted data on hospitalization for asthma exacerbation from medical records. Endotoxin exposure was measured in dust samples collected from homes. We included 26 single-nucleotide polymorphisms (SNPs) in the final analysis (5 CD14, 7LY96 and 14 TLR4). Two variants remained significantly associated with hospital admissions with asthma exacerbations after correction for multiple testing: for CD14 SNP rs5744455, carriers of T allele had decreased risk of repeated hospital admissions compared with homozygotes for C allele [OR (95% CI), 0.42 (0.25-0.88), p = 0.01, False Discovery Rate (FDR) p = 0.02]; for LY96 SNP rs17226566, C-allele carriers were at a lower risk of hospital admissions compared with T-allele homozygotes [0.59 (0.38-0.90), p = 0.01, FDR p = 0.04]. We observed two interactions between SNPs in CD14 and LY96 with environmental endotoxin exposure in relation to hospital admissions due to asthma exacerbation which remained significant after correction for multiple testing (CD14 SNPs rs2915863 and LY96 SNP rs17226566). Amongst children with asthma, genetic variants in CD14 and LY96 may increase the risk of hospital admissions with acute exacerbations. Polymorphisms in endotoxin pathway interact with domestic endotoxin exposure in further modification of the risk of hospitalization. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Comparison of Direct Sequencing, Real-Time PCR-High Resolution Melt (PCR-HRM) and PCR-Restriction Fragment Length Polymorphism (PCR-RFLP) Analysis for Genotyping of Common Thiopurine Intolerant Variant Alleles NUDT15 c.415C>T and TPMT c.719A>G (TPMT*3C).

PubMed

Fong, Wai-Ying; Ho, Chi-Chun; Poon, Wing-Tat

2017-05-12

Thiopurine intolerance and treatment-related toxicity, such as fatal myelosuppression, is related to non-function genetic variants encoding thiopurine S-methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15). Genetic testing of the common variants NUDT15:NM_018283.2:c.415C>T (Arg139Cys, dbSNP rs116855232 T allele) and TPMT: NM_000367.4:c.719A>G (TPMT*3C, dbSNP rs1142345 G allele) in East Asians including Chinese can potentially prevent treatment-related complications. Two complementary genotyping approaches, real-time PCR-high resolution melt (PCR-HRM) and PCR-restriction fragment length morphism (PCR-RFLP) analysis were evaluated using conventional PCR and Sanger sequencing genotyping as the gold standard. Sixty patient samples were tested, revealing seven patients (11.7%) heterozygous for NUDT15 c.415C>T, one patient homozygous for the variant and one patient heterozygous for the TPMT*3C non-function allele. No patient was found to harbor both variants. In total, nine out of 60 (15%) patients tested had genotypic evidence of thiopurine intolerance, which may require dosage adjustment or alternative medication should they be started on azathioprine, mercaptopurine or thioguanine. The two newly developed assays were more efficient and showed complete concordance (60/60, 100%) compared to the Sanger sequencing results. Accurate and cost-effective genotyping assays by real-time PCR-HRM and PCR-RFLP for NUDT15 c.415C>T and TPMT*3C were successfully developed. Further studies may establish their roles in genotype-informed clinical decision-making in the prevention of morbidity and mortality due to thiopurine intolerance.

Systematic Integration of Brain eQTL and GWAS Identifies ZNF323 as a Novel Schizophrenia Risk Gene and Suggests Recent Positive Selection Based on Compensatory Advantage on Pulmonary Function

PubMed Central

Luo, Xiong-Jian; Mattheisen, Manuel; Li, Ming; Huang, Liang; Rietschel, Marcella; Børglum, Anders D.; Als, Thomas D.; van den Oord, Edwin J.; Aberg, Karolina A.; Mors, Ole; Mortensen, Preben Bo; Luo, Zhenwu; Degenhardt, Franziska; Cichon, Sven; Schulze, Thomas G.; Nöthen, Markus M.; Su, Bing; Zhao, Zhongming; Gan, Lin; Yao, Yong-Gang

2015-01-01

Genome-wide association studies have identified multiple risk variants and loci that show robust association with schizophrenia. Nevertheless, it remains unclear how these variants confer risk to schizophrenia. In addition, the driving force that maintains the schizophrenia risk variants in human gene pool is poorly understood. To investigate whether expression-associated genetic variants contribute to schizophrenia susceptibility, we systematically integrated brain expression quantitative trait loci and genome-wide association data of schizophrenia using Sherlock, a Bayesian statistical framework. Our analyses identified ZNF323 as a schizophrenia risk gene (P = 2.22×10–6). Subsequent analyses confirmed the association of the ZNF323 and its expression-associated single nucleotide polymorphism rs1150711 in independent samples (gene-expression: P = 1.40×10–6; single-marker meta-analysis in the combined discovery and replication sample comprising 44123 individuals: P = 6.85×10−10). We found that the ZNF323 was significantly downregulated in hippocampus and frontal cortex of schizophrenia patients (P = .0038 and P = .0233, respectively). Evidence for pleiotropic effects was detected (association of rs1150711 with lung function and gene expression of ZNF323 in lung: P = 6.62×10–5 and P = 9.00×10–5, respectively) with the risk allele (T allele) for schizophrenia acting as protective allele for lung function. Subsequent population genetics analyses suggest that the risk allele (T) of rs1150711 might have undergone recent positive selection in human population. Our findings suggest that the ZNF323 is a schizophrenia susceptibility gene whose expression may influence schizophrenia risk. Our study also illustrates a possible mechanism for maintaining schizophrenia risk variants in the human gene pool. PMID:25759474

Functional non-synonymous variants of ABCG2 and gout risk.

PubMed

Stiburkova, Blanka; Pavelcova, Katerina; Zavada, Jakub; Petru, Lenka; Simek, Pavel; Cepek, Pavel; Pavlikova, Marketa; Matsuo, Hirotaka; Merriman, Tony R; Pavelka, Karel

2017-11-01

Common dysfunctional variants of ATP binding cassette subfamily G member 2 (Junior blood group) (ABCG2), a high-capacity urate transporter gene, that result in decreased urate excretion are major causes of hyperuricemia and gout. In the present study, our objective was to determine the frequency and effect on gout of common and rare non-synonymous and other functional allelic variants in the ABCG2 gene. The main cohort recruited from the Czech Republic consisted of 145 gout patients; 115 normouricaemic controls were used for comparison. We amplified, directly sequenced and analysed 15 ABCG2 exons. The associations between genetic variants and clinical phenotype were analysed using the t-test, Fisher's exact test and a logistic and linear regression approach. Data from a New Zealand Polynesian sample set and the UK Biobank were included for the p.V12M analysis. In the ABCG2 gene, 18 intronic (one dysfunctional splicing) and 11 exonic variants were detected: 9 were non-synonymous (2 common, 7 rare including 1 novel), namely p.V12M, p.Q141K, p.R147W, p.T153M, p.F373C, p.T434M, p.S476P, p.D620N and p.K360del. The p.Q141K (rs2231142) variant had a significantly higher minor allele frequency (0.23) in the gout patients compared with the European-origin population (0.09) and was significantly more common among gout patients than among normouricaemic controls (odds ratio = 3.26, P < 0.0001). Patients with non-synonymous allelic variants had an earlier onset of gout (42 vs 48 years, P = 0.0143) and a greater likelihood of a familial history of gout (41% vs 27%, odds ratio = 1.96, P = 0.053). In a meta-analysis p.V12M exerted a protective effect from gout (P < 0.0001). Genetic variants of ABCG2, common and rare, increased the risk of gout. Non-synonymous allelic variants of ABCG2 had a significant effect on earlier onset of gout and the presence of a familial gout history. ABCG2 should thus be considered a common and significant risk factor for gout. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Evaluation of Allele-Specific Somatic Changes of Genome-Wide Association Study Susceptibility Alleles in Human Colorectal Cancers

PubMed Central

Gerber, Madelyn M.; Hampel, Heather; Schulz, Nathan P.; Fernandez, Soledad; Wei, Lai; Zhou, Xiao-Ping; de la Chapelle, Albert; Toland, Amanda Ewart

2012-01-01

Background Tumors frequently exhibit loss of tumor suppressor genes or allelic gains of activated oncogenes. A significant proportion of cancer susceptibility loci in the mouse show somatic losses or gains consistent with the presence of a tumor susceptibility or resistance allele. Thus, allele-specific somatic gains or losses at loci may demarcate the presence of resistance or susceptibility alleles. The goal of this study was to determine if previously mapped susceptibility loci for colorectal cancer show evidence of allele-specific somatic events in colon tumors. Methods We performed quantitative genotyping of 16 single nucleotide polymorphisms (SNPs) showing statistically significant association with colorectal cancer in published genome-wide association studies (GWAS). We genotyped 194 paired normal and colorectal tumor DNA samples and 296 paired validation samples to investigate these SNPs for allele-specific somatic gains and losses. We combined analysis of our data with published data for seven of these SNPs. Results No statistically significant evidence for allele-specific somatic selection was observed for the tested polymorphisms in the discovery set. The rs6983267 variant, which has shown preferential loss of the non-risk T allele and relative gain of the risk G allele in previous studies, favored relative gain of the G allele in the combined discovery and validation samples (corrected p-value = 0.03). When we combined our data with published allele-specific imbalance data for this SNP, the G allele of rs6983267 showed statistically significant evidence of relative retention (p-value = 2.06×10−4). Conclusions Our results suggest that the majority of variants identified as colon cancer susceptibility alleles through GWAS do not exhibit somatic allele-specific imbalance in colon tumors. Our data confirm previously published results showing allele-specific imbalance for rs6983267. These results indicate that allele-specific imbalance of cancer susceptibility alleles may not be a common phenomenon in colon cancer. PMID:22629442

Complex and multi-allelic copy number variation in human disease

PubMed Central

McCarroll, Steven A.

2015-01-01

Hundreds of copy number variants are complex and multi-allelic, in that they have many structural alleles and have rearranged multiple times in the ancestors who contributed chromosomes to current humans. Not only are the relationships of these multi-allelic CNVs (mCNVs) to phenotypes generally unknown, but many mCNVs have not yet been described at the basic levels—alleles, allele frequencies, structural features—that support genetic investigation. To date, most reported disease associations to these variants have been ascertained through candidate gene studies. However, only a few associations have reached the level of acceptance defined by durable replications in many cohorts. This likely stems from longstanding challenges in making precise molecular measurements of the alleles individuals have at these loci. However, approaches for mCNV analysis are improving quickly, and some of the unique characteristics of mCNVs may assist future association studies. Their various structural alleles are likely to have different magnitudes of effect, creating a natural allelic series of growing phenotypic impact and giving investigators a set of natural predictions and testable hypotheses about the extent to which each allele of an mCNV predisposes to a phenotype. Also, mCNVs’ low-to-modest correlation to individual single-nucleotide polymorphisms (SNPs) may make it easier to distinguish between mCNVs and nearby SNPs as the drivers of an association signal, and perhaps, make it possible to preliminarily screen candidate loci, or the entire genome, for the many mCNV–disease relationships that remain to be discovered. PMID:26163405

GWAS-identified schizophrenia risk SNPs at TSPAN18 are highly diverged between Europeans and East Asians.

PubMed

Liu, Jiewei; Li, Ming; Su, Bing

2016-12-01

Genome-wide association studies (GWASs) have identified multiple schizophrenia (SCZ) risk variants for samples of European and East Asian descent, but most of the identified susceptibility variants are population-specific to either Europeans or East Asians. This strong genetic heterogeneity suggests that differential population histories may play a role in SCZ susceptibility. Here, we explored this possibility by examining the allele frequency divergence of 136 previously reported genome-wide SCZ risk SNPs between European and East Asian populations. Our results showed that two SNPs (rs11038167 and rs11038172) at TSPAN18, reported as genome-wide significant SCZ risk variants in Han Chinese, were entirely monomorphic in Europeans, indicating a deep between-population divergence at this gene locus. To explore the evolutionary history of TSPAN18 in East Asians, we conducted population genetic analyses including multiple neutrality tests, the haplotype-based iHS and EHH tests, as well as haplotype bifurcation map and network constructions. We found that the protective allele of rs11038172 (G allele) had a long extended haplotype with much slower decay compared to the A allele. The star-like shape of the G-allele-carrying haplotypes indicates a recent enrichment in East Asians. Together, the evidences suggest that the protective allele of rs11038172 has experienced recent Darwinian positive selection in East Asians. These findings provide new insights that may help explain the strong genetic heterogeneity in SCZ risk and previous inconsistent association results for SCZ among both Europeans and East Asians. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Temporal Expression Profiling Identifies Pathways Mediating Effect of Causal Variant on Phenotype

PubMed Central

Gupta, Saumya; Radhakrishnan, Aparna; Raharja-Liu, Pandu; Lin, Gen; Steinmetz, Lars M.; Gagneur, Julien; Sinha, Himanshu

2015-01-01

Even with identification of multiple causal genetic variants for common human diseases, understanding the molecular processes mediating the causal variants’ effect on the disease remains a challenge. This understanding is crucial for the development of therapeutic strategies to prevent and treat disease. While static profiling of gene expression is primarily used to get insights into the biological bases of diseases, it makes differentiating the causative from the correlative effects difficult, as the dynamics of the underlying biological processes are not monitored. Using yeast as a model, we studied genome-wide gene expression dynamics in the presence of a causal variant as the sole genetic determinant, and performed allele-specific functional validation to delineate the causal effects of the genetic variant on the phenotype. Here, we characterized the precise genetic effects of a functional MKT1 allelic variant in sporulation efficiency variation. A mathematical model describing meiotic landmark events and conditional activation of MKT1 expression during sporulation specified an early meiotic role of this variant. By analyzing the early meiotic genome-wide transcriptional response, we demonstrate an MKT1-dependent role of novel modulators, namely, RTG1/3, regulators of mitochondrial retrograde signaling, and DAL82, regulator of nitrogen starvation, in additively effecting sporulation efficiency. In the presence of functional MKT1 allele, better respiration during early sporulation was observed, which was dependent on the mitochondrial retrograde regulator, RTG3. Furthermore, our approach showed that MKT1 contributes to sporulation independent of Puf3, an RNA-binding protein that steady-state transcription profiling studies have suggested to mediate MKT1-pleiotropic effects during mitotic growth. These results uncover interesting regulatory links between meiosis and mitochondrial retrograde signaling. In this study, we highlight the advantage of analyzing allele-specific transcriptional dynamics of mediating genes. Applications in higher eukaryotes can be valuable for inferring causal molecular pathways underlying complex dynamic processes, such as development, physiology and disease progression. PMID:26039065

Routine HLA-B genotyping with PCR-sequence-specific oligonucleotides detects a B*52 variant (B*5206).

PubMed

Hoelsch, K; Lenggeler, I; Pfannes, W; Knabe, H; Klein, H-G; Woelpl, A

2005-05-01

A new human leukocyte antigen (HLA)-B allele was found during routine typing of samples for a German unrelated bone marrow donor registry, the "Aktion Knochenmarkspende Bayern". After first interpretation of data of two independent low-resolution sequence-specific oligonucleotide typing tests, a B*51 variant was suggested. Further analysis via sequence-based typing identified the sequence as new B*52 allele. This new allele officially assigned as B*5206 differs from HLA-B*520102 by one nucleotide exchange in exon 2. The mutation is located at nucleotide position 274, at which a cytosine is substituted by a thymine leading to an amino acid change at protein position 67 from serine (TCC) to phenylalanine (TTC).

Evaluation of regulatory genetic variants in POU5F1 and risk of congenital heart disease in Han Chinese

NASA Astrophysics Data System (ADS)

Lin, Yuan; Ding, Chenyue; Zhang, Kai; Ni, Bixian; da, Min; Hu, Liang; Hu, Yuanli; Xu, Jing; Wang, Xiaowei; Chen, Yijiang; Mo, Xuming; Cui, Yugui; Shen, Hongbing; Sha, Jiahao; Liu, Jiayin; Hu, Zhibin

2015-10-01

OCT4 is a transcription factor of the POU family, which plays a key role in embryonic development and stem cell pluripotency. Previous studies have shown that Oct4 is required for cardiomyocyte differentiation in mice and its depletion could result in cardiac morphogenesis in embryo. However, whether the genetic variations in OCT4 coding gene, POU5F1, confer the predisposition to congenital heart disease (CHD) is unclear. This study sought to investigate the associations between low-frequency (defined here as having minor allele frequency (MAF) between 0.1%-5%) and rare (MAF below 0.1%) variants with potential function in POU5F1 and risk of CHD. We conducted association analysis in a two-stage case-control study with a total of 2,720 CHD cases and 3,331 controls in Chinese. The low-frequency variant rs3130933 was observed to be associated with a significantly increased risk of CHD [additive model: adjusted odds ratio (OR) = 2.15, adjusted P = 3.37 × 10-6]. Furthermore, luciferase activity assay showed that the variant A allele led to significantly lower expression levels as compared to the G allele. These findings indicate for the first time that low-frequency functional variant in POU5F1 may contribute to the risk of congenital heart malformations.

The IL23R R381Q Gene Variant Protects against Immune-Mediated Diseases by Impairing IL-23-Induced Th17 Effector Response in Humans

PubMed Central

Di Meglio, Paola; Di Cesare, Antonella; Laggner, Ute; Chu, Chung-Ching; Napolitano, Luca; Villanova, Federica; Tosi, Isabella; Capon, Francesca; Trembath, Richard C.; Peris, Ketty; Nestle, Frank O.

2011-01-01

IL-23 and Th17 cells are key players in tissue immunosurveillance and are implicated in human immune-mediated diseases. Genome-wide association studies have shown that the IL23R R381Q gene variant protects against psoriasis, Crohn's disease and ankylosing spondylitis. We investigated the immunological consequences of the protective IL23R R381Q gene variant in healthy donors. The IL23R R381Q gene variant had no major effect on Th17 cell differentiation as the frequency of circulating Th17 cells was similar in carriers of the IL23R protective (A) and common (G) allele. Accordingly, Th17 cells generated from A and G donors produced similar amounts of Th17 cytokines. However, IL-23-mediated Th17 cell effector function was impaired, as Th17 cells from A allele carriers had significantly reduced IL-23-induced IL-17A production and STAT3 phosphorylation compared to G allele carriers. Our functional analysis of a human disease-associated gene variant demonstrates that IL23R R381Q exerts its protective effects through selective attenuation of IL-23-induced Th17 cell effector function without interfering with Th17 differentiation, and highlights its importance in the protection against IL-23-induced tissue pathologies. PMID:21364948

The IL23R R381Q gene variant protects against immune-mediated diseases by impairing IL-23-induced Th17 effector response in humans.

PubMed

Di Meglio, Paola; Di Cesare, Antonella; Laggner, Ute; Chu, Chung-Ching; Napolitano, Luca; Villanova, Federica; Tosi, Isabella; Capon, Francesca; Trembath, Richard C; Peris, Ketty; Nestle, Frank O

2011-02-22

IL-23 and Th17 cells are key players in tissue immunosurveillance and are implicated in human immune-mediated diseases. Genome-wide association studies have shown that the IL23R R381Q gene variant protects against psoriasis, Crohn's disease and ankylosing spondylitis. We investigated the immunological consequences of the protective IL23R R381Q gene variant in healthy donors. The IL23R R381Q gene variant had no major effect on Th17 cell differentiation as the frequency of circulating Th17 cells was similar in carriers of the IL23R protective (A) and common (G) allele. Accordingly, Th17 cells generated from A and G donors produced similar amounts of Th17 cytokines. However, IL-23-mediated Th17 cell effector function was impaired, as Th17 cells from A allele carriers had significantly reduced IL-23-induced IL-17A production and STAT3 phosphorylation compared to G allele carriers. Our functional analysis of a human disease-associated gene variant demonstrates that IL23R R381Q exerts its protective effects through selective attenuation of IL-23-induced Th17 cell effector function without interfering with Th17 differentiation, and highlights its importance in the protection against IL-23-induced tissue pathologies.

Allele-Specific Alternative mRNA processing (ASARP) | Informatics Technology for Cancer Research (ITCR)

Cancer.gov

A software pipeline for prediction of allele-specific alternative RNA processing events using single RNA-seq data. The current version focuses on prediction of alternative splicing and alternative polyadenylation modulated by genetic variants.

The effect of the cytochrome P450 CYP2C8 polymorphism on the disposition of (R)-ibuprofen enantiomer in healthy subjects

PubMed Central

Martínez, Carmen; García-Martín, Elena; Blanco, Gerardo; Gamito, Francisco J G; Ladero, José M; Agúndez, José A G

2005-01-01

Aims To study the effect of CYP2C8*3, the most common CYP2C8 variant allele on the dis-position of (R)-ibuprofen and the association of CYP2C8*3 with variant CYP2C9 alleles. Methods Three hundred and fifty-five randomly selected Spanish Caucasians were screened for the common CYP2C8 and CYP2C9 mutations. The pharmacokinetics of (R)-ibuprofen were studied in 25 individuals grouped into different CYP2C8 genotypes. Results The allele frequency of CYP2C8*3 (0.17) was found to be higher than that reported for other Caucasian populations (P = 0.0001). The frequencies of CYP2C9*2 and CYP2C9*3 were 0.19 (0.16–0.21) and 0.10 (0.08–0.12), respectively. An association between CYP2C8*3 and CYP2C9*2 alleles was observed, occurring together at a frequency 2.4-fold higher than expected for a random association of alleles (P = 0.0001). The presence of the CYP2C8*3 allele was found to influence the pharmacokinetics of (R)-ibuprofen in a gene–dose effect manner. Thus, after administration of 400 mg ibuprofen, the plasma half-life (95% confidence intervals) for individuals with genotypes CYP2C8*1/*1, CYP2C8*1/*3 and CYP2C8*3/*3, was 2.0 h (1.8–2.2), 4.2 h (1.9–6.5; P < 0.05) and 9.0 h (7.8–10.2; P < 0.002), respectively. A statistically significant trend with respect to the number of variant CYP2C8*3 alleles was also observed for the area under the concentration-time curve (P < 0.025), and drug clearance (P < 0.03). Conclusion Polymorphism of the CYP2C8 gene was found to be common, with nearly 30% of the population studied carrying the variant CYP2C8*3 allele. The presence of the latter caused a significant effect on the disposition of (R)-ibuprofen. This suggests that a substantial proportion of Caucasian subjects may show alterations in the disposition of drugs that are CYP2C8 substrates. PMID:15606441

Visualizing the geography of genetic variants.

PubMed

Marcus, Joseph H; Novembre, John

2017-02-15

One of the key characteristics of any genetic variant is its geographic distribution. The geographic distribution can shed light on where an allele first arose, what populations it has spread to, and in turn on how migration, genetic drift, and natural selection have acted. The geographic distribution of a genetic variant can also be of great utility for medical/clinical geneticists and collectively many genetic variants can reveal population structure. Here we develop an interactive visualization tool for rapidly displaying the geographic distribution of genetic variants. Through a REST API and dynamic front-end, the Geography of Genetic Variants (GGV) browser ( http://popgen.uchicago.edu/ggv/ ) provides maps of allele frequencies in populations distributed across the globe. GGV is implemented as a website ( http://popgen.uchicago.edu/ggv/ ) which employs an API to access frequency data ( http://popgen.uchicago.edu/freq_api/ ). Python and javascript source code for the website and the API are available at: http://github.com/NovembreLab/ggv/ and http://github.com/NovembreLab/ggv-api/ . jnovembre@uchicago.edu. Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press.

APOL1 allelic variants are associated with lower age of dialysis initiation and thereby increased dialysis vintage in African and Hispanic Americans with non-diabetic end-stage kidney disease.

PubMed

Tzur, Shay; Rosset, Saharon; Skorecki, Karl; Wasser, Walter G

2012-04-01

The APOL1 G1 and G2 genetic variants make a major contribution to the African ancestry risk for a number of common forms of non-diabetic end-stage kidney disease (ESKD). We sought to clarify the relationship of APOL1 variants with age of dialysis initiation and dialysis vintage (defined by the time between dialysis initiation and sample collection) in African and Hispanic Americans, diabetic and non-diabetic ESKD. We examined APOL1 genotypes in 995 African and Hispanic American dialysis patients with diabetic and non-diabetic ESKD. The mean age of dialysis initiation for non-diabetic African-American patients with two APOL1 risk alleles was 48.1 years, >9 years earlier than those without APOL1 risk alleles (t-test, P=0.0003). Similar results were found in the non-diabetic Hispanic American cohort, but not in the diabetic cohorts. G1 heterozygotes showed a 5.3-year lower mean age of dialysis initiation (t-test, P=0.0452), but G2 heterozygotes did not show such an effect. At the age of 70, 92% of individuals with two APOL1 risk alleles had already initiated dialysis, compared with 76% of the patients without APOL1 risk alleles. Although two APOL1 risk alleles are also associated with ∼2 years increased in dialysis vintage, further analysis showed that this increase is fully explained by earlier age of dialysis initiation. Two APOL1 risk alleles significantly predict lower age of dialysis initiation and thereby increased dialysis vintage in non-diabetic ESKD African and Hispanic Americans, but not in diabetic ESKD. A single APOL1 G1, but not G2, risk allele also lowers the age of dialysis initiation, apparently consistent with gain of injury or loss of function mechanisms. Hence, APOL1 mutations produce a distinct category of kidney disease that manifests at younger ages in African ancestry populations.

The effect of PCSK1 variants on waist, waist-hip ratio and glucose metabolism is modified by sex and glucose tolerance status.

PubMed

Gjesing, Anette P; Vestmar, Marie A; Jørgensen, Torben; Heni, Martin; Holst, Jens J; Witte, Daniel R; Hansen, Torben; Pedersen, Oluf

2011-01-01

We aimed to evaluate the effects of the G-allele of rs6232 and the C-allele of rs6235 within PCSK1 on measures of body fat and glucose homeostasis in Danish individuals and to assess interactions of genotypes with age, sex and glucose tolerance status. Data were included in meta-analyses of additional Europeans. Rs6232 and rs6235 were genotyped in 6,164 Danes from the Inter99 study of middle-aged people. Results from these analyses were combined with previously published studies in meta-analyses of a total of 27,786 individuals. The impact of the variants was also investigated in a subset of 62 glucose-tolerant men during a meal challenge including measures of serum incretins. In men we found an effect on body composition in sex-stratified analyses where the rs6235 C-allele conferred an increased waist circumference of 0.8 cm per allele (0.2-1.5, p = 0.008) and increased waist-to-hip ratio of 0.004 (0.0005-0.008, p = 0.027). In the meta-analyses where men and women were combined, the rs6232 G-allele associated with increased waist-to-hip ratio (p = 0.02) and the rs6235 C-allele associated with increased waist circumference (p = 0.01). Furthermore, the rs6235 C-allele was associated nominally with a 0.6% (0.1-1%, p = 0.01) reduction in fasting glucose, it interacted with glucose tolerance status for traits related to glucose metabolism and analysis among individuals having abnormal glucose tolerance revealed a 5% (-0.7-9%, p = 0.02) elevated level of acute insulin response for this variant. Finally, we found that the rs6232 G-allele associated with higher levels of GLP-1, GLP-2 and glucagon and that the rs6235 C-allele associated with higher levels of GIP and glucagon during a meal-test. PCSK1 rs6232 G-allele and rs6235 C-allele have an effect on body composition which may be modified by sex, whereas the effect of rs6235 C-allele on fasting and stimulated circulating plasma glucose and hormone levels may be influenced by glucose tolerance status.

The Effect of PCSK1 Variants on Waist, Waist-Hip Ratio and Glucose Metabolism Is Modified by Sex and Glucose Tolerance Status

PubMed Central

Gjesing, Anette P.; Vestmar, Marie A.; Jørgensen, Torben; Heni, Martin; Holst, Jens J.; Witte, Daniel R.; Hansen, Torben; Pedersen, Oluf

2011-01-01

Background We aimed to evaluate the effects of the G-allele of rs6232 and the C-allele of rs6235 within PCSK1 on measures of body fat and glucose homeostasis in Danish individuals and to assess interactions of genotypes with age, sex and glucose tolerance status. Data were included in meta-analyses of additional Europeans. Methodology/Principal Findings Rs6232 and rs6235 were genotyped in 6,164 Danes from the Inter99 study of middle-aged people. Results from these analyses were combined with previously published studies in meta-analyses of a total of 27,786 individuals. The impact of the variants was also investigated in a subset of 62 glucose-tolerant men during a meal challenge including measures of serum incretins. In men we found an effect on body composition in sex-stratified analyses where the rs6235 C-allele conferred an increased waist circumference of 0.8 cm per allele (0.2–1.5, p = 0.008) and increased waist-to-hip ratio of 0.004 (0.0005–0.008, p = 0.027). In the meta-analyses where men and women were combined, the rs6232 G-allele associated with increased waist-to-hip ratio (p = 0.02) and the rs6235 C-allele associated with increased waist circumference (p = 0.01). Furthermore, the rs6235 C-allele was associated nominally with a 0.6% (0.1–1%, p = 0.01) reduction in fasting glucose, it interacted with glucose tolerance status for traits related to glucose metabolism and analysis among individuals having abnormal glucose tolerance revealed a 5% (−0.7–9%, p = 0.02) elevated level of acute insulin response for this variant. Finally, we found that the rs6232 G-allele associated with higher levels of GLP-1, GLP-2 and glucagon and that the rs6235 C-allele associated with higher levels of GIP and glucagon during a meal-test. Conclusions/Significance PCSK1 rs6232 G-allele and rs6235 C-allele have an effect on body composition which may be modified by sex, whereas the effect of rs6235 C-allele on fasting and stimulated circulating plasma glucose and hormone levels may be influenced by glucose tolerance status. PMID:21935364

A statistical method for the detection of variants from next-generation resequencing of DNA pools.

PubMed

Bansal, Vikas

2010-06-15

Next-generation sequencing technologies have enabled the sequencing of several human genomes in their entirety. However, the routine resequencing of complete genomes remains infeasible. The massive capacity of next-generation sequencers can be harnessed for sequencing specific genomic regions in hundreds to thousands of individuals. Sequencing-based association studies are currently limited by the low level of multiplexing offered by sequencing platforms. Pooled sequencing represents a cost-effective approach for studying rare variants in large populations. To utilize the power of DNA pooling, it is important to accurately identify sequence variants from pooled sequencing data. Detection of rare variants from pooled sequencing represents a different challenge than detection of variants from individual sequencing. We describe a novel statistical approach, CRISP [Comprehensive Read analysis for Identification of Single Nucleotide Polymorphisms (SNPs) from Pooled sequencing] that is able to identify both rare and common variants by using two approaches: (i) comparing the distribution of allele counts across multiple pools using contingency tables and (ii) evaluating the probability of observing multiple non-reference base calls due to sequencing errors alone. Information about the distribution of reads between the forward and reverse strands and the size of the pools is also incorporated within this framework to filter out false variants. Validation of CRISP on two separate pooled sequencing datasets generated using the Illumina Genome Analyzer demonstrates that it can detect 80-85% of SNPs identified using individual sequencing while achieving a low false discovery rate (3-5%). Comparison with previous methods for pooled SNP detection demonstrates the significantly lower false positive and false negative rates for CRISP. Implementation of this method is available at http://polymorphism.scripps.edu/~vbansal/software/CRISP/.

Fine-Scale Mapping of the 5q11.2 Breast Cancer Locus Reveals at Least Three Independent Risk Variants Regulating MAP3K1

PubMed Central

Glubb, Dylan M.; Maranian, Mel J.; Michailidou, Kyriaki; Pooley, Karen A.; Meyer, Kerstin B.; Kar, Siddhartha; Carlebur, Saskia; O’Reilly, Martin; Betts, Joshua A.; Hillman, Kristine M.; Kaufmann, Susanne; Beesley, Jonathan; Canisius, Sander; Hopper, John L.; Southey, Melissa C.; Tsimiklis, Helen; Apicella, Carmel; Schmidt, Marjanka K.; Broeks, Annegien; Hogervorst, Frans B.; van der Schoot, C. Ellen; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Fasching, Peter A.; Ruebner, Matthias; Ekici, Arif B.; Beckmann, Matthias W.; Peto, Julian; dos-Santos-Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Pharoah, Paul D.P.; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Sawyer, Elinor J.; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Burwinkel, Barbara; Marme, Frederik; Yang, Rongxi; Surowy, Harald; Guénel, Pascal; Truong, Thérèse; Menegaux, Florence; Sanchez, Marie; Bojesen, Stig E.; Nordestgaard, Børge G.; Nielsen, Sune F.; Flyger, Henrik; González-Neira, Anna; Benitez, Javier; Zamora, M. Pilar; Arias Perez, Jose Ignacio; Anton-Culver, Hoda; Neuhausen, Susan L.; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Meindl, Alfons; Schmutzler, Rita K.; Brauch, Hiltrud; Ko, Yon-Dschun; Brüning, Thomas; Nevanlinna, Heli; Muranen, Taru A.; Aittomäki, Kristiina; Blomqvist, Carl; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Tanaka, Hideo; Dörk, Thilo; Bogdanova, Natalia V.; Helbig, Sonja; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.; Wu, Anna H.; Tseng, Chiu-chen; Van Den Berg, David; Stram, Daniel O.; Lambrechts, Diether; Zhao, Hui; Weltens, Caroline; van Limbergen, Erik; Chang-Claude, Jenny; Flesch-Janys, Dieter; Rudolph, Anja; Seibold, Petra; Radice, Paolo; Peterlongo, Paolo; Barile, Monica; Capra, Fabio; Couch, Fergus J.; Olson, Janet E.; Hallberg, Emily; Vachon, Celine; Giles, Graham G.; Milne, Roger L.; McLean, Catriona; Haiman, Christopher A.; Henderson, Brian E.; Schumacher, Fredrick; Le Marchand, Loic; Simard, Jacques; Goldberg, Mark S.; Labrèche, France; Dumont, Martine; Teo, Soo Hwang; Yip, Cheng Har; See, Mee-Hoong; Cornes, Belinda; Cheng, Ching-Yu; Ikram, M. Kamran; Kristensen, Vessela; Zheng, Wei; Halverson, Sandra L.; Shrubsole, Martha; Long, Jirong; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Tchatchou, Sandrine; Devilee, Peter; Tollenaar, Robert A.E.M.; Seynaeve, Caroline; Van Asperen, Christi J.; García-Closas, Montserrat; Figueroa, Jonine; Chanock, Stephen J.; Lissowska, Jolanta; Czene, Kamila; Klevebring, Daniel; Darabi, Hatef; Eriksson, Mikael; Hooning, Maartje J.; Hollestelle, Antoinette; Martens, John W.M.; Collée, J. Margriet; Hall, Per; Li, Jingmei; Humphreys, Keith; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Cox, Angela; Cross, Simon S.; Reed, Malcolm W.R.; Blot, William; Signorello, Lisa B.; Cai, Qiuyin; Shah, Mitul; Ghoussaini, Maya; Kang, Daehee; Choi, Ji-Yeob; Park, Sue K.; Noh, Dong-Young; Hartman, Mikael; Miao, Hui; Lim, Wei Yen; Tang, Anthony; Hamann, Ute; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; McKay, James; Olswold, Curtis; Slager, Susan; Toland, Amanda E.; Yannoukakos, Drakoulis; Shen, Chen-Yang; Wu, Pei-Ei; Yu, Jyh-Cherng; Hou, Ming-Feng; Swerdlow, Anthony; Ashworth, Alan; Orr, Nick; Jones, Michael; Pita, Guillermo; Alonso, M. Rosario; Álvarez, Nuria; Herrero, Daniel; Tessier, Daniel C.; Vincent, Daniel; Bacot, Francois; Luccarini, Craig; Baynes, Caroline; Ahmed, Shahana; Healey, Catherine S.; Brown, Melissa A.; Ponder, Bruce A.J.; Chenevix-Trench, Georgia; Thompson, Deborah J.; Edwards, Stacey L.; Easton, Douglas F.; Dunning, Alison M.; French, Juliet D.

2015-01-01

Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER+: odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21–1.27, ptrend = 5.7 × 10−44) and estrogen-receptor-negative (ER−: OR = 1.10, 95% CI = 1.05–1.15, ptrend = 3.0 × 10−4) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [pcond = 1.61 × 10−5]) and five variants composing iCHAV3 (lead rs11949391; ER+: OR = 0.90, 95% CI = 0.87–0.93, pcond = 1.4 × 10−4). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival. PMID:25529635

Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1.

PubMed

Glubb, Dylan M; Maranian, Mel J; Michailidou, Kyriaki; Pooley, Karen A; Meyer, Kerstin B; Kar, Siddhartha; Carlebur, Saskia; O'Reilly, Martin; Betts, Joshua A; Hillman, Kristine M; Kaufmann, Susanne; Beesley, Jonathan; Canisius, Sander; Hopper, John L; Southey, Melissa C; Tsimiklis, Helen; Apicella, Carmel; Schmidt, Marjanka K; Broeks, Annegien; Hogervorst, Frans B; van der Schoot, C Ellen; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Fasching, Peter A; Ruebner, Matthias; Ekici, Arif B; Beckmann, Matthias W; Peto, Julian; dos-Santos-Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Pharoah, Paul D P; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Sawyer, Elinor J; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Burwinkel, Barbara; Marme, Frederik; Yang, Rongxi; Surowy, Harald; Guénel, Pascal; Truong, Thérèse; Menegaux, Florence; Sanchez, Marie; Bojesen, Stig E; Nordestgaard, Børge G; Nielsen, Sune F; Flyger, Henrik; González-Neira, Anna; Benitez, Javier; Zamora, M Pilar; Arias Perez, Jose Ignacio; Anton-Culver, Hoda; Neuhausen, Susan L; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Meindl, Alfons; Schmutzler, Rita K; Brauch, Hiltrud; Ko, Yon-Dschun; Brüning, Thomas; Nevanlinna, Heli; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Tanaka, Hideo; Dörk, Thilo; Bogdanova, Natalia V; Helbig, Sonja; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Wu, Anna H; Tseng, Chiu-chen; Van Den Berg, David; Stram, Daniel O; Lambrechts, Diether; Zhao, Hui; Weltens, Caroline; van Limbergen, Erik; Chang-Claude, Jenny; Flesch-Janys, Dieter; Rudolph, Anja; Seibold, Petra; Radice, Paolo; Peterlongo, Paolo; Barile, Monica; Capra, Fabio; Couch, Fergus J; Olson, Janet E; Hallberg, Emily; Vachon, Celine; Giles, Graham G; Milne, Roger L; McLean, Catriona; Haiman, Christopher A; Henderson, Brian E; Schumacher, Fredrick; Le Marchand, Loic; Simard, Jacques; Goldberg, Mark S; Labrèche, France; Dumont, Martine; Teo, Soo Hwang; Yip, Cheng Har; See, Mee-Hoong; Cornes, Belinda; Cheng, Ching-Yu; Ikram, M Kamran; Kristensen, Vessela; Zheng, Wei; Halverson, Sandra L; Shrubsole, Martha; Long, Jirong; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; Andrulis, Irene L; Knight, Julia A; Glendon, Gord; Tchatchou, Sandrine; Devilee, Peter; Tollenaar, Robert A E M; Seynaeve, Caroline; Van Asperen, Christi J; García-Closas, Montserrat; Figueroa, Jonine; Chanock, Stephen J; Lissowska, Jolanta; Czene, Kamila; Klevebring, Daniel; Darabi, Hatef; Eriksson, Mikael; Hooning, Maartje J; Hollestelle, Antoinette; Martens, John W M; Collée, J Margriet; Hall, Per; Li, Jingmei; Humphreys, Keith; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Cox, Angela; Cross, Simon S; Reed, Malcolm W R; Blot, William; Signorello, Lisa B; Cai, Qiuyin; Shah, Mitul; Ghoussaini, Maya; Kang, Daehee; Choi, Ji-Yeob; Park, Sue K; Noh, Dong-Young; Hartman, Mikael; Miao, Hui; Lim, Wei Yen; Tang, Anthony; Hamann, Ute; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; McKay, James; Olswold, Curtis; Slager, Susan; Toland, Amanda E; Yannoukakos, Drakoulis; Shen, Chen-Yang; Wu, Pei-Ei; Yu, Jyh-Cherng; Hou, Ming-Feng; Swerdlow, Anthony; Ashworth, Alan; Orr, Nick; Jones, Michael; Pita, Guillermo; Alonso, M Rosario; Álvarez, Nuria; Herrero, Daniel; Tessier, Daniel C; Vincent, Daniel; Bacot, Francois; Luccarini, Craig; Baynes, Caroline; Ahmed, Shahana; Healey, Catherine S; Brown, Melissa A; Ponder, Bruce A J; Chenevix-Trench, Georgia; Thompson, Deborah J; Edwards, Stacey L; Easton, Douglas F; Dunning, Alison M; French, Juliet D

2015-01-08

Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER(+): odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21-1.27, ptrend = 5.7 × 10(-44)) and estrogen-receptor-negative (ER(-): OR = 1.10, 95% CI = 1.05-1.15, ptrend = 3.0 × 10(-4)) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [pcond = 1.61 × 10(-5)]) and five variants composing iCHAV3 (lead rs11949391; ER(+): OR = 0.90, 95% CI = 0.87-0.93, pcond = 1.4 × 10(-4)). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

A thrifty variant in CREBRF strongly influences body mass index in Samoans.

PubMed

Minster, Ryan L; Hawley, Nicola L; Su, Chi-Ting; Sun, Guangyun; Kershaw, Erin E; Cheng, Hong; Buhule, Olive D; Lin, Jerome; Reupena, Muagututi'a Sefuiva; Viali, Satupa'itea; Tuitele, John; Naseri, Take; Urban, Zsolt; Deka, Ranjan; Weeks, Daniel E; McGarvey, Stephen T

2016-09-01

Samoans are a unique founder population with a high prevalence of obesity, making them well suited for identifying new genetic contributors to obesity. We conducted a genome-wide association study (GWAS) in 3,072 Samoans, discovered a variant, rs12513649, strongly associated with body mass index (BMI) (P = 5.3 × 10(-14)), and replicated the association in 2,102 additional Samoans (P = 1.2 × 10(-9)). Targeted sequencing identified a strongly associated missense variant, rs373863828 (p.Arg457Gln), in CREBRF (meta P = 1.4 × 10(-20)). Although this variant is extremely rare in other populations, it is common in Samoans (frequency of 0.259), with an effect size much larger than that of any other known common BMI risk variant (1.36-1.45 kg/m(2) per copy of the risk-associated allele). In comparison to wild-type CREBRF, the Arg457Gln variant when overexpressed selectively decreased energy use and increased fat storage in an adipocyte cell model. These data, in combination with evidence of positive selection of the allele encoding p.Arg457Gln, support a 'thrifty' variant hypothesis as a factor in human obesity.

GCKR variants increase triglycerides while protecting from insulin resistance in Chinese children.

PubMed

Shen, Yue; Wu, Lijun; Xi, Bo; Liu, Xin; Zhao, Xiaoyuan; Cheng, Hong; Hou, Dongqing; Wang, Xingyu; Mi, Jie

2013-01-01

Variants in gene encoding glucokinase regulator protein (GCKR) were found to have converse effects on triglycerides and glucose metabolic traits. We aimed to investigate the influence of GCKR variants for triglycerides and glucose metabolic traits in Chinese children and adults. We genotyped two GCKR variants rs1260326 and rs1260333 in children and adults, and analyzed the association between two variants and triglycerides, glucose, insulin and HOMA-IR using linear regression model, and estimated the effect on insulin resistance using logistic regression model. Rs1260326 and rs1260333 associated with increased triglycerides in children and adults (p<0.05). In children, both variants significantly reduced insulin (p<0.05. for rs1260326, β = -0.07; for rs1260333, β = -0.07) and HOMA-IR (p<0.05. for rs1260326, β = -0.03; for rs1260333, β = -0.03). There were significant associations between two variants and insulin resistance for children. Under co-dominant model, for CT vs. CC, OR is 0.83 (95%CI 0.69-1.00) for rs1260326, and 0.83 (95%CI 0.68-1.00) for rs1260333; for TT vs. CC, OR is 0.72 (95%CI 0.58-0.88) for rs1260326, and 0.72 (95%CI 0.58-0.89) for rs1260333. Under allele model, for allele T vs. C, the ORs are 0.85 (95%CI 0.76-0.94) and 0.85 (95%CI 0.76-0.94) for rs1260326 and rs1260333, respectively). Our study confirmed the associations between GCKR variants and triglycerides in Chinese children and adults. Triglycerides-increasing alleles of GCKR variants reduce insulin and HOMA-IR index, and protect from insulin resistance in children. Our results suggested GCKR has an effect on development of insulin resistance in Chinese children.

A recessive form of extreme macrocephaly and mild intellectual disability complements the spectrum of PTEN hamartoma tumour syndrome.

PubMed

Schwerd, Tobias; Khaled, Andrea V; Schürmann, Manfred; Chen, Hannah; Händel, Norman; Reis, André; Gillessen-Kaesbach, Gabriele; Uhlig, Holm H; Abou Jamra, Rami

2016-06-01

PTEN hamartoma tumour syndrome (PHTS) is caused by heterozygous variants in PTEN and is characterised by tumour predisposition, macrocephaly, and cognition impairment. Bi-allelic loss of PTEN activity has not been reported so far and animal models suggest that bi-allelic loss of PTEN activity is embryonically lethal. Here, we report the identification of a novel homozygous variant in PTEN, NM_000314.4; c.545T>C; p.Leu182Ser, in two adolescent siblings with severe macrocephaly and mild intellectual disability. The variant is predicted to be damaging and is associated with significantly increased phospho-S6 downstream of PTEN. The absence of tumours in the two homozygous siblings as well as lack of symptoms of PHTS in the heterozygous carriers of the family suggest that this particular variant is functionally hypomorphic rather than deleterious.

A recessive form of extreme macrocephaly and mild intellectual disability complements the spectrum of PTEN hamartoma tumour syndrome

PubMed Central

Schwerd, Tobias; Khaled, Andrea V; Schürmann, Manfred; Chen, Hannah; Händel, Norman; Reis, André; Gillessen-Kaesbach, Gabriele; Uhlig, Holm H; Abou Jamra, Rami

2016-01-01

PTEN hamartoma tumour syndrome (PHTS) is caused by heterozygous variants in PTEN and is characterised by tumour predisposition, macrocephaly, and cognition impairment. Bi-allelic loss of PTEN activity has not been reported so far and animal models suggest that bi-allelic loss of PTEN activity is embryonically lethal. Here, we report the identification of a novel homozygous variant in PTEN, NM_000314.4; c.545T>C; p.Leu182Ser, in two adolescent siblings with severe macrocephaly and mild intellectual disability. The variant is predicted to be damaging and is associated with significantly increased phospho-S6 downstream of PTEN. The absence of tumours in the two homozygous siblings as well as lack of symptoms of PHTS in the heterozygous carriers of the family suggest that this particular variant is functionally hypomorphic rather than deleterious. PMID:26443266

The impact of RABL2B gene (rs144944885) on human male infertility in patients with oligoasthenoteratozoospermia and immotile short tail sperm defects.

PubMed

Hosseini, Seyedeh Hanieh; Sadighi Gilani, Mohammad Ali; Meybodi, Anahita Mohseni; Sabbaghian, Marjan

2017-04-01

Male infertility is a multifactorial disorder with impressively genetic basis; besides, sperm abnormalities are the cause of numerous cases of male infertility. In this study, we evaluated the genetic variants in exons 4 and 5 and their intron-exon boundaries in RABL2B gene in infertile men with oligoasthenoteratozoospermia (OAT) and immotile short tail sperm (ISTS) defects to define if there is any association between these variants and human male infertility. To this purpose, DNA was extracted from peripheral blood and after PCR reaction and sequencing, the results of sequenced segments were analyzed. In the present study, 30 infertile men with ISTS defect and 30 oligoasthenoteratozoospermic infertile men were recruited. All men were of Iranian origin and it took 3 years to collect patient's samples with ISTS defect. As a result, the 50776482 delC intronic variant (rs144944885) was identified in five patients with oligoasthenoteratozoospermia defect and one patient with ISTS defect in heterozygote form. This variant was not identified in controls. The allelic frequency of the 50776482 delC variant was significantly statistically higher in oligoasthenoteratozoospermic infertile men (p < 0.05). Bioinformatics studies suggested that the 50776482 delC allele would modify the splicing of RABL2B pre-mRNA. In addition, we identified a new genetic variant in RABL2B gene. According to the present study, 50776482 delC allele in the RABL2B gene could be a risk factor in Iranian infertile men with oligoasthenoteratozoospermia defect, but more genetic studies are required to understand the accurate role of this variant in pathogenesis of human male infertility.

The Genetic Variant I148M in PNPLA3 Is Associated With Increased Hepatic Retinyl-Palmitate Storage in Humans.

PubMed

Kovarova, Marketa; Königsrainer, Ingmar; Königsrainer, Alfred; Machicao, Fausto; Häring, Hans-Ulrich; Schleicher, Erwin; Peter, Andreas

2015-12-01

Previous studies revealed that the common sequence variant I148M in patatin-like phospholipase domain-containing protein 3 (PNPLA3) is associated with liver fat content and liver diseases, but not with insulin resistance. Recent data suggest that the PNPLA3 I148M variant has reduced retinyl-palmitate lipase activity in hepatic stellate cells. We hypothesized that the PNPLA3 I148M variant is associated with elevated retinyl-palmitate storage in human liver as a potential link to the clinical pathology. Design/Setting and Participants: Using HPLC, we quantified the retinoid metabolites in liver tissue extracts obtained from 42 human subjects, including 13 heterozygous and six homozygous carriers of the minor PNPLA3 I148M variant. Retinyl-palmitate is elevated in human livers of homozygous PNPLA3 I148M allele carriers Results: The PNPLA3 I148M variant was associated with a significant increase (1.4-fold) in liver fat. The content of retinyl-palmitate was elevated and the ratio of retinol/retinyl-palmitate was reduced in liver extracts obtained from homozygous PNPLA3 I148M minor allele carriers. In a multivariate model including liver fat content, these differences remained significant independent of liver fat content. The content of the minor retinyl-fatty acid esters was similarly increased in homozygous PNPLA3 I148M carriers. The increased content of hepatic retinyl-palmitate and the reduced ratio of retinol/retinyl-palmitate in PNPLA3 I148M minor allele carriers support in vitro findings of an altered retinyl-palmitate lipase activity. Our results indicate that the PNPLA3 I148M variant is relevant for the retinyl-palmitate content in human liver, providing a possible link to chronic liver disease.

Genetic variants in RNA-induced silencing complex genes and prostate cancer.

PubMed

Nikolić, Z; Savić Pavićević, D; Vučić, N; Cerović, S; Vukotić, V; Brajušković, G

2017-04-01

The purpose of this study is to evaluate the potential association between genetic variants in genes encoding the components of RNA-induced silencing complex and prostate cancer (PCa) risk. Genetic variants chosen for this study are rs3742330 in DICER1, rs4961280 in AGO2, rs784567 in TARBP2, rs7813 in GEMIN4 and rs197414 in GEMIN3. The study involved 355 PCa patients, 360 patients with benign prostatic hyperplasia and 318 healthy controls. For individuals diagnosed with PCa, clinicopathological characteristics including serum prostate-specific antigen level at diagnosis, Gleason score (GS) and clinical stage were determined. Genotyping was performed using high-resolution melting analysis, PCR-RFLP, TaqMan SNP Genotyping Assay and real-time PCR-based genotyping assay using specific probes. Allelic and genotypic associations were evaluated by unconditional linear and logistic regression methods. The study provided no evidence of association between the analyzed genetic variants and PCa risk. Nevertheless, allele A of rs784567 was found to confer the reduced risk of higher serum PSA level at diagnosis (P = 0.046; Difference = -66.64, 95 % CI -131.93 to 1.35, for log-additive model). Furthermore, rs4961280, as well as rs3742330, were shown to be associated with GS. These variants, together with rs7813, were found to be associated with the lower clinical stage of PCa. Also, rs3742330 minor allele G was found to be associated with lower PCa aggressiveness (P = 0.036; OR 0.14, 95 % CI 0.023-1.22, for recessive model). According to our data, rs3742330, rs4961280 and rs7813 qualify for potentially protective genetic variants against PCa progression. These variants were not shown to be associated with PCa risk.

Harnessing Scientific and Technological Advances to Improve Equity in Kidney Allocation Policies.

PubMed

Tambur, A R; Audry, B; Antoine, C; Suberbielle, C; Glotz, D; Jacquelinet, C

2017-12-01

We reported that current assignment of HLA-DQ is a barrier to organ allocation. Here we simulated the impact of incorporating HLA-DQ antigens and antibodies as A/B and αβ allelic variants, respectively, on calculated panel reactive antibody (cPRA) and probability of finding potential compatible donors (PCD). A cohort of 1224 donors and 2075 sensitized candidates was analyzed using HLA-DQαβ allelic (study) versus serologic (current practice) nomenclature. A significant (p < 10 -4 ) decrease in cPRA was observed with higher impact for male versus female, and first transplant versus retransplant (p < 10 -4 ), affecting mostly patients with moderate cPRA (30-80%). Consequently, the number of patients qualifying for 100% cPRA points according to the United Network for Organ Sharing-Kidney Allocation System decreased by 37%. More critically, by using allelic versus serologic nomenclature for HLA-DQ, the number of PCDs for all patients was increased, with male and first-transplant patients showing a higher expansion compared with female and retransplants. Patients of blood group O showed the highest benefit. The goal of reporting unacceptable antigens is to improve accuracy of virtual crossmatching and increase the likelihood of finding immunologically compatible donors. Our simulation provides strong support for the need to re-evaluate the use of allele typing and how HLA-DQ antigens and antibodies are incorporated into allocation policies to ensure equity. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.

A Unified Approach to Genotype Imputation and Haplotype-Phase Inference for Large Data Sets of Trios and Unrelated Individuals

PubMed Central

Browning, Brian L.; Browning, Sharon R.

2009-01-01

We present methods for imputing data for ungenotyped markers and for inferring haplotype phase in large data sets of unrelated individuals and parent-offspring trios. Our methods make use of known haplotype phase when it is available, and our methods are computationally efficient so that the full information in large reference panels with thousands of individuals is utilized. We demonstrate that substantial gains in imputation accuracy accrue with increasingly large reference panel sizes, particularly when imputing low-frequency variants, and that unphased reference panels can provide highly accurate genotype imputation. We place our methodology in a unified framework that enables the simultaneous use of unphased and phased data from trios and unrelated individuals in a single analysis. For unrelated individuals, our imputation methods produce well-calibrated posterior genotype probabilities and highly accurate allele-frequency estimates. For trios, our haplotype-inference method is four orders of magnitude faster than the gold-standard PHASE program and has excellent accuracy. Our methods enable genotype imputation to be performed with unphased trio or unrelated reference panels, thus accounting for haplotype-phase uncertainty in the reference panel. We present a useful measure of imputation accuracy, allelic R2, and show that this measure can be estimated accurately from posterior genotype probabilities. Our methods are implemented in version 3.0 of the BEAGLE software package. PMID:19200528

Effects of polymorphism rs3123554 in the cannabinoid receptor gene type 2 (CB2R) on metabolic and adiposity parameters after weight loss with two hypocaloric diets.

PubMed

de Luis, D A; Mulero, I; Primo, D; Izaola, O; Aller, R

2018-05-01

The role of CB2R gene variants on weight loss after a dietary intervention remained unclear. Our aim was to analyze the effects of rs3123554 of CB2R receptor gene on metabolic and adiposity parameters after two different hypocaloric diets in obese subjects. A Caucasian population of 280 obese patients was enrolled. Patients were randomly allocated during 3 months to one of two diets (Diet I - moderate in carbohydrate. Vs Diet II - normal in carbohydrate). In both genotype groups (GG vs GA + AA), body weight, body mass index (BMI), fat mass, waist circumference and systolic blood pressure decreased after diet I and II. The decrease of these parameters was higher in non A allele carriers than A allele carriers. Pre- and post-dietary intervention, body weight, BMI, fat mass and waist circumference were higher in A allele carriers than non A allele carriers. In non A allele carriers, the decrease of glucose, insulin, HOMA-IR and Interleukin-6 levels was higher than A allele carriers after both diets. Carriers of the minor allele of rs3123554 variant of CB2R gene loose less body weight during two different hypocaloric diets. The improvement of metabolic parameters was better in no A allele carriers than A allele carriers. Copyright © 2018 Elsevier B.V. All rights reserved.

Identification of contemporary selection signatures using composite log likelihood and their associations with marbling score in Korean cattle.

PubMed

Ryu, Jihye; Lee, Chaeyoung

2014-12-01

Positive selection not only increases beneficial allele frequency but also causes augmentation of allele frequencies of sequence variants in close proximity. Signals for positive selection were detected by the statistical differences in subsequent allele frequencies. To identify selection signatures in Korean cattle, we applied a composite log-likelihood (CLL)-based method, which calculates a composite likelihood of the allelic frequencies observed across sliding windows of five adjacent loci and compares the value with the critical statistic estimated by 50,000 permutations. Data for a total of 11,799 nucleotide polymorphisms were used with 71 Korean cattle and 209 foreign beef cattle. As a result, 147 signals were identified for Korean cattle based on CLL estimates (P < 0.01). The signals might be candidate genetic factors for meat quality by which the Korean cattle have been selected. Further genetic association analysis with 41 intragenic variants in the selection signatures with the greatest CLL for each chromosome revealed that marbling score was associated with five variants. Intensive association studies with all the selection signatures identified in this study are required to exclude signals associated with other phenotypes or signals falsely detected and thus to identify genetic markers for meat quality. © 2014 Stichting International Foundation for Animal Genetics.

Molecular characterization of allelic variants of (GATA)n microsatellite loci in parthenogenetic lizards Darevskia unisexualis (Lacertidae).

PubMed

Korchagin, V I; Badaeva, T N; Tokarskaya, O N; Martirosyan, I A; Darevsky, I S; Ryskov, A P

2007-05-01

Populations of parthenogenetic lizards of the genus Darevskia consist of genetically identical animals, and represent a unique model for studying the molecular mechanisms underlying the variability and evolution of hypervariable DNA repeats. As unisexual lineages, parthenogenetic lizards are characterized by some level of genetic diversity at microsatellite loci. We cloned and sequenced a number of (GATA)n microsatellite loci of Darevskia unisexualis. PCR products from these loci were also sequenced and the degree of intraspecific polymorphism was assessed. Among the five (GATA)n loci analysed, two (Du215 and Du281) were polymorphic. Cross-species analysis of Du215 and Du281 indicate that the priming sites at the D. unisexualis loci are conserved in the bisexual parental species, D. raddei and D. valentini. Sequencing the PCR products amplified from Du215 and Du281 and from monomorphic Du323 showed that allelic differences at the polymorphic loci are caused by microsatellite mutations and by point mutations in the flanking regions. The haplotypes identified among the allelic variants of Du281 and among its orthologues in the parental species provide new evidence of the cross-species origin of D. unisexualis. To our knowledge, these data are the first to characterize the nucleotide sequences of allelic variants at microsatellite loci within parthenogenetic vertebrate animals.

ABCA1 gene variants regulate postprandial lipid metabolism in healthy men

PubMed Central

Delgado-Lista, Javier; Perez-Martinez, Pablo; Perez-Jimenez, Francisco; Garcia-Rios, Antonio; Fuentes, Francisco; Marin, Carmen; Gómez-Luna, Purificación; Camargo, Antonio; Parnell, Laurence D; Ordovas, Jose Maria; Lopez-Miranda, Jose

2010-01-01

Objective Genetic variants of ABCA1, an ATP-binding cassette (ABC) transporter, have been linked to altered atherosclerosis progression and fasting lipid concentration, mainly high density lipoproteins (HDL) and Apolipoprotein A1 (APOA1), but results from different studies have been inconsistent. Methods and results In order to further characterize the effects of ABCA1 variants in human postprandial lipid metabolism, we studied the influence of three single nucleotide polymorphisms (SNPs) [i27943 (rs2575875); i48168 (rs4149272); R219K (rs2230806)] in the postprandial lipemia of 88 normolipidemic young men, who were given a fatty meal. For i27943 and i48168 SNPs, fasting and postprandial values of APOA1 were higher, and postprandial lipemia was much lower in homozygotes for the major alleles, for total triglycerides in plasma, and large-triglyceride rich lipoproteins (TRL) triglycerides. These persons also showed higher APOA1/APOB ratio. Major allele homozygotes for i48168 and i27943 showed additionally higher HDL and lower postprandial Apolipoprotein B (ApoB). Conclusions Our work shows that major allele homozygotes for ABCA1 SNPs i27943 and i48168 have a lower postprandial response as compared to minor allele carriers. This finding may further characterize the role of ABCA1 in lipid metabolism. PMID:20185793

Meta-analysis on the association of TIRAP S180L variant and tuberculosis susceptibility.

PubMed

Miao, Ruifen; Li, Jiequan; Sun, Zhaoping; Xu, Fei; Shen, Hongbing

2011-05-01

The missense variant S180L in TIRAP (Toll-interleukin-1 receptor domain-containing adaptor protein) gene is implicated in attenuating TLRs signal transaction and may affect individual response to Mycobacterium tuberculosis infection. Several studies investigated the association between TIRAP S180L and risk of tuberculosis (TB), but the results were controversial. In this study, we quantitatively synthesized nine studies relevant to the association between TIRAP S180L polymorphism and TB risk with total 6584 TB cases and 7294 controls using meta-analysis. We found that the variant allele Leu180 and heterozygous genotype Ser/Leu were not significantly associated with risk of TB (allelic OR = 0.99, 95%CI: 0.88-1.11; Ser/Leu vs Ser/Ser: OR = 0.99, 95%CI: 0.87-1.13) with heterogeneity P values > 0.05. In subgroup analysis, none of the significant associations were observed for S180L and TB risk in Africans (allelic OR = 0.58, 95%CI: 0.29-1.61; heterozygous OR = 0.65, 95%CI: 0.32-1.32) or Asians (allelic OR = 1.30, 95%CI: 0.97-1.74; heterozygous OR = 1.17, 95%CI: 0.84-1.65) or risk of pulmonary tuberculosis (PTB) (allelic OR = 0.92, 95%CI: 0.69-1.22; heterozygous OR = 0.98, 95%CI: 0.86-1.12). This meta-analysis indicates that TIRAP S180L polymorphism is unlikely to substantially contribute to TB susceptibility. Copyright © 2011 Elsevier Ltd. All rights reserved.

APOL1 Genetic Variants in Focal Segmental Glomerulosclerosis and HIV-Associated Nephropathy

PubMed Central

Nelson, George W.; Sampath, Karmini; Johnson, Randall C.; Genovese, Giulio; An, Ping; Friedman, David; Briggs, William; Dart, Richard; Korbet, Stephen; Mokrzycki, Michele H.; Kimmel, Paul L.; Limou, Sophie; Ahuja, Tejinder S.; Berns, Jeffrey S.; Fryc, Justyna; Simon, Eric E.; Smith, Michael C.; Trachtman, Howard; Michel, Donna M.; Schelling, Jeffrey R.; Vlahov, David; Pollak, Martin; Winkler, Cheryl A.

2011-01-01

Trypanolytic variants in APOL1, which encodes apolipoprotein L1, associate with kidney disease in African Americans, but whether APOL1-associated glomerular disease has a distinct clinical phenotype is unknown. Here we determined APOL1 genotypes for 271 African American cases, 168 European American cases, and 939 control subjects. In a recessive model, APOL1 variants conferred seventeenfold higher odds (95% CI 11 to 26) for focal segmental glomerulosclerosis (FSGS) and twenty-nine-fold higher odds (95% CI 13 to 68) for HIV-associated nephropathy (HIVAN). FSGS associated with two APOL1 risk alleles associated with earlier age of onset (P = 0.01) and faster progression to ESRD (P < 0.01) but similar sensitivity to steroids compared with other subjects. Individuals with two APOL1 risk alleles have an estimated 4% lifetime risk for developing FSGS, and untreated HIV-infected individuals have a 50% risk for developing HIVAN. The effect of carrying two APOL1 risk alleles explains 18% of FSGS and 35% of HIVAN; alternatively, eliminating this effect would reduce FSGS and HIVAN by 67%. A survey of world populations indicated that the APOL1 kidney risk alleles are present only on African chromosomes. In summary, African Americans carrying two APOL1 risk alleles have a greatly increased risk for glomerular disease, and APOL1-associated FSGS occurs earlier and progresses to ESRD more rapidly. These data add to the evidence base required to determine whether genetic testing for APOL1 has a use in clinical practice. PMID:21997394

Genome-wide high-throughput SNP discovery and genotyping for understanding natural (functional) allelic diversity and domestication patterns in wild chickpea

PubMed Central

Bajaj, Deepak; Das, Shouvik; Badoni, Saurabh; Kumar, Vinod; Singh, Mohar; Bansal, Kailash C.; Tyagi, Akhilesh K.; Parida, Swarup K.

2015-01-01

We identified 82489 high-quality genome-wide SNPs from 93 wild and cultivated Cicer accessions through integrated reference genome- and de novo-based GBS assays. High intra- and inter-specific polymorphic potential (66–85%) and broader natural allelic diversity (6–64%) detected by genome-wide SNPs among accessions signify their efficacy for monitoring introgression and transferring target trait-regulating genomic (gene) regions/allelic variants from wild to cultivated Cicer gene pools for genetic improvement. The population-specific assignment of wild Cicer accessions pertaining to the primary gene pool are more influenced by geographical origin/phenotypic characteristics than species/gene-pools of origination. The functional significance of allelic variants (non-synonymous and regulatory SNPs) scanned from transcription factors and stress-responsive genes in differentiating wild accessions (with potential known sources of yield-contributing and stress tolerance traits) from cultivated desi and kabuli accessions, fine-mapping/map-based cloning of QTLs and determination of LD patterns across wild and cultivated gene-pools are suitably elucidated. The correlation between phenotypic (agromorphological traits) and molecular diversity-based admixed domestication patterns within six structured populations of wild and cultivated accessions via genome-wide SNPs was apparent. This suggests utility of whole genome SNPs as a potential resource for identifying naturally selected trait-regulating genomic targets/functional allelic variants adaptive to diverse agroclimatic regions for genetic enhancement of cultivated gene-pools. PMID:26208313

[Association analysis of SNP-63 and indel-19 variant in the calpain-10 gene with polycystic ovary syndrome in women of reproductive age].

PubMed

Flores-Martínez, Silvia Esperanza; Castro-Martínez, Anna Gabriela; López-Quintero, Andrés; García-Zapién, Alejandra Guadalupe; Torres-Rodríguez, Ruth Noemí; Sánchez-Corona, José

2015-01-01

Polycystic ovary syndrome is a complex and heterogeneous disease involving both reproductive and metabolic problems. It has been suggested a genetic predisposition in the etiology of this syndrome. The identification of calpain-10 gene (CAPN10) as the first candidate gene for type 2 diabetes mellitus, has focused the interest in investigating their possible relation with the polycystic ovary syndrome, because this syndrome is associated with hyperinsulinemia and insulin resistance, two metabolic abnormalities associated with type 2 diabetes mellitus. To investigate if there is association between the SNP-63 and the variant indel-19 of the CAPN10 gene and polycystic ovary syndrome in women of reproductive age. This study included 101 women (55 with polycystic ovary syndrome and 46 without polycystic ovary syndrome). The genetic variant indel-19 was identified by electrophoresis of the amplified fragments by PCR, and the SNP-63 by PCR-RFLP. The allele and genotype frequencies of the two variants do not differ significatly between women with polycystic ovary syndrome and control women group. The haplotype 21 (defined by the insertion allele of indel-19 variant and C allele of SNP-63) was found with higher frequency in both study groups, being more frequent in the polycystic ovary syndrome patients group, however, this difference was not statistically significant (p = 0.8353). The results suggest that SNP-63 and indel-19 variant of the CAPN10 gene do not represent a risk factor for polycystic ovary syndrome in our patients group. Copyright © 2015. Published by Masson Doyma México S.A.

The common PNPLA3 variant p.I148M is associated with liver fat contents as quantified by controlled attenuation parameter (CAP).

PubMed

Arslanow, Anita; Stokes, Caroline S; Weber, Susanne N; Grünhage, Frank; Lammert, Frank; Krawczyk, Marcin

2016-03-01

Non-alcoholic fatty liver disease (NAFLD) is becoming the most prevalent liver disorder. The PNPLA3 (adiponutrin) variant p.I148M has been identified as common genetic modifier of NAFLD. Our aim was to assess the relationships between genetic risk and non-invasively measured liver fat content. Hepatic steatosis was quantified by transient elastography, using the controlled attenuation parameter (CAP) in 174 patients with chronic liver diseases (50% women, age 18-77 years). In addition, a cohort of 174 gender-matched healthy controls (50% women, age 32-77 years) was recruited. The PNPLA3 mutation as well as the novel NAFLD-predisposing genetic variant (TM6SF2 p.E167K) were genotyped with allele-specific probes. The PNPLA3 genotype correlated significantly (P = 0.001) with hepatic CAP measurements. The p.148M risk allele increased the odds of developing liver steatosis (OR = 2.39, P = 0.023). In multivariate models, BMI and PNPLA3 mutation were both independently associated with CAP values (P < 0.001 and P = 0.007, respectively). Carriers of the TM6SF2 risk allele presented with increased aminotransferase activities (ALT: P = 0.007, AST: P = 0.004), but the presence of this variant did not affect CAP values. The PNPLA3 p.I148M variant represents the most important prosteatotic genetic risk factor. NAFLD carriers of this variant should be followed up carefully, with elastography and CAP being ideally suited for this purpose. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Association of prostate cancer risk variants with clinicopathologic characteristics of the disease

PubMed Central

Xu, Jianfeng; Isaacs, Sarah D.; Sun, Jielin; Li, Ge; Wiley, Kathleen E.; Zhu, Yi; Hsu, Fang-Chi; Wiklund, Fredrik; Turner, Aubrey R.; Adams, Tamara S.; Liu, Wennuan; Trock, Bruce J.; Partin, Alan W.; Chang, Baoli; Walsh, Patrick C.; Grönberg, Henrik; Isaacs, William; Zheng, Siqun

2009-01-01

Purpose Fifteen independent genetic variants have been implicated in prostate cancer risk by recent genome-wide association studies. However, their association with clinicopathologic features of prostate cancer is uncertain. Experimental Design We systematically evaluated these 15 variants in 1,563 prostate cancer patients undergoing radical prostatectomy, taking advantage of the uniform tumor stage and grade information available for each of these cases. Associations of these variants with aggressiveness, pathologic Gleason scores, pathologic stage, age at diagnosis, or serum PSA levels were tested. Results After adjusting for multiple testing, none of the SNPs was individually or cumulatively associated with aggressiveness or individual clinicopathologic variables of prostate cancer such as Gleason scores, pathologic stage, or age at diagnosis of prostate cancer. The reported risk allele (G) for SNP rs2735839 in the KLK3 gene at 19q13 was more frequent in less aggressive prostate cancer patients (0.89) than in more aggressive prostate cancer patients (0.86), nominal P = 0.03, or in controls (0.86), nominal P = 0.04. Considering that this allele was also significantly associated with higher serum PSA levels among controls (nominal P = 0.003), the observed trend of higher frequency of this risk allele between less and more aggressive prostate cancer, or between less aggressive and controls may be due to detection bias of PSA screening. Conclusions Prostate cancer risk variants recently discovered from genome-wide case-control association studies are not associated with clinicopathologic variables in this population. Case-case studies are urgently needed in order to discover genetic variants that predict tumor aggressiveness. PMID:18794092

Variant allele of CHEK2 is associated with a decreased risk of esophageal cancer lymph node metastasis in a Chinese population.

PubMed

Gu, Haiyong; Qiu, Wanshan; Wan, Ying; Ding, Guowen; Tang, Weifeng; Liu, Chao; Shi, Yijun; Chen, Yijang; Chen, Suocheng

2012-05-01

Growing evidence suggests that the checkpoint kinase 2 (CHEK2) signaling pathway occupies a central position in the signaling networks of DNA-damage signaling. Many functional and molecular epidemiological studies have evaluated the association between genetic variants of CHEK2 and various cancers. To evaluate the relationship between CHEK2 functional genetic variants and esophageal cancer risk and the risk of lymph node metastasis among a Chinese population. We genotyped CHEK2 rs738722, rs2236141 and rs2236142 single nucleotide polymorphisms (SNPs) using the matrix assisted laser desorption/ionization time-of-flight mass spectrometry assay in a case-controlled study, including 380 esophageal cancer cases and 380 healthy controls in a Chinese population. We found that none of the three polymorphisms achieved significant difference in their distributions between esophageal cancer cases and controls. Multiple logistic regression analyses revealed that esophageal cancer risk was not associated significantly with the variant genotypes of the three CHEK2 polymorphisms as compared with their wild-type genotypes. However, we found that functional variant rs738722 and rs2236142 in CHEK2 might contribute to susceptibility to lymph node metastasis. Our data did not support a significant association between CHEK2 SNPs and the risk of esophageal cancer. Functional variant CHEK2 rs738722 and rs2236142 might contribute to lymph node metastasis susceptibility. The CT allele of SNP rs738722 and the GC allele of SNP rs2236142 might be a protective factor of the risk for lymph node metastasis of esophageal cancer.

Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data

PubMed Central

Holmes, Michael V; Dale, Caroline E; Zuccolo, Luisa; Silverwood, Richard J; Guo, Yiran; Ye, Zheng; Prieto-Merino, David; Dehghan, Abbas; Trompet, Stella; Wong, Andrew; Cavadino, Alana; Drogan, Dagmar; Padmanabhan, Sandosh; Yesupriya, Ajay; Leusink, Maarten; Sundstrom, Johan; Hubacek, Jaroslav A; Pikhart, Hynek; Swerdlow, Daniel I; Panayiotou, Andrie G; Borinskaya, Svetlana A; Finan, Chris; Shah, Sonia; Kuchenbaecker, Karoline B; Shah, Tina; Engmann, Jorgen; Folkersen, Lasse; Eriksson, Per; Ricceri, Fulvio; Melander, Olle; Sacerdote, Carlotta; Gamble, Dale M; Rayaprolu, Sruti; Ross, Owen A; McLachlan, Stela; Vikhireva, Olga; Sluijs, Ivonne; Scott, Robert A; Adamkova, Vera; Flicker, Leon; van Bockxmeer, Frank M; Power, Christine; Marques-Vidal, Pedro; Meade, Tom; Marmot, Michael G; Ferro, Jose M; Paulos-Pinheiro, Sofia; Humphries, Steve E; Talmud, Philippa J; Leach, Irene Mateo; Verweij, Niek; Linneberg, Allan; Skaaby, Tea; Doevendans, Pieter A; Cramer, Maarten J; van der Harst, Pim; Klungel, Olaf H; Dowling, Nicole F; Dominiczak, Anna F; Kumari, Meena; Nicolaides, Andrew N; Weikert, Cornelia; Boeing, Heiner; Ebrahim, Shah; Gaunt, Tom R; Price, Jackie F; Lannfelt, Lars; Peasey, Anne; Kubinova, Ruzena; Pajak, Andrzej; Malyutina, Sofia; Voevoda, Mikhail I; Tamosiunas, Abdonas; Maitland-van der Zee, Anke H; Norman, Paul E; Hankey, Graeme J; Bergmann, Manuela M; Hofman, Albert; Franco, Oscar H; Cooper, Jackie; Palmen, Jutta; Spiering, Wilko; de Jong, Pim A; Kuh, Diana; Hardy, Rebecca; Uitterlinden, Andre G; Ikram, M Arfan; Ford, Ian; Hyppönen, Elina; Almeida, Osvaldo P; Wareham, Nicholas J; Khaw, Kay-Tee; Hamsten, Anders; Husemoen, Lise Lotte N; Tjønneland, Anne; Tolstrup, Janne S; Rimm, Eric; Beulens, Joline W J; Verschuren, W M Monique; Onland-Moret, N Charlotte; Hofker, Marten H; Wannamethee, S Goya; Whincup, Peter H; Morris, Richard; Vicente, Astrid M; Watkins, Hugh; Farrall, Martin; Jukema, J Wouter; Meschia, James; Cupples, L Adrienne; Sharp, Stephen J; Fornage, Myriam; Kooperberg, Charles; LaCroix, Andrea Z; Dai, James Y; Lanktree, Matthew B; Siscovick, David S; Jorgenson, Eric; Spring, Bonnie; Coresh, Josef; Buxbaum, Sarah G; Schreiner, Pamela J; Ellison, R Curtis; Tsai, Michael Y; Patel, Sanjay R; Redline, Susan; Johnson, Andrew D; Hoogeveen, Ron C; Hakonarson, Hakon; Rotter, Jerome I; Boerwinkle, Eric; de Bakker, Paul I W; Kivimaki, Mika; Asselbergs, Folkert W; Sattar, Naveed; Lawlor, Debbie A; Whittaker, John; Davey Smith, George; Mukamal, Kenneth; Psaty, Bruce M; Wilson, James G; Lange, Leslie A; Hamidovic, Ajna; Hingorani, Aroon D; Nordestgaard, Børge G; Bobak, Martin; Leon, David A; Langenberg, Claudia; Palmer, Tom M; Reiner, Alex P; Keating, Brendan J; Dudbridge, Frank

2014-01-01

Objective To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease. Design Mendelian randomisation meta-analysis of 56 epidemiological studies. Participants 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers. Main outcome measures Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption. Results Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (−0.88 (−1.19 to −0.56) mm Hg), interleukin-6 levels (−5.2% (−7.8 to −2.4%)), waist circumference (−0.3 (−0.6 to −0.1) cm), and body mass index (−0.17 (−0.24 to −0.10) kg/m2). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)). Conclusions Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health. PMID:25011450

Genetic risk variants for membranous nephropathy: extension of and association with other chronic kidney disease aetiologies.

PubMed

Sekula, Peggy; Li, Yong; Stanescu, Horia C; Wuttke, Matthias; Ekici, Arif B; Bockenhauer, Detlef; Walz, Gerd; Powis, Stephen H; Kielstein, Jan T; Brenchley, Paul; Eckardt, Kai-Uwe; Kronenberg, Florian; Kleta, Robert; Köttgen, Anna

2017-02-01

Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. Previous genome-wide association studies (GWAS) of 300 000 genotyped variants identified MN-associated loci at HLA-DQA1 and PLA2R1. We used a combined approach of genotype imputation, GWAS, human leucocyte antigen (HLA) imputation and extension to other aetiologies of chronic kidney disease (CKD) to investigate genetic MN risk variants more comprehensively. GWAS using 9 million high-quality imputed genotypes and classical HLA alleles were conducted for 323 MN European-ancestry cases and 345 controls. Additionally, 4960 patients with different CKD aetiologies in the German Chronic Kidney Disease (GCKD) study were genotyped for risk variants at HLA-DQA1 and PLA2R1. In GWAS, lead variants in known loci [rs9272729, HLA-DQA1, odds ratio (OR) = 7.3 per risk allele, P = 5.9 × 10 -27 and rs17830558, PLA2R1, OR = 2.2, P = 1.9 × 10 -8 ] were significantly associated with MN. No novel signals emerged in GWAS of X-chromosomal variants or in sex-specific analyses. Classical HLA alleles (DRB1*0301-DQA1*0501-DQB1*0201 haplotype) were associated with MN but provided little additional information beyond rs9272729. Associations were replicated in 137 GCKD patients with MN (HLA-DQA1: P = 6.4 × 10 -24 ; PLA2R1: P = 5.0 × 10 -4 ). MN risk increased steeply for patients with high-risk genotype combinations (OR > 79). While genetic variation in PLA2R1 exclusively associated with MN across 19 CKD aetiologies, the HLA-DQA1 risk allele was also associated with lupus nephritis (P = 2.8 × 10 -6 ), type 1 diabetic nephropathy (P = 6.9 × 10 -5 ) and focal segmental glomerulosclerosis (P = 5.1 × 10 -5 ), but not with immunoglobulin A nephropathy. PLA2R1 and HLA-DQA1 are the predominant risk loci for MN detected by GWAS. While HLA-DQA1 risk variants show an association with other CKD aetiologies, PLA2R1 variants are specific to MN. © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

The M405V allele of the glutaryl-CoA dehydrogenase gene is an important marker for glutaric aciduria type I (GA-I) low excretors.

PubMed

Schillaci, Lori-Anne P; Greene, Carol L; Strovel, Erin; Rispoli-Joines, Jessica; Spector, Elaine; Woontner, Michael; Scharer, Gunter; Enns, Gregory M; Gallagher, Renata; Zinn, Arthur B; McCandless, Shawn E; Hoppel, Charles L; Goodman, Stephen I; Bedoyan, Jirair K

2016-09-01

Glutaric aciduria type I (GA-I) is an autosomal recessive organic aciduria resulting from a functional deficiency of glutaryl-CoA dehydrogenase, encoded by GCDH. Two clinically indistinguishable diagnostic subgroups of GA-I are known; low and high excretors (LEs and HEs, respectively). Early medical and dietary interventions can result in significantly better outcomes and improved quality of life for patients with GA-I. We report on nine cases of GA-I LE patients all sharing the M405V allele with two cases missed by newborn screening (NBS) using tandem mass spectrometry (MS/MS). We describe a novel case with the known pathogenic M405V variant and a novel V133L variant, and present updated and previously unreported clinical, biochemical, functional and molecular data on eight other patients all sharing the M405V allele. Three of the nine patients are of African American ancestry, with two as siblings. GCDH activity was assayed in six of the nine patients and varied from 4 to 25% of the control mean. We support the use of urine glutarylcarnitine as a biochemical marker of GA-I by demonstrating that glutarylcarnitine is efficiently cleared by the kidney (50-90%) and that plasma and urine glutarylcarnitine follow a linear relationship. We report the allele frequencies for three known GA-I LE GCDH variants (M405V, V400M and R227P) and note that both the M405V and V400M variants are significantly more common in the population of African ancestry compared to the general population. This report highlights the M405V allele as another important molecular marker in patients with the GA-I LE phenotype. Therefore, the incorporation into newborn screening of molecular screening for the M405V and V400M variants in conjunction with MS/MS could help identify asymptomatic at-risk GA-I LE patients that could potentially be missed by current NBS programs. Copyright © 2016 Elsevier Inc. All rights reserved.

Association of Genetic Variants with Isolated Fasting Hyperglycaemia and Isolated Postprandial Hyperglycaemia in a Han Chinese Population

PubMed Central

Chen, Ying; Chen, Li; Zhao, Zhigang; Li, Qiang; Ge, Jiapu; Chen, Gang; Guo, Xiaohui; Lu, Juming; Weng, Jianping; Jia, Weiping; Ji, Linong; Xiao, Jianzhong; Shan, Zhongyan; Liu, Jie; Tian, Haoming; Ji, Qiuhe; Zhu, Dalong; Zhou, Zhiguang; Shan, Guangliang; Yang, Wenying

2013-01-01

Background Though multiple single nucleotide polymorphisms (SNPs) associated with type 2 diabetes have been identified, the genetic bases of isolated fasting hyperglycaemia (IFH) and isolated postprandial hyperglycaemia (IPH) were still unclear. In present study, we aimed to investigate the association of genome-wide association study-validated genetic variants and IFH or IPH in Han Chinese. Methods/Principal Findings We genotyped 27 validated SNPs in 6,663 unrelated individuals comprising 341 IFH, 865 IPH, 1,203 combined fasting hyperglycaemia and postprandial hyperglycaemia, and 4,254 normal glycaemic subjects of Han ancestry. The distributions of genotype frequencies of FTO, CDKAL1 and GCKR were significant different between individuals with IFH and those with IPH (SNP(ptrend): rs8050136(0.0024), rs9939609(0.0049), rs7756992(0.0122), rs780094(0.0037)). Risk allele of FTO specifically increased the risk of IFH (rs8050136: OR 1.403 [95% CI 1.125–1.750], p = 0.0027; rs9939609: 1.398 [1.120–1.744], p = 0.0030). G allele of CDKAL1 specifically increased the risk of IPH (1.217 [1.092–1.355], p = 0.0004). G allele of GCKR increased the risk of IFH (1.167 [0.999–1.362], p = 0.0513), but decreased the risk of IPH (0.891 [0.801–0.991], p = 0.0331). In addition, TCF7L2 and KCNQ1 increased the risk of both IFH and IPH. When combined, each additional risk allele associated with IFH increased the risk for IFH by 1.246-fold (p<0.0001), while each additional risk allele associated with IPH increased the risk for IPH by 1.190-fold (p<0.0001). Conclusion/Significance Our results indicate that genotype distributions of variants from FTO, GCKR, CDKAL1 were different between IPH and IFH in Han Chinese. Variants of genes modulating insulin sensitivity (FTO, GCKR) contributed to the risk of IFH, while variants of genes related to beta cell function (CDKAL1) increase the risk of IPH. PMID:23990951

Analysis of protein-altering variants in telomerase genes and their association with MUC5B common variant status in patients with idiopathic pulmonary fibrosis: a candidate gene sequencing study.

PubMed

Dressen, Amy; Abbas, Alexander R; Cabanski, Christopher; Reeder, Janina; Ramalingam, Thirumalai R; Neighbors, Margaret; Bhangale, Tushar R; Brauer, Matthew J; Hunkapiller, Julie; Reeder, Jens; Mukhyala, Kiran; Cuenco, Karen; Tom, Jennifer; Cowgill, Amy; Vogel, Jan; Forrest, William F; Collard, Harold R; Wolters, Paul J; Kropski, Jonathan A; Lancaster, Lisa H; Blackwell, Timothy S; Arron, Joseph R; Yaspan, Brian L

2018-06-08

Idiopathic pulmonary fibrosis (IPF) risk has a strong genetic component. Studies have implicated variations at several loci, including TERT, surfactant genes, and a single nucleotide polymorphism at chr11p15 (rs35705950) in the intergenic region between TOLLIP and MUC5B. Patients with IPF who have risk alleles at rs35705950 have longer survival from the time of IPF diagnosis than do patients homozygous for the non-risk allele, whereas patients with shorter telomeres have shorter survival times. We aimed to assess whether rare protein-altering variants in genes regulating telomere length are enriched in patients with IPF homozygous for the non-risk alleles at rs35705950. Between Nov 1, 2014, and Nov 1, 2016, we assessed blood samples from patients aged 40 years or older and of European ancestry with sporadic IPF from three international phase 3 clinical trials (INSPIRE, CAPACITY, ASCEND), one phase 2 study (RIFF), and US-based observational studies (Vanderbilt Clinical Interstitial Lung Disease Registry and the UCSF Interstitial Lung Disease Clinic registry cohorts) at the Broad Institute (Cambridge, MA, USA) and Human Longevity (San Diego, CA, USA). We also assessed blood samples from non-IPF controls in several clinical trials. We did whole-genome sequencing to assess telomere length and identify rare protein-altering variants, stratified by rs35705950 genotype. We also assessed rare functional variation in TERT exons and compared telomere length and disease progression across genotypes. We assessed samples from 1510 patients with IPF and 1874 non-IPF controls. 30 (3%) of 1046 patients with an rs35705950 risk allele had a rare protein-altering variant in TERT compared with 34 (7%) of 464 non-risk allele carriers (odds ratio 0·40 [95% CI 0·24-0·66], p=0·00039). Subsequent analyses identified enrichment of rare protein-altering variants in PARN and RTEL1, and rare variation in TERC in patients with IPF compared with controls. We expanded our study population to provide a more accurate estimation of rare variant frequency in these four loci, and to calculate telomere length. The proportion of patients with at least one rare variant in TERT, PARN, TERC, or RTEL1 was higher in patients with IPF than in controls (149 [9%] of 1739 patients vs 205 [2%] of 8645 controls, p=2·44 × 10 -8 ). Patients with IPF who had a variant in any of the four identified telomerase component genes had telomeres that were 3·69-16·10% shorter than patients without a variant in any of the four genes and had an earlier mean age of disease onset than patients without one or more variants (65·1 years [SD 7·8] vs 67·1 years [7·9], p=0·004). In the placebo arms of clinical trials, shorter telomeres were significantly associated with faster disease progression (1·7% predicted forced vital capacity per kb per year, p=0·002). Pirfenidone had treatment benefit regardless of telomere length (p=4·24 × 10 -8 for telomere length lower than the median, p=0·0044 for telomere length greater than the median). Rare protein-altering variants in TERT, PARN, TERC, and RTEL1 are enriched in patients with IPF compared with controls, and, in the case of TERT, particularly in individuals without a risk allele at the rs35705950 locus. This suggests that multiple genetic factors contribute to sporadic IPF, which might implicate distinct mechanisms of pathogenesis and disease progression. Genentech, National Institutes of Health, Francis Family Foundation, Pulmonary Fibrosis Foundation, Nina Ireland Program for Lung Health, US Department of Veterans Affairs. Copyright © 2018 Elsevier Ltd. All rights reserved.

SLC30A8 nonsynonymous variant is associated with recovery following exercise and skeletal muscle size and strength.

PubMed

Sprouse, Courtney; Gordish-Dressman, Heather; Orkunoglu-Suer, E Funda; Lipof, Jason S; Moeckel-Cole, Stephanie; Patel, Ronak R; Adham, Kasra; Larkin, Justin S; Hubal, Monica J; Kearns, Amy K; Clarkson, Priscilla M; Thompson, Paul D; Angelopoulos, Theodore J; Gordon, Paul M; Moyna, Niall M; Pescatello, Linda S; Visich, Paul S; Zoeller, Robert F; Hoffman, Eric P; Tosi, Laura L; Devaney, Joseph M

2014-01-01

Genome-wide association studies have identified thousands of variants that are associated with numerous phenotypes. One such variant, rs13266634, a nonsynonymous single nucleotide polymorphism in the solute carrier family 30 (zinc transporter) member eight gene, is associated with a 53% increase in the risk of developing type 2 diabetes (T2D). We hypothesized that individuals with the protective allele against T2D would show a positive response to short-term and long-term resistance exercise. Two cohorts of young adults-the Eccentric Muscle Damage (EMD; n = 156) cohort and the Functional Single Nucleotide Polymorphisms Associated with Muscle Size and Strength Study (FAMuSS; n = 874)-were tested for association of the rs13266634 variant with measures of skeletal muscle response to resistance exercise. Our results were sexually dimorphic in both cohorts. Men in the EMD study with two copies of the protective allele showed less post-exercise bout strength loss, less soreness, and lower creatine kinase values. In addition, men in the FAMuSS, homozygous for the protective allele, showed higher pre-exercise strength and larger arm skeletal muscle volume, but did not show a significant difference in skeletal muscle hypertrophy or strength with resistance training.

Characterization of pathogenic SORL1 genetic variants for association with Alzheimer’s disease: a clinical interpretation strategy

PubMed Central

Holstege, Henne; van der Lee, Sven J; Hulsman, Marc; Wong, Tsz Hang; van Rooij, Jeroen GJ; Weiss, Marjan; Louwersheimer, Eva; Wolters, Frank J; Amin, Najaf; Uitterlinden, André G; Hofman, Albert; Ikram, M Arfan; van Swieten, John C; Meijers-Heijboer, Hanne; van der Flier, Wiesje M; Reinders, Marcel JT; van Duijn, Cornelia M; Scheltens, Philip

2017-01-01

Accumulating evidence suggests that genetic variants in the SORL1 gene are associated with Alzheimer disease (AD), but a strategy to identify which variants are pathogenic is lacking. In a discovery sample of 115 SORL1 variants detected in 1908 Dutch AD cases and controls, we identified the variant characteristics associated with SORL1 variant pathogenicity. Findings were replicated in an independent sample of 103 SORL1 variants detected in 3193 AD cases and controls. In a combined sample of the discovery and replication samples, comprising 181 unique SORL1 variants, we developed a strategy to classify SORL1 variants into five subtypes ranging from pathogenic to benign. We tested this pathogenicity screen in SORL1 variants reported in two independent published studies. SORL1 variant pathogenicity is defined by the Combined Annotation Dependent Depletion (CADD) score and the minor allele frequency (MAF) reported by the Exome Aggregation Consortium (ExAC) database. Variants predicted strongly damaging (CADD score >30), which are extremely rare (ExAC-MAF <1 × 10−5) increased AD risk by 12-fold (95% CI 4.2–34.3; P=5 × 10−9). Protein-truncating SORL1 mutations were all unknown to ExAC and occurred exclusively in AD cases. More common SORL1 variants (ExAC-MAF≥1 × 10−5) were not associated with increased AD risk, even when predicted strongly damaging. Findings were independent of gender and the APOE-ε4 allele. High-risk SORL1 variants were observed in a substantial proportion of the AD cases analyzed (2%). Based on their effect size, we propose to consider high-risk SORL1 variants next to variants in APOE, PSEN1, PSEN2 and APP for personalized risk assessments in clinical practice. PMID:28537274

Comparative polymorphism of BAT-26 between healthy individuals and cancer patients and its cancer risk implication for local Chinese.

PubMed

Zheng, Yanying; Liu, Li; Sun, Yi; Chen, Jie; Wang, Jianrong; Zhu, Changle; Lai, Rensheng; Xie, Ling

2016-07-30

BAT-26 is one of the representative markers for microsatellite instability evaluation and presents different polymorphisms in different ethnic populations. The current knowledge of its comparative polymorphism between healthy individuals and cancer patients in the Chinese population is insufficient. This study aims to analyze germline polymorphic variations of BAT-26 between healthy individuals and cancer patients in Chinese from Jiangsu province and the associated cancer risk implications. The various BAT-26 alleles and their percentages in cervical cells from 500 healthy women were assessed by direct sequencing. Twenty of these samples were also analyzed by fragment analysis. BAT-26 of blood DNA from 24 healthy individuals and 247 cancer patients was analyzed by fragment analysis. Compared with the sequencing results, 122.6-122.9 bp, 123.4-123.8 bp and 124.1-124.8 bp corresponded to the A25, A26 and A27 alleles, respectively. The 524 healthy individuals showed 4.58%, 92.18% and 3.24% of A25, A26 and A27, respectively. The variant alleles A18, A24, A28, A29 and A32 were only found in cancer patients, accounting for 0.81%, 0.40%, 0.40%, 0.40% and 0.40%, respectively; the A25, A26 and A27 alleles in cancer patients accounted for 6.48%, 77.33% and 13.77%. Healthy individuals had a stable BAT-26 profile within the quasimonomorphic variation range (QMVR), but cancer patients harbored variant alleles outside QMVR and showed a trend from quasimonomorph to polymonomorph, suggesting that variant alleles of BAT-26 in germline cells may be regarded as a potential marker of higher cancer risk in the Chinese population from Jiangsu province.

Common susceptibility alleles and SQSTM1 mutations predict disease extent and severity in a multinational study of patients with Paget's disease.

PubMed

Albagha, Omar M E; Visconti, Micaela Rios; Alonso, Nerea; Wani, Sachin; Goodman, Kirsteen; Fraser, William D; Gennari, Luigi; Merlotti, Daniela; Gianfrancesco, Fernando; Esposito, Teresa; Rendina, Domenico; di Stefano, Marco; Isaia, Giancarlo; Brandi, Maria Luisa; Giusti, Francesca; Del Pino-Montes, Javier; Corral-Gudino, Luis; Gonzalez-Sarmiento, Rogelio; Ward, Lynley; Rea, Sarah L; Ratajczak, Thomas; Walsh, John P; Ralston, Stuart H

2013-11-01

Paget's disease of bone (PDB) has a strong genetic component. Here, we investigated possible associations between genetic variants that predispose to PDB and disease severity. Allelic variants identified as predictors of PDB from genome-wide association studies were analyzed in 1940 PDB patients from the United Kingdom, Italy, Western Australia, and Spain. A cumulative risk allele score was constructed by adding the variants together and relating this to markers of disease severity, alone and in combination with SQSTM1 mutations. In SQSTM1-negative patients, risk allele scores in the highest tertile were associated with a 27% increase in disease extent compared with the lowest tertile (p < 0.00001) with intermediate values in the middle tertile (20% increase; p = 0.0007). The effects were similar for disease severity score, which was 15% (p = 0.01) and 25% (p < 0.00001) higher in the middle and upper tertiles, respectively. Risk allele score remained a significant predictor of extent and severity when SQSTM-positive individuals were included, with an effect size approximately one-third of that observed with SQSTM1 mutations. A genetic risk score was developed by combining information from both markers, which identified subgroups of individuals with low, medium, and high levels of severity with a specificity of 70% and sensitivity of 55%. Risk allele scores and SQSTM1 mutations both predict extent and severity of PDB. It is possible that with further refinement, genetic profiling may be of clinical value in identifying individuals at high risk of severe disease who might benefit from enhanced surveillance and early intervention. © 2013 American Society for Bone and Mineral Research.

Pathogenic variants for Mendelian and complex traits in exomes of 6,517 European and African Americans: implications for the return of incidental results.

PubMed

Tabor, Holly K; Auer, Paul L; Jamal, Seema M; Chong, Jessica X; Yu, Joon-Ho; Gordon, Adam S; Graubert, Timothy A; O'Donnell, Christopher J; Rich, Stephen S; Nickerson, Deborah A; Bamshad, Michael J

2014-08-07

Exome sequencing (ES) is rapidly being deployed for use in clinical settings despite limited empirical data about the number and types of incidental results (with potential clinical utility) that could be offered for return to an individual. We analyzed deidentified ES data from 6,517 participants (2,204 African Americans and 4,313 European Americans) from the National Heart, Lung, and Blood Institute Exome Sequencing Project. We characterized the frequencies of pathogenic alleles in genes underlying Mendelian conditions commonly assessed by newborn-screening (NBS, n = 39) programs, genes associated with age-related macular degeneration (ARMD, n = 17), and genes known to influence drug response (PGx, n = 14). From these 70 genes, we identified 10,789 variants and curated them by manual review of OMIM, HGMD, locus-specific databases, or primary literature to a total of 399 validated pathogenic variants. The mean number of risk alleles per individual was 15.3. Every individual had at least five known PGx alleles, 99% of individuals had at least one ARMD risk allele, and 45% of individuals were carriers for at least one pathogenic NBS allele. The carrier burden for severe recessive childhood disorders was 0.57. Our results demonstrate that risk alleles of potential clinical utility for both Mendelian and complex traits are detectable in every individual. These findings highlight the necessity of developing guidelines and policies that consider the return of results to all individuals and underscore the need to develop innovative approaches and tools that enable individuals to exercise their choice about the return of incidental results. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

TRPV1 Gene Polymorphisms Are Associated with Type 2 Diabetes by Their Interaction with Fat Consumption in the Korean Genome Epidemiology Study.

PubMed

Park, Sunmin; Zhang, Xin; Lee, Na Ra; Jin, Hyun-Seok

2016-01-01

Different transient receptor potential vanilloid 1 (TRPV1) variants may be differently activated by noxious stimuli. We investigated how TRPV1 variants modulated the prevalence of type 2 diabetes and specific gene-nutrient interactions. Among 8,842 adults aged 40-69 years in the Korean Genome Epidemiology Study, the associations between TRPV1 genotypes and the prevalence of type 2 diabetes as well as their gene-nutrient interactions were investigated after adjusting for the covariates of age, gender, residence area, body mass index, daily energy intake, and total activity. The TRPV1 rs161364 and rs8065080 minor alleles lowered HOMA-IR and the risk of type 2 diabetes after adjusting for covariates. There were gene-nutrient interactions between TRPV1 variants rs161364 and rs8065080 and preference for oily taste, intake of oily foods, and fat intake after adjusting for covariates. Among subjects with the minor alleles of TRPV1 rs161364 and rs8065080, the group with a high preference for oily foods had a lower odds ratio for type 2 diabetes. Consistent with the preference for taste, among subjects with the minor alleles, the group with high fat intake from oily foods also exhibited a lower risk of type 2 diabetes than subjects with the major alleles. People with the minor alleles of the TRPV1 single nucleotide polymorphisms rs161364 and rs8065080 have a lower risk of diabetes with a high-fat diet, but people with the major alleles are at a higher risk of type 2 diabetes when consuming high-fat diets. The majority of people should be careful about a high fat intake. © 2016 S. Karger AG, Basel.

Influence of SNPs in Genes that Modulate Lung Disease Severity in a Group of Mexican Patients with Cystic Fibrosis.

PubMed

Yokoyama, Emiy; Chávez-Saldaña, Margarita; Orozco, Lorena; Cuevas, Francisco; Lezana, José Luis; Vigueras-Villaseñor, Rosa María; Rojas-Castañeda, Julio Cesar; Landero, Daniel Adrian

2018-04-24

The variation in cystic fibrosis (CF) lung disease not always is explained by the CFTR genotype, so it has become apparent that modifier genes must play a considerable role in the phenotypic heterogeneity of CF, so we investigated the association of allelic variants in modifier genes that modulate the severity of lung function in a group of Mexican patients diagnosed with CF. We included 140 CF patients classified according to lung phenotype and analyzed 17 single nucleotide polymorphisms (SNPs) by TaqMan ® allelic discrimination. We demonstrated that patients with GG or GC genotype of the allelic variant rs11003125 (MBL2-550) of the MBL2 gene exhibit most of the lung manifestations at an earlier age; and the rs1042713 allelic variant of ADRB2 gene, showed statistical difference only with the age of first spirometry. When we used the dominant model, the MBL2 allele rs11003125 (MBL2-550; p = 0.022, Odds Ratio (OR) 2.87, 95% CI 1.14-7.27) was significantly associated with CF patients as risk factor, and the ADRB2 allele rs1042713 (p.Arg16Gly; p = 0.005, Odds Ratio (OR) 0.37, 95% CI 0.19-0.75) was significantly associated with CF patients as protect factor. Our findings suggest that the MBL2 and ADRB2 genes exerts an important genetic influence on the lung disease in our patients. Taking into account our results, we insist on not leaving aside this type of studies, since having techniques such as GWAS or WES will be able to advance in achieving a better quality of life for CF patients with severe lung disease. Copyright © 2018 IMSS. Published by Elsevier Inc. All rights reserved.

[Association study between 834+7G/A and +1332C/T polymorphisms in the growth arrest specific 6 gene and risk of severe preeclampsia in Chinese population].

PubMed

Ye, Liyan; Guan, Linbo; Fan, Ping; Liu, Xinghui; Liu, Rui; Chen, Jinxin; Zhu, Yue; Wei, Xin; Liu, Yu; Bai, Huai

2017-02-10

To investigate the relationship between polymorphisms of the growth arrest specific 6 (GAS6) gene and severe preeclampsia in a South West Han Chinese population. Blood samples from 167 patients with severe preeclampsia and 312 normal pregnant women as controls from Han Chinese in Chengdu area were analyzed by polymerase chain reaction-restriction fragment length polymorphisms. C and T allele frequencies for +1332C/T site were 85.63% and 14.37% in the patient group, respectively, and 78.04% and 21.96% in control group, respectively. The TT genotype and variant T allelic frequencies of the +1332C/T polymorphism were significantly lower in patients with severe preeclampsia than in the control group (both P<0.05), and the odds ratio for the risk of severe preeclampsia was 0.602 (95%CI: 0.401-0.904) in carriers for the variant T allele (χ 2 =6.045, P=0.014). G and A allele frequencies for 834+7G/A site were 72.75% and 27.25% in case group, respectively, and 74.36% and 25.64% in control group, respectively. The genotype and allele frequencies of the 834+7G/A polymorphism in patients with severe preeclampsia and controls showed no significant differences (both P>0.05). In addition, there was no significant association between the polymorphisms and blood pressure levels in the patient or control groups. The variant GAS6+1332 T allele is associated with a decreased risk for severe preeclampsia in a South West Han Chinese population. On the other hand, the 834+7G/A polymorphism has no effect on the severe preeclampsia.

Association of polymorphic variants of PTPN22, TNF and VDR genes in children with lupus nephritis: A study in Colombian family triads.

PubMed

Garavito, Gloria; Egea, Eduardo; Fang, Luis; Malagón, Clara; Olmos, Carlos; González, Luz; Guarnizo, Pilar; Aroca, Gustavo; López, Guillermo; Iglesias, Antonio

2017-06-01

Systemic lupus erythematosus is an autoimmune disease in which the severity varies according to race, sex and age of onset. This variation is also observed in the genetic markers associated with the disease, including PTPN22, VDR and TNF genes. The genetic stratification in different populations worldwide can influence the variability. To analyze the heritability of PTPN22, VDR and TNF genetic variants and their association with pediatric lupus nephritis in Colombian families. We conducted a family-based study including 46 triads (case, father and mother). The variants rs2476601 of PTPN22; rs361525 and rs1800629 of TNF, and TaqI [rs731236], ApaI [rs7975232], BsmI [rs1544410] and FokI [rs2228570] of VDR were genotyped by qPCR. The effects of overtransmission of the risk allele from parents to children and linkage disequilibrium at the VDR and TNF loci were estimated. We found that allele A of rs2476601 in PTPN22 was distributed among 8.69 % (n=16) of the parents and 19.5 % (n=18) of the cases; this allele was overtransmitted from parents to children 17 times more often than the G allele (p=0.028). TNF and VDR polymorphisms did not exhibit transmission disequilibrium. VDR TaqI, ApaI and BsmI variants exhibited linkage disequilibrium. These findings showed an association between the PTPN22 rs2476601 polymorphism and pediatric lupus nephritis due to its overtransmission in the group of families studied.

The Mendelian inheritance of rare flesh and shell colour variants in the black-lipped pearl oyster (Pinctada margaritifera).

PubMed

Ky, Chin-Long; Nakasai, Seiji; Pommier, Steve; Sham Koua, Manaarii; Devaux, Dominique

2016-10-01

Pinctada margaritifera is French Polynesia's most economically important aquaculture species. This pearl oyster has the specific ability to produce cultured pearls with a very wide range of colours, depending on the colour phenotypes of donor oysters used. Its aquaculture is still based on natural spat collection from wild stocks. We investigated three rare colour variants of P. margaritifera - orange flesh, and red and white shell colour phenotypes - in comparison with the wild-type black flesh and shell commonly found in this species. The study aimed to assess the geographic distribution and genetic basis of these colour variants. Colour frequencies were evaluated during transfer and graft processes of pearl oyster seed captured at collector stations. Among the collection locations studied, Mangareva Island showed the highest rate of the orange flesh phenotype, whereas Takaroa and Takume atolls had relatively high rates of red and white shell phenotypes respectively. Broodstocks were made of these rare colour variants, and crosses were performed to produce first- and second-generation progenies to investigate segregation. The results were consistent with Mendelian ratios and suggest a distinct model with no co-dominance: (i) a two-allele model for flesh trait, whereby the orange allele is recessive to the black fleshed type, and (ii) a three-allele model for shell trait, whereby the black wild-type allele is dominant to the red coloration, which is dominant to the white shell. Furthermore, the proposed model provides the basis for producing selected donor pearl oyster lines through hatchery propagation. © 2016 Stichting International Foundation for Animal Genetics.

RAAS polymorphisms alter the acute blood pressure response to aerobic exercise among men with hypertension.

PubMed

Blanchard, Bruce E; Tsongalis, Gregory J; Guidry, Margaux A; LaBelle, Lisa A; Poulin, Michelle; Taylor, Amy L; Maresh, Carl M; Devaney, Joseph; Thompson, Paul D; Pescatello, Linda S

2006-05-01

Limited evidence suggests renin-angiotensin-aldosterone system (RAAS) polymorphisms alter the blood pressure (BP) response to aerobic exercise training. We examined if RAAS polymorphisms influenced postexercise hypotension in men with high normal to Stage 1 hypertension. Forty-seven men (44.2+/-1.4 years, 145.1+/-1.6/85.5+/-1.1 mmHg) randomly completed three experiments: seated rest (control) and two cycle exercise bouts at 40% (LITE) and 60% (MOD) of maximal oxygen consumption. Ambulating BP was measured for 14 h after each experiment. RAAS polymorphisms associated with hypertension (i.e. angiotensin converting I enzyme, ACE I/D; angiotensin II type 1 receptor, AT1R A/C; and intron 2 of aldosterone synthase, Int2 W/C) were analyzed using polymerase chain reaction and restriction enzyme digestion. Repeated measure ANOVA tested if BP differed between experimental conditions by RAAS genotypes. Compared to men with 0-2 variant alleles, men with > or =3 combined RAAS variant alleles had lower average systolic BP (SBP) (P=0.030) and lower average diastolic BP (DBP) (P=0.009) for 14 h only after LITE. In contrast, average BP was not different for MOD and control between RAAS variant allele groups over this time period (P> or =0.05). LITE reduced BP in men with > or =3 variant RAAS alleles for 14 h, whereas MOD had no influence on BP in these men. In order to optimally prescribe exercise for its BP lowering benefits in those with hypertension, additional knowledge of how genetic variation affects the BP response to exercise is needed.

Trans-ancestry Fine Mapping and Molecular Assays Identify Regulatory Variants at the ANGPTL8 HDL-C GWAS Locus

PubMed Central

Cannon, Maren E.; Duan, Qing; Wu, Ying; Zeynalzadeh, Monica; Xu, Zheng; Kangas, Antti J.; Soininen, Pasi; Ala-Korpela, Mika; Civelek, Mete; Lusis, Aldons J.; Kuusisto, Johanna; Collins, Francis S.; Boehnke, Michael; Tang, Hua; Laakso, Markku; Li, Yun; Mohlke, Karen L.

2017-01-01

Recent genome-wide association studies (GWAS) have identified variants associated with high-density lipoprotein cholesterol (HDL-C) located in or near the ANGPTL8 gene. Given the extensive sharing of GWAS loci across populations, we hypothesized that at least one shared variant at this locus affects HDL-C. The HDL-C–associated variants are coincident with expression quantitative trait loci for ANGPTL8 and DOCK6 in subcutaneous adipose tissue; however, only ANGPTL8 expression levels are associated with HDL-C levels. We identified a 400-bp promoter region of ANGPTL8 and enhancer regions within 5 kb that contribute to regulating expression in liver and adipose. To identify variants functionally responsible for the HDL-C association, we performed fine-mapping analyses and selected 13 candidate variants that overlap putative regulatory regions to test for allelic differences in regulatory function. Of these variants, rs12463177-G increased transcriptional activity (1.5-fold, P = 0.004) and showed differential protein binding. Six additional variants (rs17699089, rs200788077, rs56322906, rs3760782, rs737337, and rs3745683) showed evidence of allelic differences in transcriptional activity and/or protein binding. Taken together, these data suggest a regulatory mechanism at the ANGPTL8 HDL-C GWAS locus involving tissue-selective expression and at least one functional variant. PMID:28754724

Effects of a 17q21 chromosome gene variant, tobacco smoke and furred pets on infant wheeze.

PubMed

Bräuner, E V; Loft, S; Raaschou-Nielsen, O; Vogel, U; Andersen, P S; Sørensen, M

2012-01-01

The first common genetic factor identified for pediatric asthma by genome-wide association is the chromosome 17q21 locus, harbouring the ORMDL3 gene. ORMDL3 is involved in facilitation of endoplasmic reticulum-mediated inflammatory responses, believed to underlie its asthma association. We investigated associations between the rs7216389 polymorphism in the 17q21 locus affecting ORMDL3 expression and the risk for recurrent wheeze and interactions with exposure to tobacco smoke and furred pets during pregnancy and infancy using a birth cohort of 101,042 infants. Rs7216389 was significantly associated with recurrent wheeze risk among 18-month-old infants. There was a 1.35-fold higher risk of recurrent wheeze among homozygous variant allele carriers compared with homozygous wild-type allele carriers. There was significant interaction between rs7216389 and domestic furred pets, with a positive association between pets and wheeze among homozygous wild-type carriers and a negative association among homozygous variant allele carriers. There was no interaction between rs7216389 and tobacco smoke exposure.

Haplotype analysis of the germacrene A synthase gene and association with cynaropicrin content and biological activities in Cynara cardunculus.

PubMed

Ferro, Ana Margarida; Ramos, Patrícia; Guerra, Ângela; Parreira, Paula; Brás, Teresa; Guerreiro, Olinda; Jerónimo, Eliana; Capel, Carmen; Capel, Juan; Yuste-Lisbona, Fernando J; Duarte, Maria F; Lozano, Rafael; Oliveira, M Margarida; Gonçalves, Sónia

2018-04-01

Cynara cardunculus: L. represents a natural source of terpenic compounds, with the predominant molecule being cynaropicrin. Cynaropicrin is gaining interest since it has been correlated to anti-hyperlipidaemia, antispasmodic and cytotoxicity activity against leukocyte cancer cells. The objective of this work was to screen a collection of C. cardunculus, from different origins, for new allelic variants in germacrene A synthase (GAS) gene involved in the cynaropicrin biosynthesis and correlate them with improved cynaropicrin content and biological activities. Using high-resolution melting, nine haplotypes were identified. The putative impact of the identified allelic variants in GAS protein was evaluated by bioinformatic tools and polymorphisms that putatively lead to protein conformational changes were described. Additionally, cynaropicrin and main pentacyclic triterpenes contents, and antithrombin, antimicrobial and antiproliferative activities were also determined in C. cardunculus leaf lipophilic-derived extracts. In this work we identified allelic variants with putative impact on GAS protein, which are significantly associated with cynaropicrin content and antiproliferative activity. The results obtained suggest that the identified polymorphisms should be explored as putative genetic markers correlated with biological properties in Cynara cardunculus.

Genetic fine-mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

PubMed Central

Mahajan, Anubha; Locke, Adam; Rayner, N William; Robertson, Neil; Scott, Robert A; Prokopenko, Inga; Scott, Laura J; Green, Todd; Sparso, Thomas; Thuillier, Dorothee; Yengo, Loic; Grallert, Harald; Wahl, Simone; Frånberg, Mattias; Strawbridge, Rona J; Kestler, Hans; Chheda, Himanshu; Eisele, Lewin; Gustafsson, Stefan; Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Qi, Lu; Karssen, Lennart C; van Leeuwen, Elisabeth M; Willems, Sara M; Li, Man; Chen, Han; Fuchsberger, Christian; Kwan, Phoenix; Ma, Clement; Linderman, Michael; Lu, Yingchang; Thomsen, Soren K; Rundle, Jana K; Beer, Nicola L; van de Bunt, Martijn; Chalisey, Anil; Kang, Hyun Min; Voight, Benjamin F; Abecasis, Goncalo R; Almgren, Peter; Baldassarre, Damiano; Balkau, Beverley; Benediktsson, Rafn; Blüher, Matthias; Boeing, Heiner; Bonnycastle, Lori L; Borringer, Erwin P; Burtt, Noël P; Carey, Jason; Charpentier, Guillaume; Chines, Peter S; Cornelis, Marilyn C; Couper, David J; Crenshaw, Andrew T; van Dam, Rob M; Doney, Alex SF; Dorkhan, Mozhgan; Edkins, Sarah; Eriksson, Johan G; Esko, Tonu; Eury, Elodie; Fadista, João; Flannick, Jason; Fontanillas, Pierre; Fox, Caroline; Franks, Paul W; Gertow, Karl; Gieger, Christian; Gigante, Bruna; Gottesman, Omri; Grant, George B; Grarup, Niels; Groves, Christopher J; Hassinen, Maija; Have, Christian T; Herder, Christian; Holmen, Oddgeir L; Hreidarsson, Astradur B; Humphries, Steve E; Hunter, David J; Jackson, Anne U; Jonsson, Anna; Jørgensen, Marit E; Jørgensen, Torben; Kerrison, Nicola D; Kinnunen, Leena; Klopp, Norman; Kong, Augustine; Kovacs, Peter; Kraft, Peter; Kravic, Jasmina; Langford, Cordelia; Leander, Karin; Liang, Liming; Lichtner, Peter; Lindgren, Cecilia M; Lindholm, Eero; Linneberg, Allan; Liu, Ching-Ti; Lobbens, Stéphane; Luan, Jian’an; Lyssenko, Valeriya; Männistö, Satu; McLeod, Olga; Meyer, Julia; Mihailov, Evelin; Mirza, Ghazala; Mühleisen, Thomas W; Müller-Nurasyid, Martina; Navarro, Carmen; Nöthen, Markus M; Oskolkov, Nikolay N; Owen, Katharine R; Palli, Domenico; Pechlivanis, Sonali; Perry, John RB; Platou, Carl GP; Roden, Michael; Ruderfer, Douglas; Rybin, Denis; van der Schouw, Yvonne T; Sennblad, Bengt; Sigurðsson, Gunnar; Stančáková, Alena; Steinbach, Gerald; Storm, Petter; Strauch, Konstantin; Stringham, Heather M; Sun, Qi; Thorand, Barbara; Tikkanen, Emmi; Tonjes, Anke; Trakalo, Joseph; Tremoli, Elena; Tuomi, Tiinamaija; Wennauer, Roman; Wood, Andrew R; Zeggini, Eleftheria; Dunham, Ian; Birney, Ewan; Pasquali, Lorenzo; Ferrer, Jorge; Loos, Ruth JF; Dupuis, Josée; Florez, Jose C; Boerwinkle, Eric; Pankow, James S; van Duijn, Cornelia; Sijbrands, Eric; Meigs, James B; Hu, Frank B; Thorsteinsdottir, Unnur; Stefansson, Kari; Lakka, Timo A; Rauramaa, Rainer; Stumvoll, Michael; Pedersen, Nancy L; Lind, Lars; Keinanen-Kiukaanniemi, Sirkka M; Korpi-Hyövälti, Eeva; Saaristo, Timo E; Saltevo, Juha; Kuusisto, Johanna; Laakso, Markku; Metspalu, Andres; Erbel, Raimund; Jöckel, Karl-Heinz; Moebus, Susanne; Ripatti, Samuli; Salomaa, Veikko; Ingelsson, Erik; Boehm, Bernhard O; Bergman, Richard N; Collins, Francis S; Mohlke, Karen L; Koistinen, Heikki; Tuomilehto, Jaakko; Hveem, Kristian; Njølstad, Inger; Deloukas, Panagiotis; Donnelly, Peter J; Frayling, Timothy M; Hattersley, Andrew T; de Faire, Ulf; Hamsten, Anders; Illig, Thomas; Peters, Annette; Cauchi, Stephane; Sladek, Rob; Froguel, Philippe; Hansen, Torben; Pedersen, Oluf; Morris, Andrew D; Palmer, Collin NA; Kathiresan, Sekar; Melander, Olle; Nilsson, Peter M; Groop, Leif C; Barroso, Inês; Langenberg, Claudia; Wareham, Nicholas J; O’Callaghan, Christopher A; Gloyn, Anna L; Altshuler, David; Boehnke, Michael; Teslovich, Tanya M; McCarthy, Mark I; Morris, Andrew P

2015-01-01

We performed fine-mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in/near KCNQ1. “Credible sets” of variants most likely to drive each distinct signal mapped predominantly to non-coding sequence, implying that T2D association is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine-mapping implicated rs10830963 as driving T2D association. We confirmed that this T2D-risk allele increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D-risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease. PMID:26551672

Integrating common and rare genetic variation in diverse human populations.

PubMed

Altshuler, David M; Gibbs, Richard A; Peltonen, Leena; Altshuler, David M; Gibbs, Richard A; Peltonen, Leena; Dermitzakis, Emmanouil; Schaffner, Stephen F; Yu, Fuli; Peltonen, Leena; Dermitzakis, Emmanouil; Bonnen, Penelope E; Altshuler, David M; Gibbs, Richard A; de Bakker, Paul I W; Deloukas, Panos; Gabriel, Stacey B; Gwilliam, Rhian; Hunt, Sarah; Inouye, Michael; Jia, Xiaoming; Palotie, Aarno; Parkin, Melissa; Whittaker, Pamela; Yu, Fuli; Chang, Kyle; Hawes, Alicia; Lewis, Lora R; Ren, Yanru; Wheeler, David; Gibbs, Richard A; Muzny, Donna Marie; Barnes, Chris; Darvishi, Katayoon; Hurles, Matthew; Korn, Joshua M; Kristiansson, Kati; Lee, Charles; McCarrol, Steven A; Nemesh, James; Dermitzakis, Emmanouil; Keinan, Alon; Montgomery, Stephen B; Pollack, Samuela; Price, Alkes L; Soranzo, Nicole; Bonnen, Penelope E; Gibbs, Richard A; Gonzaga-Jauregui, Claudia; Keinan, Alon; Price, Alkes L; Yu, Fuli; Anttila, Verneri; Brodeur, Wendy; Daly, Mark J; Leslie, Stephen; McVean, Gil; Moutsianas, Loukas; Nguyen, Huy; Schaffner, Stephen F; Zhang, Qingrun; Ghori, Mohammed J R; McGinnis, Ralph; McLaren, William; Pollack, Samuela; Price, Alkes L; Schaffner, Stephen F; Takeuchi, Fumihiko; Grossman, Sharon R; Shlyakhter, Ilya; Hostetter, Elizabeth B; Sabeti, Pardis C; Adebamowo, Clement A; Foster, Morris W; Gordon, Deborah R; Licinio, Julio; Manca, Maria Cristina; Marshall, Patricia A; Matsuda, Ichiro; Ngare, Duncan; Wang, Vivian Ota; Reddy, Deepa; Rotimi, Charles N; Royal, Charmaine D; Sharp, Richard R; Zeng, Changqing; Brooks, Lisa D; McEwen, Jean E

2010-09-02

Despite great progress in identifying genetic variants that influence human disease, most inherited risk remains unexplained. A more complete understanding requires genome-wide studies that fully examine less common alleles in populations with a wide range of ancestry. To inform the design and interpretation of such studies, we genotyped 1.6 million common single nucleotide polymorphisms (SNPs) in 1,184 reference individuals from 11 global populations, and sequenced ten 100-kilobase regions in 692 of these individuals. This integrated data set of common and rare alleles, called 'HapMap 3', includes both SNPs and copy number polymorphisms (CNPs). We characterized population-specific differences among low-frequency variants, measured the improvement in imputation accuracy afforded by the larger reference panel, especially in imputing SNPs with a minor allele frequency of

A recognizable type of syndromic short stature with arthrogryposis caused by bi-allelic SEMA3A loss-of-function variants.

PubMed

Baumann, M; Steichen-Gersdorf, E; Krabichler, B; Müller, T; Janecke, A R

2017-07-01

The semaphorins constitute a large family of secreted and membrane-associated proteins that regulate many developmental processes, including neural circuit assembly, bone formation and angiogenesis. Recently, bi-allelic loss-of-function variants in SEMA3A (semaphorin 3A) were identified in a single patient with a particular pattern of multiple congenital anomalies (MCA). Using homozygosity mapping combined with exome sequencing, we identified a homozygous SEMA3A variant causing a premature stop codon in an 8 year old boy with the same pattern of MCA. The phenotype of these patients is characterized by postnatal short stature, skeletal anomalies of the thorax, a minor congenital heart or vascular defect, camptodactyly, micropenis, and variable additional anomalies. Motor development is delayed in both patients, and intellectual development is delayed in one patient. Our observation of a second case supports the notion that bi-allelic mutations in SEMA3A cause an autosomal recessive type of syndromic short stature. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Association Between Vitamin D Receptor rs731236 (Taq1) Polymorphism and Risk for Restless Legs Syndrome in the Spanish Caucasian Population.

PubMed

Jiménez-Jiménez, Félix Javier; García-Martín, Elena; Alonso-Navarro, Hortensia; Martínez, Carmen; Zurdo, Martín; Turpín-Fenoll, Laura; Millán-Pascual, Jorge; Adeva-Bartolomé, Teresa; Cubo, Esther; Navacerrada, Francisco; Rojo-Sebastián, Ana; Rubio, Lluisa; Ortega-Cubero, Sara; Pastor, Pau; Calleja, Marisol; Plaza-Nieto, José Francisco; Pilo-De-La-Fuente, Belén; Arroyo-Solera, Margarita; García-Albea, Esteban; Agúndez, José A G

2015-11-01

Several recent works suggest a possible role of vitamin D deficiency in the etiology or restless legs syndrome (RLS). We analyzed the possible relationship of 2 common single nucleotide polymorphisms (SNPs) in the vitamin D3 receptor (VDR) gene with the risk for RLS.We studied the genotype and allelic variant frequencies of VDR rs2228570 and VDR rs731236 SNPs in 205 RLS patients and 445 healthy controls using a TaqMan essay.The frequencies of the rs731236AA genotype and the allelic variant rs731236A were significantly lower in RLS patients than in controls (P < 0.005 and < 0.01, respectively). Restless legs syndrome patients carrying the allelic variant rs731236G had an earlier age at onset, and those carrying the rs731236GG genotype had higher severity of RLS, although these data disappeared after multivariate analyses. None of the SNPs studied was related with the positivity of family history of RLS.These results suggest a modest, but significant association between VDR rs731236 SNP and the risk for RLS.

The Tumor Necrosis Factor α (-308 A/G) Polymorphism Is Associated with Cystic Fibrosis in Mexican Patients

PubMed Central

Sanchez-Dominguez, Celia N.; Reyes-Lopez, Miguel A.; Bustamante, Adriana; Cerda-Flores, Ricardo M.; Villalobos-Torres, Maria del C.; Gallardo-Blanco, Hugo L.; Rojas-Martinez, Augusto; Martinez-Rodriguez, Herminia G.; Barrera-Saldaña, Hugo A.; Ortiz-Lopez, Rocio

2014-01-01

Environmental and genetic factors may modify or contribute to the phenotypic differences observed in multigenic and monogenic diseases, such as cystic fibrosis (CF). An analysis of modifier genes can be helpful for estimating patient prognosis and directing preventive care. The aim of this study is to determine the association between seven genetic variants of four modifier genes and CF by comparing their corresponding allelic and genotypic frequencies in CF patients (n = 81) and control subjects (n = 104). Genetic variants of MBL2 exon 1 (A, B, C and D), the IL-8 promoter (−251 A/T), the TNFα promoter (TNF1/TNF2), and SERPINA1 (PI*Z and PI*S) were tested in CF patients and control subjects from northeastern Mexico by PCR-RFLP. Results The TNF2 allele (P = 0.012, OR 3.43, 95% CI 1.25–9.38) was significantly associated with CF under the dominant and additive models but was not associated with CF under the recessive model. This association remained statistically significant after adjusting for multiple tests using the Bonferroni correction (P = 0.0482). The other tested variants and genotypes did not show any association with the disease. Conclusion An analysis of seven genetic variants of four modifier genes showed that one variant, the TNF2 allele, appears to be significantly associated with CF in Mexican patients. PMID:24603877

Somatic mutation dynamics in MDS patients treated with azacitidine indicate clonal selection in patients-responders

PubMed Central

Polgarova, Kamila; Vargova, Karina; Kulvait, Vojtech; Dusilkova, Nina; Minarik, Lubomir; Zemanova, Zuzana; Pesta, Michal; Jonasova, Anna; Stopka, Tomas

2017-01-01

Azacitidine (AZA) for higher risk MDS patients is a standard therapy with limited durability. To monitor mutation dynamics during AZA therapy we utilized massive parallel sequencing of 54 genes previously associated with MDS/AML pathogenesis. Serial sampling before and during AZA therapy of 38 patients (reaching median overall survival 24 months (Mo) with 60% clinical responses) identified 116 somatic pathogenic variants with allele frequency (VAF) exceeding 5%. High accuracy of data was achieved via duplicate libraries from myeloid cells and T-cell controls. We observed that nearly half of the variants were stable while other variants were highly dynamic. Patients with marked decrease of allelic burden upon AZA therapy achieved clinical responses. In contrast, early-progressing patients on AZA displayed minimal changes of the mutation pattern. We modeled the VAF dynamics on AZA and utilized a joint model for the overall survival and response duration. While the presence of certain variants associated with clinical outcomes, such as the mutations of CDKN2A were adverse predictors while KDM6A mutations yield lower risk of dying, the data also indicate that allelic burden volatility represents additional important prognostic variable. In addition, preceding 5q- syndrome represents strong positive predictor of longer overall survival and response duration in high risk MDS patients treated with AZA. In conclusion, variants dynamics detected via serial sampling represents another parameter to consider when evaluating AZA efficacy and predicting outcome. PMID:29340104

A trans-acting Variant within the Transcription Factor RIM101 Interacts with Genetic Background to Determine its Regulatory Capacity.

PubMed

Read, Timothy; Richmond, Phillip A; Dowell, Robin D

2016-01-01

Most genetic variants associated with disease occur within regulatory regions of the genome, underscoring the importance of defining the mechanisms underlying differences in regulation of gene expression between individuals. We discovered a pair of co-regulated, divergently oriented transcripts, AQY2 and ncFRE6, that are expressed in one strain of Saccharomyces cerevisiae, ∑1278b, but not in another, S288c. By combining classical genetics techniques with high-throughput sequencing, we identified a trans-acting single nucleotide polymorphism within the transcription factor RIM101 that causes the background-dependent expression of both transcripts. Subsequent RNA-seq experiments revealed that RIM101 regulates many more targets in S288c than in ∑1278b and that deletion of RIM101 in both backgrounds abrogates the majority of differential expression between the strains. Strikingly, only three transcripts undergo a significant change in expression after swapping RIM101 alleles between backgrounds, implying that the differences in the RIM101 allele lead to a remarkably focused transcriptional response. However, hundreds of RIM101-dependent targets undergo a subtle but consistent shift in expression in the S288c RIM101-swapped strain, but not its ∑1278b counterpart. We conclude that ∑1278b may harbor a variant(s) that buffers against widespread transcriptional dysregulation upon introduction of a non-native RIM101 allele, emphasizing the importance of accounting for genetic background when assessing the impact of a regulatory variant.

Genetic variants on apolipoprotein gene cluster influence triglycerides with a risk of coronary artery disease among Indians.

PubMed

AshokKumar, Manickaraj; Subhashini, Navaneethan Gnana Veera; SaiBabu, Ramineni; Ramesh, Arabandi; Cherian, Kotturathu Mammen; Emmanuel, Cyril

2010-01-01

Apolipoprotein C3 and apolipoprotien A5 are proteins coded from the APOA1/C3/A4/A5 gene cluster. Sst I polymorphism on apolipoprotein C3 and -1131C polymorphism of apolipoprotien A5 are key variants involved in triglyceride metabolism and cause a significant cardio-metabolic risk. Here, we have evaluated these two variants for their roles in coronary artery disease in patients of the Indian population. The apolipoprotein gene cluster variants were analysed in 416 angiographically determined coronary artery disease patients and matched 416 controls using polymerase chain reaction-restriction fragment length polymorphism. The characteristics of the study subjects were analyzed statistically for their association with the polymorphisms. The alleles were combined as haplotypes and their combined risks were evaluated. The minor allele genotypes of both apolipoprotein C3 (S2) and apolipoprotien A5 (C) had a significant risk for coronary artery disease. The S2 allele genotyped patients had a significantly increased triglyceride level (P < 0.001) and increased triglycerides were observed among both patient and control CC genotype carriers. We identified the haplotype S2/C with a significant increased risk (P < 0.001) to coronary artery disease with increased levels of circulating triglycerides compared to other haplotypes in patients. We conclude that the variants on apolipoprotein C3 and apolipoprotien A5 modulate serum triglyceride levels and increase the risk of coronary artery disease.

Further evidence that the rs1858830 C variant in the promoter region of the MET gene is associated with autistic disorder.

PubMed

Jackson, Pamela B; Boccuto, Luigi; Skinner, Cindy; Collins, Julianne S; Neri, Giovanni; Gurrieri, Fiorella; Schwartz, Charles E

2009-08-01

Previous studies in three independent cohorts have shown that the rs1858830 C allele variant in the promoter region of the MET gene on chromosome 7q31 is associated with autism. Another study has found correlations between other alterations in the MET gene and autism in two unrelated cohorts. This study screened two cohorts, an Autistic Disorder cohort from South Carolina and a Pervasive Developmental Disorder (PDD) cohort from Italy, for the presence of the C allele variant in rs1858830. A significant increase in the C allele variant frequency was found in the South Carolina Autistic Disorder patients as compared to South Carolina Controls (chi(2)=5.8, df=1, P=0.02). In the South Carolina cohort, a significant association with Autistic Disorder was found when comparing the CC and CG genotypes to the GG genotype (odds ratio (OR)=1.64; 95% confidence interval (CI)=1.12-2.40; chi(2)=6.5, df=1, P=0.01) in cases and controls. In the Italian cohort, no significant association with PDD was found when comparing the CC or CG genotype to the GG genotype (OR=1.20; 95% CI=0.56-2.56; chi(2)=0.2, df=1, P=0.64). This study is the third independent study to find the rs1858830 C variant in the MET gene promoter to be associated with autism.

Variants in the ATM-CHEK2-BRCA1 axis determine genetic predisposition and clinical presentation of papillary thyroid carcinoma.

PubMed

Wójcicka, Anna; Czetwertyńska, Małgorzata; Świerniak, Michał; Długosińska, Joanna; Maciąg, Monika; Czajka, Agnieszka; Dymecka, Kinga; Kubiak, Anna; Kot, Adam; Płoski, Rafał; de la Chapelle, Albert; Jażdżewski, Krystian

2014-06-01

The risk of developing papillary thyroid carcinoma (PTC), the most frequent form of thyroid malignancy, is elevated up to 8.6-fold in first-degree relatives of PTC patients. The familial risk could be explained by high-penetrance mutations in yet unidentified genes, or polygenic action of low-penetrance alleles. Since the DNA-damaging exposure to ionizing radiation is a known risk factor for thyroid cancer, polymorphisms in DNA repair genes are likely to affect this risk. In a search for low-penetrance susceptibility alleles we employed Sequenom technology to genotype deleterious polymorphisms in ATM, CHEK2, and BRCA1 in 1,781 PTC patients and 2,081 healthy controls. As a result of the study, we identified CHEK2 rs17879961 (OR = 2.2, P = 2.37e-10) and BRCA1 rs16941 (odds ratio [OR] = 1.16, P = 0.005) as risk alleles for PTC. The ATM rs1801516 variant modifies the risk associated with the BRCA1 variant by 0.78 (P = 0.02). Both the ATM and BRCA1 variants modify the impact of male gender on clinical variables: T status (P = 0.007), N status (P = 0.05), and stage (P = 0.035). Our findings implicate an important role of variants in the ATM- CHEK2- BRCA1 axis in modification of the genetic predisposition to PTC and its clinical manifestations. Copyright © 2014 Wiley Periodicals, Inc.

An allelic series at pax7a is associated with colour polymorphism diversity in Lake Malawi cichlid fish.

PubMed

Roberts, Reade B; Moore, Emily C; Kocher, Thomas D

2017-05-01

Despite long-standing interest in the evolution and maintenance of discrete phenotypic polymorphisms, the molecular genetic basis of such polymorphism in the wild is largely unknown. Female sex-associated blotched colour polymorphisms found in cichlids of Lake Malawi, East Africa, represent a highly successful polymorphic phenotype, found and maintained in four genera across the geographic expanse of the lake. Previously, we identified an association with an allelic variant of the paired-box transcription factor gene pax7a and blotched colour morphs in Lake Malawi cichlid fishes. Although a diverse range of blotched phenotypes are present in Lake Malawi cichlid species, they all appeared to result from an allele of pax7a that produces increased levels of transcript. Here, we examine the developmental and genetic basis of variation among blotched morphs. First, we confirm that pax7a-associated blotch morphs result primarily from modulation of melanophore development and survival. From laboratory crosses and natural population studies, we identify at least three alleles of pax7a associated with discrete subtypes of blotched morphs, in addition to the ancestral pax7a allele. Genotypes at pax7a support initial evolution of a novel pax7a allele to produce the blotched class of morphs, followed by subsequent evolution of that pax7a blotched allele to produce additional alleles associated with discrete colour morphs. Variant alleles of pax7a produce different levels of pax7a transcript, correlating with pigmentation phenotype at the cellular level. This naturally selected allelic series should serve as a case study for understanding the molecular genetic control of pax7a expression and the evolution of sex-associated alleles. © 2016 John Wiley & Sons Ltd.

Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African Ancestry Anthropometry Genetics Consortium.

PubMed

Ng, Maggie C Y; Graff, Mariaelisa; Lu, Yingchang; Justice, Anne E; Mudgal, Poorva; Liu, Ching-Ti; Young, Kristin; Yanek, Lisa R; Feitosa, Mary F; Wojczynski, Mary K; Rand, Kristin; Brody, Jennifer A; Cade, Brian E; Dimitrov, Latchezar; Duan, Qing; Guo, Xiuqing; Lange, Leslie A; Nalls, Michael A; Okut, Hayrettin; Tajuddin, Salman M; Tayo, Bamidele O; Vedantam, Sailaja; Bradfield, Jonathan P; Chen, Guanjie; Chen, Wei-Min; Chesi, Alessandra; Irvin, Marguerite R; Padhukasahasram, Badri; Smith, Jennifer A; Zheng, Wei; Allison, Matthew A; Ambrosone, Christine B; Bandera, Elisa V; Bartz, Traci M; Berndt, Sonja I; Bernstein, Leslie; Blot, William J; Bottinger, Erwin P; Carpten, John; Chanock, Stephen J; Chen, Yii-Der Ida; Conti, David V; Cooper, Richard S; Fornage, Myriam; Freedman, Barry I; Garcia, Melissa; Goodman, Phyllis J; Hsu, Yu-Han H; Hu, Jennifer; Huff, Chad D; Ingles, Sue A; John, Esther M; Kittles, Rick; Klein, Eric; Li, Jin; McKnight, Barbara; Nayak, Uma; Nemesure, Barbara; Ogunniyi, Adesola; Olshan, Andrew; Press, Michael F; Rohde, Rebecca; Rybicki, Benjamin A; Salako, Babatunde; Sanderson, Maureen; Shao, Yaming; Siscovick, David S; Stanford, Janet L; Stevens, Victoria L; Stram, Alex; Strom, Sara S; Vaidya, Dhananjay; Witte, John S; Yao, Jie; Zhu, Xiaofeng; Ziegler, Regina G; Zonderman, Alan B; Adeyemo, Adebowale; Ambs, Stefan; Cushman, Mary; Faul, Jessica D; Hakonarson, Hakon; Levin, Albert M; Nathanson, Katherine L; Ware, Erin B; Weir, David R; Zhao, Wei; Zhi, Degui; Arnett, Donna K; Grant, Struan F A; Kardia, Sharon L R; Oloapde, Olufunmilayo I; Rao, D C; Rotimi, Charles N; Sale, Michele M; Williams, L Keoki; Zemel, Babette S; Becker, Diane M; Borecki, Ingrid B; Evans, Michele K; Harris, Tamara B; Hirschhorn, Joel N; Li, Yun; Patel, Sanjay R; Psaty, Bruce M; Rotter, Jerome I; Wilson, James G; Bowden, Donald W; Cupples, L Adrienne; Haiman, Christopher A; Loos, Ruth J F; North, Kari E

2017-04-01

Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained ≤ 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations.

Environmental Stability of Seed Carbohydrate Profiles in Soybeans Containing Different Alleles of the Raffinose Synthase 2 (RS2) Gene.

PubMed

Bilyeu, Kristin D; Wiebold, William J

2016-02-10

Soybean [Glycine max (L.) Merr.] is important for the high protein meal used for livestock feed formulations. Carbohydrates contribute positively or negatively to the potential metabolizable energy in soybean meal. The positive carbohydrate present in soybean meal consists primarily of sucrose, whereas the negative carbohydrate components are the raffinose family of oligosaccharides (RFOs), raffinose and stachyose. Increasing sucrose and decreasing raffinose and stachyose are critical targets to improve soybean. In three recently characterized lines, variant alleles of the soybean raffinose synthase 2 (RS2) gene were associated with increased sucrose and decreased RFOs. The objective of this research was to compare the environmental stability of seed carbohydrates in soybean lines containing wild-type or variant alleles of RS2 utilizing a field location study and a date of planting study. The results define the carbohydrate variation in distinct regional and temporal environments using soybean lines with different alleles of the RS2 gene.

Genetic risk variants in the CDKN2A/B, RTEL1 and EGFR genes are associated with somatic biomarkers in glioma.

PubMed

Ghasimi, Soma; Wibom, Carl; Dahlin, Anna M; Brännström, Thomas; Golovleva, Irina; Andersson, Ulrika; Melin, Beatrice

2016-05-01

During the last years, genome wide association studies have discovered common germline genetic variants associated with specific glioma subtypes. We aimed to study the association between these germline risk variants and tumor phenotypes, including copy number aberrations and protein expression. A total of 91 glioma patients were included. Thirteen well known genetic risk variants in TERT, EGFR, CCDC26, CDKN2A, CDKN2B, PHLDB1, TP53, and RTEL1 were selected for investigation of possible correlations with the glioma somatic markers: EGFR amplification, 1p/19q codeletion and protein expression of p53, Ki-67, and mutated IDH1. The CDKN2A/B risk variant, rs4977756, and the CDKN2B risk variant, rs1412829 were inversely associated (p = 0.049 and p = 0.002, respectively) with absence of a mutated IDH1, i.e., the majority of patients homozygous for the risk allele showed no or low expression of mutated IDH1. The RTEL1 risk variant, rs6010620 was associated (p = 0.013) with not having 1p/19q codeletion, i.e., the majority of patients homozygous for the risk allele did not show 1p/19q codeletion. In addition, the EGFR risk variant rs17172430 and the CDKN2B risk variant rs1412829, both showed a trend for association (p = 0.055 and p = 0.051, respectively) with increased EGFR copy number, i.e., the majority of patients homozygote for the risk alleles showed chromosomal gain or amplification of EGFR. Our findings indicate that CDKN2A/B risk genotypes are associated with primary glioblastoma without IDH mutation, and that there is an inverse association between RTEL1 risk genotypes and 1p/19q codeletion, suggesting that these genetic variants have a molecular impact on the genesis of high graded brain tumors. Further experimental studies are needed to delineate the functional mechanism of the association between genotype and somatic genetic aberrations.

A probabilistic model to predict clinical phenotypic traits from genome sequencing.

PubMed

Chen, Yun-Ching; Douville, Christopher; Wang, Cheng; Niknafs, Noushin; Yeo, Grace; Beleva-Guthrie, Violeta; Carter, Hannah; Stenson, Peter D; Cooper, David N; Li, Biao; Mooney, Sean; Karchin, Rachel

2014-09-01

Genetic screening is becoming possible on an unprecedented scale. However, its utility remains controversial. Although most variant genotypes cannot be easily interpreted, many individuals nevertheless attempt to interpret their genetic information. Initiatives such as the Personal Genome Project (PGP) and Illumina's Understand Your Genome are sequencing thousands of adults, collecting phenotypic information and developing computational pipelines to identify the most important variant genotypes harbored by each individual. These pipelines consider database and allele frequency annotations and bioinformatics classifications. We propose that the next step will be to integrate these different sources of information to estimate the probability that a given individual has specific phenotypes of clinical interest. To this end, we have designed a Bayesian probabilistic model to predict the probability of dichotomous phenotypes. When applied to a cohort from PGP, predictions of Gilbert syndrome, Graves' disease, non-Hodgkin lymphoma, and various blood groups were accurate, as individuals manifesting the phenotype in question exhibited the highest, or among the highest, predicted probabilities. Thirty-eight PGP phenotypes (26%) were predicted with area-under-the-ROC curve (AUC)>0.7, and 23 (15.8%) of these were statistically significant, based on permutation tests. Moreover, in a Critical Assessment of Genome Interpretation (CAGI) blinded prediction experiment, the models were used to match 77 PGP genomes to phenotypic profiles, generating the most accurate prediction of 16 submissions, according to an independent assessor. Although the models are currently insufficiently accurate for diagnostic utility, we expect their performance to improve with growth of publicly available genomics data and model refinement by domain experts.

Linkage disequilibrium between the CYP2C19*2,*17 and CYP2C9*1 alleles and impact of VKORC1, CYP2C9, CYP2C19 gene polymorphisms and gene-gene interactions on warfarin therapy.

PubMed

Khalighi, Koroush; Cheng, Gang; Mirabbasi, Seyedabbas; Khalighi, Bahar; Wu, Yin; Fan, Wuqiang

2017-01-01

Warfarin therapy is complicated by its large inter-individual and intra-individual variability. Both genetic and non-genetic factors can affect warfarin therapy. This study aims to investigate the allele distribution of VKORC1, CYP2C9 and CYP2C19, contribution of different allele variants and possible gene-gene interaction on warfarin therapy. Four hundreds and ninety-two patients were enrolled and single nucleotide polymorphisms for vitamin K epoxide reductase complex subunit 1 (VKORC1), cytochrome P450 CYP2C9 and cytochrome P450 CYP2C19 were genotyped. CYP2C9*1 allele is in complete linkage disequilibrium with CYP2C19*2 and CYP2C19*17 (D' = 1) in our study population. Patient with VKORC1-1639 G > A, CYP2C9*2 and CYP2C9*3 genetic variants need significant lower warfarin dose than patient with wild type allele of VKORC1 1639 G or CYP2C9*1. There is no significant differences between CYP2C19 allele variants for warfarin stable dose and INR > 5 event. Because of the complete linkage disequilibrium between CYP2C19*2,*17 and CYP2C9*1, patient with CYP2C19 *2/*2, *2/*17 and *17/*17 genotypes tend to have higher warfarin dose than patient with CYP2C19*1/*1 genotype. Stepwise regression analysis showed that VKORC1, CYP2C9, body mass index (BMI), age and gender were included as a factor significantly contributing to warfarin dose, whereas CYP2C19 did not contribute to warfarin dose. No statistically significant interaction between CYP2C9 and VKORC1 on warfarin dose and INR > 5 event was detected in univariate general linear model analysis. Our study suggests that polymorphic variants of VKORC1 and CYP2C9 affect warfarin dose independently, whereas CYP2C19 did not contribute to warfarin therapy.

Interactive effects of C-reactive protein levels on the association between APOE variants and triglyceride levels in a Taiwanese population.

PubMed

Wu, Semon; Hsu, Lung-An; Teng, Ming-Sheng; Lin, Jeng-Feng; Chou, Hsin-Hua; Lee, Ming-Cheng; Wu, Yi-Ming; Su, Cheng-Wen; Ko, Yu-Lin

2016-05-13

Apolipoprotein E (APOE) plays a major role in lipid metabolism and inflammation. However, the association between APOE gene polymorphisms and serum triglyceride levels remains controversial. We tested the effects of APOE variants on triglyceride levels and their interactions with the inflammatory marker C-reactive protein (CRP) in a Taiwanese population. Two APOE single nucleotide polymorphisms (SNPs) rs429358 and rs7412 were genotyped by TaqMan Assay using real time PCR in 595 healthy subjects attending the clinic for routine visits. After adjustment for clinical covariates, subjects carrying the rs429358-TT genotype and non-ε4 alleles were found to have higher CRP levels, whereas those with rs7412-CC genotype and non-ε2 alleles had significantly higher total and low-density lipoprotein cholesterol levels (all P < 0.01). Using subgroup and interaction analyses, we observed significantly lower triglyceride levels in subjects carrying the rs429358-TT genotype and non-ε4 alleles in the low CRP group (P = 2.71 × 10(-4) and P = 4.32 × 10(-4), respectively), but not in those in the high CRP group (interaction P = 0.013 and 0.045, respectively). In addition, multivariate stepwise linear regression analysis showed that subjects carrying the rs429358-TT genotype and non-ε4 alleles with low CRP levels had significantly lower triglyceride levels (P < 0.001 and P < 0.001, respectively). In addition, when combined with the risk alleles of GCKR, APOA5 and LPL gene variants, we observed that triglyceride levels increased significantly with the number of risk alleles (P = 2.9 × 10(-12)). The combination of SNPs and ε alleles at the APOE locus is involved in managing lipid and CRP levels in the Taiwanese population. APOE polymorphisms interact with CRP to regulate triglyceride levels, thus triglyceride concentration is influenced by both the genetic background of the APOE locus and the inflammatory status of a subject.

rs10767664 Gene Variant in Brain-Derived Neurotrophic Factor Is Associated with Diabetes Mellitus Type 2 in Caucasian Females with Obesity.

PubMed

de Luis, Daniel Antonio; Aller, Rocío; Izaola, Olatz; Primo, David; Romero, Enrique

2017-01-01

The role of brain-derived neurotrophic factor (BDNF) variants on diabetes prevalence, basal adipokine levels, body weight, and cardiovascular risk factors remains unclear in obese patients. This study is aimed at analyzing the effects of rs10767664 BDNF gene polymorphism on diabetes mellitus prevalence, body weight, cardiovascular risk factors, and serum adipokine levels in obese female patients. A total of 507 obese women were enrolled in a prospective way. Biochemical evaluation and anthropometric measures were recorded. The frequency of diabetes mellitus in the group of patients with non-T allele was 20.1 and 28.3% in T-allele carriers. Logistic regression showed a risk of diabetes mellitus of 1.33 (95% CI 1.17-2.08) in subjects with T allele adjusted by age and body mass index (BMI). T-allele carriers with diabetes mellitus have a higher weight, BMI, waist circumference, blood pressure, glucose, homeostasis model assessment insulin resistance (HOMA-IR), insulin, and C-reactive protein (CRP) levels than non-T-allele carriers. rs10767664 polymorphism of BDNF gene is associated with prevalence of diabetes mellitus in obese female patients. T-allele carriers with diabetes mellitus have a higher weight, fat mass, blood pressure, level of insulin, glucose, HOMA-IR, and CRP than non-T-allele carriers. © 2017 S. Karger AG, Basel.

Biology, Genetics, and Environment: Underlying Factors Influencing Alcohol Metabolism.

PubMed

Wall, Tamara L; Luczak, Susan E; Hiller-Sturmhöfel, Susanne

2016-01-01

Gene variants encoding several of the alcohol-metabolizing enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), are among the largest genetic associations with risk for alcohol dependence. Certain genetic variants (i.e., alleles)--particularly the ADH1B*2, ADH1B*3, ADH1C*1, and ALDH2*2 alleles--have been associated with lower rates of alcohol dependence. These alleles may lead to an accumulation of acetaldehyde during alcohol metabolism, which can result in heightened subjective and objective effects. The prevalence of these alleles differs among ethnic groups; ADH1B*2 is found frequently in northeast Asians and occasionally Caucasians, ADH1B*3 is found predominantly in people of African ancestry, ADH1C*1 varies substantially across populations, and ALDH2*2 is found almost exclusively in northeast Asians. Differences in the prevalence of these alleles may account at least in part for ethnic differences in alcohol consumption and alcohol use disorder (AUD). However, these alleles do not act in isolation to influence the risk of AUD. For example, the gene effects of ALDH2*2 and ADH1B*2 seem to interact. Moreover, other factors have been found to influence the extent to which these alleles affect a person's alcohol involvement, including developmental stage, individual characteristics (e.g., ethnicity, antisocial behavior, and behavioral undercontrol), and environmental factors (e.g., culture, religion, family environment, and childhood adversity).

Association of a Human FABP1 Gene Promoter Region Polymorphism with Altered Serum Triglyceride Levels.

PubMed

Peng, Xian-E; Wu, Yun-Li; Zhu, Yi-Bing; Huang, Rong-Dong; Lu, Qing-Qing; Lin, Xu

2015-01-01

Liver fatty acid-binding protein (L-FABP), also known as fatty acid-binding protein 1 (FABP1), is a key regulator of hepatic lipid metabolism. Elevated FABP1 levels are associated with an increased risk of cardiovascular disease (CVD) and metabolic syndromes. In this study, we examine the association of FABP1 gene promoter variants with serum FABP1 and lipid levels in a Chinese population. Four promoter single-nucleotide polymorphisms (SNPs) of FABP1 gene were genotyped in a cross-sectional survey of healthy volunteers (n = 1,182) from Fuzhou city of China. Results showed that only the rs2919872 G>A variant was significantly associated with serum TG concentration(P = 0.032).Compared with the rs2919872 G allele, rs2919872 A allele contributed significantly to reduced serum TG concentration, and this allele dramatically decreased the FABP1 promoter activity(P < 0.05). The rs2919872 A allele carriers had considerably lower serum FABP1 levels than G allele carriers (P < 0.01). In the multivariable linear regression analysis, the rs2919872 A allele was negatively associated with serum FABP1 levels (β = -0.320, P = 0.003), while serum TG levels were positively associated with serum FABP1 levels (β = 0.487, P = 0.014). Our data suggest that compared with the rs2919872 G allele, the rs2919872 A allele reduces the transcriptional activity of FABP1 promoter, and thereby may link FABP1 gene variation to TG level in humans.

Association of a Human FABP1 Gene Promoter Region Polymorphism with Altered Serum Triglyceride Levels

PubMed Central

Zhu, Yi-bing; Huang, Rong-dong; Lu, Qing-Qing; Lin, Xu

2015-01-01

Liver fatty acid-binding protein (L-FABP), also known as fatty acid-binding protein 1 (FABP1), is a key regulator of hepatic lipid metabolism. Elevated FABP1 levels are associated with an increased risk of cardiovascular disease (CVD) and metabolic syndromes. In this study, we examine the association of FABP1 gene promoter variants with serum FABP1 and lipid levels in a Chinese population. Four promoter single-nucleotide polymorphisms (SNPs) of FABP1 gene were genotyped in a cross-sectional survey of healthy volunteers (n = 1,182) from Fuzhou city of China. Results showed that only the rs2919872 G>A variant was significantly associated with serum TG concentration(P = 0.032).Compared with the rs2919872 G allele, rs2919872 A allele contributed significantly to reduced serum TG concentration, and this allele dramatically decreased the FABP1 promoter activity(P < 0.05). The rs2919872 A allele carriers had considerably lower serum FABP1 levels than G allele carriers (P < 0.01). In the multivariable linear regression analysis, the rs2919872 A allele was negatively associated with serum FABP1 levels (β = —0.320, P = 0.003), while serum TG levels were positively associated with serum FABP1 levels (β = 0.487, P = 0.014). Our data suggest that compared with the rs2919872 G allele, the rs2919872 A allele reduces the transcriptional activity of FABP1 promoter, and thereby may link FABP1 gene variation to TG level in humans. PMID:26439934

Polygenic obesity in humans.

PubMed

Hinney, Anke; Hebebrand, Johannes

2008-01-01

The molecular genetic analysis of obesity has led to the identification of a limited number of confirmed major genes. While such major genes have a clear influence on the development of the phenotype, the underlying mutations are however (extremely) infrequent and thus of minor clinical importance only. The genetic predisposition to obesity must thus be polygenic; a number of such variants should be found in most obese subjects; however, these variants predisposing to obesity are also found in normal weight and even lean individuals. Therefore, a polygene can only be identified and validated by statistical analyses: the appropriate gene variant (allele) occurs more frequently in obese than in non-obese subjects. Each single polygene makes only a small contribution to the development of obesity. The 103Ile allele of the Val103Ile single nucleotide polymorphism (SNP) of the melanocortin-4 receptor gene (MC4R) was the first confirmed polygenetic variant with an influence on the body mass index (BMI); the more common Val103 allele is more frequent in obese individuals. As determined in a recent, large-scaled meta-analysis the effect size of this allele on mean BMI was approximately -0.5 kg/m(2). The first genome-wide association study (GWA) for obesity, based on approximately 100,000 SNPs analyzed in families of the Framingham study, revealed that a SNP in the proximity of the insulin-induced gene 2 (INSIG2) was associated with obesity. The positive result was replicated in independent samples; however, some other study groups detected no association. Currently, a meta-analysis is ongoing; its result will contribute to the evaluation of the importance of the INSIG2 polymorphism in body weight regulation. SNP alleles in intron 1 of the fat mass and obesity associated gene (FTO) confer the most relevant polygenic effect on obesity. In the first GWA for extreme early onset obesity we substantiated that variation in FTO strongly contributes to early onset obesity. Copyright 2008 S. Karger AG, Basel.

A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans.

PubMed

Timpson, Nicholas J; Walter, Klaudia; Min, Josine L; Tachmazidou, Ioanna; Malerba, Giovanni; Shin, So-Youn; Chen, Lu; Futema, Marta; Southam, Lorraine; Iotchkova, Valentina; Cocca, Massimiliano; Huang, Jie; Memari, Yasin; McCarthy, Shane; Danecek, Petr; Muddyman, Dawn; Mangino, Massimo; Menni, Cristina; Perry, John R B; Ring, Susan M; Gaye, Amadou; Dedoussis, George; Farmaki, Aliki-Eleni; Burton, Paul; Talmud, Philippa J; Gambaro, Giovanni; Spector, Tim D; Smith, George Davey; Durbin, Richard; Richards, J Brent; Humphries, Steve E; Zeggini, Eleftheria; Soranzo, Nicole

2014-09-16

The analysis of rich catalogues of genetic variation from population-based sequencing provides an opportunity to screen for functional effects. Here we report a rare variant in APOC3 (rs138326449-A, minor allele frequency ~0.25% (UK)) associated with plasma triglyceride (TG) levels (-1.43 s.d. (s.e.=0.27 per minor allele (P-value=8.0 × 10(-8))) discovered in 3,202 individuals with low read-depth, whole-genome sequence. We replicate this in 12,831 participants from five additional samples of Northern and Southern European origin (-1.0 s.d. (s.e.=0.173), P-value=7.32 × 10(-9)). This is consistent with an effect between 0.5 and 1.5 mmol l(-1) dependent on population. We show that a single predicted splice donor variant is responsible for association signals and is independent of known common variants. Analyses suggest an independent relationship between rs138326449 and high-density lipoprotein (HDL) levels. This represents one of the first examples of a rare, large effect variant identified from whole-genome sequencing at a population scale.

Lack of association between the P413L variant of chromogranin B and ALS risk or age at onset: a meta-analysis.

PubMed

Yang, Xinglong; Li, Shimei; Xing, Dongmei; Li, Peiyun; Li, Ci; Qi, Ling; Xu, Yanming; Ren, Hui

2018-02-01

Amyotrophic lateral sclerosis (ALS), the most common motor neuron disease, is thought to result from interaction of genetic and environmental risk factors. Whether the potentially functional exonic P413L variant in the chromogranin B gene influences ALS risk and age at onset is controversial. We meta-analysed or other studies assessing the association between the P413L variant and ALS risk or age at ALS onset indexed in Web of Science, PubMed, Embase, Chinese National Knowledge Infrastructure, Wanfang, and SinoMed databases. Five case-control studies were analysed, involving 2639 patients with sporadic ALS, 201 with familial ALS and 3381 controls. No association was detected between risk of either ALS type and the CT + TT genotype or T-allele of the P413L variant. Age at ALS onset was similar between carriers and non-carriers of the T-allele. The available evidence suggests that the P413L variant of chromogranin B is not associated with ALS risk or age at ALS onset. These results should be validated in large, well-designed studies.

Multiplexed enrichment of rare DNA variants via sequence-selective and temperature-robust amplification

PubMed Central

Wu, Lucia R.; Chen, Sherry X.; Wu, Yalei; Patel, Abhijit A.; Zhang, David Yu

2018-01-01

Rare DNA-sequence variants hold important clinical and biological information, but existing detection techniques are expensive, complex, allele-specific, or don’t allow for significant multiplexing. Here, we report a temperature-robust polymerase-chain-reaction method, which we term blocker displacement amplification (BDA), that selectively amplifies all sequence variants, including single-nucleotide variants (SNVs), within a roughly 20-nucleotide window by 1,000-fold over wild-type sequences. This allows for easy detection and quantitation of hundreds of potential variants originally at ≤0.1% in allele frequency. BDA is compatible with inexpensive thermocycler instrumentation and employs a rationally designed competitive hybridization reaction to achieve comparable enrichment performance across annealing temperatures ranging from 56 °C to 64 °C. To show the sequence generality of BDA, we demonstrate enrichment of 156 SNVs and the reliable detection of single-digit copies. We also show that the BDA detection of rare driver mutations in cell-free DNA samples extracted from the blood plasma of lung-cancer patients is highly consistent with deep sequencing using molecular lineage tags, with a receiver operator characteristic accuracy of 95%. PMID:29805844

Population frequencies of the Triallelic 5HTTLPR in six Ethnicially diverse samples from North America, Southeast Asia, and Africa.

PubMed

Haberstick, Brett C; Smolen, Andrew; Williams, Redford B; Bishop, George D; Foshee, Vangie A; Thornberry, Terence P; Conger, Rand; Siegler, Ilene C; Zhang, Xiaodong; Boardman, Jason D; Frajzyngier, Zygmunt; Stallings, Michael C; Brent Donnellan, M; Halpern, Carolyn T; Harris, Kathleen Mullan

2015-03-01

Genetic differences between populations are potentially an important contributor to health disparities around the globe. As differences in gene frequencies influence study design, it is important to have a thorough understanding of the natural variation of the genetic variant(s) of interest. Along these lines, we characterized the variation of the 5HTTLPR and rs25531 polymorphisms in six samples from North America, Southeast Asia, and Africa (Cameroon) that differ in their racial and ethnic composition. Allele and genotype frequencies were determined for 24,066 participants. Results indicated higher frequencies of the rs25531 G-allele among Black and African populations as compared with White, Hispanic and Asian populations. Further, we observed a greater number of 'extra-long' ('XL') 5HTTLPR alleles than have previously been reported. Extra-long alleles occurred almost entirely among Asian, Black and Non-White Hispanic populations as compared with White and Native American populations where they were completely absent. Lastly, when considered jointly, we observed between sample differences in the genotype frequencies within racial and ethnic populations. Taken together, these data underscore the importance of characterizing the L-G allele to avoid misclassification of participants by genotype and for further studies of the impact XL alleles may have on the transcriptional efficiency of SLC6A4.

A thrifty variant in CREBRF strongly influences body mass index in Samoans

PubMed Central

Kershaw, Erin E; Cheng, Hong; Buhule, Olive D; Lin, Jerome; Reupena, Muagututi‘a Sefuiva; Viali, Satupa‘itea; Tuitele, John; Naseri, Take; Urban, Zsolt; Deka, Ranjan; Weeks, Daniel E; McGarvey, Stephen T

2016-01-01

Samoans are a unique founder population with a high prevalence of obesity1–3, making them well suited for identifying new genetic contributors to obesity4. We conducted a genome-wide association study (GWAS) in 3,072 Samoans, discovered a variant, rs12513649, strongly associated with body mass index (BMI) (P = 5.3 × 10−14), and replicated the association in 2,102 additional Samoans (P = 1.2 × 10−9). Targeted sequencing identified a strongly associated missense variant, rs373863828 (p.Arg457Gln), in CREBRF (meta P = 1.4 × 10−20). Although this variant is extremely rare in other populations, it is common in Samoans (frequency of 0.259), with an effect size much larger than that of any other known common BMI risk variant (1.36–1.45 kg/m2 per copy of the risk-associated allele). In comparison to wild-type CREBRF, the Arg457Gln variant when overexpressed selectively decreased energy use and increased fat storage in an adipocyte cell model. These data, in combination with evidence of positive selection of the allele encoding p.Arg457Gln, support a ‘thrifty’ variant hypothesis as a factor in human obesity. PMID:27455349

SG-ADVISER CNV: copy-number variant annotation and interpretation.

PubMed

Erikson, Galina A; Deshpande, Neha; Kesavan, Balachandar G; Torkamani, Ali

2015-09-01

Copy-number variants have been associated with a variety of diseases, especially cancer, autism, schizophrenia, and developmental delay. The majority of clinically relevant events occur de novo, necessitating the interpretation of novel events. In this light, we present the Scripps Genome ADVISER CNV annotation pipeline and Web server, which aims to fill the gap between copy number variant detection and interpretation by performing in-depth annotations and functional predictions for copy number variants. The Scripps Genome ADVISER CNV suite includes a Web server interface to a high-performance computing environment for calculations of annotations and a table-based user interface that allows for the execution of numerous annotation-based variant filtration strategies and statistics. The annotation results include details regarding location, impact on the coding portion of genes, allele frequency information (including allele frequencies from the Scripps Wellderly cohort), and overlap information with other reference data sets (including ClinVar, DGV, DECIPHER). A summary variant classification is produced (ADVISER score) based on the American College of Medical Genetics and Genomics scoring guidelines. We demonstrate >90% sensitivity/specificity for detection of pathogenic events. Scripps Genome ADVISER CNV is designed to allow users with no prior bioinformatics expertise to manipulate large volumes of copy-number variant data. Scripps Genome ADVISER CNV is available at http://genomics.scripps.edu/ADVISER/.

Whole genome sequencing of an African American family highlights toll like receptor 6 variants in Kawasaki disease susceptibility.

PubMed

Kim, Jihoon; Shimizu, Chisato; Kingsmore, Stephen F; Veeraraghavan, Narayanan; Levy, Eric; Ribeiro Dos Santos, Andre M; Yang, Hai; Flatley, Jay; Hoang, Long Truong; Hibberd, Martin L; Tremoulet, Adriana H; Harismendy, Olivier; Ohno-Machado, Lucila; Burns, Jane C

2017-01-01

Kawasaki disease (KD) is the most common acquired pediatric heart disease. We analyzed Whole Genome Sequences (WGS) from a 6-member African American family in which KD affected two of four children. We sought rare, potentially causative genotypes by sequentially applying the following WGS filters: sequence quality scores, inheritance model (recessive homozygous and compound heterozygous), predicted deleteriousness, allele frequency, genes in KD-associated pathways or with significant associations in published KD genome-wide association studies (GWAS), and with differential expression in KD blood transcriptomes. Biologically plausible genotypes were identified in twelve variants in six genes in the two affected children. The affected siblings were compound heterozygous for the rare variants p.Leu194Pro and p.Arg247Lys in Toll-like receptor 6 (TLR6), which affect TLR6 signaling. The affected children were also homozygous for three common, linked (r2 = 1) intronic single nucleotide variants (SNVs) in TLR6 (rs56245262, rs56083757 and rs7669329), that have previously shown association with KD in cohorts of European descent. Using transcriptome data from pre-treatment whole blood of KD subjects (n = 146), expression quantitative trait loci (eQTL) analyses were performed. Subjects homozygous for the intronic risk allele (A allele of TLR6 rs56245262) had differential expression of Interleukin-6 (IL-6) as a function of genotype (p = 0.0007) and a higher erythrocyte sedimentation rate at diagnosis. TLR6 plays an important role in pathogen-associated molecular pattern recognition, and sequence variations may affect binding affinities that in turn influence KD susceptibility. This integrative genomic approach illustrates how the analysis of WGS in multiplex families with a complex genetic disease allows examination of both the common disease-common variant and common disease-rare variant hypotheses.

TM6SF2 Glu167Lys polymorphism is associated with low levels of LDL-cholesterol and increased liver injury in obese children.

PubMed

Grandone, A; Cozzolino, D; Marzuillo, P; Cirillo, G; Di Sessa, A; Ruggiero, L; Di Palma, M R; Perrone, L; Miraglia Del Giudice, E

2016-04-01

The Glu167Lys (E167K) transmembrane 6 superfamily member 2 (TM6SF2) variant has been associated with liver steatosis, high alanine transaminase (ALT) levels and reduced plasma levels of liver-derived triglyceride-rich lipoproteins. The objectives of this study were to investigate in a group of obese children the association among the 167K allele of TM6SF2 gene and ALT, cholesterol and triglycerides levels, and hepatic steatosis, and to evaluate the potential interaction between this variant and the I148M patatin like phospholipase 3 gene (PNPLA3) polymorphism on liver enzymes. We genotyped 1010 obese children for TM6SF2 E167K and PNPLA3 I148M polymorphisms. Anthropometrical and biochemical data were collected. Ultrasound imaging of the liver was performed. The 167K allele showed an association with steatosis (P < 0.0001), higher ALT levels (P < 0.001) and lower total cholesterol (P < 0.00001), low-density lipoprotein cholesterol (P < 0.0001), triglycerides (P = 0.02) and non-high-density lipoprotein cholesterol levels (P < 0.000001). The subjects homozygous for the PNPLA3 148M allele carrying the rare variant of TM6SF2 showed an odds ratio of 12.2 (confidence interval 3.8-39.6, P = 0.000001) to present hypertransaminasaemia compared with the remaining patients. Although the TMS6SF2 E167K variant predisposes the obese children to non-alcoholic fatty liver disease, there is an association between this variant and lower levels of cardiovascular risk factors. Overall, the data suggest differential effects of TMS6SF2 E167K variant on liver and heart health. © 2015 World Obesity.

A population-based analysis of germline BAP1 mutations in melanoma.

PubMed

O'Shea, Sally J; Robles-Espinoza, Carla Daniela; McLellan, Lauren; Harrigan, Jeanine; Jacq, Xavier; Hewinson, James; Iyer, Vivek; Merchant, Will; Elliott, Faye; Harland, Mark; Bishop, D Timothy; Newton-Bishop, Julia A; Adams, David J

2017-02-15

Germline mutation of the BRCA1 associated protein-1 (BAP1) gene has been linked to uveal melanoma, mesothelioma, meningioma, renal cell carcinoma and basal cell carcinoma. Germline variants have also been found in familial cutaneous melanoma pedigrees, but their contribution to sporadic melanoma has not been fully assessed. We sequenced BAP1 in 1,977 melanoma cases and 754 controls and used deubiquitinase assays, a pedigree analysis, and a histopathological review to assess the consequences of the mutations found. Sequencing revealed 30 BAP1 variants in total, of which 27 were rare (ExAc allele frequency <0.002). Of the 27 rare variants, 22 were present in cases (18 missense, one splice acceptor, one frameshift and two near splice regions) and five in controls (all missense). A missense change (S98R) in a case that completely abolished BAP1 deubiquitinase activity was identified. Analysis of cancers in the pedigree of the proband carrying the S98R variant and in two other pedigrees carrying clear loss-of-function alleles showed the presence of BAP1-associated cancers such as renal cell carcinoma, mesothelioma and meningioma, but not uveal melanoma. Two of these three probands carrying BAP1 loss-of-function variants also had melanomas with histopathological features suggestive of a germline BAP1 mutation. The remaining cases with germline mutations, which were predominantly missense mutations, were associated with less typical pedigrees and tumours lacking a characteristic BAP1-associated histopathological appearances, but may still represent less penetrant variants. Germline BAP1 alleles defined as loss-of-function or predicted to be deleterious/damaging are rare in cutaneous melanoma. © The Author 2017. Published by Oxford University Press.

A population-based analysis of germline BAP1 mutations in melanoma

PubMed Central

O’Shea, Sally J.; Robles-Espinoza, Carla Daniela; Harrigan, Jeanine; Jacq, Xavier; Hewinson, James; Iyer, Vivek; Merchant, Will; Elliott, Faye; Harland, Mark; Bishop, D. Timothy; Newton-Bishop, Julia A.

2017-01-01

Abstract Germline mutation of the BRCA1 associated protein-1 (BAP1) gene has been linked to uveal melanoma, mesothelioma, meningioma, renal cell carcinoma and basal cell carcinoma. Germline variants have also been found in familial cutaneous melanoma pedigrees, but their contribution to sporadic melanoma has not been fully assessed. We sequenced BAP1 in 1,977 melanoma cases and 754 controls and used deubiquitinase assays, a pedigree analysis, and a histopathological review to assess the consequences of the mutations found. Sequencing revealed 30 BAP1 variants in total, of which 27 were rare (ExAc allele frequency <0.002). Of the 27 rare variants, 22 were present in cases (18 missense, one splice acceptor, one frameshift and two near splice regions) and five in controls (all missense). A missense change (S98R) in a case that completely abolished BAP1 deubiquitinase activity was identified. Analysis of cancers in the pedigree of the proband carrying the S98R variant and in two other pedigrees carrying clear loss-of-function alleles showed the presence of BAP1-associated cancers such as renal cell carcinoma, mesothelioma and meningioma, but not uveal melanoma. Two of these three probands carrying BAP1 loss-of-function variants also had melanomas with histopathological features suggestive of a germline BAP1 mutation. The remaining cases with germline mutations, which were predominantly missense mutations, were associated with less typical pedigrees and tumours lacking a characteristic BAP1-associated histopathological appearances, but may still represent less penetrant variants. Germline BAP1 alleles defined as loss-of-function or predicted to be deleterious/damaging are rare in cutaneous melanoma. PMID:28062663

Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21

PubMed Central

Adoue, Véronique; Michailidou, Kyriaki; Canisius, Sander; Lemaçon, Audrey; Droit, Arnaud; Andrulis, Irene L; Anton-Culver, Hoda; Arndt, Volker; Baynes, Caroline; Blomqvist, Carl; Bogdanova, Natalia V.; Bojesen, Stig E.; Bolla, Manjeet K.; Bonanni, Bernardo; Borresen-Dale, Anne-Lise; Brand, Judith S.; Brauch, Hiltrud; Brenner, Hermann; Broeks, Annegien; Burwinkel, Barbara; Chang-Claude, Jenny; Couch, Fergus J.; Cox, Angela; Cross, Simon S.; Czene, Kamila; Darabi, Hatef; Dennis, Joe; Devilee, Peter; Dörk, Thilo; Dos-Santos-Silva, Isabel; Eriksson, Mikael; Fasching, Peter A.; Figueroa, Jonine; Flyger, Henrik; García-Closas, Montserrat; Giles, Graham G.; Goldberg, Mark S.; González-Neira, Anna; Grenaker-Alnæs, Grethe; Guénel, Pascal; Haeberle, Lothar; Haiman, Christopher A.; Hamann, Ute; Hallberg, Emily; Hooning, Maartje J.; Hopper, John L.; Jakubowska, Anna; Jones, Michael; Kabisch, Maria; Kataja, Vesa; Lambrechts, Diether; Marchand, Loic Le; Lindblom, Annika; Lubinski, Jan; Mannermaa, Arto; Maranian, Mel; Margolin, Sara; Marme, Frederik; Milne, Roger L.; Neuhausen, Susan L.; Nevanlinna, Heli; Neven, Patrick; Olswold, Curtis; Peto, Julian; Plaseska-Karanfilska, Dijana; Pylkäs, Katri; Radice, Paolo; Rudolph, Anja; Sawyer, Elinor J.; Schmidt, Marjanka K.; Shu, Xiao-Ou; Southey, Melissa C.; Swerdlow, Anthony; Tollenaar, Rob A.E.M.; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; Vachon, Celine; Van Den Ouweland, Ans M. W.; Wang, Qin; Winqvist, Robert; Investigators, kConFab/AOCS; Zheng, Wei; Benitez, Javier; Chenevix-Trench, Georgia; Dunning, Alison M.; Pharoah, Paul D. P.; Kristensen, Vessela; Hall, Per; Easton, Douglas F.; Pastinen, Tomi; Nord, Silje; Simard, Jacques

2016-01-01

There are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, cis-acting variants represent an important source of phenotypic variation. Consequently, cis-regulatory SNPs associated with differential allelic expression are functional candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a list of genes was established on the basis of their involvement in cancer related pathways and/or mechanisms. Thereafter, using data from a genome-wide map of allelic expression associated SNPs, 313 genetic variants were selected and their association with breast cancer risk was then evaluated in 46,451 breast cancer cases and 42,599 controls of European ancestry ascertained from 41 studies participating in the Breast Cancer Association Consortium. The associations were evaluated with overall breast cancer risk and with estrogen receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, P = 5.6x10-6). rs11099601 lies in a 135 kb linkage disequilibrium block containing several genes, including, HELQ, encoding the protein HEL308 a DNA dependant ATPase and DNA Helicase involved in DNA repair, MRPS18C encoding the Mitochondrial Ribosomal Protein S18C and FAM175A (ABRAXAS), encoding a BRCA1 BRCT domain-interacting protein involved in DNA damage response and double-strand break (DSB) repair. Expression QTL analysis in breast cancer tissue showed rs11099601 to be associated with HELQ (P = 8.28x10-14), MRPS18C (P = 1.94x10-27) and FAM175A (P = 3.83x10-3), explaining about 20%, 14% and 1%, respectively of the variance inexpression of these genes in breast carcinomas. PMID:27792995

Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21.

PubMed

Hamdi, Yosr; Soucy, Penny; Adoue, Véronique; Michailidou, Kyriaki; Canisius, Sander; Lemaçon, Audrey; Droit, Arnaud; Andrulis, Irene L; Anton-Culver, Hoda; Arndt, Volker; Baynes, Caroline; Blomqvist, Carl; Bogdanova, Natalia V; Bojesen, Stig E; Bolla, Manjeet K; Bonanni, Bernardo; Borresen-Dale, Anne-Lise; Brand, Judith S; Brauch, Hiltrud; Brenner, Hermann; Broeks, Annegien; Burwinkel, Barbara; Chang-Claude, Jenny; Couch, Fergus J; Cox, Angela; Cross, Simon S; Czene, Kamila; Darabi, Hatef; Dennis, Joe; Devilee, Peter; Dörk, Thilo; Dos-Santos-Silva, Isabel; Eriksson, Mikael; Fasching, Peter A; Figueroa, Jonine; Flyger, Henrik; García-Closas, Montserrat; Giles, Graham G; Goldberg, Mark S; González-Neira, Anna; Grenaker-Alnæs, Grethe; Guénel, Pascal; Haeberle, Lothar; Haiman, Christopher A; Hamann, Ute; Hallberg, Emily; Hooning, Maartje J; Hopper, John L; Jakubowska, Anna; Jones, Michael; Kabisch, Maria; Kataja, Vesa; Lambrechts, Diether; Le Marchand, Loic; Lindblom, Annika; Lubinski, Jan; Mannermaa, Arto; Maranian, Mel; Margolin, Sara; Marme, Frederik; Milne, Roger L; Neuhausen, Susan L; Nevanlinna, Heli; Neven, Patrick; Olswold, Curtis; Peto, Julian; Plaseska-Karanfilska, Dijana; Pylkäs, Katri; Radice, Paolo; Rudolph, Anja; Sawyer, Elinor J; Schmidt, Marjanka K; Shu, Xiao-Ou; Southey, Melissa C; Swerdlow, Anthony; Tollenaar, Rob A E M; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; Vachon, Celine; Van Den Ouweland, Ans M W; Wang, Qin; Winqvist, Robert; Zheng, Wei; Benitez, Javier; Chenevix-Trench, Georgia; Dunning, Alison M; Pharoah, Paul D P; Kristensen, Vessela; Hall, Per; Easton, Douglas F; Pastinen, Tomi; Nord, Silje; Simard, Jacques

2016-12-06

There are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, cis-acting variants represent an important source of phenotypic variation. Consequently, cis-regulatory SNPs associated with differential allelic expression are functional candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a list of genes was established on the basis of their involvement in cancer related pathways and/or mechanisms. Thereafter, using data from a genome-wide map of allelic expression associated SNPs, 313 genetic variants were selected and their association with breast cancer risk was then evaluated in 46,451 breast cancer cases and 42,599 controls of European ancestry ascertained from 41 studies participating in the Breast Cancer Association Consortium. The associations were evaluated with overall breast cancer risk and with estrogen receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, P = 5.6x10-6). rs11099601 lies in a 135 kb linkage disequilibrium block containing several genes, including, HELQ, encoding the protein HEL308 a DNA dependant ATPase and DNA Helicase involved in DNA repair, MRPS18C encoding the Mitochondrial Ribosomal Protein S18C and FAM175A (ABRAXAS), encoding a BRCA1 BRCT domain-interacting protein involved in DNA damage response and double-strand break (DSB) repair. Expression QTL analysis in breast cancer tissue showed rs11099601 to be associated with HELQ (P = 8.28x10-14), MRPS18C (P = 1.94x10-27) and FAM175A (P = 3.83x10-3), explaining about 20%, 14% and 1%, respectively of the variance inexpression of these genes in breast carcinomas.

Balancing selection is common in the extended MHC region but most alleles with opposite risk profile for autoimmune diseases are neutrally evolving

PubMed Central

2011-01-01

Background Several susceptibility genetic variants for autoimmune diseases have been identified. A subset of these polymorphisms displays an opposite risk profile in different autoimmune conditions. This observation open interesting questions on the evolutionary forces shaping the frequency of these alleles in human populations. We aimed at testing the hypothesis whereby balancing selection has shaped the frequency of opposite risk alleles. Results Since balancing selection signatures are expected to extend over short genomic portions, we focused our analyses on 11 regions carrying putative functional polymorphisms that may represent the disease variants (and the selection targets). No exceptional nucleotide diversity was observed for ZSCAN23, HLA-DMB, VARS2, PTPN22, BAT3, C6orf47, and IL10; summary statistics were consistent with evolutionary neutrality for these gene regions. Conversely, CDSN/PSORS1C1, TRIM10/TRIM40, BTNL2, and TAP2 showed extremely high nucleotide diversity and most tests rejected neutrality, suggesting the action of balancing selection. For TAP2 and BTNL2 these signatures are not secondary to linkage disequilibrium with HLA class II genes. Nonetheless, with the exception of variants in TRIM40 and CDSN, our data suggest that opposite risk SNPs are not selection targets but rather have accumulated as neutral variants. Conclusion Data herein indicate that balancing selection is common within the extended MHC region and involves several non-HLA loci. Yet, the evolutionary history of most SNPs with an opposite effect for autoimmune diseases is consistent with evolutionary neutrality. We suggest that variants with an opposite effect on autoimmune diseases should not be considered a distinct class of disease alleles from the evolutionary perspective and, in a few cases, the opposite effect on distinct diseases may derive from complex haplotype structures in regions with high genetic diversity. PMID:21682861

Systematic Integration of Brain eQTL and GWAS Identifies ZNF323 as a Novel Schizophrenia Risk Gene and Suggests Recent Positive Selection Based on Compensatory Advantage on Pulmonary Function.

PubMed

Luo, Xiong-Jian; Mattheisen, Manuel; Li, Ming; Huang, Liang; Rietschel, Marcella; Børglum, Anders D; Als, Thomas D; van den Oord, Edwin J; Aberg, Karolina A; Mors, Ole; Mortensen, Preben Bo; Luo, Zhenwu; Degenhardt, Franziska; Cichon, Sven; Schulze, Thomas G; Nöthen, Markus M; Su, Bing; Zhao, Zhongming; Gan, Lin; Yao, Yong-Gang

2015-11-01

Genome-wide association studies have identified multiple risk variants and loci that show robust association with schizophrenia. Nevertheless, it remains unclear how these variants confer risk to schizophrenia. In addition, the driving force that maintains the schizophrenia risk variants in human gene pool is poorly understood. To investigate whether expression-associated genetic variants contribute to schizophrenia susceptibility, we systematically integrated brain expression quantitative trait loci and genome-wide association data of schizophrenia using Sherlock, a Bayesian statistical framework. Our analyses identified ZNF323 as a schizophrenia risk gene (P = 2.22×10(-6)). Subsequent analyses confirmed the association of the ZNF323 and its expression-associated single nucleotide polymorphism rs1150711 in independent samples (gene-expression: P = 1.40×10(-6); single-marker meta-analysis in the combined discovery and replication sample comprising 44123 individuals: P = 6.85×10(-10)). We found that the ZNF323 was significantly downregulated in hippocampus and frontal cortex of schizophrenia patients (P = .0038 and P = .0233, respectively). Evidence for pleiotropic effects was detected (association of rs1150711 with lung function and gene expression of ZNF323 in lung: P = 6.62×10(-5) and P = 9.00×10(-5), respectively) with the risk allele (T allele) for schizophrenia acting as protective allele for lung function. Subsequent population genetics analyses suggest that the risk allele (T) of rs1150711 might have undergone recent positive selection in human population. Our findings suggest that the ZNF323 is a schizophrenia susceptibility gene whose expression may influence schizophrenia risk. Our study also illustrates a possible mechanism for maintaining schizophrenia risk variants in the human gene pool. © The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

The Contribution of Common UGT2B10 and CYP2A6 Alleles to Variation in Nicotine Glucuronidation among European Americans

PubMed Central

Bloom, A. Joseph; von Weymarn, Linda B.; Martinez, Maribel; Bierut, Laura J.; Goate, Alison; Murphy, Sharon E.

2014-01-01

UDP-glucuronosytransferase-2B10 (UGT2B10) is the primary catalyst of nicotine glucuronidation. To develop a predictive genetic model of nicotine metabolism, the conversion of deuterated (D2)-nicotine to D2-nicotine-glucuronide, D2-cotinine, D2-cotinine-glucuronide, and D2-trans-3'-hydroxycotinine were quantified in 188 European Americans, and the contribution of UGT2B10 genotype to variability in first-pass nicotine glucuronidation assessed, following a procedure previously applied to nicotine C-oxidation. The proportion of total nicotine converted to nicotine-glucuronide (D2-nicotine-glucuronide/ (D2-nicotine +D2-nicotine-glucuronide +D2-cotinine +D2-cotinine-glucuronide +D2-trans-3'-hydroxycotinine)) was the primary phenotype. The variant, rs61750900T (D67Y) (minor allele frequency (MAF) = 10%), is confirmed to abolish nicotine glucuronidation activity. Another variant, rs112561475G (N397D) (MAF = 2%), is significantly associated with enhanced glucuronidation. rs112561475G is the ancestral allele of a well-conserved amino acid, indicating that the majority of human UGT2B10 alleles are derived hypomorphic alleles. CYP2A6 and UGT2B10 genotype explain 53% of the variance in oral nicotine glucuronidation in this sample. CYP2A6 and UGT2B10 genetic variants are also significantly associated with un-deuterated (D0) nicotine glucuronidation in subjects smoking ad libitum. We find no evidence for further common variation markedly influencing hepatic UGT2B10 expression in European Americans. PMID:24192532

Allelic combinations of promoter and exon 2 in DQB1 in dogs and wolves.

PubMed

Berggren, Karin T; Seddon, Jennifer M

2008-07-01

Polymorphism of PBRs of the major histocompatibility complex (MHC) genes is well recognized, but the polymorphism also extends to proximal promoter regions. Examining DQB1 variability in dogs and wolves, we identified 7 promoter variants and 13 exon 2 alleles among 89 dogs, including a previously unknown DQB1 exon 2 allele, and 8 promoter variants and 9 exon 2 alleles among 85 wolves. As expected from previous studies and from a close chromosomal location, strong linkage disequilibrium was demonstrated in both wolves and dogs by having significantly fewer promoter/exon 2 combinations than expected from simulations of randomized data sets. Interestingly, we noticed weaker haplotypic associations in dogs than in wolves. Dogs had twice as many promoter/exon 2 combinations as wolves and an almost 2-fold difference in the number of exon 2 alleles per promoter variant. This difference was not caused by an admixture of breeds in our group of dogs because the high ratio of observed to expected number of haplotypes persisted within a single dog breed, the German Shepherd. Ewens-Watterson tests indicated that both the promoter and exon 2 are under the balancing selection, and both regions appear to be more recently derived in the dog than in the wolf. Hence, although reasons for the differences are unknown, they may relate to altered selection pressure on patterns of expression. Deviations from normal MHC expression patterns have been associated with autoimmune diseases, which occur frequently in several dog breeds. Further knowledge about these deviations may help us understand the source of such diseases.

Mutation databases and other online sites as a resource for transfusion medicine: history and attributes.

PubMed

Blumenfeld, Olga O

2002-04-01

Recent advances in molecular biology and technology have provided evidence, at a molecular level, for long-known observations that the human genome is not unique but is characterized by individual sequence variation. At the present time, documentation of genetic variation occurring in a large number of genes is increasing exponentially. The characterization of alleles that encode a variety of blood group antigens has been particularly fruitful for transfusion medicine. Phenotypic variation, as identified by the serologic study of blood group variants, is required to identify the presence of a variant allele. Many of the other alleles currently recorded have been selected and identified on the basis of inherited disease traits. New approaches document single nucleotide polymorphisms that occur throughout the genome and best show how the DNA sequence varies in the human population. The primary data dealing with variant alleles or more general genomic variation are scattered throughout the scientific literature and only within the last few years has information begun to be organized into databases. This article provides guidance on how to access those databases online as a source of information about genetic variation for purposes of molecular, clinical, and diagnostic medicine, research, and teaching. The attributes of the sites are described. A more detailed view of the database dealing specifically with alleles of genes encoding the blood group antigens includes a brief preliminary analysis of the molecular basis for observed polymorphisms. Other online sites that may be particularly useful to the transfusion medicine readership as well as a brief historical account are also presented. Copyright 2002, Elsevier Science (USA). All rights reserved.

DMET-Miner: Efficient discovery of association rules from pharmacogenomic data.

PubMed

Agapito, Giuseppe; Guzzi, Pietro H; Cannataro, Mario

2015-08-01

Microarray platforms enable the investigation of allelic variants that may be correlated to phenotypes. Among those, the Affymetrix DMET (Drug Metabolism Enzymes and Transporters) platform enables the simultaneous investigation of all the genes that are related to drug absorption, distribution, metabolism and excretion (ADME). Although recent studies demonstrated the effectiveness of the use of DMET data for studying drug response or toxicity in clinical studies, there is a lack of tools for the automatic analysis of DMET data. In a previous work we developed DMET-Analyzer, a methodology and a supporting platform able to automatize the statistical study of allelic variants, that has been validated in several clinical studies. Although DMET-Analyzer is able to correlate a single variant for each probe (related to a portion of a gene) through the use of the Fisher test, it is unable to discover multiple associations among allelic variants, due to its underlying statistic analysis strategy that focuses on a single variant for each time. To overcome those limitations, here we propose a new analysis methodology for DMET data based on Association Rules mining, and an efficient implementation of this methodology, named DMET-Miner. DMET-Miner extends the DMET-Analyzer tool with data mining capabilities and correlates the presence of a set of allelic variants with the conditions of patient's samples by exploiting association rules. To face the high number of frequent itemsets generated when considering large clinical studies based on DMET data, DMET-Miner uses an efficient data structure and implements an optimized search strategy that reduces the search space and the execution time. Preliminary experiments on synthetic DMET datasets, show how DMET-Miner outperforms off-the-shelf data mining suites such as the FP-Growth algorithms available in Weka and RapidMiner. To demonstrate the biological relevance of the extracted association rules and the effectiveness of the proposed approach from a medical point of view, some preliminary studies on a real clinical dataset are currently under medical investigation. Copyright © 2015 Elsevier Inc. All rights reserved.

Stabilizing selection on microsatellite allele length at arginine vasopressin 1a receptor and oxytocin receptor loci

PubMed Central

Kallio, Eva R.; Koskela, Esa; Lonn, Eija

2017-01-01

The loci arginine vasopressin receptor 1a (avpr1a) and oxytocin receptor (oxtr) have evolutionarily conserved roles in vertebrate social and sexual behaviour. Allelic variation at a microsatellite locus in the 5′ regulatory region of these genes is associated with fitness in the bank vole Myodes glareolus. Given the low frequency of long and short alleles at these microsatellite loci in wild bank voles, we used breeding trials to determine whether selection acts against long and short alleles. Female bank voles with intermediate length avpr1a alleles had the highest probability of breeding, while male voles whose avpr1a alleles were very different in length had reduced probability of breeding. Moreover, there was a significant interaction between male and female oxtr genotypes, where potential breeding pairs with dissimilar length alleles had reduced probability of breeding. These data show how genetic variation at microsatellite loci associated with avpr1a and oxtr is associated with fitness, and highlight complex patterns of selection at these loci. More widely, these data show how stabilizing selection might act on allele length frequency distributions at gene-associated microsatellite loci. PMID:29237850

Identification of Candidate Gene Variants in Korean MODY Families by Whole-Exome Sequencing.

PubMed

Shim, Ye Jee; Kim, Jung Eun; Hwang, Su-Kyeong; Choi, Bong Seok; Choi, Byung Ho; Cho, Eun-Mi; Jang, Kyoung Mi; Ko, Cheol Woo

2015-01-01

To date, 13 genes causing maturity-onset diabetes of the young (MODY) have been identified. However, there is a big discrepancy in the genetic locus between Asian and Caucasian patients with MODY. Thus, we conducted whole-exome sequencing in Korean MODY families to identify causative gene variants. Six MODY probands and their family members were included. Variants in the dbSNP135 and TIARA databases for Koreans and the variants with minor allele frequencies >0.5% of the 1000 Genomes database were excluded. We selected only the functional variants (gain of stop codon, frameshifts and nonsynonymous single-nucleotide variants) and conducted a case-control comparison in the family members. The selected variants were scanned for the previously introduced gene set implicated in glucose metabolism. Three variants c.620C>T:p.Thr207Ile in PTPRD, c.559C>G:p.Gln187Glu in SYT9, and c.1526T>G:p.Val509Gly in WFS1 were respectively identified in 3 families. We could not find any disease-causative alleles of known MODY 1-13 genes. Based on the predictive program, Thr207Ile in PTPRD was considered pathogenic. Whole-exome sequencing is a valuable method for the genetic diagnosis of MODY. Further evaluation is necessary about the role of PTPRD, SYT9 and WFS1 in normal insulin release from pancreatic beta cells. © 2015 S. Karger AG, Basel.

Selection in a subdivided population with local extinction and recolonization.

PubMed Central

Cherry, Joshua L

2003-01-01

In a subdivided population, local extinction and subsequent recolonization affect the fate of alleles. Of particular interest is the interaction of this force with natural selection. The effect of selection can be weakened by this additional source of stochastic change in allele frequency. The behavior of a selected allele in such a population is shown to be equivalent to that of an allele with a different selection coefficient in an unstructured population with a different size. This equivalence allows use of established results for panmictic populations to predict such quantities as fixation probabilities and mean times to fixation. The magnitude of the quantity N(e)s(e), which determines fixation probability, is decreased by extinction and recolonization. Thus deleterious alleles are more likely to fix, and advantageous alleles less likely to do so, in the presence of extinction and recolonization. Computer simulations confirm that the theoretical predictions of both fixation probabilities and mean times to fixation are good approximations. PMID:12807797

Significance of common variants on human chromosome 8q24 in relation to the risk of prostate cancer in native Japanese men

PubMed Central

Liu, Miao; Kurosaki, Takayuki; Suzuki, Motofumi; Enomoto, Yutaka; Nishimatsu, Hiroaki; Arai, Tomio; Sawabe, Motoji; Hosoi, Takayuki; Homma, Yukio; Kitamura, Tadaichi

2009-01-01

Background Common variants on human chromosome 8q24, rs1447295 (C/A) and rs6983267 (T/G), have been recently linked to the prevalence of prostate cancer in European and American populations. Here, we evaluated whether the single-nucleotide polymorphisms rs1447295 and rs6983267 were associated with the risk of sporadic prostate cancer as well as latent prostate cancer in a native Japanese population. Results We analyzed genomic DNA samples from 391 sporadic prostate cancer patients, 323 controls who had died from causes unrelated to cancer and 112 Japanese men who were diagnosed as having latent prostate cancer based on autopsy results. The polymorphisms were determined by allelic discrimination using a fluorescent-based TaqMan assay. The A allele of rs1447295 was significantly associated with the risk of sporadic prostate cancer (p = 0.04; age-adjusted OR, 1.34), while the G allele of rs6983267 showed a trend towards being a high-risk allele (p = 0.06; age-adjusted OR, 1.27). No significant difference between these two polymorphisms and the risk of latent prostate cancer was observed in the present Japanese population. Conclusion Known variants on human chromosome 8q24 may be risk factors for sporadic prostate cancer in native Japanese men. PMID:19602258

GeneiASE: Detection of condition-dependent and static allele-specific expression from RNA-seq data without haplotype information

PubMed Central

Edsgärd, Daniel; Iglesias, Maria Jesus; Reilly, Sarah-Jayne; Hamsten, Anders; Tornvall, Per; Odeberg, Jacob; Emanuelsson, Olof

2016-01-01

Allele-specific expression (ASE) is the imbalance in transcription between maternal and paternal alleles at a locus and can be probed in single individuals using massively parallel DNA sequencing technology. Assessing ASE within a single sample provides a static picture of the ASE, but the magnitude of ASE for a given transcript may vary between different biological conditions in an individual. Such condition-dependent ASE could indicate a genetic variation with a functional role in the phenotypic difference. We investigated ASE through RNA-sequencing of primary white blood cells from eight human individuals before and after the controlled induction of an inflammatory response, and detected condition-dependent and static ASE at 211 and 13021 variants, respectively. We developed a method, GeneiASE, to detect genes exhibiting static or condition-dependent ASE in single individuals. GeneiASE performed consistently over a range of read depths and ASE effect sizes, and did not require phasing of variants to estimate haplotypes. We observed condition-dependent ASE related to the inflammatory response in 19 genes, and static ASE in 1389 genes. Allele-specific expression was confirmed by validation of variants through real-time quantitative RT-PCR, with RNA-seq and RT-PCR ASE effect-size correlations r = 0.67 and r = 0.94 for static and condition-dependent ASE, respectively. PMID:26887787

CYP2C9 Genotypes Modify Benzodiazepine-Related Fall Risk: Original Results From Three Studies With Meta-Analysis.

PubMed

Ham, Annelies C; Ziere, Gijsbertus; Broer, Linda; Swart, Karin M A; Enneman, Anke W; van Dijk, Suzanne C; van Wijngaarden, Janneke P; van der Zwaluw, Nikita L; Brouwer-Brolsma, Elske M; Dhonukshe-Rutten, Rosalie A M; van Schoor, Natasja M; Zillikens, M Carola; van Gelder, Teun; de Vries, Oscar J; Lips, Paul; Deeg, Dorly J H; de Groot, Lisette C P G M; Hofman, Albert; Witkamp, Renger F; Uitterlinden, André G; Stricker, Bruno H; van der Velde, Nathalie

2017-01-01

To investigate whether the CYP2C9*2 and *3 variants modify benzodiazepine-related fall risk. Three prospective studies; the Rotterdam Study, B-PROOF, and LASA. Community-dwelling individuals living in or near five Dutch cities. There were 11,485 participants aged ≥55 years. Fall incidents were recorded prospectively. Benzodiazepine use was determined using pharmacy dispensing records or interviews. Cox proportional hazard models adjusted for age and sex were applied to determine the association between benzodiazepine use and fall risk stratified for CYP2C9 genotype and comparing benzodiazepine users to nonusers. The results of the three studies were combined applying meta-analysis. Within benzodiazepine users, the association between genotypes and fall risk was also assessed. Three thousand seven hundred five participants (32%) encountered a fall during 91,996 follow-up years, and 4% to 15% (depending on the study population) used benzodiazepines. CYP2C9 variants had frequencies of 13% for the *2 allele and 6% for the *3 allele. Compared to nonusers, current benzodiazepine use was associated with an 18% to 36% increased fall risk across studies with a combined hazard ratio (HR) = 1.26 (95% confidence interval [CI], 1.13; 1.40). CYP2C9*2 or *3 allele variants modified benzodiazepine-related fall risk. Compared to nonusers, those carrying a CYP2C9*2 or *3 allele and using benzodiazepines had a 45% increased fall risk (HR, 1.45 95% CI, 1.21; 1.73), whereas CYP2C9*1 homozygotes using benzodiazepines had no increased fall risk (HR, 1.14; 95% CI, 0.90; 1.45). Within benzodiazepine users, having a CYP2C9*2 or *3 allele was associated with an increased fall risk (HR, 1.35; 95% CI, 1.06; 1.72). Additionally, we observed an allele dose effect; heterozygous allele carriers had a fall risk of (HR = 1.30; 95% CI, 1.05; 1.61), and homozygous allele carriers of (HR = 1.91 95% CI, 1.23; 2.96). CYP2C9*2 and *3 allele variants modify benzodiazepine-related fall risk. Those using benzodiazepines and having reduced CYP2C9 enzyme activity based on their genotype are at increased fall risk. In clinical practice, genotyping might be considered for elderly patients with an indication for benzodiazepine use. However, because the exact role of CYP2C9 in benzodiazepine metabolism is still unclear, additional research is warranted. Copyright © 2016 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.

Genetic profiling of GSTP1, DPYD, FCGR2A, FCGR3A and CCND1 genes in an Argentinian population.

PubMed

Galván, Cristian A; Elbarcha, Osvaldo C; Fernández, Eduardo J; Beltramo, Dante M; Soria, Néstor W

2011-09-01

To determine the frequencies of relevant allelic variants in oncology for the GSTP1, DPYD, FCGR2A, FCGR3A and CCND1 genes in a population from Central Argentina. To compare the allelic distribution found with the frequencies reported for other ethnic groups. Genotyping was carried out in a total of 102 unrelated Argentinian subjects. FCGR3A (rs396991) was detected using allele specific polymerase chain reaction (PCR) assay, while GSTP1 (rs1695), DPYD (rs3918290), FCGR2A (rs1801274) and CCND1 (rs9344) variants were assessed by PCR-restriction fragment length polymorphism (PCR-RFLP). The allele frequencies for GSTP*1B, DPYD*2A, FCGR2A (131R), FCGR3A (158F) and CCND1 (870G) in Argentinians were 0.35, 0.005, 0.41, 0.77 and 0.47, respectively. We found that the Argentinian population tested resembles other Caucasians populations, especially Spaniards; yet the differences in allele distribution with other Caucasian groups, uncover population admixture with native Amerindian and other ethnic groups, consistent with the well documented immigration flows landing Argentina from several countries. Copyright © 2011. Published by Elsevier Inc.

Mobile Interspersed Repeats Are Major Structural Variants in the Human Genome

PubMed Central

Huang, Cheng Ran Lisa; Schneider, Anna M.; Lu, Yunqi; Niranjan, Tejasvi; Shen, Peilin; Robinson, Matoya A.; Steranka, Jared P.; Valle, David; Civin, Curt I.; Wang, Tao; Wheelan, Sarah J.; Ji, Hongkai; Boeke, Jef D.; Burns, Kathleen H.

2010-01-01

Summary Characterizing structural variants in the human genome is of great importance, but a genome wide analysis to detect interspersed repeats has not been done. Thus, the degree to which mobile DNAs contribute to genetic diversity, heritable disease, and oncogenesis remains speculative. We perform transposon insertion profiling by microarray (TIP-chip) to map human L1(Ta) retrotransposons (LINE-1 s) genome-wide. This identified numerous novel human L1(Ta) insertional polymorphisms with highly variant allelic frequencies. We also explored TIP-chip's usefulness to identify candidate alleles associated with different phenotypes in clinical cohorts. Our data suggest that the occurrence of new insertions is twice as high as previously estimated, and that these repeats are under-recognized as sources of human genomic and phenotypic diversity. We have just begun to probe the universe of human L1(Ta) polymorphisms, and as TIP-chip is applied to other insertions such as Alu SINEs, it will expand the catalog of genomic variants even further. PMID:20602999

ACE I/D and MMP-7 A-181G variants and the risk of end stage renal disease.

PubMed

Rahimi, Zohreh; Abdi, Hamed; Tanhapoor, Maryam; Rahimi, Ziba; Vaisi-Raygani, Asad; Nomani, Hamid

2017-03-01

The variants of angiotensin converting enzyme ( ACE ) and matrix metalloproteinases (MMPs) genes might be involved in the pathogenesis of end stage renal disease (ESRD) and hypertension. We studied the ACE insertion/deletion (I/D) and MMP-7 A-181G variants in 99 unrelated ESRD patients and 117 individuals without renal complications from Western Iran with Kurdish ethnic background. The frequency of ACE I/D variants was not significantly different between ESRD patients and controls. However, the presence of ACE D allele increased the risk of hypertension in ESRD patients by 2.14-fold (P=0.036). The MMP-7 -181 AG genotype increased the risk of ESRD by 2.04 times (P=0.026). The present study indicated the absence of an association between the ACE I/D polymorphism with the risk of ESRD. However, the ACE D allele increased the risk of hypertension in ESRD patients. Also, the present study suggests a role for MMP-7 AG genotype in the pathogenesis of ESRD.

Epidermal growth factor receptor gene polymorphisms are associated with prognostic features of breast cancer

PubMed Central

2014-01-01

Background The epidermal growth factor receptor (EGFR) is differently expressed in breast cancer, and its presence may favor cancer progression. We hypothesized that two EGFR functional polymorphisms, a (CA)n repeat in intron 1, and a single nucleotide polymorphism, R497K, may affect EGFR expression and breast cancer clinical profile. Methods The study population consisted of 508 Brazilian women with unilateral breast cancer, and no distant metastases. Patients were genotyped for the (CA)n and R497K polymorphisms, and the associations between (CA)n polymorphism and EGFR transcript levels (n = 129), or between either polymorphism and histopathological features (n = 505) were evaluated. The REMARK criteria of tumor marker evaluation were followed. Results (CA)n lengths ranged from 14 to 24 repeats, comprehending 11 alleles and 37 genotypes. The most frequent allele was (CA)16 (0.43; 95% CI = 0.40–0.46), which was set as the cut-off length to define the Short allele. Variant (CA)n genotypes had no significant effect in tumoral EGFR mRNA levels, but patients with two (CA)n Long alleles showed lower chances of being negative for progesterone receptor (ORadjusted = 0.42; 95% CI = 0.19–0.91). The evaluation of R497K polymorphism indicated a frequency of 0.21 (95% CI = 0.19 – 0.24) for the variant (Lys) allele. Patients with variant R497K genotypes presented lower proportion of worse lymph node status (pN2 or pN3) when compared to the reference genotype Arg/Arg (ORadjusted = 0.32; 95% CI = 0.17–0.59), which resulted in lower tumor staging (ORadjusted = 0.34; 95% CI = 0.19-0.63), and lower estimated recurrence risk (OR = 0.50; 95% CI = 0.30-0.81). The combined presence of both EGFR polymorphisms (Lys allele of R497K and Long/Long (CA)n) resulted in lower TNM status (ORadjusted = 0.22; 95% CI = 0.07-0.75) and lower ERR (OR = 0.25; 95% CI = 0.09-0.71). When tumors were stratified according to biological classification, the favorable effects of variant EGFR polymorphisms were preserved for luminal A tumors, but not for other subtypes. Conclusions The data suggest that the presence of the variant forms of EGFR polymorphisms may lead to better prognosis in breast cancer, especially in patients with luminal A tumors. PMID:24629097

An FTO variant is associated with Type 2 diabetes in South Asian populations after accounting for body mass index and waist circumference

PubMed Central

Rees, S. D.; Islam, M.; Hydrie, M. Z. I.; Chaudhary, B.; Bellary, S.; Hashmi, S.; O’Hare, J. P.; Kumar, S.; Sanghera, D. K.; Chaturvedi, N.; Barnett, A. H.; Shera, A. S.; Weedon, M. N.; Basit, A.; Frayling, T. M.; Kelly, M. A.; Jafar, T. H.

2011-01-01

Aims A common variant, rs9939609, in the FTO (fat mass and obesity) gene is associated with adiposity in Europeans, explaining its relationship with diabetes. However, data are inconsistent in South Asians. Our aim was to investigate the association of the FTO rs9939609 variant with obesity, obesity-related traits and Type 2 diabetes in South Asian individuals, and to use meta-analyses to attempt to clarify to what extent BMI influences the association of FTO variants with diabetes in South Asians. Methods We analysed rs9939609 in two studies of Pakistani individuals: 1666 adults aged ≥ 40 years from the Karachi population-based Control of Blood Pressure and Risk Attenuation (COBRA) study and 2745 individuals of Punjabi ancestry who were part of a Type 2 diabetes case–control study (UK Asian Diabetes Study/Diabetes Genetics in Pakistan; UKADS/DGP). The main outcomes were BMI, waist circumference and diabetes. Regression analyses were performed to determine associations between FTO alleles and outcomes. Summary estimates were combined in a meta-analysis of 8091 South Asian individuals (3919 patients with Type 2 diabetes and 4172 control subjects), including those from two previous studies. Results In the 4411 Pakistani individuals from this study, the age-, sex- and diabetes-adjusted association of FTO variant rs9939609 with BMI was 0.45 (95% CI 0.24–0.67) kg/m2 per A-allele (P = 3.0× 10−5) and with waist circumference was 0.88 (95% CI 0.36–1.41) cm per A-allele (P = 0.001). The A-allele (30% frequency) was also significantly associated with Type 2 diabetes [per A-allele odds ratio (95% CI) 1.18 (1.07–1.30); P = 0.0009]. A meta-analysis of four South Asian studies with 8091 subjects showed that the FTO A-allele predisposes to Type 2 diabetes [1.22 (95% CI 1.14–1.31); P = 1.07× 10−8] even after adjusting for BMI [1.18 (95% CI 1.10–1.27); P = 1.02× 10−5] or waist circumference [1.18 (95% CI 1.10–1.27); P = 3.97× 10−5]. Conclusions The strong association between FTO genotype and BMI and waist circumference in South Asians is similar to that observed in Europeans. In contrast, the strong association of FTO genotype with diabetes is only partly accounted for by BMI. PMID:21294771

Intronic SNP in ESR1 encoding human estrogen receptor alpha is associated with brain ESR1 mRNA isoform expression and behavioral traits.

PubMed

Pinsonneault, Julia K; Frater, John T; Kompa, Benjamin; Mascarenhas, Roshan; Wang, Danxin; Sadee, Wolfgang

2017-01-01

Genetic variants of ESR1 have been implicated in multiple diseases, including behavioral disorders, but causative variants remain uncertain. We have searched for regulatory variants affecting ESR1 expression in human brain, measuring allelic ESR1 mRNA expression in human brain tissues with marker SNPs in exon4 representing ESR1-008 (or ESRα-36), and in the 3'UTR of ESR1-203, two main ESR1 isoforms in brain. In prefrontal cortex from subjects with bipolar disorder, schizophrenia, and controls (n = 35 each; Stanley Foundation brain bank), allelic ESR1 mRNA ratios deviated from unity up to tenfold at the exon4 marker SNP, with large allelic ratios observed primarily in bipolar and schizophrenic subjects. SNP scanning and targeted sequencing identified rs2144025, associated with large allelic mRNA ratios (p = 1.6E10-6). Moreover, rs2144025 was significantly associated with ESR1 mRNA levels in the Brain eQTL Almanac and in brain regions in the Genotype-Tissue Expression project. In four GWAS cohorts, rs2104425 was significantly associated with behavioral traits, including: hypomanic episodes in female bipolar disorder subjects (GAIN bipolar disorder study; p = 0.0004), comorbid psychological symptoms in both males and females with attention deficit hyperactivity disorder (GAIN ADHD, p = 0.00002), psychological diagnoses in female children (eMERGE study of childhood health, subject age ≥9, p = 0.0009), and traits in schizophrenia (e.g., grandiose delusions, GAIN schizophrenia, p = 0.0004). The first common ESR1 variant (MAF 12-33% across races) linked to regulatory functions, rs2144025 appears conditionally to affect ESR1 mRNA expression in the brain and modulate traits in behavioral disorders.

Intronic SNP in ESR1 encoding human estrogen receptor alpha is associated with brain ESR1 mRNA isoform expression and behavioral traits

PubMed Central

Kompa, Benjamin; Mascarenhas, Roshan; Wang, Danxin; Sadee, Wolfgang

2017-01-01

Genetic variants of ESR1 have been implicated in multiple diseases, including behavioral disorders, but causative variants remain uncertain. We have searched for regulatory variants affecting ESR1 expression in human brain, measuring allelic ESR1 mRNA expression in human brain tissues with marker SNPs in exon4 representing ESR1-008 (or ESRα-36), and in the 3’UTR of ESR1-203, two main ESR1 isoforms in brain. In prefrontal cortex from subjects with bipolar disorder, schizophrenia, and controls (n = 35 each; Stanley Foundation brain bank), allelic ESR1 mRNA ratios deviated from unity up to tenfold at the exon4 marker SNP, with large allelic ratios observed primarily in bipolar and schizophrenic subjects. SNP scanning and targeted sequencing identified rs2144025, associated with large allelic mRNA ratios (p = 1.6E10-6). Moreover, rs2144025 was significantly associated with ESR1 mRNA levels in the Brain eQTL Almanac and in brain regions in the Genotype-Tissue Expression project. In four GWAS cohorts, rs2104425 was significantly associated with behavioral traits, including: hypomanic episodes in female bipolar disorder subjects (GAIN bipolar disorder study; p = 0.0004), comorbid psychological symptoms in both males and females with attention deficit hyperactivity disorder (GAIN ADHD, p = 0.00002), psychological diagnoses in female children (eMERGE study of childhood health, subject age ≥9, p = 0.0009), and traits in schizophrenia (e.g., grandiose delusions, GAIN schizophrenia, p = 0.0004). The first common ESR1 variant (MAF 12–33% across races) linked to regulatory functions, rs2144025 appears conditionally to affect ESR1 mRNA expression in the brain and modulate traits in behavioral disorders. PMID:28617822

Pre-B-cell colony-enhancing factor gene polymorphisms and risk of acute respiratory distress syndrome.

PubMed

Bajwa, Ednan K; Yu, Chu-Ling; Gong, Michelle N; Thompson, B Taylor; Christiani, David C

2007-05-01

Pre-B-cell colony-enhancing factor (PBEF) levels are elevated in bronchoalveolar lavage fluid and serum of patients with acute lung injury. There are several suspected functional polymorphisms of the corresponding PBEF gene. We hypothesized that variations in PBEF gene polymorphisms alter the risk of developing acute respiratory distress syndrome (ARDS). Nested case-control study. Tertiary academic medical center. We studied 375 patients with ARDS and 787 at-risk controls genotyped for the PBEF T-1001G and C-1543T polymorphisms. None. Patients with the -1001G (variant) allele had significantly greater odds of developing ARDS than wild-type homozygotes (odds ratio, 1.35; 95% confidence interval, 1.02-1.78). Patients with the -1543T (variant) allele did not have significantly different odds of developing ARDS than wild-type homozygotes (odds ratio, 0.86; 95% confidence interval, 0.65-1.13). When analysis was stratified by ARDS risk factor, -1543T was associated with decreased odds of developing ARDS in septic shock patients (odds ratio, 0.66; 95% confidence interval, 0.45-0.97). Also, -1001G was associated with increased hazard of intensive care unit mortality, whereas -1543T was associated with decreased hazard of 28-day and 60-day ARDS mortality, as well as shorter duration of mechanical ventilation. Similar results were found in analyses of the related GC (-1001G:-1543C) and TT (-1001T:-1543T) haplotypes. The PBEFT-1001G variant allele and related haplotype are associated with increased odds of developing ARDS and increased hazard of intensive care unit mortality among at-risk patients, whereas the C-1543T variant allele and related haplotype are associated with decreased odds of ARDS among patients with septic shock and better outcomes among patients with ARDS.

Extreme High Prevalence of a Defective Mannose-Binding Lectin (MBL2) Genotype in Native South American West Andean Populations

PubMed Central

Sandoval, José Raul; Madsen, Hans O.; De Stefano, Gianfranco; Descailleaux-Dulanto, Jaime; Velazquez-Reinoso, Margarita; Ñique, Cesar; Fujita, Ricardo; Garred, Peter

2014-01-01

Mannose-binding lectin (MBL) is one of the five recognition molecules in the lectin complement pathway. Common variant alleles in the promoter and structural regions of the human MBL gene (MBL2) influence the stability and serum concentration of the protein. Epidemiological studies have shown that MBL2 variant alleles are associated with susceptibility to and the course of different types of infectious and inflammatory conditions. However, it has been suggested that these alleles are maintained in different populations due to selected advantages for carriers. We investigated the MBL2 allelic variation in indigenous individuals from 12 different West Central South America localities spanning from the desert coast, high altitude Andean plates and the Amazon tropical forest within the territories of Peru (n = 249) (Departments of Loreto, Ucayali, Lambayeque, Junin, Ayacucho, Huancayo and Puno), and Ecuador (n = 182) (Region of Esmeraldas and Santo Domingo de los Colorados). The distribution of MBL2 genotypes among the populations showed that the defective variant LYPB haplotype was very common. It showed the highest frequencies in Puno (Taquile (0.80), Amantani (0.80) and Anapia (0.58) islander communities of the Lake Titicaca), but lower frequencies of 0.22 in Junin (Central Andean highland) and Ucayali (Central Amazonian forest), as well as 0.27 and 0.24 in the Congoma and Cayapa/Chachis populations in the Amazonian forest in Ecuador were also observed. Our results suggest that the high prevalence of the MBL2 LYPB variant causing low levels of functional MBL in serum may mainly reflect a random distribution due to a population bottleneck in the founder populations. PMID:25313559

Regulation of gene expression in autoimmune disease loci and the genetic basis of proliferation in CD4+ effector memory T cells.

PubMed

Hu, Xinli; Kim, Hyun; Raj, Towfique; Brennan, Patrick J; Trynka, Gosia; Teslovich, Nikola; Slowikowski, Kamil; Chen, Wei-Min; Onengut, Suna; Baecher-Allan, Clare; De Jager, Philip L; Rich, Stephen S; Stranger, Barbara E; Brenner, Michael B; Raychaudhuri, Soumya

2014-06-01

Genome-wide association studies (GWAS) and subsequent dense-genotyping of associated loci identified over a hundred single-nucleotide polymorphism (SNP) variants associated with the risk of rheumatoid arthritis (RA), type 1 diabetes (T1D), and celiac disease (CeD). Immunological and genetic studies suggest a role for CD4-positive effector memory T (CD+ TEM) cells in the pathogenesis of these diseases. To elucidate mechanisms of autoimmune disease alleles, we investigated molecular phenotypes in CD4+ effector memory T cells potentially affected by these variants. In a cohort of genotyped healthy individuals, we isolated high purity CD4+ TEM cells from peripheral blood, then assayed relative abundance, proliferation upon T cell receptor (TCR) stimulation, and the transcription of 215 genes within disease loci before and after stimulation. We identified 46 genes regulated by cis-acting expression quantitative trait loci (eQTL), the majority of which we detected in stimulated cells. Eleven of the 46 genes with eQTLs were previously undetected in peripheral blood mononuclear cells. Of 96 risk alleles of RA, T1D, and/or CeD in densely genotyped loci, eleven overlapped cis-eQTLs, of which five alleles completely explained the respective signals. A non-coding variant, rs389862A, increased proliferative response (p=4.75 × 10-8). In addition, baseline expression of seventeen genes in resting cells reliably predicted proliferative response after TCR stimulation. Strikingly, however, there was no evidence that risk alleles modulated CD4+ TEM abundance or proliferation. Our study underscores the power of examining molecular phenotypes in relevant cells and conditions for understanding pathogenic mechanisms of disease variants.

Dihydropyrimidine dehydrogenase pharmacogenetics for predicting fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients

PubMed Central

Ruzzo, A; Graziano, F; Galli, Fabio; Galli, Francesca; Rulli, E; Lonardi, S; Ronzoni, M; Massidda, B; Zagonel, V; Pella, N; Mucciarini, C; Labianca, R; Ionta, M T; Bagaloni, I; Veltri, E; Sozzi, P; Barni, S; Ricci, V; Foltran, L; Nicolini, M; Biondi, E; Bramati, A; Turci, D; Lazzarelli, S; Verusio, C; Bergamo, F; Sobrero, A; Frontini, L; Menghi, M; Magnani, M

2017-01-01

Background: Dihydropyrimidine dehydrogenase (DPD) catabolises ∼85% of the administered dose of fluoropyrimidines. Functional DPYD gene variants cause reduced/abrogated DPD activity. DPYD variants analysis may help for defining individual patients’ risk of fluoropyrimidine-related severe toxicity. Methods: The TOSCA Italian randomised trial enrolled colon cancer patients for 3 or 6 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In an ancillary pharmacogenetic study, 10 DPYD variants (*2A rs3918290 G>A, *13 rs55886062 T>G, rs67376798 A>T, *4 rs1801158 G>A, *5 rs1801159 A>G, *6 rs1801160 G>A, *9A rs1801265 T>C, rs2297595 A>G, rs17376848 T>C, and rs75017182 C>G), were retrospectively tested for associations with ⩾grade 3 fluoropyrimidine-related adverse events (FAEs). An association analysis and a time-to-toxicity (TTT) analysis were planned. To adjust for multiple testing, the Benjamini and Hochberg’s False Discovery Rate (FDR) procedure was used. Results: FAEs occurred in 194 out of 508 assessable patients (38.2%). In the association analysis, FAEs occurred more frequently in *6 rs1801160 A allele carriers (FDR=0.0083). At multivariate TTT analysis, significant associations were found for *6 rs1801160 A allele carriers (FDR<0.0001), *2A rs3918290 A allele carriers (FDR<0.0001), and rs2297595 GG genotype carriers (FDR=0.0014). Neutropenia was the most common FAEs (28.5%). *6 rs1801160 (FDR<0.0001), and *2A rs3918290 (FDR=0.0004) variant alleles were significantly associated with time to neutropenia. Conclusions: This study adds evidence on the role of DPYD pharmacogenetics for safety of patients undergoing fluoropyrimidine-based chemotherapy. PMID:29065426

Dihydropyrimidine dehydrogenase pharmacogenetics for predicting fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients.

PubMed

Ruzzo, A; Graziano, F; Galli, Fabio; Galli, Francesca; Rulli, E; Lonardi, S; Ronzoni, M; Massidda, B; Zagonel, V; Pella, N; Mucciarini, C; Labianca, R; Ionta, M T; Bagaloni, I; Veltri, E; Sozzi, P; Barni, S; Ricci, V; Foltran, L; Nicolini, M; Biondi, E; Bramati, A; Turci, D; Lazzarelli, S; Verusio, C; Bergamo, F; Sobrero, A; Frontini, L; Menghi, M; Magnani, M

2017-10-24

Dihydropyrimidine dehydrogenase (DPD) catabolises ∼85% of the administered dose of fluoropyrimidines. Functional DPYD gene variants cause reduced/abrogated DPD activity. DPYD variants analysis may help for defining individual patients' risk of fluoropyrimidine-related severe toxicity. The TOSCA Italian randomised trial enrolled colon cancer patients for 3 or 6 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In an ancillary pharmacogenetic study, 10 DPYD variants (*2A rs3918290 G>A, *13 rs55886062 T>G, rs67376798 A>T, *4 rs1801158 G>A, *5 rs1801159 A>G, *6 rs1801160 G>A, *9A rs1801265 T>C, rs2297595 A>G, rs17376848 T>C, and rs75017182 C>G), were retrospectively tested for associations with ⩾grade 3 fluoropyrimidine-related adverse events (FAEs). An association analysis and a time-to-toxicity (TTT) analysis were planned. To adjust for multiple testing, the Benjamini and Hochberg's False Discovery Rate (FDR) procedure was used. FAEs occurred in 194 out of 508 assessable patients (38.2%). In the association analysis, FAEs occurred more frequently in *6 rs1801160 A allele carriers (FDR=0.0083). At multivariate TTT analysis, significant associations were found for *6 rs1801160 A allele carriers (FDR<0.0001), *2A rs3918290 A allele carriers (FDR<0.0001), and rs2297595 GG genotype carriers (FDR=0.0014). Neutropenia was the most common FAEs (28.5%). *6 rs1801160 (FDR<0.0001), and *2A rs3918290 (FDR=0.0004) variant alleles were significantly associated with time to neutropenia. This study adds evidence on the role of DPYD pharmacogenetics for safety of patients undergoing fluoropyrimidine-based chemotherapy.

Extreme high prevalence of a defective mannose-binding lectin (MBL2) genotype in native South American West Andean populations.

PubMed

Sandoval, José Raul; Madsen, Hans O; De Stefano, Gianfranco; Descailleaux-Dulanto, Jaime; Velazquez-Reinoso, Margarita; Ñique, Cesar; Fujita, Ricardo; Garred, Peter

2014-01-01

Mannose-binding lectin (MBL) is one of the five recognition molecules in the lectin complement pathway. Common variant alleles in the promoter and structural regions of the human MBL gene (MBL2) influence the stability and serum concentration of the protein. Epidemiological studies have shown that MBL2 variant alleles are associated with susceptibility to and the course of different types of infectious and inflammatory conditions. However, it has been suggested that these alleles are maintained in different populations due to selected advantages for carriers. We investigated the MBL2 allelic variation in indigenous individuals from 12 different West Central South America localities spanning from the desert coast, high altitude Andean plates and the Amazon tropical forest within the territories of Peru (n = 249) (Departments of Loreto, Ucayali, Lambayeque, Junin, Ayacucho, Huancayo and Puno), and Ecuador (n = 182) (Region of Esmeraldas and Santo Domingo de los Colorados). The distribution of MBL2 genotypes among the populations showed that the defective variant LYPB haplotype was very common. It showed the highest frequencies in Puno (Taquile (0.80), Amantani (0.80) and Anapia (0.58) islander communities of the Lake Titicaca), but lower frequencies of 0.22 in Junin (Central Andean highland) and Ucayali (Central Amazonian forest), as well as 0.27 and 0.24 in the Congoma and Cayapa/Chachis populations in the Amazonian forest in Ecuador were also observed. Our results suggest that the high prevalence of the MBL2 LYPB variant causing low levels of functional MBL in serum may mainly reflect a random distribution due to a population bottleneck in the founder populations.

[Pharmacogenomics study of 620 whole-exome sequencing: focusing on aspirin application].

PubMed

Yang, L; Lu, Y L; Wang, H J; Zhou, W H

2016-05-01

To investigate the allele frequencies of aspirin-response-related variants in different population. The allele frequencies of reported clinically significant aspirin-response-related variants were evaluated based on 620 whole exome sequencing (WES) data collected from 2013 to 2016 in Children's Hospital of Fudan University.Then the local allele frequencies were compared with 1 000 Genomes project database, and χ(2) test was used. Thirty-eight aspirin-response-related variants that had clinical significance had been detected in the 620 WES data.Ten (26%) of them were related with drug efficacy while 28 (74%) were related with toxicity or adverse drug reaction (ADR). These variants were distributed in 33 genes.There were 23 aspirin-related variants further analysised, and the frequency of 7 (rs1050891, rs6065, rs7862221, rs1065776, rs3818822, rs3775291 and rs1126643) had no significant difference compared with frequency of European and East Asian population of 1 000 Genome project (P>0.01 for both), 10 (rs2228079, rs1613662, rs4523, rs28360521, rs1131882, rs1047626, rs3856806, rs2768759, rs7572857 and rs1126510) of them had no significant difference compared with East Asian but were significantly different from European population, 1 (rs2075797) had no significant difference compared with frequency of European and different with frequency of East Asian, and 5 variants(rs10279545, rs730012, rs16851030, rs1353411, rs1800469)were different from frequency of both East Asian(0.019, 0.058, 0.167, 0.452, 0.340 vs. 0.100, 0.151, 0.396, 0.568, 0.453, χ(2)=21.798, 20.400, 67.543, 16.531, 15.807, P all<0.01) and European population(0.531, 0.312, 0.037, 0.179, 0.688, χ(2)=325.799, 92.877, 144.811, 156.471, 174.533, P all<0.01). Most variants that have clinical significance in aspirin response are related with drug efficacy or drug toxicity or ADR, indicating the urgency of variants screen in clinical practice.Significant population-specificity is detected in local 620 WES data in aspirin-response-related variants.

Three New Alpha1-Antitrypsin Deficiency Variants Help to Define a C-Terminal Region Regulating Conformational Change and Polymerization

PubMed Central

Fra, Anna M.; Gooptu, Bibek; Ferrarotti, Ilaria; Miranda, Elena; Scabini, Roberta; Ronzoni, Riccardo; Benini, Federica; Corda, Luciano; Medicina, Daniela; Luisetti, Maurizio; Schiaffonati, Luisa

2012-01-01

Alpha1-antitrypsin (AAT) deficiency is a hereditary disorder associated with reduced AAT plasma levels, predisposing adults to pulmonary emphysema. The most common genetic AAT variants found in patients are the mildly deficient S and the severely deficient Z alleles, but several other pathogenic rare alleles have been reported. While the plasma AAT deficiency is a common trait of the disease, only a few AAT variants, including the prototypic Z AAT and some rare variants, form cytotoxic polymers in the endoplasmic reticulum of hepatocytes and predispose to liver disease. Here we report the identification of three new rare AAT variants associated to reduced plasma levels and characterize their molecular behaviour in cellular models. The variants, called Mpisa (Lys259Ile), Etaurisano (Lys368Glu) and Yorzinuovi (Pro391His), showed reduced secretion compared to control M AAT, and accumulated to different extents in the cells as ordered polymeric structures resembling those formed by the Z variant. Structural analysis of the mutations showed that they may facilitate polymerization both by loosening ‘latch’ interactions constraining the AAT reactive loop and through effects on core packing. In conclusion, the new AAT deficiency variants, besides increasing the risk of lung disease, may predispose to liver disease, particularly if associated with the common Z variant. The new mutations cluster structurally, thus defining a region of the AAT molecule critical for regulating its conformational state. PMID:22723858

Identifying Mendelian disease genes with the Variant Effect Scoring Tool

PubMed Central

2013-01-01

Background Whole exome sequencing studies identify hundreds to thousands of rare protein coding variants of ambiguous significance for human health. Computational tools are needed to accelerate the identification of specific variants and genes that contribute to human disease. Results We have developed the Variant Effect Scoring Tool (VEST), a supervised machine learning-based classifier, to prioritize rare missense variants with likely involvement in human disease. The VEST classifier training set comprised ~ 45,000 disease mutations from the latest Human Gene Mutation Database release and another ~45,000 high frequency (allele frequency >1%) putatively neutral missense variants from the Exome Sequencing Project. VEST outperforms some of the most popular methods for prioritizing missense variants in carefully designed holdout benchmarking experiments (VEST ROC AUC = 0.91, PolyPhen2 ROC AUC = 0.86, SIFT4.0 ROC AUC = 0.84). VEST estimates variant score p-values against a null distribution of VEST scores for neutral variants not included in the VEST training set. These p-values can be aggregated at the gene level across multiple disease exomes to rank genes for probable disease involvement. We tested the ability of an aggregate VEST gene score to identify candidate Mendelian disease genes, based on whole-exome sequencing of a small number of disease cases. We used whole-exome data for two Mendelian disorders for which the causal gene is known. Considering only genes that contained variants in all cases, the VEST gene score ranked dihydroorotate dehydrogenase (DHODH) number 2 of 2253 genes in four cases of Miller syndrome, and myosin-3 (MYH3) number 2 of 2313 genes in three cases of Freeman Sheldon syndrome. Conclusions Our results demonstrate the potential power gain of aggregating bioinformatics variant scores into gene-level scores and the general utility of bioinformatics in assisting the search for disease genes in large-scale exome sequencing studies. VEST is available as a stand-alone software package at http://wiki.chasmsoftware.org and is hosted by the CRAVAT web server at http://www.cravat.us PMID:23819870

Common breast cancer risk variants in the post-COGS era: a comprehensive review.

PubMed

Maxwell, Kara N; Nathanson, Katherine L

2013-12-20

Breast cancer has a strong heritable component, with approximately 15% of cases exhibiting a family history of the disease. Mutations in genes such as BRCA1, BRCA2 and TP53 lead to autosomal dominant inherited cancer susceptibility and confer a high lifetime risk of breast cancers. Identification of mutations in these genes through clinical genetic testing enables patients to undergo screening and prevention strategies, some of which provide overall survival benefit. In addition, a number of mutant alleles have been identified in genes such as CHEK2, PALB2, ATM and BRIP1, which often display incomplete penetrance and confer moderate lifetime risks of breast cancer. Studies are underway to determine how to use the identification of mutations in these genes to guide clinical practice. Altogether, however, mutations in high and moderate penetrance genes probably account for approximately 25% of familial breast cancer risk; the remainder may be due to mutations in as yet unidentified genes or lower penetrance variants. Common low penetrance alleles, which have been mainly identified through genome-wide association studies (GWAS), are generally present at 10 to 50% population frequencies and confer less than 1.5-fold increases in breast cancer risk. A number of single nucleotide polymorphisms (SNPs) have been identified and risk associations extensively replicated in populations of European ancestry, the number of which has substantially increased as a result of GWAS performed by the Collaborative Oncological Gene-environment Study consortium. It is now estimated that 28% of familial breast cancer risk is explained by common breast cancer susceptibility loci. In some cases, SNP associations may be specific to different subsets of women with breast cancer, as defined by ethnicity or estrogen receptor status. Although not yet clinically established, it is hoped that identification of common risk variants may eventually allow identification of women at higher risk of breast cancer and enable implementation of breast cancer screening, prevention or treatment strategies that provide clinical benefit.

Common breast cancer risk variants in the post-COGS era: a comprehensive review

PubMed Central

2013-01-01

Breast cancer has a strong heritable component, with approximately 15% of cases exhibiting a family history of the disease. Mutations in genes such as BRCA1, BRCA2 and TP53 lead to autosomal dominant inherited cancer susceptibility and confer a high lifetime risk of breast cancers. Identification of mutations in these genes through clinical genetic testing enables patients to undergo screening and prevention strategies, some of which provide overall survival benefit. In addition, a number of mutant alleles have been identified in genes such as CHEK2, PALB2, ATM and BRIP1, which often display incomplete penetrance and confer moderate lifetime risks of breast cancer. Studies are underway to determine how to use the identification of mutations in these genes to guide clinical practice. Altogether, however, mutations in high and moderate penetrance genes probably account for approximately 25% of familial breast cancer risk; the remainder may be due to mutations in as yet unidentified genes or lower penetrance variants. Common low penetrance alleles, which have been mainly identified through genome-wide association studies (GWAS), are generally present at 10 to 50% population frequencies and confer less than 1.5-fold increases in breast cancer risk. A number of single nucleotide polymorphisms (SNPs) have been identified and risk associations extensively replicated in populations of European ancestry, the number of which has substantially increased as a result of GWAS performed by the Collaborative Oncological Gene–environment Study consortium. It is now estimated that 28% of familial breast cancer risk is explained by common breast cancer susceptibility loci. In some cases, SNP associations may be specific to different subsets of women with breast cancer, as defined by ethnicity or estrogen receptor status. Although not yet clinically established, it is hoped that identification of common risk variants may eventually allow identification of women at higher risk of breast cancer and enable implementation of breast cancer screening, prevention or treatment strategies that provide clinical benefit. PMID:24359602

The effect of APOA5 and APOC3 variants on lipid parameters in European Whites, Indian Asians and Afro-Caribbeans with type 2 diabetes.

PubMed

Dorfmeister, Birgit; Cooper, Jackie A; Stephens, Jeffrey W; Ireland, Helen; Hurel, Steven J; Humphries, Steve E; Talmud, Philippa J

2007-03-01

Common variants in APOA5 and APOC3 have been associated with differences in plasma triglyceride (TG) levels in healthy individuals. The aim of this study was to examine the association of APOA5 (-1131T>C, S19W) and APOC3 (-482C>T, 1100C>T) polymorphisms in patients with type 2 diabetes (T2D) of European White (EW) (n=931), Indian Asian (IA) (n=610) and Afro-Caribbean (AC) (n=167) origin, with lipid and T2D parameters. Rare allele frequencies and linkage disequilibrium differed significantly amongst ethnic groups. Compared to APOA5 -1131T and 19S homozygotes, -1131C and 19W carriers had higher TGs in all groups, but this effect was only statistically significant for the -1131C in the EWs (P=0.04) and 19W in the IAs (P<0.001). APOC3 SNPs showed no significant association with lipid levels in any ethnic group. While haplotypes carrying -1131C allele showed significant TG-raising in the EWs only, the 19W defined haplotype showed significant TG-raising in both IAs and EWs. Comparing all four SNPs in EW T2D subjects with healthy EWs (n=2579), the APOC3 1100C>T frequency was significantly higher in T2D [0.26 (0.24, 0.28)] vs. healthy EWs [0.22 (0.20, 0.23)], P=0.001. While the variable size effects of the two APOA5 SNPs on TG levels may result from ethnically different gene-gene or gene-environment interactions, APOA5 and APOC3 variants did not affect parameters of T2D. However, comparison between EWs with T2D and healthy EWs suggest APOC3 1100C>T is associated with increased risk of diabetes probably through mechanisms other than direct effects on TG.

Large-Scale Analysis of Association Between LRP5 and LRP6 Variants and Osteoporosis

PubMed Central

van Meurs, Joyce B. J.; Trikalinos, Thomas A.; Ralston, Stuart H.; Balcells, Susana; Brandi, Maria Luisa; Brixen, Kim; Kiel, Douglas P.; Langdahl, Bente L.; Lips, Paul; Ljunggren, Östen; Lorenc, Roman; Obermayer-Pietsch, Barbara; Ohlsson, Claes; Pettersson, Ulrika; Reid, David M.; Rousseau, Francois; Scollen, Serena; Van Hul, Wim; Agueda, Lidia; Åkesson, Kristina; Benevolenskaya, Lidia I.; Ferrari, Serge L.; Hallmans, Göran; Hofman, Albert; Husted, Lise Bjerre; Kruk, Marcin; Kaptoge, Stephen; Karasik, David; Karlsson, Magnus K.; Lorentzon, Mattias; Masi, Laura; McGuigan, Fiona E. A.; Mellström, Dan; Mosekilde, Leif; Nogues, Xavier; Pols, Huibert A. P.; Reeve, Jonathan; Renner, Wilfried; Rivadeneira, Fernando; van Schoor, Natasja M.; Weber, Kurt; Ioannidis, John P. A.; Uitterlinden, André G.

2012-01-01

Context Mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene cause rare syndromes characterized by altered bone mineral density (BMD). More common LRP5 variants may affect osteoporosis risk in the general population. Objective To generate large-scale evidence on whether 2 common variants of LRP5 (Val667Met, Ala1330Val) and 1 variant of LRP6 (Ile1062Val) are associated with BMD and fracture risk. Design and Setting Prospective, multicenter, collaborative study of individual-level data on 37 534 individuals from 18 participating teams in Europe and North America. Data were collected between September 2004 and January 2007; analysis of the collected data was performed between February and May 2007. Bone mineral density was assessed by dual-energy x-ray absorptiometry. Fractures were identified via questionnaire, medical records, or radiographic documentation; incident fracture data were available for some cohorts, ascertained via routine surveillance methods, including radiographic examination for vertebral fractures. Main Outcome Measures Bone mineral density of the lumbar spine and femoral neck; prevalence of all fractures and vertebral fractures. Results The Met667 allele of LRP5 was associated with reduced lumbar spine BMD (n =25 052 [number of participants with available data]; 20-mg/cm2 lower BMD per Met667 allele copy; P=3.3 × 10−8), as was the Val1330 allele (n = 24 812; 14-mg/cm2 lower BMD per Val1330 copy; P=2.6 × 10−9). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/cm2 (P =3.8 × 10−5) and 8 mg/cm2 (P=5.0×10−6) for the Met667 and Val1330 alleles, respectively (n=25 193). Findings were consistent across studies for both LRP5 alleles. Both alleles were associated with vertebral fractures (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.08–1.47 for Met667 [2001 fractures among 20 488 individuals] and OR, 1.12; 95% CI, 1.01–1.24 for Val1330 [1988 fractures among 20 096 individuals]). Risk of all fractures was also increased with Met667 (OR, 1.14; 95% CI, 1.05–1.24 per allele [7876 fractures among 31 435 individuals)]) and Val1330 (OR, 1.06; 95% CI, 1.01–1.12 per allele [7802 fractures among 31 199 individuals]). Effects were similar when adjustments were made for age, weight, height, menopausal status, and use of hormone therapy. Fracture risks were partly attenuated by adjustment for BMD. Haplotype analysis indicated that Met667 and Val1330 variants both independently affected BMD. The LRP6 Ile1062Val polymorphism was not associated with any osteoporosis phenotype. All aforementioned associations except that between Val1330 and all fractures and vertebral fractures remained significant after multiple-comparison adjustments. Conclusions Common LRP5 variants are consistently associated with BMD and fracture risk across different white populations. The magnitude of the effect is modest. LRP5 may be the first gene to reach a genome-wide significance level (a conservative level of significance [herein, unadjusted P<10−7] that accounts for the many possible comparisons in the human genome) for a phenotype related to osteoporosis. PMID:18349089

The global prevalence of HFE and non-HFE hemochromatosis estimated from analysis of next-generation sequencing data.

PubMed

Wallace, Daniel F; Subramaniam, V Nathan

2016-06-01

The prevalence of HFE-related hereditary hemochromatosis (HH) among European populations has been well studied. There are no prevalence data for atypical forms of HH caused by mutations in HFE2, HAMP, TFR2, or SLC40A1. The purpose of this study was to estimate the population prevalence of these non-HFE forms of HH. A list of HH pathogenic variants in publically available next-generation sequence (NGS) databases was compiled and allele frequencies were determined. Of 161 variants previously associated with HH, 43 were represented among the NGS data sets; an additional 40 unreported functional variants also were identified. The predicted prevalence of HFE HH and the p.Cys282Tyr mutation closely matched previous estimates from similar populations. Of the non-HFE forms of iron overload, TFR2-, HFE2-, and HAMP-related forms are predicted to be rare, with pathogenic allele frequencies in the range of 0.00007 to 0.0005. Significantly, SLC40A1 variants that have been previously associated with autosomal-dominant ferroportin disease were identified in several populations (pathogenic allele frequency 0.0004), being most prevalent among Africans. We have, for the first time, estimated the population prevalence of non-HFE HH. This methodology could be applied to estimate the population prevalence of a wide variety of genetic disorders.Genet Med 18 6, 618-626.

CK-MM Polymorphism is Associated With Physical Fitness Test Scores in Military Recruits.

PubMed

Sprouse, Courtney; Tosi, Laura L; Gordish-Dressman, Heather; Abdel-Ghani, Mai S; Panchapakesan, Karuna; Niederberger, Brenda; Devaney, Joseph M; Kelly, Karen R

2015-09-01

Muscle-specific creatine kinase is thought to play an integral role in maintaining energy homeostasis by providing a supply of creatine phosphate. The genetic variant, rs8111989, contributes to individual differences in physical performance, and thus the purpose of this study was to determine if rs8111989 variant is predictive of Physical Fitness Test (PFT) scores in male, military infantry recruits. DNA was extracted from whole blood, and genotyping was performed in 176 Marines. Relationships between PFT measures (run, sit-ups, and pull-ups) and genotype were determined. Participants with 2 copies of the T allele for rs8111989 variant had higher PFT scores for run time, pull-ups, and total PFT score. Specifically, participants with 2 copies of the TT allele (variant) (n = 97) demonstrated an overall higher total PFT score as compared with those with one copy of the C allele (n = 79) (TT: 250 ± 31 vs. 238 ± 31; p = 0.02), run score (TT: 82 ± 10 vs. 78 ± 11; p = 0.04) and pull-up score (TT: 78 ± 11 vs. 65 ± 21; p = 0.04) or those with the CC/CT genotype. These results demonstrate an association between physical performance measures and genetic variation in the muscle-specific creatine kinase gene (rs8111989). Reprint & Copyright © 2015 Association of Military Surgeons of the U.S.

REV-ERB-ALPHA circadian gene variant associates with obesity in two independent populations: Mediterranean and North American.

PubMed

Garaulet, Marta; Smith, Caren E; Gomez-Abellán, Purificación; Ordovás-Montañés, María; Lee, Yu-Chi; Parnell, Laurence D; Arnett, Donna K; Ordovás, José M

2014-04-01

Despite the solid connection between REV-ERB and obesity, the information about whether genetic variations at this locus may be associated with obesity traits is scarce. Therefore our objective was to study the association between REV-ERB-ALPHA1 rs2314339 and obesity in two independent populations. Participants were 2214 subjects from Spanish Mediterranean (n = 1404) and North American (n = 810) populations. Anthropometric, biochemical, dietary, and genotype analyses were performed. We found novel associations between the REV-ERB-ALPHA1 rs2314339 genotype and obesity in two independent populations: in Spanish Mediterranean and North American groups, the frequency of the minor-allele-carriers (AA+ AG) was significantly lower in the "abdominally obese" group than in those of the "nonabdominally obese" group (p < 0.05). Minor allele carriers had lower probability of abdominal obesity than noncarriers, and the effect was of similar magnitude for both populations (OR ≈ 1.50). There were consistent associations between REV-ERB-ALPHA1 genotype and obesity-related traits (p < 0.05). Energy intake was not significantly associated with REV-ERB-ALPHA1 rs2314339. However, physical activity significantly differed by genotype. A significant interaction between the REV-ERB-ALPHA1 variant and monounsaturated-fatty-acids (MUFA) intake for obesity was also detected in the Mediterranean population. This new discovery highlights the importance of REV-ERB-ALPHA1 in obesity and provides evidence for the connection between our biological clock and obesity-related traits. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The Germline MLH1 K618A Variant and Susceptibility to Lynch Syndrome-Associated Tumors

PubMed Central

Medeiros, Fabiola; Lindor, Noralane M.; Couch, Fergus J.; Highsmith, W. Edward

2013-01-01

Missense variants discovered during sequencing of cancer susceptibility genes can be problematic for clinical interpretation. MLH1 K618A, which results from a 2-bp alteration (AAG→GCG) leading to a substitution of lysine to alanine in codon 618, has variously been interpreted as a pathogenic mutation, a variant of unknown significance, and a benign polymorphism. We evaluated the role of MLH1 K618A in predisposition to cancer by genotyping 1512 control subjects to assess its frequency in the general population. We also reviewed the literature concerning MLH1 K618A in families with colorectal cancer. The measured allele frequency of the K618A variant was 0.40%, which is remarkably close to the 0.44% summarized from 2491 control subjects in the literature. K618A was over-represented in families with suspected Lynch syndrome. In 1366 families, the allele frequency was 0.88% (OR = 2.1, 95% CI = 1.3 to 3.5; P = 0.006). In studies of sporadic cancers of the type associated with Lynch syndrome, K618A was over-represented in 1742 cases (allele frequency of 0.83) (OR = 2.0, 95% CI = 1.2 to 3.2; P = 0.008). We conclude that MLH1 K618A is not a fully penetrant Lynch syndrome mutation, although it is not without effect, appearing to increase the risk of Lynch syndrome-associated tumors approximately twofold. Our systematic assessment approach may be useful for variants in other genes. PMID:22426235

The Evolution and Functional Impact of Human Deletion Variants Shared with Archaic Hominin Genomes

PubMed Central

Lin, Yen-Lung; Pavlidis, Pavlos; Karakoc, Emre; Ajay, Jerry; Gokcumen, Omer

2015-01-01

Allele sharing between modern and archaic hominin genomes has been variously interpreted to have originated from ancestral genetic structure or through non-African introgression from archaic hominins. However, evolution of polymorphic human deletions that are shared with archaic hominin genomes has yet to be studied. We identified 427 polymorphic human deletions that are shared with archaic hominin genomes, approximately 87% of which originated before the Human–Neandertal divergence (ancient) and only approximately 9% of which have been introgressed from Neandertals (introgressed). Recurrence, incomplete lineage sorting between human and chimp lineages, and hominid-specific insertions constitute the remaining approximately 4% of allele sharing between humans and archaic hominins. We observed that ancient deletions correspond to more than 13% of all common (>5% allele frequency) deletion variation among modern humans. Our analyses indicate that the genomic landscapes of both ancient and introgressed deletion variants were primarily shaped by purifying selection, eliminating large and exonic variants. We found 17 exonic deletions that are shared with archaic hominin genomes, including those leading to three fusion transcripts. The affected genes are involved in metabolism of external and internal compounds, growth and sperm formation, as well as susceptibility to psoriasis and Crohn’s disease. Our analyses suggest that these “exonic” deletion variants have evolved through different adaptive forces, including balancing and population-specific positive selection. Our findings reveal that genomic structural variants that are shared between humans and archaic hominin genomes are common among modern humans and can influence biomedically and evolutionarily important phenotypes. PMID:25556237

Characterizing Genetic Susceptibility to Breast Cancer in Women of African Ancestry.

PubMed

Feng, Ye; Rhie, Suhn Kyong; Huo, Dezheng; Ruiz-Narvaez, Edward A; Haddad, Stephen A; Ambrosone, Christine B; John, Esther M; Bernstein, Leslie; Zheng, Wei; Hu, Jennifer J; Ziegler, Regina G; Nyante, Sarah; Bandera, Elisa V; Ingles, Sue A; Press, Michael F; Deming, Sandra L; Rodriguez-Gil, Jorge L; Zheng, Yonglan; Yao, Song; Han, Yoo-Jeong; Ogundiran, Temidayo O; Rebbeck, Timothy R; Adebamowo, Clement; Ojengbede, Oladosu; Falusi, Adeyinka G; Hennis, Anselm; Nemesure, Barbara; Ambs, Stefan; Blot, William; Cai, Qiuyin; Signorello, Lisa; Nathanson, Katherine L; Lunetta, Kathryn L; Sucheston-Campbell, Lara E; Bensen, Jeannette T; Chanock, Stephen J; Marchand, Loic Le; Olshan, Andrew F; Kolonel, Laurence N; Conti, David V; Coetzee, Gerhard A; Stram, Daniel O; Olopade, Olufunmilayo I; Palmer, Julie R; Haiman, Christopher A

2017-07-01

Background: Genome-wide association studies have identified approximately 100 common genetic variants associated with breast cancer risk, the majority of which were discovered in women of European ancestry. Because of different patterns of linkage disequilibrium, many of these genetic markers may not represent signals in populations of African ancestry. Methods: We tested 74 breast cancer risk variants and conducted fine-mapping of these susceptibility regions in 6,522 breast cancer cases and 7,643 controls of African ancestry from three genetic consortia (AABC, AMBER, and ROOT). Results: Fifty-four of the 74 variants (73%) were found to have ORs that were directionally consistent with those previously reported, of which 12 were nominally statistically significant ( P < 0.05). Through fine-mapping, in six regions ( 3p24, 12p11, 14q13, 16q12/FTO, 16q23, 19p13 ), we observed seven markers that better represent the underlying risk variant for overall breast cancer or breast cancer subtypes, whereas in another two regions ( 11q13, 16q12/TOX3 ), we identified suggestive evidence of signals that are independent of the reported index variant. Overlapping chromatin features and regulatory elements suggest that many of the risk alleles lie in regions with biological functionality. Conclusions: Through fine-mapping of known susceptibility regions, we have revealed alleles that better characterize breast cancer risk in women of African ancestry. Impact: The risk alleles identified represent genetic markers for modeling and stratifying breast cancer risk in women of African ancestry. Cancer Epidemiol Biomarkers Prev; 26(7); 1016-26. ©2017 AACR . ©2017 American Association for Cancer Research.

Haplotype diversity in the equine myostatin gene with focus on variants associated with race distance propensity and muscle fiber type proportions

PubMed Central

Petersen, Jessica L; Valberg, Stephanie J; Mickelson, James R; McCue, Molly E

2014-01-01

Summary Two variants in the equine myostatin gene (MSTN), including a T/C SNP substitution in the first intron and a 227-bp SINE insertion in the promoter, are associated with muscle fiber type proportions in the Quarter Horse (QH) and with the prediction of race distance propensity in the Thoroughbred (TB). Genotypes from these loci, along with 18 additional variants surrounding MSTN, were examined in 301 horses of 14 breeds to evaluate haplotype relationships and diversity. The C allele of intron 1 was found in 12 of 14 breeds at a frequency of 0.27; the SINE was observed in five breeds, but common in only the TB and QH (0.73 and 0.48 respectively). Haplotype data suggest the SINE insertion is contemporary to and arose upon a haplotype containing the intron 1 C allele. Gluteal muscle biopsies of TBs showed a significant association of the intron 1 C allele and SINE with a higher proportion of Type 2B and lower proportion of Type 1 fibers. However, in the Belgian horse, in which the SINE is not present, the intron 1 SNP was not associated with fiber type proportions, and evaluation of fiber type proportions across the Belgian, TB and QH breeds shows the significant effect of breed on fiber type proportions is negated when evaluating horses without the SINE variant. These data suggest the SINE, rather than the intron 1 SNP, is driving the observed muscle fiber type characteristics and is the variant targeted by selection for short-distance racing. PMID:25160752

Multiple lupus-associated ITGAM variants alter Mac-1 functions on neutrophils.

PubMed

Zhou, Yebin; Wu, Jianming; Kucik, Dennis F; White, Nathan B; Redden, David T; Szalai, Alexander J; Bullard, Daniel C; Edberg, Jeffrey C

2013-11-01

Multiple studies have demonstrated that single-nucleotide polymorphisms (SNPs) in the ITGAM locus (including the nonsynonymous SNPs rs1143679, rs1143678, and rs1143683) are associated with systemic lupus erythematosus (SLE). ITGAM encodes the protein CD11b, a subunit of the β2 integrin Mac-1. The purpose of this study was to determine the effects of ITGAM genetic variation on the biologic functions of neutrophil Mac-1. Neutrophils from ITGAM-genotyped and -sequenced healthy donors were isolated for functional studies. The phagocytic capacity of neutrophil ITGAM variants was probed with complement-coated erythrocytes, serum-treated zymosan, heat-treated zymosan, and IgG-coated erythrocytes. The adhesion capacity of ITGAM variants, in adhering to either purified intercellular adhesion molecule 1 or tumor necrosis factor α-stimulated endothelial cells, was assessed in a flow chamber. Expression levels of total CD11b and activation of CD11b were assessed by flow cytometry. Mac-1-mediated neutrophil phagocytosis, determined in cultures with 2 different complement-coated particles, was significantly reduced in individuals with nonsynonymous variant alleles of ITGAM. This reduction in phagocytosis was related to variation at either rs1143679 (in the β-propeller region) or rs1143678/rs1143683 (highly linked SNPs in the cytoplasmic/calf-1 regions). Phagocytosis mediated by Fcγ receptors was also significantly reduced in donors with variant ITGAM alleles. Similarly, firm adhesion of neutrophils was significantly reduced in individuals with variant ITGAM alleles. These functional alterations were not attributable to differences in total receptor expression or activation. The nonsynonymous ITGAM variants rs1143679 and rs1143678/rs113683 contribute to altered Mac-1 function on neutrophils. These results underscore the need to consider multiple nonsynonymous SNPs when assessing the functional consequences of ITGAM variation on immune cell processes and the risk of SLE. Copyright © 2013 by the American College of Rheumatology.

Association between variants in or near PNPLA3, GCKR, and PPP1R3B with ultrasound-defined steatosis based on data from the third National Health and Nutrition Examination Survey.

PubMed

Hernaez, Ruben; McLean, Jody; Lazo, Mariana; Brancati, Frederick L; Hirschhorn, Joel N; Borecki, Ingrid B; Harris, Tamara B; Nguyen, Thutrang; Kamel, Ihab R; Bonekamp, Susanne; Eberhardt, Mark S; Clark, Jeanne M; Kao, Wen Hong Linda; Speliotes, Elizabeth K

2013-09-01

A genome-wide association study associated 5 genetic variants with hepatic steatosis (identified by computerized tomography) in individuals of European ancestry. We investigated whether these variants were associated with measures of hepatic steatosis (HS) in non-Hispanic white (NHW), non-Hispanic black, and Mexican American (MA) participants in the US population-based National Health and Nutrition Examination Survey III, phase 2. We analyzed data from 4804 adults (1825 NHW, 1442 non-Hispanic black, and 1537 MA; 51.7% women; mean age at examination, 42.5 y); the weighted prevalence of HS was 37.3%. We investigated whether ultrasound-measured HS, with and without increased levels of alanine aminotransferase (ALT), or level of ALT alone, was associated with rs738409 (patatin-like phospholipase domain-containing protein 3 [PNPLA3]), rs2228603 (neurocan [NCAN]), rs12137855 (lysophospholipase-like 1), rs780094 (glucokinase regulatory protein [GCKR]), and rs4240624 (protein phosphatase 1, regulatory subunit 3b [PPP1R3B]) using regression modeling in an additive genetic model, controlling for age, age-squared, sex, and alcohol consumption. The G allele of rs738409 (PNPLA3) and the T allele of rs780094 (GCKR) were associated with HS with a high level of ALT (odds ratio [OR], 1.36; P = .01; and OR, 1.30; P = .03, respectively). The A allele of rs4240624 (PPP1R3B) and the T allele of rs2228603 (NCAN) were associated with HS (OR, 1.28; P = .03; and OR, 1.40; P = .04, respectively). Variants of PNPLA3 and NCAN were associated with ALT level among all 3 ancestries. Some single-nucleotide polymorphisms were associated with particular races or ethnicities: variants in PNPLA3, NCAN, GCKR, and PPP1R3B were associated with NHW and variants in PNPLA3 were associated with MA. No variants were associated with NHB. We used data from the National Health and Nutrition Examination Survey III to validate the association between rs738409 (PNPLA3), rs780094 (GCKR), and rs4240624 (PPP1R3B) with HS, with or without increased levels of ALT, among 3 different ancestries. Some, but not all, associations between variants in NCAN, lysophospholipase-like 1, GCKR, and PPP1R3B with HS (with and without increased ALT level) were significant within subpopulations. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

Transfusion strategy for weak D type 4.0 based on RHD alleles and RH haplotypes in Tunisia

PubMed Central

Ouchari, Mouna; Srivastava, Kshitij; Romdhane, Houda; Yacoub, Saloua Jemni; Flegel, Willy Albert

2017-01-01

Background With more than 460 RHD alleles, this gene is the most complex and polymorphic among all blood group systems. The Tunisian population has the largest known prevalence of weak D type 4.0 alleles, occurring in 1 of 105 RH haplotypes. We aimed to establish a rationale for the transfusion strategy of weak D type 4.0 in Tunisia. Study design and methods Donors were randomly screened for the serological weak D phenotype. The RHD coding sequence and parts of the introns were sequenced. To establish the RH haplotype, the RHCE gene was tested for characteristic single nucleotide positions. Results We determined all RHD alleles and the RH haplotypes coding for the serologic weak D phenotype among 13,431 Tunisian donations. A serologic weak D phenotype was found in 67 individuals (0.50%). Among them, 60 carried a weak D type 4 allele: 53 weak D type 4.0, 6 weak D type 4.2.2 (DAR), and 1 weak D type 4.1. Another 4 donors had 1 variant allele each: DVII, weak D type 1, weak D type 3, and weak D type 100, while 3 donors showed a normal RHD sequence. The weak D type 4.0 was most often linked to RHCE*ceVS.04.01, weak D type 4.2.2 to RHCE*ceAR, and weak D type 4.1 to RHCE*ceVS.02, while the other RHD alleles were linked to one of the common RHCE alleles. Conclusions Among the weak D phenotypes in Tunisia, no novel RHD allele was found and almost 90% were caused by alleles of the weak D type 4 cluster, of which 88% represented the weak D type 4.0 allele. Based on established RH haplotypes for variant RHD and RHCE alleles and the lack of adverse clinical reports, we recommend D positive transfusions for patients with weak D type 4.0 in Tunisia. PMID:29193104

Transfusion strategy for weak D Type 4.0 based on RHD alleles and RH haplotypes in Tunisia.

PubMed

Ouchari, Mouna; Srivastava, Kshitij; Romdhane, Houda; Jemni Yacoub, Saloua; Flegel, Willy Albert

2018-02-01

With more than 460 RHD alleles, this gene is the most complex and polymorphic among all blood group systems. The Tunisian population has the largest known prevalence of weak D Type 4.0 alleles, occurring in one of 105 RH haplotypes. We aimed to establish a rationale for the transfusion strategy of weak D Type 4.0 in Tunisia. Donors were randomly screened for the serologic weak D phenotype. The RHD coding sequence and parts of the introns were sequenced. To establish the RH haplotype, the RHCE gene was tested for characteristic single-nucleotide positions. We determined all RHD alleles and the RH haplotypes coding for the serologic weak D phenotype among 13,431 Tunisian donations. A serologic weak D phenotype was found in 67 individuals (0.50%). Among them, 60 carried a weak D Type 4 allele: 53 weak D Type 4.0, six weak D Type 4.2.2 (DAR), and one weak D Type 4.1. An additional four donors had one variant allele each: DVII, weak D Type 1, weak D Type 3, and weak D type 100, while three donors showed a normal RHD sequence. The weak D Type 4.0 was most often linked to RHCE*ceVS.04.01, weak D Type 4.2.2 to RHCE*ceAR, and weak D Type 4.1 to RHCE*ceVS.02, while the other RHD alleles were linked to one of the common RHCE alleles. Among the weak D phenotypes in Tunisia, no novel RHD allele was found and almost 90% were caused by alleles of the weak D Type 4 cluster, of which 88% represented the weak D Type 4.0 allele. Based on established RH haplotypes for variant RHD and RHCE alleles and the lack of adverse clinical reports, we recommend D+ transfusions for patients with weak D Type 4.0 in Tunisia. © 2017 AABB.

Genomic variants in an inbred mouse model predict mania-like behaviors.

PubMed

Saul, Michael C; Stevenson, Sharon A; Zhao, Changjiu; Driessen, Terri M; Eisinger, Brian E; Gammie, Stephen C

2018-01-01

Contemporary rodent models for bipolar disorders split the bipolar spectrum into complimentary behavioral endophenotypes representing mania and depression. Widely accepted mania models typically utilize single gene transgenics or pharmacological manipulations, but inbred rodent strains show great potential as mania models. Their acceptance is often limited by the lack of genotypic data needed to establish construct validity. In this study, we used a unique strategy to inexpensively explore and confirm population allele differences in naturally occurring candidate variants in a manic rodent strain, the Madison (MSN) mouse strain. Variants were identified using whole exome resequencing on a small population of animals. Interesting candidate variants were confirmed in a larger population with genotyping. We enriched these results with observations of locomotor behavior from a previous study. Resequencing identified 447 structural variants that are mostly fixed in the MSN strain relative to control strains. After filtering and annotation, we found 11 non-synonymous MSN variants that we believe alter protein function. The allele frequencies for 6 of these variants were consistent with explanatory variants for the Madison strain's phenotype. The variants are in the Npas2, Cp, Polr3c, Smarca4, Trpv1, and Slc5a7 genes, and many of these genes' products are in pathways implicated in human bipolar disorders. Variants in Smarca4 and Polr3c together explained over 40% of the variance in locomotor behavior in the Hsd:ICR founder strain. These results enhance the MSN strain's construct validity and implicate altered nucleosome structure and transcriptional regulation as a chief molecular system underpinning behavior.

Genetic diversity of Plasmodium falciparum merozoite surface protein-1 (block 2), glutamate-rich protein and sexual stage antigen Pfs25 from Chandigarh, North India.

PubMed

Kaur, Hargobinder; Sehgal, Rakesh; Goyal, Kapil; Makkar, Nikita; Yadav, Richa; Bharti, Praveen K; Singh, Neeru; Sarmah, Nilanju P; Mohapatra, Pradyumna K; Mahanta, Jagadish; Bansal, Devendra; Sultan, Ali A; Kanwar, Jagat R

2017-12-01

To elucidate the genetic diversity of Plasmodium falciparum in residual transmission foci of northern India. Clinically suspected patients with malaria were screened for malaria infection by microscopy. 48 P. falciparum-infected patients were enrolled from tertiary care hospital in Chandigarh, India. Blood samples were collected from enrolled patients, genomic DNA extraction and nested PCR was performed for further species confirmation. Sanger sequencing was carried out using block 2 region of msp1, R2 region of glurp and pfs25-specific primers. Extensive diversity was found in msp1 alleles with predominantly RO33 alleles. Overall allelic prevalence was 55.8% for RO33, 39.5% for MAD20 and 4.7% for K1. Six variants were observed in MAD20, whereas no variant was found in RO33 and K1 alleles. A phylogenetic analysis of RO33 alleles indicated more similarity to South African isolates, whereas MAD20 alleles showed similarity with South-East Asian isolates. In glurp, extensive variation was observed with eleven different alleles based on the AAU repeats. However, pfs25 showed less diversity and was the most stable among the targeted genes. Our findings document the genetic diversity among circulating strains of P. falciparum in an area of India with low malaria transmission and could have implications for control strategies to reach the national goal of malaria elimination. © 2017 John Wiley & Sons Ltd.

ApoE -491A/T promoter polymorphism is not an independent risk factor, but associated with the epsilon4 allele in Hungarian Alzheimer's dementia population.

PubMed

Juhász, Anna; Palotás, András; Janka, Zoltán; Rimanóczy, Agnes; Palotás, Miklós; Bódi, Nikoletta; Boda, Krisztina; Zana, Marianna; Vincze, Gábor; Kálmán, János

2005-05-01

Apolipoprotein E gene (Apo(epsilon)) has three common alleles (epsilon2, epsilon3, and epsilon4), of which epsilon4 has been shown to be associated with an increased risk for Alzheimer's disease (AD). Possible additional genetic factors, like the -491A variant of ApoE promoter may modify the development of AD, independently of the ApoE allele status. The objective of this study was to investigate whether A/T allelic polymorphism at site-491 of the ApoE promoter is associated with AD in a Hungarian population. The genomic DNA isolated from peripheral blood lymphocytes of 52 late-onset AD and 53 control individuals was used as a template for the two examined polymorphisms and PCR assay was applied. The epsilon4 allele was significantly over-represented in the AD group (28%) as compared with the control population (7%). No significant differences have been found between the control and the AD populations regarding the occurrence of the promoter A allele frequencies (control: 77%, AD: 70%). However, the AA genotype was more frequent in the AD group (48%) than in the control (10%) when the presence of epsilon4 allele was also considered. It is unlikely therefore that the -491A variant of the ApoE promoter gene is an independent risk factor in the Hungarian AD population, but a linkage disequilibrium exists between the two examined mutations.

MicroRNA-3148 modulates allelic expression of toll-like receptor 7 variant associated with systemic lupus erythematosus.

PubMed

Deng, Yun; Zhao, Jian; Sakurai, Daisuke; Kaufman, Kenneth M; Edberg, Jeffrey C; Kimberly, Robert P; Kamen, Diane L; Gilkeson, Gary S; Jacob, Chaim O; Scofield, R Hal; Langefeld, Carl D; Kelly, Jennifer A; Ramsey-Goldman, Rosalind; Petri, Michelle A; Reveille, John D; Vilá, Luis M; Alarcón, Graciela S; Vyse, Timothy J; Pons-Estel, Bernardo A; Freedman, Barry I; Gaffney, Patrick M; Sivils, Kathy Moser; James, Judith A; Gregersen, Peter K; Anaya, Juan-Manuel; Niewold, Timothy B; Merrill, Joan T; Criswell, Lindsey A; Stevens, Anne M; Boackle, Susan A; Cantor, Rita M; Chen, Weiling; Grossman, Jeniffer M; Hahn, Bevra H; Harley, John B; Alarcόn-Riquelme, Marta E; Brown, Elizabeth E; Tsao, Betty P

2013-01-01

We previously reported that the G allele of rs3853839 at 3'untranslated region (UTR) of Toll-like receptor 7 (TLR7) was associated with elevated transcript expression and increased risk for systemic lupus erythematosus (SLE) in 9,274 Eastern Asians [P = 6.5×10(-10), odds ratio (OR) (95%CI) = 1.27 (1.17-1.36)]. Here, we conducted trans-ancestral fine-mapping in 13,339 subjects including European Americans, African Americans, and Amerindian/Hispanics and confirmed rs3853839 as the only variant within the TLR7-TLR8 region exhibiting consistent and independent association with SLE (Pmeta = 7.5×10(-11), OR = 1.24 [1.18-1.34]). The risk G allele was associated with significantly increased levels of TLR7 mRNA and protein in peripheral blood mononuclear cells (PBMCs) and elevated luciferase activity of reporter gene in transfected cells. TLR7 3'UTR sequence bearing the non-risk C allele of rs3853839 matches a predicted binding site of microRNA-3148 (miR-3148), suggesting that this microRNA may regulate TLR7 expression. Indeed, miR-3148 levels were inversely correlated with TLR7 transcript levels in PBMCs from SLE patients and controls (R(2) = 0.255, P = 0.001). Overexpression of miR-3148 in HEK-293 cells led to significant dose-dependent decrease in luciferase activity for construct driven by TLR7 3'UTR segment bearing the C allele (P = 0.0003). Compared with the G-allele construct, the C-allele construct showed greater than two-fold reduction of luciferase activity in the presence of miR-3148. Reduced modulation by miR-3148 conferred slower degradation of the risk G-allele containing TLR7 transcripts, resulting in elevated levels of gene products. These data establish rs3853839 of TLR7 as a shared risk variant of SLE in 22,613 subjects of Asian, EA, AA, and Amerindian/Hispanic ancestries (Pmeta  = 2.0×10(-19), OR = 1.25 [1.20-1.32]), which confers allelic effect on transcript turnover via differential binding to the epigenetic factor miR-3148.

A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer.

PubMed

Haiman, Christopher A; Chen, Gary K; Vachon, Celine M; Canzian, Federico; Dunning, Alison; Millikan, Robert C; Wang, Xianshu; Ademuyiwa, Foluso; Ahmed, Shahana; Ambrosone, Christine B; Baglietto, Laura; Balleine, Rosemary; Bandera, Elisa V; Beckmann, Matthias W; Berg, Christine D; Bernstein, Leslie; Blomqvist, Carl; Blot, William J; Brauch, Hiltrud; Buring, Julie E; Carey, Lisa A; Carpenter, Jane E; Chang-Claude, Jenny; Chanock, Stephen J; Chasman, Daniel I; Clarke, Christine L; Cox, Angela; Cross, Simon S; Deming, Sandra L; Diasio, Robert B; Dimopoulos, Athanasios M; Driver, W Ryan; Dünnebier, Thomas; Durcan, Lorraine; Eccles, Diana; Edlund, Christopher K; Ekici, Arif B; Fasching, Peter A; Feigelson, Heather S; Flesch-Janys, Dieter; Fostira, Florentia; Försti, Asta; Fountzilas, George; Gerty, Susan M; Giles, Graham G; Godwin, Andrew K; Goodfellow, Paul; Graham, Nikki; Greco, Dario; Hamann, Ute; Hankinson, Susan E; Hartmann, Arndt; Hein, Rebecca; Heinz, Judith; Holbrook, Andrea; Hoover, Robert N; Hu, Jennifer J; Hunter, David J; Ingles, Sue A; Irwanto, Astrid; Ivanovich, Jennifer; John, Esther M; Johnson, Nicola; Jukkola-Vuorinen, Arja; Kaaks, Rudolf; Ko, Yon-Dschun; Kolonel, Laurence N; Konstantopoulou, Irene; Kosma, Veli-Matti; Kulkarni, Swati; Lambrechts, Diether; Lee, Adam M; Marchand, Loïc Le; Lesnick, Timothy; Liu, Jianjun; Lindstrom, Sara; Mannermaa, Arto; Margolin, Sara; Martin, Nicholas G; Miron, Penelope; Montgomery, Grant W; Nevanlinna, Heli; Nickels, Stephan; Nyante, Sarah; Olswold, Curtis; Palmer, Julie; Pathak, Harsh; Pectasides, Dimitrios; Perou, Charles M; Peto, Julian; Pharoah, Paul D P; Pooler, Loreall C; Press, Michael F; Pylkäs, Katri; Rebbeck, Timothy R; Rodriguez-Gil, Jorge L; Rosenberg, Lynn; Ross, Eric; Rüdiger, Thomas; Silva, Isabel dos Santos; Sawyer, Elinor; Schmidt, Marjanka K; Schulz-Wendtland, Rüdiger; Schumacher, Fredrick; Severi, Gianluca; Sheng, Xin; Signorello, Lisa B; Sinn, Hans-Peter; Stevens, Kristen N; Southey, Melissa C; Tapper, William J; Tomlinson, Ian; Hogervorst, Frans B L; Wauters, Els; Weaver, JoEllen; Wildiers, Hans; Winqvist, Robert; Van Den Berg, David; Wan, Peggy; Xia, Lucy Y; Yannoukakos, Drakoulis; Zheng, Wei; Ziegler, Regina G; Siddiq, Afshan; Slager, Susan L; Stram, Daniel O; Easton, Douglas; Kraft, Peter; Henderson, Brian E; Couch, Fergus J

2011-10-30

Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 × 10(-10)). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 × 10(-9)), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 × 10(-9)). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations.

Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.

PubMed

Gaulton, Kyle J; Ferreira, Teresa; Lee, Yeji; Raimondo, Anne; Mägi, Reedik; Reschen, Michael E; Mahajan, Anubha; Locke, Adam; Rayner, N William; Robertson, Neil; Scott, Robert A; Prokopenko, Inga; Scott, Laura J; Green, Todd; Sparso, Thomas; Thuillier, Dorothee; Yengo, Loic; Grallert, Harald; Wahl, Simone; Frånberg, Mattias; Strawbridge, Rona J; Kestler, Hans; Chheda, Himanshu; Eisele, Lewin; Gustafsson, Stefan; Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Qi, Lu; Karssen, Lennart C; van Leeuwen, Elisabeth M; Willems, Sara M; Li, Man; Chen, Han; Fuchsberger, Christian; Kwan, Phoenix; Ma, Clement; Linderman, Michael; Lu, Yingchang; Thomsen, Soren K; Rundle, Jana K; Beer, Nicola L; van de Bunt, Martijn; Chalisey, Anil; Kang, Hyun Min; Voight, Benjamin F; Abecasis, Gonçalo R; Almgren, Peter; Baldassarre, Damiano; Balkau, Beverley; Benediktsson, Rafn; Blüher, Matthias; Boeing, Heiner; Bonnycastle, Lori L; Bottinger, Erwin P; Burtt, Noël P; Carey, Jason; Charpentier, Guillaume; Chines, Peter S; Cornelis, Marilyn C; Couper, David J; Crenshaw, Andrew T; van Dam, Rob M; Doney, Alex S F; Dorkhan, Mozhgan; Edkins, Sarah; Eriksson, Johan G; Esko, Tonu; Eury, Elodie; Fadista, João; Flannick, Jason; Fontanillas, Pierre; Fox, Caroline; Franks, Paul W; Gertow, Karl; Gieger, Christian; Gigante, Bruna; Gottesman, Omri; Grant, George B; Grarup, Niels; Groves, Christopher J; Hassinen, Maija; Have, Christian T; Herder, Christian; Holmen, Oddgeir L; Hreidarsson, Astradur B; Humphries, Steve E; Hunter, David J; Jackson, Anne U; Jonsson, Anna; Jørgensen, Marit E; Jørgensen, Torben; Kao, Wen-Hong L; Kerrison, Nicola D; Kinnunen, Leena; Klopp, Norman; Kong, Augustine; Kovacs, Peter; Kraft, Peter; Kravic, Jasmina; Langford, Cordelia; Leander, Karin; Liang, Liming; Lichtner, Peter; Lindgren, Cecilia M; Lindholm, Eero; Linneberg, Allan; Liu, Ching-Ti; Lobbens, Stéphane; Luan, Jian'an; Lyssenko, Valeriya; Männistö, Satu; McLeod, Olga; Meyer, Julia; Mihailov, Evelin; Mirza, Ghazala; Mühleisen, Thomas W; Müller-Nurasyid, Martina; Navarro, Carmen; Nöthen, Markus M; Oskolkov, Nikolay N; Owen, Katharine R; Palli, Domenico; Pechlivanis, Sonali; Peltonen, Leena; Perry, John R B; Platou, Carl G P; Roden, Michael; Ruderfer, Douglas; Rybin, Denis; van der Schouw, Yvonne T; Sennblad, Bengt; Sigurðsson, Gunnar; Stančáková, Alena; Steinbach, Gerald; Storm, Petter; Strauch, Konstantin; Stringham, Heather M; Sun, Qi; Thorand, Barbara; Tikkanen, Emmi; Tonjes, Anke; Trakalo, Joseph; Tremoli, Elena; Tuomi, Tiinamaija; Wennauer, Roman; Wiltshire, Steven; Wood, Andrew R; Zeggini, Eleftheria; Dunham, Ian; Birney, Ewan; Pasquali, Lorenzo; Ferrer, Jorge; Loos, Ruth J F; Dupuis, Josée; Florez, Jose C; Boerwinkle, Eric; Pankow, James S; van Duijn, Cornelia; Sijbrands, Eric; Meigs, James B; Hu, Frank B; Thorsteinsdottir, Unnur; Stefansson, Kari; Lakka, Timo A; Rauramaa, Rainer; Stumvoll, Michael; Pedersen, Nancy L; Lind, Lars; Keinanen-Kiukaanniemi, Sirkka M; Korpi-Hyövälti, Eeva; Saaristo, Timo E; Saltevo, Juha; Kuusisto, Johanna; Laakso, Markku; Metspalu, Andres; Erbel, Raimund; Jöcke, Karl-Heinz; Moebus, Susanne; Ripatti, Samuli; Salomaa, Veikko; Ingelsson, Erik; Boehm, Bernhard O; Bergman, Richard N; Collins, Francis S; Mohlke, Karen L; Koistinen, Heikki; Tuomilehto, Jaakko; Hveem, Kristian; Njølstad, Inger; Deloukas, Panagiotis; Donnelly, Peter J; Frayling, Timothy M; Hattersley, Andrew T; de Faire, Ulf; Hamsten, Anders; Illig, Thomas; Peters, Annette; Cauchi, Stephane; Sladek, Rob; Froguel, Philippe; Hansen, Torben; Pedersen, Oluf; Morris, Andrew D; Palmer, Collin N A; Kathiresan, Sekar; Melander, Olle; Nilsson, Peter M; Groop, Leif C; Barroso, Inês; Langenberg, Claudia; Wareham, Nicholas J; O'Callaghan, Christopher A; Gloyn, Anna L; Altshuler, David; Boehnke, Michael; Teslovich, Tanya M; McCarthy, Mark I; Morris, Andrew P

2015-12-01

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.

Association Between Vitamin D Receptor rs731236 (Taq1) Polymorphism and Risk for Restless Legs Syndrome in the Spanish Caucasian Population

PubMed Central

Jiménez-Jiménez, Félix Javier; García-Martín, Elena; Alonso-Navarro, Hortensia; Martínez, Carmen; Zurdo, Martín; Turpín-Fenoll, Laura; Millán-Pascual, Jorge; Adeva-Bartolomé, Teresa; Cubo, Esther; Navacerrada, Francisco; Rojo-Sebastián, Ana; Rubio, Lluisa; Ortega-Cubero, Sara; Pastor, Pau; Calleja, Marisol; Plaza-Nieto, José Francisco; Pilo-De-La-Fuente, Belén; Arroyo-Solera, Margarita; García-Albea, Esteban; Agúndez, José A.G.

2015-01-01

Abstract Several recent works suggest a possible role of vitamin D deficiency in the etiology or restless legs syndrome (RLS). We analyzed the possible relationship of 2 common single nucleotide polymorphisms (SNPs) in the vitamin D3 receptor (VDR) gene with the risk for RLS. We studied the genotype and allelic variant frequencies of VDR rs2228570 and VDR rs731236 SNPs in 205 RLS patients and 445 healthy controls using a TaqMan essay. The frequencies of the rs731236AA genotype and the allelic variant rs731236A were significantly lower in RLS patients than in controls (P < 0.005 and < 0.01, respectively). Restless legs syndrome patients carrying the allelic variant rs731236G had an earlier age at onset, and those carrying the rs731236GG genotype had higher severity of RLS, although these data disappeared after multivariate analyses. None of the SNPs studied was related with the positivity of family history of RLS. These results suggest a modest, but significant association between VDR rs731236 SNP and the risk for RLS. PMID:26632733

Polymorphism discovery and allele frequency estimation using high-throughput DNA sequencing of target-enriched pooled DNA samples

PubMed Central

2012-01-01

Background The central role of the somatotrophic axis in animal post-natal growth, development and fertility is well established. Therefore, the identification of genetic variants affecting quantitative traits within this axis is an attractive goal. However, large sample numbers are a pre-requisite for the identification of genetic variants underlying complex traits and although technologies are improving rapidly, high-throughput sequencing of large numbers of complete individual genomes remains prohibitively expensive. Therefore using a pooled DNA approach coupled with target enrichment and high-throughput sequencing, the aim of this study was to identify polymorphisms and estimate allele frequency differences across 83 candidate genes of the somatotrophic axis, in 150 Holstein-Friesian dairy bulls divided into two groups divergent for genetic merit for fertility. Results In total, 4,135 SNPs and 893 indels were identified during the resequencing of the 83 candidate genes. Nineteen percent (n = 952) of variants were located within 5' and 3' UTRs. Seventy-two percent (n = 3,612) were intronic and 9% (n = 464) were exonic, including 65 indels and 236 SNPs resulting in non-synonymous substitutions (NSS). Significant (P < 0.01) mean allele frequency differentials between the low and high fertility groups were observed for 720 SNPs (58 NSS). Allele frequencies for 43 of the SNPs were also determined by genotyping the 150 individual animals (Sequenom® MassARRAY). No significant differences (P > 0.1) were observed between the two methods for any of the 43 SNPs across both pools (i.e., 86 tests in total). Conclusions The results of the current study support previous findings of the use of DNA sample pooling and high-throughput sequencing as a viable strategy for polymorphism discovery and allele frequency estimation. Using this approach we have characterised the genetic variation within genes of the somatotrophic axis and related pathways, central to mammalian post-natal growth and development and subsequent lactogenesis and fertility. We have identified a large number of variants segregating at significantly different frequencies between cattle groups divergent for calving interval plausibly harbouring causative variants contributing to heritable variation. To our knowledge, this is the first report describing sequencing of targeted genomic regions in any livestock species using groups with divergent phenotypes for an economically important trait. PMID:22235840

Role of stochastic processes in maintaining discrete strain structure in antigenically diverse pathogen populations.

PubMed

Buckee, Caroline O; Recker, Mario; Watkins, Eleanor R; Gupta, Sunetra

2011-09-13

Many highly diverse pathogen populations appear to exist stably as discrete antigenic types despite evidence of genetic exchange. It has been shown that this may arise as a consequence of immune selection on pathogen populations, causing them to segregate permanently into discrete nonoverlapping subsets of antigenic variants to minimize competition for available hosts. However, discrete antigenic strain structure tends to break down under conditions where there are unequal numbers of allelic variants at each locus. Here, we show that the inclusion of stochastic processes can lead to the stable recovery of discrete strain structure through loss of certain alleles. This explains how pathogen populations may continue to behave as independently transmitted strains despite inevitable asymmetries in allelic diversity of major antigens. We present evidence for this type of structuring across global meningococcal isolates in three diverse antigens that are currently being developed as vaccine components.

[THE INFLUENCE OF SEROTONIN TRANSPORTER AND MONOAMINE OXIDASE A GENES POLYMORPHISM ON PSYCHO-EMOTION AND KARYOLOGICAL STABILITY OF ATHLETES].

PubMed

Kalaev, V N; Nechaeva, M S; Korneeva, O S; Cherenkov, D A

2015-11-01

The influence of polymorphism of the serotonin transporter and monoamine oxidase A genes, associated with man's aggressiveness on the psycho-emotional state and karyological status of single combat athletes. It was revealed that the carriers of less active ("short"), monoamine oxidase A gene variant have a high motivation to succeed and less rigidity and frustrated, compared to the carriers of more active ("long") version of the gene. Heterozygote carriers of less active ("short") variant of the serotonin transporter gene 5-HTTL had more physical aggression, guilt and were less frustrated compared with carriers of two long alleles. It has been revealed the association of studied genes with the karyological status of athletes. So fighters who are carriers of the short and long alleles of the serotonin transporter gene had more cells with nuclear abnormalities in the buccal epithelium than single combat athletes which both alleles were long.

Hotspot mutations in cancer genes may be missed in routine diagnostics due to neighbouring sequence variants.

PubMed

Bartels, Stephan; Schipper, Elisa; Hasemeier, Britta; Kreipe, Hans; Lehmann, Ulrich

2018-05-27

The detection of hotspot mutations in key cancer genes is now an essential part of the diagnostic work-up in molecular pathology. Nearly all assays for mutation detection involve an amplification step. A second single nucleotide variant (SNV) on the same allele adjacent to a mutational hotspot can interfere with primer binding, leading to unnoticed allele-specific amplification of the wild type allele and thereby false-negative mutation testing. We present two diagnostic cases with false negative sequence results for JAK2 and SRSF2. In both cases mutations would have escaped detection if only one strand of DNA had been analysed. Because many commercially available diagnostic kits rely on the analysis of only one DNA strand they are prone to fail in cases like these. Detailed protocols and quality control measures to prevent corresponding pitfalls are presented. Copyright © 2017. Published by Elsevier Inc.

Primary structural variation in anaplasma marginale Msp2 efficiently generates immune escape variants

USDA-ARS?s Scientific Manuscript database

Antigenic variation allows microbial pathogens to evade immune clearance and establish persistent infection. Anaplasma marginale utilizes gene conversion of a repertoire of silent msp2 alleles into a single active expression site to encode unique Msp2 variants. As the genomic complement of msp2 alle...

Investigation of rare and low-frequency variants using high-throughput sequencing with pooled DNA samples

PubMed Central

Wang, Jingwen; Skoog, Tiina; Einarsdottir, Elisabet; Kaartokallio, Tea; Laivuori, Hannele; Grauers, Anna; Gerdhem, Paul; Hytönen, Marjo; Lohi, Hannes; Kere, Juha; Jiao, Hong

2016-01-01

High-throughput sequencing using pooled DNA samples can facilitate genome-wide studies on rare and low-frequency variants in a large population. Some major questions concerning the pooling sequencing strategy are whether rare and low-frequency variants can be detected reliably, and whether estimated minor allele frequencies (MAFs) can represent the actual values obtained from individually genotyped samples. In this study, we evaluated MAF estimates using three variant detection tools with two sets of pooled whole exome sequencing (WES) and one set of pooled whole genome sequencing (WGS) data. Both GATK and Freebayes displayed high sensitivity, specificity and accuracy when detecting rare or low-frequency variants. For the WGS study, 56% of the low-frequency variants in Illumina array have identical MAFs and 26% have one allele difference between sequencing and individual genotyping data. The MAF estimates from WGS correlated well (r = 0.94) with those from Illumina arrays. The MAFs from the pooled WES data also showed high concordance (r = 0.88) with those from the individual genotyping data. In conclusion, the MAFs estimated from pooled DNA sequencing data reflect the MAFs in individually genotyped samples well. The pooling strategy can thus be a rapid and cost-effective approach for the initial screening in large-scale association studies. PMID:27633116

Effects of CYP2C19 Variants on Fluoxetine Metabolism in vitro.

PubMed

Fang, Ping; He, Jia-Yang; Han, Ai-Xia; Lan, Tian; Dai, Da-Peng; Cai, Jian-Ping; Hu, Guo-Xin

2017-01-01

CYP2C19 is an important member of the cytochrome P450 enzyme superfamily. We recently identified 31 CYP2C19 alleles in the Han Chinese population. The aim of this study was to assess the catalytic activities of these allelic isoforms and their effects on the metabolism of fluoxetine in vitro. The wild-type and 30 CYP2C19 variants were expressed in insect cells and each variant was characterized using fluoxetine as the substrate. Reactions were performed at 37°C with 20-1,000 µmol/L substrate for 30 min. By using ultra-high performance liquid chromatography-mass spectrometry to detect the products, the kinetic parameters Km, Vmax, and intrinsic clearance (Vmax/Km) of norfluoxetine were determined. Among the CYP2C19 variants tested, T130M showed similar intrinsic clearance (Vmax/Km) values with CYP2C19*1, while the intrinsic clearance values of other variants were significantly decreased (from 9.56 to 77.77%). In addition, CYP2C19*3 and *35FS could not be detected because they have no detectable enzyme activity. In China, the assessment of CYP2C19 variants in vitro offers valuable information relevant to the personalized medicine for CYP2C19-metabolized drug. © 2017 S. Karger AG, Basel.

CFTR-France, a national relational patient database for sharing genetic and phenotypic data associated with rare CFTR variants.

PubMed

Claustres, Mireille; Thèze, Corinne; des Georges, Marie; Baux, David; Girodon, Emmanuelle; Bienvenu, Thierry; Audrezet, Marie-Pierre; Dugueperoux, Ingrid; Férec, Claude; Lalau, Guy; Pagin, Adrien; Kitzis, Alain; Thoreau, Vincent; Gaston, Véronique; Bieth, Eric; Malinge, Marie-Claire; Reboul, Marie-Pierre; Fergelot, Patricia; Lemonnier, Lydie; Mekki, Chadia; Fanen, Pascale; Bergougnoux, Anne; Sasorith, Souphatta; Raynal, Caroline; Bareil, Corinne

2017-10-01

Most of the 2,000 variants identified in the CFTR (cystic fibrosis transmembrane regulator) gene are rare or private. Their interpretation is hampered by the lack of available data and resources, making patient care and genetic counseling challenging. We developed a patient-based database dedicated to the annotations of rare CFTR variants in the context of their cis- and trans-allelic combinations. Based on almost 30 years of experience of CFTR testing, CFTR-France (https://cftr.iurc.montp.inserm.fr/cftr) currently compiles 16,819 variant records from 4,615 individuals with cystic fibrosis (CF) or CFTR-RD (related disorders), fetuses with ultrasound bowel anomalies, newborns awaiting clinical diagnosis, and asymptomatic compound heterozygotes. For each of the 736 different variants reported in the database, patient characteristics and genetic information (other variations in cis or in trans) have been thoroughly checked by a dedicated curator. Combining updated clinical, epidemiological, in silico, or in vitro functional data helps to the interpretation of unclassified and the reassessment of misclassified variants. This comprehensive CFTR database is now an invaluable tool for diagnostic laboratories gathering information on rare variants, especially in the context of genetic counseling, prenatal and preimplantation genetic diagnosis. CFTR-France is thus highly complementary to the international database CFTR2 focused so far on the most common CF-causing alleles. © 2017 Wiley Periodicals, Inc.

Biology, Genetics, and Environment

PubMed Central

Wall, Tamara L.; Luczak, Susan E.; Hiller-Sturmhöfel, Susanne

2016-01-01

Gene variants encoding several of the alcohol-metabolizing enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), are among the largest genetic associations with risk for alcohol dependence. Certain genetic variants (i.e., alleles)—particularly the ADH1B*2, ADH1B*3, ADH1C*1, and ALDH2*2 alleles—have been associated with lower rates of alcohol dependence. These alleles may lead to an accumulation of acetaldehyde during alcohol metabolism, which can result in heightened subjective and objective effects. The prevalence of these alleles differs among ethnic groups; ADH1B*2 is found frequently in northeast Asians and occasionally Caucasians, ADH1B*3 is found predominantly in people of African ancestry, ADH1C*1 varies substantially across populations, and ALDH2*2 is found almost exclusively in northeast Asians. Differences in the prevalence of these alleles may account at least in part for ethnic differences in alcohol consumption and alcohol use disorder (AUD). However, these alleles do not act in isolation to influence the risk of AUD. For example, the gene effects of ALDH2*2 and ADH1B*2 seem to interact. Moreover, other factors have been found to influence the extent to which these alleles affect a person’s alcohol involvement, including developmental stage, individual characteristics (e.g., ethnicity, antisocial behavior, and behavioral undercontrol), and environmental factors (e.g., culture, religion, family environment, and childhood adversity). PMID:27163368

C9ORF72 G4C2-repeat expansion and frontotemporal dementia first reported case in Argentina.

PubMed

Fernández Suarez, M; Surace, Ezequiel; Harris, P; Tapajoz, F; Sevlever, G; Allegri, R; Russo, G N

2016-06-01

We present a female patient aged 51 who developed behavioral disorders followed by cognitive impairment over 3 years. Neuropsychological, neuropsychiatric, and radiological features suggested a probable behavioral variant of frontotemporal dementia (bvFTD). A family history of amyotrophic lateral sclerosis and parkinsonism suggested the hexanucleotide repeat expansion G4C2 in C9ORF72 . We set up a two-step genotyping algorithm for the detection of the expansion using fragment-length analysis polymerase chain reaction (PCR) and repeat-primed PCR with fluorescent primers. We confirmed the presence of an expanded G4C2 allele in the patient. This represents the first documented case of bvFTD due to a C9ORF72 expansion in Argentina.

Association of low-activity MAOA allelic variants with violent crime in incarcerated offenders

PubMed Central

Stetler, Dean A.; Davis, Chad; Leavitt, Kathryn; Schriger, Ilana; Benson, Katie; Bhakta, Samir; Wang, Lam Chee; Oben, Cynthia; Watters, Matthew; Haghnegahdar, Tara; Bortolato, Marco

2015-01-01

The main enzyme for serotonin degradation, monoamine oxidase (MAO) A, has recently emerged as a key biological factor in the predisposition to impulsive aggression. Male carriers of low-activity variants of the main functional polymorphism of the MAOA gene (MAOA-uVNTR) have been shown to exhibit a greater proclivity to engage in violent acts. Thus, we hypothesized that low-activity MAOA-uVNTR alleles may be associated with a higher risk for criminal violence among male offenders. To test this possibility, we analyzed the MAOA-uVNTR variants of violent (n=49) and non-violent (n=40) male Caucasian and African-American convicts in a correctional facility. All participants were also tested with the Childhood Trauma Questionnaire (CTQ), Barratt Impulsivity Scale (BIS-11) and Buss-Perry Aggression Questionnaire (BPAQ) to assess their levels of childhood trauma exposure, impulsivity and aggression, respectively. Our results revealed a robust (P<0.0001) association between low-activity MAOA-uVNTR alleles and violent crime. This association was replicated in the group of Caucasian violent offenders (P<0.01), but reached only a marginal trend (P=0.08) in their African American counterparts. While violent crime charges were not associated with CTQ, BIS-11 and BPAQ scores, carriers of low-activity alleles exhibited a mild, yet significant (P<0.05) increase in BIS-11 total and attentional-impulsiveness scores. In summary, these findings support the role of MAOA gene as a prominent genetic determinant for criminal violence. Further studies are required to confirm these results in larger samples of inmates and evaluate potential interactions between MAOA alleles and environmental vulnerability factors. PMID:25082653

Immunogenicity of Recombinant Proteins Consisting of Plasmodium vivax Circumsporozoite Protein Allelic Variant-Derived Epitopes Fused with Salmonella enterica Serovar Typhimurium Flagellin

PubMed Central

Leal, Monica Teixeira Andrade; Camacho, Ariane Guglielmi Ariza; Teixeira, Laís Helena; Bargieri, Daniel Youssef; Soares, Irene Silva; Tararam, Cibele Aparecida

2013-01-01

A Plasmodium falciparum circumsporozoite protein (CSP)-based recombinant fusion vaccine is the first malaria vaccine to reach phase III clinical trials. Resistance to infection correlated with the production of antibodies to the immunodominant central repeat region of the CSP. In contrast to P. falciparum, vaccine development against the CSP of Plasmodium vivax malaria is far behind. Based on this gap in our knowledge, we generated a recombinant chimeric protein containing the immunodominant central repeat regions of the P. vivax CSP fused to Salmonella enterica serovar Typhimurium-derived flagellin (FliC) to activate the innate immune system. The recombinant proteins that were generated contained repeat regions derived from each of the 3 different allelic variants of the P. vivax CSP or a fusion of regions derived from each of the 3 allelic forms. Mice were subcutaneously immunized with the fusion proteins alone or in combination with the Toll-like receptor 3 (TLR-3) agonist poly(I·C), and the anti-CSP serum IgG response was measured. Immunization with a mixture of the 3 recombinant proteins, each containing immunodominant epitopes derived from a single allelic variant, rather than a single recombinant protein carrying a fusion of regions derived from each of 3 allelic forms elicited a stronger immune response. This response was independent of TLR-4 but required TLR-5/MyD88 activation. Antibody titers significantly increased when poly(I·C) was used as an adjuvant with a mixture of the 3 recombinant proteins. These recombinant fusion proteins are novel candidates for the development of an effective malaria vaccine against P. vivax. PMID:23863502

TBX6 Null Variants and a Common Hypomorphic Allele in Congenital Scoliosis

PubMed Central

Wu, N.; Ming, X.; Xiao, J.; Wu, Z.; Chen, X.; Shinawi, M.; Shen, Y.; Yu, G.; Liu, J.; Xie, H.; Gucev, Z.S.; Liu, S.; Yang, N.; Al-Kateb, H.; Chen, J.; Zhang, Jian; Hauser, N.; Zhang, T.; Tasic, V.; Liu, P.; Su, X.; Pan, X.; Liu, C.; Wang, L.; Shen, Joseph; Shen, Jianxiong; Chen, Y.; Zhang, T.; Zhang, Jianguo; Choy, K.W.; Wang, Jun; Wang, Q.; Li, S.; Zhou, W.; Guo, J.; Wang, Y.; Zhang, C.; Zhao, H.; An, Y.; Zhao, Y.; Wang, Jiucun; Liu, Z.; Zuo, Y.; Tian, Y.; Weng, X.; Sutton, V.R.; Wang, H.; Ming, Y.; Kulkarni, S.; Zhong, T.P.; Giampietro, P.F.; Dunwoodie, S.L.; Cheung, S.W.; Zhang, X.; Jin, L.; Lupski, J.R.; Qiu, G.; Zhang, F.

2015-01-01

BACKGROUND Congenital scoliosis is a common type of vertebral malformation. Genetic susceptibility has been implicated in congenital scoliosis. METHODS We evaluated 161 Han Chinese persons with sporadic congenital scoliosis, 166 Han Chinese controls, and 2 pedigrees, family members of which had a 16p11.2 deletion, using comparative genomic hybridization, quantitative polymerase-chain-reaction analysis, and DNA sequencing. We carried out tests of replication using an additional series of 76 Han Chinese persons with congenital scoliosis and a multi-center series of 42 persons with 16p11.2 deletions. RESULTS We identified a total of 17 heterozygous TBX6 null mutations in the 161 persons with sporadic congenital scoliosis (11%); we did not observe any null mutations in TBX6 in 166 controls (P<3.8×10−6). These null alleles include copy-number variants (12 instances of a 16p11.2 deletion affecting TBX6) and single-nucleotide variants (1 nonsense and 4 frame-shift mutations). However, the discordant intrafamilial phenotypes of 16p11.2 deletion carriers suggest that heterozygous TBX6 null mutation is insufficient to cause congenital scoliosis. We went on to identify a common TBX6 haplotype as the second risk allele in all 17 carriers of TBX6 null mutations (P<1.1×10−6). Replication studies involving additional persons with congenital scoliosis who carried a deletion affecting TBX6 confirmed this compound inheritance model. In vitro functional assays suggested that the risk haplotype is a hypomorphic allele. Hemivertebrae are characteristic of TBX6-associated congenital scoliosis. CONCLUSIONS Compound inheritance of a rare null mutation and a hypomorphic allele of TBX6 accounted for up to 11% of congenital scoliosis cases in the series that we analyzed. PMID:25564734

A Caucasian JK*A/JK*B woman with Jk(a+b-) red blood cells, anti-Jkb, and a novel JK*B allele c.1038delG.

PubMed

Ramsey, Glenn; Sumugod, Ricardo D; Lindholm, Paul F; Zinni, Jules G; Keller, Jessica A; Horn, Trina; Keller, Margaret A

2016-09-01

The Kidd blood group on the red blood cell (RBC) glycoprotein urea transporter-B has a growing number of weak and null alleles in its gene SLC14A1 that are emerging from more widespread genotyping of blood donors and patients. We investigated a 64-year-old Caucasian woman of Polish-Czech descent who developed anti-Jkb detected in solid-phase RBC adherence testing within 12 days after 7 units of RBCs were transfused. Her RBCs subsequently typed Jk(a+b–) by licensed reagents and human antisera. Nevertheless, in RBC genotyping (BioArray HEA BeadChip, Immucor, Warren, NJ) performed in our transfusion service on all patients with alloantibodies, her Kidd typing was JK*A/JK*B based on the Jka/Jkb single nucleotide polymorphism in exon 9 (c.838G>A, p.Asp280Asn). Genomic analysis and cDNA sequencing of her JK*B allele revealed a novel single-nucleotide deletion of c.1038G in exon 11, predicting a frameshift and premature stop (p.Thr346Thrfs*5) after translation of nearly 90 percent of the expressed exons 4–11. This allele has been provisionally named JK*02N.14, subject to approval by the International Society of Blood Transfusion Working Party. The site of this variant is closer to the C-terminus than that of any allele associated with the Jk(a–b–) phenotype reported to date. Routine genotyping of patients with RBC alloantibodies can reveal variants posing potential risk of alloimmunization. Continuing investigation of Kidd variants may shed light on the structure of Kidd antigens and the function of urea transporter-B.

Association of low-activity MAOA allelic variants with violent crime in incarcerated offenders.

PubMed

Stetler, Dean A; Davis, Chad; Leavitt, Kathryn; Schriger, Ilana; Benson, Katie; Bhakta, Samir; Wang, Lam Chee; Oben, Cynthia; Watters, Matthew; Haghnegahdar, Tara; Bortolato, Marco

2014-11-01

The main enzyme for serotonin degradation, monoamine oxidase (MAO) A, has recently emerged as a key biological factor in the predisposition to impulsive aggression. Male carriers of low-activity variants of the main functional polymorphism of the MAOA gene (MAOA-uVNTR) have been shown to exhibit a greater proclivity to engage in violent acts. Thus, we hypothesized that low-activity MAOA-uVNTR alleles may be associated with a higher risk for criminal violence among male offenders. To test this possibility, we analyzed the MAOA-uVNTR variants of violent (n = 49) and non-violent (n = 40) male Caucasian and African-American convicts in a correctional facility. All participants were also tested with the Childhood Trauma Questionnaire (CTQ), Barratt Impulsivity Scale (BIS-11) and Buss-Perry Aggression Questionnaire (BPAQ) to assess their levels of childhood trauma exposure, impulsivity and aggression, respectively. Our results revealed a robust (P < 0.0001) association between low-activity MAOA-uVNTR alleles and violent crime. This association was replicated in the group of Caucasian violent offenders (P < 0.01), but reached only a marginal trend (P = 0.08) in their African American counterparts. While violent crime charges were not associated with CTQ, BIS-11 and BPAQ scores, carriers of low-activity alleles exhibited a mild, yet significant (P < 0.05) increase in BIS-11 total and attentional-impulsiveness scores. In summary, these findings support the role of MAOA gene as a prominent genetic determinant for criminal violence. Further studies are required to confirm these results in larger samples of inmates and evaluate potential interactions between MAOA alleles and environmental vulnerability factors. Copyright © 2014 Elsevier Ltd. All rights reserved.

Autoimmunity-Associated PTPN22 Polymorphisms in Latent Autoimmune Diabetes of the Adult Differ from Those of Type 1 Diabetes Patients.

PubMed

Heneberg, Petr; Kocková, Lucie; Čecháková, Marie; Daňková, Pavlína; Černá, Marie

2018-06-12

A portion of adults with humoral immune changes have clinical diabetes that is initially not insulin-requiring (latent autoimmune diabetes of the adult, LADA). One of the genes strongly associated with autoimmune diabetes is PTPN22. We hypothesized that the manifestation and clinical features of LADA are linked to functional variants of PTPN22. We genotyped allelic frequencies of 1 protective and 3 risk-associated PTPN22 variants in 156 Czech LADA patients, 194 type 2 diabetes mellitus patients with LADA-like progression to insulinotherapy and 324 type 1 diabetes mellitus patients, and subsequently examined the associations of PTPN22 variants with the expression of autoantibodies and other clinical features of LADA. We challenged the paradigm that stated that the PTPN22 c.1858T allele serves as a risk allele for LADA, although we confirmed its risk status in the geographically matched T1DM cohort. In contrast, the frequencies of other PTPN22 alleles (c.-1123C, c.788A and c.1970-852C) differed significantly from the healthy controls. We confirmed gender-related differences in the frequency of some PTPN22 polymorphisms (but not c.1858C>T) in LADA. The particular PTPN22 alleles and genotypes were associated with specific clinical features of the examined patients (autoantibodies, HbA1c and age at diagnosis of diabetes). The variability in PTPN22 haplotypes suggests that the genetic signature of LADA is independent and should not be considered a hybrid form of T1DM and T2DM. Further studies should elucidate the associations with clinical characteristics of the LADA patients and focus on the newly emerging types of diabetes with the disease onset in early to mid-adulthood. © 2018 S. Karger AG, Basel.

A population-specific uncommon variant in GRIN3A associated with schizophrenia.

PubMed

Takata, Atsushi; Iwayama, Yoshimi; Fukuo, Yasuhisa; Ikeda, Masashi; Okochi, Tomo; Maekawa, Motoko; Toyota, Tomoko; Yamada, Kazuo; Hattori, Eiji; Ohnishi, Tetsuo; Toyoshima, Manabu; Ujike, Hiroshi; Inada, Toshiya; Kunugi, Hiroshi; Ozaki, Norio; Nanko, Shinichiro; Nakamura, Kazuhiko; Mori, Norio; Kanba, Shigenobu; Iwata, Nakao; Kato, Tadafumi; Yoshikawa, Takeo

2013-03-15

Genome-wide association studies have successfully identified several common variants showing robust association with schizophrenia. However, individually, these variants only produce a weak effect. To identify genetic variants with larger effect sizes, increasing attention is now being paid to uncommon and rare variants. From the 1000 Genomes Project data, we selected 47 candidate single nucleotide variants (SNVs), which were: 1) uncommon (minor allele frequency < 5%); 2) Asian-specific; 3) missense, nonsense, or splice site variants predicted to be damaging; and 4) located in candidate genes for schizophrenia and bipolar disorder. We examined their association with schizophrenia, using a Japanese case-control cohort (2012 cases and 2781 control subjects). Additional meta-analysis was performed using genotyping data from independent Han-Chinese case-control (333 cases and 369 control subjects) and family samples (9 trios and 284 quads). We identified disease association of a missense variant in GRIN3A (p.R480G, rs149729514, p = .00042, odds ratio [OR] = 1.58), encoding a subunit of the N-methyl-D-aspartate type glutamate receptor, with study-wide significance (threshold p = .0012). This association was supported by meta-analysis (combined p = 3.3 × 10(-5), OR = 1.61). Nominally significant association was observed in missense variants from FAAH, DNMT1, MYO18B, and CFB, with ORs of risk alleles ranging from 1.41 to 2.35. The identified SNVs, particularly the GRIN3A R480G variant, are good candidates for further replication studies and functional evaluation. The results of this study indicate that association analyses focusing on uncommon and rare SNVs are a promising way to discover risk variants with larger effects. Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Genetic polymorphisms in Na+-taurocholate co-transporting polypeptide (NTCP) and ileal apical sodium-dependent bile acid transporter (ASBT) and ethnic comparisons of functional variants of NTCP among Asian populations.

PubMed

Pan, Wei; Song, Im-Sook; Shin, Ho-Jung; Kim, Min-Hye; Choi, Yeong-Lim; Lim, Su-Jeong; Kim, Woo-Young; Lee, Sang-Seop; Shin, Jae-Gook

2011-06-01

Genetic variants of Na(+)-taurocholate co-transporting polypeptide (NTCP; SLC10A1) and ileal apical sodium-dependent bile acid transporter (ASBT; SLC10A2), which greatly contribute to bile acid homeostasis, were extensively explored in the Korean population and functional variants of NTCP were compared among Asian populations. From direct DNA sequencing, six SNPs were identified in the SLC10A1 gene and 14 SNPs in the SLC10A2 gene. Three of seven coding variants were non-synonymous SNPs: two variants from SLC10A1 (A64T, S267F) and one from SLC10A2 (A171S). No linkage was analysed in the SLC10A1 gene because of low frequencies of genetic variants, and the SLC10A2 gene was composed of two separated linkage disequilibrium blocks contrary to the white population. The stably transfected NTCP-A64T variant showed significantly decreased uptakes of taurocholate and rosuvastatin compared with wild-type NTCP. The decreased taurocholate uptake and increased rosuvastatin uptake were shown in the NTCP-S267F variant. The allele frequencies of these functional variants were 1.0% and 3.1%, respectively, in a Korean population. However, NTCP-A64T was not found in Chinese and Vietnamese subjects. The frequency distribution of NTCP-S267F in Koreans was significantly lower than those in Chinese and Vietnamese populations. Our data suggest that NTCP-A64T and -S267F variants cause substrate-dependent functional change in vitro, and show ethnic difference in their allelic frequencies among Asian populations although the clinical relevance of these variants is remained to be evaluated.

Identification of Inherited Retinal Disease-Associated Genetic Variants in 11 Candidate Genes.

PubMed

Astuti, Galuh D N; van den Born, L Ingeborgh; Khan, M Imran; Hamel, Christian P; Bocquet, Béatrice; Manes, Gaël; Quinodoz, Mathieu; Ali, Manir; Toomes, Carmel; McKibbin, Martin; El-Asrag, Mohammed E; Haer-Wigman, Lonneke; Inglehearn, Chris F; Black, Graeme C M; Hoyng, Carel B; Cremers, Frans P M; Roosing, Susanne

2018-01-10

Inherited retinal diseases (IRDs) display an enormous genetic heterogeneity. Whole exome sequencing (WES) recently identified genes that were mutated in a small proportion of IRD cases. Consequently, finding a second case or family carrying pathogenic variants in the same candidate gene often is challenging. In this study, we searched for novel candidate IRD gene-associated variants in isolated IRD families, assessed their causality, and searched for novel genotype-phenotype correlations. Whole exome sequencing was performed in 11 probands affected with IRDs. Homozygosity mapping data was available for five cases. Variants with minor allele frequencies ≤ 0.5% in public databases were selected as candidate disease-causing variants. These variants were ranked based on their: (a) presence in a gene that was previously implicated in IRD; (b) minor allele frequency in the Exome Aggregation Consortium database (ExAC); (c) in silico pathogenicity assessment using the combined annotation dependent depletion (CADD) score; and (d) interaction of the corresponding protein with known IRD-associated proteins. Twelve unique variants were found in 11 different genes in 11 IRD probands. Novel autosomal recessive and dominant inheritance patterns were found for variants in Small Nuclear Ribonucleoprotein U5 Subunit 200 ( SNRNP200 ) and Zinc Finger Protein 513 ( ZNF513 ), respectively. Using our pathogenicity assessment, a variant in DEAH-Box Helicase 32 ( DHX32 ) was the top ranked novel candidate gene to be associated with IRDs, followed by eight medium and lower ranked candidate genes. The identification of candidate disease-associated sequence variants in 11 single families underscores the notion that the previously identified IRD-associated genes collectively carry > 90% of the defects implicated in IRDs. To identify multiple patients or families with variants in the same gene and thereby provide extra proof for pathogenicity, worldwide data sharing is needed.

Recent Mitochondrial DNA Mutations Increase the Risk of Developing Common Late-Onset Human Diseases

PubMed Central

Hudson, Gavin; Gomez-Duran, Aurora; Wilson, Ian J.; Chinnery, Patrick F.

2014-01-01

Mitochondrial DNA (mtDNA) is highly polymorphic at the population level, and specific mtDNA variants affect mitochondrial function. With emerging evidence that mitochondrial mechanisms are central to common human diseases, it is plausible that mtDNA variants contribute to the “missing heritability” of several complex traits. Given the central role of mtDNA genes in oxidative phosphorylation, the same genetic variants would be expected to alter the risk of developing several different disorders, but this has not been shown to date. Here we studied 38,638 individuals with 11 major diseases, and 17,483 healthy controls. Imputing missing variants from 7,729 complete mitochondrial genomes, we captured 40.41% of European mtDNA variation. We show that mtDNA variants modifying the risk of developing one disease also modify the risk of developing other diseases, thus providing independent replication of a disease association in different case and control cohorts. High-risk alleles were more common than protective alleles, indicating that mtDNA is not at equilibrium in the human population, and that recent mutations interact with nuclear loci to modify the risk of developing multiple common diseases. PMID:24852434

A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans

PubMed Central

Timpson, Nicholas J.; Walter, Klaudia; Min, Josine L.; Tachmazidou, Ioanna; Malerba, Giovanni; Shin, So-Youn; Chen, Lu; Futema, Marta; Southam, Lorraine; Iotchkova, Valentina; Cocca, Massimiliano; Huang, Jie; Memari, Yasin; McCarthy, Shane; Danecek, Petr; Muddyman, Dawn; Mangino, Massimo; Menni, Cristina; Perry, John R. B.; Ring, Susan M.; Gaye, Amadou; Dedoussis, George; Farmaki, Aliki-Eleni; Burton, Paul; Talmud, Philippa J.; Gambaro, Giovanni; Spector, Tim D.; Smith, George Davey; Durbin, Richard; Richards, J Brent; Humphries, Steve E.; Zeggini, Eleftheria; Soranzo, Nicole; Al Turki, Saeed; Anderson, Carl; Anney, Richard; Antony, Dinu; Soler Artigas, Maria; Ayub, Muhammad; Balasubramaniam, Senduran; Barrett, Jeffrey C.; Barroso, Inês; Beales, Phil; Bentham, Jamie; Bhattacharya, Shoumo; Birney, Ewan; Blackwood, Douglas; Bobrow, Martin; Bochukova, Elena; Bolton, Patrick; Bounds, Rebecca; Boustred, Chris; Breen, Gerome; Calissano, Mattia; Carss, Keren; Chatterjee, Krishna; Chen, Lu; Ciampi, Antonio; Cirak, Sebhattin; Clapham, Peter; Clement, Gail; Coates, Guy; Collier, David; Cosgrove, Catherine; Cox, Tony; Craddock, Nick; Crooks, Lucy; Curran, Sarah; Curtis, David; Daly, Allan; Danecek, Petr; Davey Smith, George; Day-Williams, Aaron; Day, Ian N. M.; Down, Thomas; Du, Yuanping; Dunham, Ian; Durbin, Richard; Edkins, Sarah; Ellis, Peter; Evans, David; Faroogi, Sadaf; Fatemifar, Ghazaleh; Fitzpatrick, David R.; Flicek, Paul; Flyod, James; Foley, A Reghan; Franklin, Christopher S; Futema, Marta; Gallagher, Louise; Gaunt, Tom; Geihs, Matthias; Geschwind, Daniel; Greenwood, Celia; Griffin, Heather; Grozeva, Detelina; Guo, Xueqin; Guo, Xiaosen; Gurling, Hugh; Hart, Deborah; Hendricks, Audrey; Holmans, Peter; Howie, Bryan; Huang, Jie; Huang, Liren; Hubbard, Tim; Humphries, Steve E.; Hurles, Matthew E.; Hysi, Pirro; Jackson, David K.; Jamshidi, Yalda; Jing, Tian; Joyce, Chris; Kaye, Jane; Keane, Thomas; Keogh, Julia; Kemp, John; Kennedy, Karen; Kolb-Kokocinski, Anja; Lachance, Genevieve; Langford, Cordelia; Lawson, Daniel; Lee, Irene; Lek, Monkol; Liang, Jieqin; Lin, Hong; Li, Rui; Li, Yingrui; Liu, Ryan; Lönnqvist, Jouko; Lopes, Margarida; Lotchkova, Valentina; MacArthur, Daniel; Marchini, Jonathan; Maslen, John; Massimo, Mangino; Mathieson, Iain; Marenne, Gaëlle; McCarthy, Shane; McGuffin, Peter; McIntosh, Andrew; McKechanie, Andrew G.; McQuillin, Andrew; Memari, Yasin; Metrustry, Sarah; Min, Josine; Mitchison, Hannah; Moayyeri, Alireza; Morris, James; Muddyman, Dawn; Muntoni, Francesco; Northstone, Kate; O'Donnovan, Michael; Onoufriadis, Alexandros; O'Rahilly, Stephen; Oualkacha, Karim; Owen, Michael J.; Palotie, Aarno; Panoutsopoulou, Kalliope; Parker, Victoria; Parr, Jeremy R.; Paternoster, Lavinia; Paunio, Tiina; Payne, Felicity; Perry, John; Pietilainen, Olli; Plagnol, Vincent; Quaye, Lydia; Quail, Michael A.; Raymond, Lucy; Rehnström, Karola; Richards, Brent; Ring, Susan; Ritchie, Graham R. S.; Roberts, Nicola; Savage, David B.; Scambler, Peter; Schiffels, Stephen; Schmidts, Miriam; Schoenmakers, Nadia; Semple, Robert K.; Serra, Eva; Sharp, Sally I.; Shihab, Hasheem; Shin, So-Youn; Skuse, David; Small, Kerrin; Soranzo, Nicole; Southam, Lorraine; Spasic-Boskovic, Olivera; Spector, Tim; St Clair, David; Stalker, Jim; Stevens, Elizabeth; St Pourcian, Beate; Sun, Jianping; Surdulescu, Gabriela; Suvisaari, Jaana; Tachmazidou, Ionna; Timpson, Nicholas; Tobin, Martin D.; Valdes, Ana; Van Kogelenberg, Margriet; Vijayarangakannan, Parthiban; Visscher, Peter M.; Wain, Louise V.; Walter, Klaudia; Walters, James T. R.; Wang, Guangbiao; Wang, Jun; Wang, Yu; Ward, Kirsten; Wheeler, Elanor; Whyte, Tamieka; Williams, Hywel; Williamson, Kathleen A.; Wilson, Crispian; Wilson, Scott G.; Wong, Kim; Xu, ChangJiang; Yang, Jian; Zeggini, Eleftheria; Zhang, Fend; Zhang, Pingbo; Zheng, Hou-Feng

2014-01-01

The analysis of rich catalogues of genetic variation from population-based sequencing provides an opportunity to screen for functional effects. Here we report a rare variant in APOC3 (rs138326449-A, minor allele frequency ~0.25% (UK)) associated with plasma triglyceride (TG) levels (−1.43 s.d. (s.e.=0.27 per minor allele (P-value=8.0 × 10−8)) discovered in 3,202 individuals with low read-depth, whole-genome sequence. We replicate this in 12,831 participants from five additional samples of Northern and Southern European origin (−1.0 s.d. (s.e.=0.173), P-value=7.32 × 10−9). This is consistent with an effect between 0.5 and 1.5 mmol l−1 dependent on population. We show that a single predicted splice donor variant is responsible for association signals and is independent of known common variants. Analyses suggest an independent relationship between rs138326449 and high-density lipoprotein (HDL) levels. This represents one of the first examples of a rare, large effect variant identified from whole-genome sequencing at a population scale. PMID:25225788

A Functional ATG16L1 (T300A) Variant is Associated with Necrotizing Enterocolitis in Premature Infants

PubMed Central

Sampath, Venkatesh; Bhandari, Vineet; Berger, Jessica; Merchant, Daniel; Zhang, Liyun; Ladd, Mihoko; Menden, Heather; Garland, Jeffery; Ambalavanan, Namasivayam; Mulrooney, Neil; Quasney, Michael; Dagle, John; Lavoie, Pascal M; Simpson, Pippa; Dahmer, Mary

2017-01-01

Background The genetic basis of dysfunctional immune responses in necrotizing enterocolitis (NEC) remains unknown. We hypothesized that variants in Nucleotide binding and Oligomerization Domain (NOD)-Like Receptors (NLRs) and Autophagy (ATG) genes modulate vulnerability to NEC. Methods We genotyped a multi-center cohort of premature infants with and without NEC for NOD1, NOD2, ATG16L1, CARD8 and NLRP3 variants. Chi-square tests and logistic regression were used for statistical analysis. Results In our primary cohort (n=1015), 86 (8.5%) infants developed NEC. The A allele of the ATG16L1 (Thr300Ala) variant was associated with increased NEC (AA vs. AG vs. GG; 11.3% vs. 8.4% vs. 4.8%, p=0.009). In regression models for NEC that adjusted for epidemiological confounders, GA (p=0.033) and the AA genotype (p=0.038) of ATG16L1 variant were associated with NEC. The association between the A allele of the ATG16L1 variant and NEC remained significant among Caucasian infants (p=0.02). In a replication cohort (n=259), NEC rates were highest among infants with the AA genotype but did not reach statistical significance. Conclusion We report a novel association between a hypomorphic variant in an autophagy gene (ATG16L1) and NEC in premature infants. Our data suggest that decreased autophagy arising from genetic variants may confer protection against NEC. PMID:27893720

Evolution of Fitness Cost-Neutral Mutant PfCRT Conferring P. falciparum 4-Aminoquinoline Drug Resistance Is Accompanied by Altered Parasite Metabolism and Digestive Vacuole Physiology

PubMed Central

Gabryszewski, Stanislaw J.; Dhingra, Satish K.; Lewis, Ian A.; Callaghan, Paul S.; Hassett, Matthew R.; Siriwardana, Amila; Henrich, Philipp P.; Lee, Andrew H.; Gnädig, Nina F.; Musset, Lise; Llinás, Manuel; Egan, Timothy J.; Roepe, Paul D.

2016-01-01

Southeast Asia is an epicenter of multidrug-resistant Plasmodium falciparum strains. Selective pressures on the subcontinent have recurrently produced several allelic variants of parasite drug resistance genes, including the P. falciparum chloroquine resistance transporter (pfcrt). Despite significant reductions in the deployment of the 4-aminoquinoline drug chloroquine (CQ), which selected for the mutant pfcrt alleles that halted CQ efficacy decades ago, the parasite pfcrt locus is continuously evolving. This is highlighted by the presence of a highly mutated allele, Cam734 pfcrt, which has acquired the singular ability to confer parasite CQ resistance without an associated fitness cost. Here, we used pfcrt-specific zinc-finger nucleases to genetically dissect this allele in the pathogenic setting of asexual blood-stage infection. Comparative analysis of drug resistance and growth profiles of recombinant parasites that express Cam734 or variants thereof, Dd2 (the most common Southeast Asian variant), or wild-type pfcrt, revealed previously unknown roles for PfCRT mutations in modulating parasite susceptibility to multiple antimalarial agents. These results were generated in the GC03 strain, used in multiple earlier pfcrt studies, and might differ in natural isolates harboring this allele. Results presented herein show that Cam734-mediated CQ resistance is dependent on the rare A144F mutation that has not been observed beyond Southeast Asia, and reveal distinct impacts of this and other Cam734-specific mutations on CQ resistance and parasite growth rates. Biochemical assays revealed a broad impact of mutant PfCRT isoforms on parasite metabolism, including nucleoside triphosphate levels, hemoglobin catabolism and disposition of heme, as well as digestive vacuole volume and pH. Results from our study provide new insights into the complex molecular basis and physiological impact of PfCRT-mediated antimalarial drug resistance, and inform ongoing efforts to characterize novel pfcrt alleles that can undermine the efficacy of first-line antimalarial drug regimens. PMID:27832198

The serotonin transporter (5-HTTLPR) but not serotonin receptor (5-HT2C Cys23Ser) variant is associated with bipolar I disorder in Kurdish population from Western Iran.

PubMed

Mohammadi, Sahar; Khazaie, Habibolah; Rahimi, Ziba; Vaisi-Raygani, Asad; Zargooshi, Newsha; Rahimi, Zohreh

2015-03-17

The role of 5-HTTLPR and 5-HT2C Cys23Ser polymorphisms in the psychopathology of mood disorders and suicide behavior is controversial. The aim of present study was to investigate the association between 5-HTTLPR and 5-HT2C Cys23Ser variants and susceptibility to bipolar I disorder (BID). The 5-HT2C genotypes were studied in 152 patients with BID and 173 gender- and age-matched healthy individuals with Kurds ethnic background from Western Iran using PCR and PCR-RFLP methods. In recessive model (SS vs. LL+LS) the SS genotype was associated with 1.79-fold increased risk of BID (p=0.018). Also, the presence of S allele increased the risk of adult-onset BID by 1.76-fold (p=0.027). No association was detected between 5-HTTLPR genotypes and alleles with suicide attempt. The frequency of 5-HT2C Ser allele in patients and controls were 12.3 and 12.5%, respectively. Mutant allele of HT2C Ser had higher frequency in female (14.7%) than male (10.5%, p=0.27) patients. The frequency of HT2C Ser allele in patients with a family history of BID tended to be higher (15.7%) than those without a family history of the disease (11.8%). The frequency of HT2C Ser allele in suicide attempter women was higher (16.7%) than those without a suicide attempt (14.3%). Our findings demonstrate 5-HTTLPR polymorphism might be a risk factor for BID and adult-onset BID in Kurds population. However, we found the lack of an association between 5-HT2C Cys/Ser variants and the risk of BID. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

The Association of SNP276G>T at Adiponectin Gene with Insulin Resistance and Circulating Adiponectin in Morbid Obese Patients After a Biliopancreatic Diversion Surgery.

PubMed

de Luis, Daniel Antonio; Pacheco, David; Primo, D; Izaola, Olatz; Aller, R

2017-12-01

The effects of rs1501299 variant of ADIPO gene on weight loss after bariatric surgery have not been evaluated. We decided to investigate the role of this genetic variant on anthropometric and biochemical outcomes such as serum adiponectin levels after biliopancreatic diversion (BPD) surgery in morbidly obese patients during 3 years. A sample of 64 patients with morbid obesity without diabetes mellitus was operated. Biochemical and anthropometric evaluation were realized at basal visit and at each visit during 3 years (1, 2, and 3 years). Percent excess weight loss, body mass index, weight, waist circumference, fat mass, blood pressure, fasting glucose, LDL cholesterol, total cholesterol, and triglycerides levels improved in both genotype groups. Fasting insulin levels and HOMA-IR decreased significantly only in non-T allele carriers. The decrease of fasting insulin levels at 3 years (delta -9.2 ± 3.4 vs -2.9 ± 2.2 mUI/L; p = 0.01) and HOMA-IR (delta -1.3 ± 0.3 vs -0.8 ± 0.4 units; p = 0.03) were higher in non-T allele carriers than T carriers. Adiponectin levels increased in all times after surgery in non-T allele carriers, too. The increase of adiponectin levels at 3 years (delta 12.2 ± 3.6 vs 1.8 ± 1.2 ng/mL; p = 0.01) was higher in non-T allele carriers than T carriers. Non-T allele of ADIPOQ gene variant (rs1501299) is associated with increases in adiponectin levels and better improvements of insulin and HOMA-IR after BPD massive weight loss. These parameters remained unchanged in T allele carriers.

APOE E4 status predicts age-related cognitive decline in the ninth decade: longitudinal follow-up of the Lothian Birth Cohort 1921.

PubMed

Schiepers, O J G; Harris, S E; Gow, A J; Pattie, A; Brett, C E; Starr, J M; Deary, I J

2012-03-01

Carriers of the APOE E4 allele have an increased risk of developing Alzheimer's disease. However, it is less clear whether APOE E4 status may also be involved in non-pathological cognitive ageing. The present study investigated the associations between APOE genotypes and cognitive change over 8 years in older community-dwelling individuals. APOE genotype was determined in 501 participants of the Lothian Birth Cohort 1921, whose intelligence had been measured in childhood in the Scottish Mental Survey 1932. A polymorphic variant of TOMM40 (rs10524523) was included to differentiate between the effects of the APOE E3 and E4 allelic variants. Cognitive performance on the domains of verbal memory, abstract reasoning and verbal fluency was assessed at mean age 79 years (n=501), and again at mean ages of 83 (n=284) and 87 (n=187). Using linear mixed models adjusted for demographic variables, vascular risk factors and IQ at age 11 years, possession of the APOE E4 allele was associated with a higher relative rate of cognitive decline over the subsequent 8 years for verbal memory and abstract reasoning. Individuals with the long allelic variant of TOMM40, which is linked to APOE E4, showed similar results. Verbal fluency was not affected by APOE E4 status. APOE E2 status was not associated with change in cognitive performance over 8 years. In non-demented older individuals, possession of the APOE E4 allele predicted a higher rate of cognitive decline on tests of verbal memory and abstract reasoning between 79 and 87 years. Thus, possession of the APOE E4 allele may not only predispose to Alzheimer's disease, but also appears to be a risk factor for non-pathological decline in verbal memory and abstract reasoning in the ninth decade of life.

Association Between Low-Density Lipoprotein Cholesterol-Lowering Genetic Variants and Risk of Type 2 Diabetes: A Meta-analysis.

PubMed

Lotta, Luca A; Sharp, Stephen J; Burgess, Stephen; Perry, John R B; Stewart, Isobel D; Willems, Sara M; Luan, Jian'an; Ardanaz, Eva; Arriola, Larraitz; Balkau, Beverley; Boeing, Heiner; Deloukas, Panos; Forouhi, Nita G; Franks, Paul W; Grioni, Sara; Kaaks, Rudolf; Key, Timothy J; Navarro, Carmen; Nilsson, Peter M; Overvad, Kim; Palli, Domenico; Panico, Salvatore; Quirós, Jose-Ramón; Riboli, Elio; Rolandsson, Olov; Sacerdote, Carlotta; Salamanca, Elena C; Slimani, Nadia; Spijkerman, Annemieke Mw; Tjonneland, Anne; Tumino, Rosario; van der A, Daphne L; van der Schouw, Yvonne T; McCarthy, Mark I; Barroso, Inês; O'Rahilly, Stephen; Savage, David B; Sattar, Naveed; Langenberg, Claudia; Scott, Robert A; Wareham, Nicholas J

2016-10-04

Low-density lipoprotein cholesterol (LDL-C)-lowering alleles in or near NPC1L1 or HMGCR, encoding the respective molecular targets of ezetimibe and statins, have previously been used as proxies to study the efficacy of these lipid-lowering drugs. Alleles near HMGCR are associated with a higher risk of type 2 diabetes, similar to the increased incidence of new-onset diabetes associated with statin treatment in randomized clinical trials. It is unknown whether alleles near NPC1L1 are associated with the risk of type 2 diabetes. To investigate whether LDL-C-lowering alleles in or near NPC1L1 and other genes encoding current or prospective molecular targets of lipid-lowering therapy (ie, HMGCR, PCSK9, ABCG5/G8, LDLR) are associated with the risk of type 2 diabetes. The associations with type 2 diabetes and coronary artery disease of LDL-C-lowering genetic variants were investigated in meta-analyses of genetic association studies. Meta-analyses included 50 775 individuals with type 2 diabetes and 270 269 controls and 60 801 individuals with coronary artery disease and 123 504 controls. Data collection took place in Europe and the United States between 1991 and 2016. Low-density lipoprotein cholesterol-lowering alleles in or near NPC1L1, HMGCR, PCSK9, ABCG5/G8, and LDLR. Odds ratios (ORs) for type 2 diabetes and coronary artery disease. Low-density lipoprotein cholesterol-lowering genetic variants at NPC1L1 were inversely associated with coronary artery disease (OR for a genetically predicted 1-mmol/L [38.7-mg/dL] reduction in LDL-C of 0.61 [95% CI, 0.42-0.88]; P = .008) and directly associated with type 2 diabetes (OR for a genetically predicted 1-mmol/L reduction in LDL-C of 2.42 [95% CI, 1.70-3.43]; P < .001). For PCSK9 genetic variants, the OR for type 2 diabetes per 1-mmol/L genetically predicted reduction in LDL-C was 1.19 (95% CI, 1.02-1.38; P = .03). For a given reduction in LDL-C, genetic variants were associated with a similar reduction in coronary artery disease risk (I2 = 0% for heterogeneity in genetic associations; P = .93). However, associations with type 2 diabetes were heterogeneous (I2 = 77.2%; P = .002), indicating gene-specific associations with metabolic risk of LDL-C-lowering alleles. In this meta-analysis, exposure to LDL-C-lowering genetic variants in or near NPC1L1 and other genes was associated with a higher risk of type 2 diabetes. These data provide insights into potential adverse effects of LDL-C-lowering therapy.

Lower frequency of TLR9 variant associated with protection from breast cancer among African Americans

PubMed Central

Tuomela, Johanna M.; Forero-Torres, Andres; Desmond, Renee; Vuopala, Katri S.; Harris, Kevin W.; Merner, Nancy D.

2017-01-01

Introduction Toll-like receptor 9 (TLR9) is an innate immune system DNA-receptor that regulates tumor invasion and immunity in vitro. Low tumor TLR9 expression has been associated with poor survival in Caucasian patients with triple negative breast cancer (TNBC). African American (AA) patients with TNBC have worse prognosis than Caucasians but whether this is due to differences in tumor biology remains controversial. We studied the prognostic significance of tumor Toll like receptor-9 (TLR9) protein expression among African American (AA) triple negative breast cancer (TNBC) patients. Germline TLR9 variants in European Americans (EAs) and AAs were investigated, to determine their contribution to AA breast cancer risk. Methods TLR9 expression was studied with immunohistochemistry in archival tumors. Exome Variant Server and The Cancer Genome Atlas were used to determine the genetic variation in the general EA and AA populations, and AA breast cancer cases. Minor allele frequencies (MAFs) were compared between EAs (n = 4300), AAs (n = 2203), and/or AA breast cancer cases (n = 131). Results Thirty-two TLR9 variants had a statistically significant MAF difference between general EAs and AAs. Twenty-one of them affect a CpG site. Rs352140, a variant previously associated with protection from breast cancer, is more common in EAs than AAs (p = 2.20E-16). EAs had more synonymous alleles, while AAs had more rare coding alleles. Similar analyses comparing AA breast cancer cases with AA controls did not reveal any variant class differences; however, three previously unreported TLR9 variants were associated with late onset breast cancer. Although not statistically significant, rs352140 was observed less frequently in AA cases compared to controls. Tumor TLR9 protein expression was not associated with prognosis. Conclusions Tumor TLR9 expression is not associated with prognosis in AA TNBC. Significant differences were detected in TLR9 variant MAFs between EAs and AAs. They may affect TLR9 expression and function. Rs352140, which may protect from breast cancer, is 1.6 X more common among EAs. These findings call for a detailed analysis of the contribution of TLR9 to breast cancer pathophysiology and health disparities. PMID:28886076

Lower frequency of TLR9 variant associated with protection from breast cancer among African Americans.

PubMed

Chandler, Madison R; Keene, Kimberly S; Tuomela, Johanna M; Forero-Torres, Andres; Desmond, Renee; Vuopala, Katri S; Harris, Kevin W; Merner, Nancy D; Selander, Katri S

2017-01-01

Toll-like receptor 9 (TLR9) is an innate immune system DNA-receptor that regulates tumor invasion and immunity in vitro. Low tumor TLR9 expression has been associated with poor survival in Caucasian patients with triple negative breast cancer (TNBC). African American (AA) patients with TNBC have worse prognosis than Caucasians but whether this is due to differences in tumor biology remains controversial. We studied the prognostic significance of tumor Toll like receptor-9 (TLR9) protein expression among African American (AA) triple negative breast cancer (TNBC) patients. Germline TLR9 variants in European Americans (EAs) and AAs were investigated, to determine their contribution to AA breast cancer risk. TLR9 expression was studied with immunohistochemistry in archival tumors. Exome Variant Server and The Cancer Genome Atlas were used to determine the genetic variation in the general EA and AA populations, and AA breast cancer cases. Minor allele frequencies (MAFs) were compared between EAs (n = 4300), AAs (n = 2203), and/or AA breast cancer cases (n = 131). Thirty-two TLR9 variants had a statistically significant MAF difference between general EAs and AAs. Twenty-one of them affect a CpG site. Rs352140, a variant previously associated with protection from breast cancer, is more common in EAs than AAs (p = 2.20E-16). EAs had more synonymous alleles, while AAs had more rare coding alleles. Similar analyses comparing AA breast cancer cases with AA controls did not reveal any variant class differences; however, three previously unreported TLR9 variants were associated with late onset breast cancer. Although not statistically significant, rs352140 was observed less frequently in AA cases compared to controls. Tumor TLR9 protein expression was not associated with prognosis. Tumor TLR9 expression is not associated with prognosis in AA TNBC. Significant differences were detected in TLR9 variant MAFs between EAs and AAs. They may affect TLR9 expression and function. Rs352140, which may protect from breast cancer, is 1.6 X more common among EAs. These findings call for a detailed analysis of the contribution of TLR9 to breast cancer pathophysiology and health disparities.

Oxytocin receptor gene polymorphisms, attachment, and PTSD: Results from the National Health and Resilience in Veterans Study.

PubMed

Sippel, Lauren M; Han, Shizhong; Watkins, Laura E; Harpaz-Rotem, Ilan; Southwick, Steven M; Krystal, John H; Olff, Miranda; Sherva, Richard; Farrer, Lindsay A; Kranzler, Henry R; Gelernter, Joel; Pietrzak, Robert H

2017-11-01

The human oxytocin system is implicated in social behavior and stress recovery. Polymorphisms in the oxytocin receptor gene (OXTR) may interact with attachment style to predict stress-related psychopathology like posttraumatic stress disorder (PTSD). The objective of this study was to examine independent and interactive effects of the OXTR single nucleotide polymorphism (SNP) rs53576, which has been associated with stress reactivity, support-seeking, and PTSD in prior studies, and attachment style on risk for PTSD in a nationally representative sample of 2163 European-American (EA) U.S. military veterans who participated in two independent waves of the National Health and Resilience in Veterans Study (NHRVS). Results revealed that insecure attachment style [adjusted odds ratio (OR) = 4.29; p < 0.001] and the interaction of rs53576 and attachment style (OR = 2.58, p = 0.02) were associated with probable lifetime PTSD. Among individuals with the minor A allele, the prevalence of probable PTSD was significantly higher among those with an insecure attachment style (23.9%) than those with a secure attachment style (2.0%), equivalent to an adjusted OR of 10.7. We attempted to replicate these findings by utilizing dense marker data from a genome-wide association study of 2215 high-risk civilians; one OXTR variant, though not rs53576, was associated with PTSD. Exploratory analyses in the veteran sample revealed that the interaction between this variant and attachment style predicting probable PTSD approached statistical significance. Results indicate that polymorphisms in the OXTR gene and attachment style may contribute to vulnerability to PTSD in U.S. military veterans. Published by Elsevier Ltd.

Frequency of 3' VNTR Polymorphism in the Dopamine Transporter Gene SLC6A3 in Humans Predisposed to Antisocial Behavior.

PubMed

Cherepkova, E V; Aftanas, L I; Maksimov, N; Menshanov, P N

2016-11-01

Predisposition to antisocial behavior can be related to the presence of certain polymorphic variants of genes encoding dopaminergic system proteins. We studied the frequencies of allele variants and genotypes of variable number tandem repeat polymorphism in 3' untranslated region (3' VTNR) of the dopaminergic transporter SLC6A3 gene in Caucasian men committed socially dangerous violent and non-violent crimes. Alleles with 9 and 10 repeats were most frequent in both the control group and group of men predisposed to antisocial behavior. At the same time, the 10/10 genotype was more frequently observed in the group of men prone to antisocial non-violent behavior. Hence, the presence of certain variants of 3' VTNR polymorphism of SLC6A3 gene in men is associated with predisposition to certain forms of antisocial behavior.

Strong linkage disequilibrium of a HbE variant with the (AT)9(T)5 repeat in the BP1 binding site upstream of the beta-globin gene in the Thai population.

PubMed

Ohashi, Jun; Naka, Izumi; Patarapotikul, Jintana; Hananantachai, Hathairad; Brittenham, Gary; Looareesuwan, Sornchai; Clark, Andrew G; Tokunaga, Katsushi

2005-01-01

A binding site for the repressor protein BP1, which contains a tandem (AT)x(T)y repeat, is located approximately 530 bp 5' to the human beta-globin gene (HBB). There is accumulating evidence that BP1 binds to the (AT)9(T)5 allele more strongly than to other alleles, thereby reducing the expression of HBB. In this study, we investigated polymorphisms in the (AT)x(T)y repeat in 57 individuals living in Thailand, including three homozygotes for the hemoglobin E variant (HbE; beta26Glu-->Lys), 22 heterozygotes, and 32 normal homozygotes. We found that (AT)9(T)5 and (AT)7(T)7 alleles were predominant in the studied population and that the HbE variant is in strong linkage disequilibrium with the (AT)9(T)5 allele, which can explain why the betaE chain is inefficiently synthesized compared to the normal betaA chain. Moreover, the mildness of the HbE disease compared to other hemoglobinopathies in Thai may be due, in part, to the presence of the (AT)9(T)5 repeat on the HbE chromosome. In addition, a novel (AC)n polymorphism adjacent to the (AT)x(T)y repeat (i.e., (AC)3(AT)7(T)5) was found through the variation screening in this study.

Impact of EZH2 polymorphisms on urothelial cell carcinoma susceptibility and clinicopathologic features.

PubMed

Yu, Yung-Luen; Su, Kuo-Jung; Hsieh, Ming-Ju; Wang, Shian-Shiang; Wang, Po-Hui; Weng, Wei-Chun; Yang, Shun-Fa

2014-01-01

The gene EZH2, the polycomb group protein enhancer of zeste 2, encodes a transcriptional repressor that also serves as a histone methyltransferase that is associated with progression to more advanced disease in a variety of malignancies. EZH2 expression level in urothelial cell carcinoma (UCC) is highly correlated with tumor aggressiveness, but it has not been determined if specific EZH2 genetic variants are associated with UCC risk. This study investigated the potential associations of EZH2 single-nucleotide polymorphisms with UCC susceptibility and its clinicopathologic characteristics. A total of 233 UCC patients and 552 cancer-free controls, all of whom were from Taiwan, were analyzed for four EZH2 single-nucleotide polymorphisms (rs6950683, rs2302427, rs3757441, and rs41277434) using real-time PCR genotyping. After adjusting for other co-variants, we found that individuals carrying at least one C allele at EZH2 rs6950683 had a lower risk of developing UCC than did major allele carriers. The CCCA or TGTA haplotype among the four EZH2 sites was also associated with a reduced risk of UCC. Furthermore, UCC patients who carried at least one G allele at rs2302427 had a lower invasive tumor stage than did patients carrying the major allele. The rs6950683 SNPs of EZH2 might contribute to the prediction of UCC susceptibility. This is the first study to provide insight into risk factors associated with EZH2 variants in carcinogenesis of UCC in Taiwan.

Promoter Variation and Expression Levels of Inflammatory Genes IL1A, IL1B, IL6 and TNF in Blood of Spinocerebellar Ataxia Type 3 (SCA3) Patients.

PubMed

Raposo, Mafalda; Bettencourt, Conceição; Ramos, Amanda; Kazachkova, Nadiya; Vasconcelos, João; Kay, Teresa; Bruges-Armas, Jácome; Lima, Manuela

2017-03-01

Age at onset in spinocerebellar ataxia type 3 (SCA3/MJD) is incompletely explained by the size of the CAG tract at the ATXN3 gene, implying the existence of genetic modifiers. A role of inflammation in SCA3 has been postulated, involving altered cytokines levels; promoter variants leading to alterations in cytokines expression could influence onset. Using blood from 86 SCA3 patients and 106 controls, this work aimed to analyse promoter variation of four cytokines (IL1A, IL1B, IL6 and TNF) and to investigate the association between variants detected and their transcript levels, evaluated by quantitative PCR. Moreover, the effect of APOE isoforms, known to modulate cytokines, was investigated. Correlations between cytokine variants and onset were tested; the cumulative modifier effects of cytokines and APOE were analysed. Patients carrying the IL6*C allele had a significant earlier onset (4 years in average) than patients carrying the G allele, in agreement with lower mRNA levels produced by IL6*C carriers. The presence of APOE*ɛ2 allele seems to anticipate onset in average 10 years in patients carrying the IL6*C allele; a larger number of patients will be needed to confirm this result. These results highlight the pertinence of conducting further research on the role of cytokines as SCA3 modulators, pointing to the presence of shared mechanisms involving IL6 and APOE.

A promoter variant of the APOA5 gene increases atherogenic LDL levels and arterial stiffness in hypertriglyceridemic patients.

PubMed

Kim, Minjoo; Kim, Minkyung; Yoo, Hye Jin; Lee, Eunji; Chae, Jey Sook; Lee, Sang-Hyun; Lee, Jong Ho

2017-01-01

Hypertriglyceridemia is recognized as an independent risk factor for coronary artery disease. The apolipoprotein A5 gene (APOA5) is a key regulator of triglyceride levels. We aimed to evaluate the associations of single nucleotide polymorphisms (SNPs) in APOA5, including -1131T>C and c.553G>T, with hypertriglyceridemia, apoA5 concentrations, atherogenic LDL cholesterol levels, and arterial stiffness in hypertriglyceridemic patients. The study population included 599 hypertriglyceridemic patients (case) and 1,549 untreated normotriglyceridemic subjects (control). We genotyped two APOA5 variants, -1131T>C (rs662799) and c.553G>T (rs2075291). The frequencies of the CC genotype of -1131T>C (0.165) and the T allele of c.553G>T (0.119) were significantly higher in hypertriglyceridemic patients than in normotriglyceridemic subjects (0.061 and 0.070, respectively; all p<0.001). In the control and case groups, both the -1131T>C and c.553G>T variants were associated with higher triglyceride and lower HDL cholesterol levels. Controls with the -1131CC variant had lower apoA5 concentrations than controls with the -1131TT variant. Similar effects of the -1131T>C variant on apoA5 were observed in the cases. In the hypertriglyceridemic group, the -1131T>C variant was associated with a smaller LDL particle size, higher levels of oxidized LDL and malondialdehyde, and higher brachial-ankle pulse wave velocity. The -1131T>C and c.553G>T polymorphisms were associated with hypertriglyceridemia in the study population, but only the -1131T>C polymorphism directly affected apoA5 concentrations. Hypertriglyceridemic patients carrying the APOA5 -1131T>C polymorphism exhibited increased atherogenic LDL levels and arterial stiffness, probably due to an effect of the -1131T>C polymorphism on apoA5 concentrations.

Identification of variants of CYP3A4 and characterization of their abilities to metabolize testosterone and chlorpyrifos.

PubMed

Dai, D; Tang, J; Rose, R; Hodgson, E; Bienstock, R J; Mohrenweiser, H W; Goldstein, J A

2001-12-01

CYP3A4 is the most abundant isoform of cytochrome P450 (CYP) in adult human liver. It metabolizes numerous clinically, physiologically, and toxicologically important compounds. The expression of CYP3A4 varies 40-fold in individual human livers, and metabolism of CYP3A4 substrates varies at least 10-fold in vivo. Single nucleotide polymorphisms (SNPs) in CYP3A4 were identified by direct sequencing of genomic DNA in 72 individuals from three different ethnic groups, including Caucasians, Blacks (African-Americans and African pygmies), and Asians. A total of 28 SNPs were identified, including five which produced coding changes M445T (CYP3A4*3), R162Q (CYP3A4*15), F189S (CYP3A4*17), L293P (CYP3A4*18), and P467S (CYP3A4*19). The latter four represent new alleic variants. Racial variability was observed for the frequency of individual SNPs. CYP3A R162Q was identified only in Black populations with an allelic frequency of 4%. CYP3A4 F189S and CYP3A4 M445T were identified in Caucasians with allelic frequencies 2% and 4%, respectively. L293P and P467S were only observed in Asians at allelic frequencies of 2%. The cDNAs for the F189S, L293P, M445T, and P467S mutant alleles were constructed by site-directed mutagenesis and expressed in an Escherichia coli expression system. Testosterone and the insecticide chlorpyrifos were used to assess the catalytic activities of the most common CYP3A4 allele (CYP3A4*1) and its allelic variants. CYP3A4 F189S exhibited lower turnover numbers for testosterone and chlorpyrifos, while CYP3A4 L293P had higher turnover numbers for both substrates. The turnover numbers of the CYP3A4 M445T and P467S alleles to metabolize these compounds were not significantly different from those of wild-type CYP3A4.

Two variants in the KIT gene as candidate causative mutations for a dominant white and a white spotting phenotype in the donkey.

PubMed

Haase, B; Rieder, S; Leeb, T

2015-06-01

White spotting phenotypes have been intensively studied in horses, and although similar phenotypes occur in the donkey, little is known about the molecular genetics underlying these patterns in donkeys. White spotting in donkeys can range from only a few white areas to almost complete depigmentation and is characterised by a loss of pigmentation usually progressing from a white spot in the hip area. Completely white-born donkeys are rare, and the phenotype is characterised by the complete absence of pigment resulting in pink skin and a white coat. A dominant mode of inheritance has been demonstrated for spotting in donkeys. Although the mode of inheritance for the completely white phenotype in donkeys is not clear, the phenotype shows similarities to dominant white in horses. As variants in the KIT gene are known to cause a range of white phenotypes in the horse, we investigated the KIT gene as a potential candidate gene for two phenotypes in the donkey, white spotting and white. A mutation analysis of all 21 KIT exons identified a missense variant in exon 4 (c.662A>C; p.Tyr221Ser) present only in a white-born donkey. A second variant affecting a splice donor site (c.1978+2T>A) was found exclusively in donkeys with white spotting. Both variants were absent in 24 solid-coloured controls. To the authors' knowledge, this is the first study investigating genetic mechanisms underlying white phenotypes in donkeys. Our results suggest that two independent KIT alleles are probably responsible for white spotting and white in donkeys. © 2015 Stichting International Foundation for Animal Genetics.

Adiponectin and adiponectin receptor gene variants in relation to resting metabolic rate, respiratory quotient, and adiposity-related phenotypes in the Quebec Family Study.

PubMed

Loos, Ruth J F; Ruchat, Stéphanie; Rankinen, Tuomo; Tremblay, Angelo; Pérusse, Louis; Bouchard, Claude

2007-01-01

Despite adiponectin's presumed role in fatty acid oxidation and energy homeostasis, little is known about the effect of gene variants on substrate oxidation, energy expenditure, and adiposity-related phenotypes. We examined the effects of genetic variation in adiponectin (ADIPOQ) and adiponectin receptors 1 and 2 (ADIPOR1 and ADIPOR2) on resting metabolic rate, respiratory quotient (RQ), and adiposity-related phenotypes. We studied the associations of ADIPOQ, ADIPOR1, and ADIPOR2 polymorphisms with resting metabolic rate, RQ, and body mass index, percentage body fat, sum of 6 skinfold thicknesses, waist circumference, and total, subcutaneous, and visceral fat in 759 participants in the Québec Family Study. The ADIPOQ 45T-->G single-nucleotide polymorphism (SNP) was significantly (P = 0.0002 to 0.04) associated with overall adiposity and abdominal adiposity; the rare homozygotes (G/G) had a leaner phenotype than did the carriers of the common allele. One SNP each in the putative promoter of ADIPOR1 (ie, -3882T-->C) and ADIPOR2 (ie, IVS1 -1352G-->A) was associated with RQ (P = 0.03 and 0.04, respectively), and the association was even stronger in nonobese persons (P = 0.02 and 0.003). Carriers of the common alleles (ADIPOR1 T and ADIPOR2 G alleles) had a lower RQ than did the rare homozygotes. A significant genotype-by-genotype interaction (P = 0.0002 to 0.02) was found between SNPs in the promoters of ADIPOQ (-3971A-->G) and ADIPOR1 (-3882T-->C). Subjects carrying the minor ADIPOQ allele (G allele) who were rare homozygotes (C/C) for the ADIPOR1 SNP had a higher RQ (P = 0.003) and greater overall (P < 0.03) and abdominal (P < 0.05) adiposity than did persons with other genotype combinations. Previous findings that the ADIPOQ 45T-->G variant contributes to overall fatness and abdominal obesity are confirmed. Moreover, variants in the promoter region of both ADIPOR genes contribute to substrate oxidation.

Influence of the genetic polymorphism in the 5'-noncoding region of the CYP1A2 gene on CYP1A2 phenotype and urinary mutagenicity in smokers.

PubMed

Pavanello, Sofia; Pulliero, Alessandra; Lupi, Silvia; Gregorio, Pasquale; Clonfero, Erminio

2005-11-10

The functional significance of genetic polymorphisms on tobacco smoke-induced CYP1A2 activity was examined. The influence of three polymorphisms of the cytochrome P450 1A2 gene (CYP1A2) (-3860 G-->A (allele *1C), -2467 T-->delT (allele *1D), -163C-->A (allele *1F)), located in the 5'-noncoding promoter region of the gene, on CYP1A2 activity (measured as caffeine metabolic ratio, CMR), was studied in Caucasian current smokers (n=95). Tobacco smoke intake was calculated from the number of cigarettes/day. Also, studied was the influence of these CYP1A2 genotypes on smoking-associated urinary mutagenicity, detected in Salmonella typhimurium strain YG1024 with S9 mix, considering the urinary excretion of nicotine plus its metabolites as an internal indicator of tobacco smoke exposure. Smokers with at least one of the variant alleles CYP1A2 -3860A and -2467 delT showed a significantly increased CYP1A2 CMR (-3860 G/A versus G/G, p<0.05; -2467 delT/delT versus T/delT and T/T, p<0.01). Multiple regression analysis showed that the increase in CYP1A2 CMR (ln values) was again significantly related to the presence of CYP1A2 variants -2467delT and also to variant -163A (p<0.05), but moderately to -3860A (p=0.084). No influence of the number of cigarettes smoked per day by each subject was found. Heavy smokers (n=48, with urinary nicotine plus its metabolites>or=0.69 mg/mmol creatinine) with variant allele -2467delT or -163A had significantly increased urinary mutagenicity (p<0.01 and <0.05). CYP1A2 genetic polymorphisms are shown to influence the CYP1A2 phenotype in smokers, -2467 T-->delT having the main effect. This information is of interest for future studies assessing the possible role of tobacco smoke-inducible CYP1A2 genotypes as individual susceptibility factors in exposure to carcinogens.

Characterization CYP1A2, CYP2C9, CYP2C19 and CYP2D6 polymorphisms using HRMA in Psychiatry patients with schizophrenia and bipolar disease for personalized medicine.

PubMed

Yenilmez, Ebru Dundar; Tamam, Lut; Karaytug, Onur; Tuli, Abdullah

2018-06-19

The interindividual genetic variations in drug metabolizing enzymes effects the impact and toxicity in plenty of drugs. The CYP1A2, CYP2C9, CYP2C19 and CYP2D6 gene polymorphisms characterized using high resolution melting analysis (HRMA) in follow-up patients in psychiatry clinic as a preliminary preparation for personalized medicine. Genotyping of CYP1A2*1F, CYP2C9 *2, *3, CYP2C19 *2, *3 and *17 and CYP2D6 *3, *4 was conducted in 101 patients using HRMA. Genotype and allele frequencies of the CYP variants were found to be in equilibrium with the Hardy-Weinberg equation. The frequency of the CYP1A2*1F allele in schizophrenia and bipolar disease was 0.694 and 0.255, respectively. The CYP2C9 allele frequencies were 0.087 (CYP2C9*2), and 0.549 (CYP2C9*3) for bipolar; 0.278 (CYP2C9*2) and 0.648 (CYP2C9*3) in schizophrenias. The CYP2C19*2 and *17 allele frequencies was 0.111 and 0.185 in schizophrenia and variant *2 was 0.117 and variant *17 was 0.255 in bipolar group. The frequency of the CYP2D6*3 allele was 0.027 in schizophrenias. The frequencies for the CYP2D6*4 variant was 0.092 and 0.096 in schizophrenia and bipolar groups, respectively. The knowledge in pharmacogenomics and also the developments in molecular genetics are growing rapidly. In the future this can be expected to provide new methodologies in the prediction of the activity in drug metabolizing enzymes. The HRMA is a rapid and useful technique to identify the genotypes for drug dosage adjustment before therapy in psychiatry patients. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Vitamin D-related host genetic variants alter HIV disease progression in children.

PubMed

Moodley, Amaran; Qin, Min; Singh, Kumud K; Spector, Stephen A

2013-11-01

Vitamin D deficiency is common in HIV infection and has been associated with advanced disease. This study investigated whether vitamin D-related genetic variants were associated with disease progression in HIV-infected children. The Fok-I (C/T), Bsm-I (G/A), GC (A/C), DHCR7 (G/T) and CYP2R1 (G/A) genetic variants were detected by real-time polymerase chain reaction in HIV-infected children who participated in the Pediatric AIDS Clinical Trials Group P152 and P300 protocols, which predated the availability of effective combination antiretroviral therapy. The primary endpoints included time to progression to the first HIV-related disease endpoint (≥2 opportunistic infection, weight growth failure) or death, which constituted the progression-free survival. Analyses were performed for age>2 years and ≤2 years separately adjusting for race and treatment effect. Of the 998 children evaluated, 139 experienced HIV disease progression. For children>2 years, rapid disease progression was associated with the DHCR7 G allele compared with the T allele (G/G vs. T/T: hazard ratio [HR]=5.0, P = 0.035; G/T vs. T/T: HR=4.5, P=0.042; G/G+G/T vs. T/T: HR=4.8, P=0.036) and the Bsm-I A allele compared with the G allele (A/G vs. G/G: HR=2.2, P=0.014 and A/G+A/A vs. G/G: HR=2.0, P=0.026). In children≤2 years, the Bsm-I A allele increased the risk of disease progression in Hispanics (A/A vs. G/A+G/G: HR=2.8, P=0.03 and A/A vs. G/G: HR=2.8, P=0.046) and whites (A/A vs. G/G: HR=6.6, P=0.025 and A/A vs. G/A+G/G: HR=3.6, P=0.038). Vitamin D-related host genetic variants that alter the availability and activity of vitamin D are associated with risk of HIV disease progression in children and may vary by age and race.

Single-nucleotide polymorphisms of TNFA and IL1 in allergic rhinitis.

PubMed

Nasiri, R; Amirzargar, A Akbar; Movahedi, M; Hirbod-Mobarakeh, A; Farhadi, E; Behniafard, N; Tavakkol, M; Ansaripour, B; Moradi, B; Zare, A; Rezaei, N

2013-01-01

Allergic rhinitis is a complex polygenic disorder of the upper respiratory tract. Given that proinflammatory cytokines such as tumor necrosis factor (TNF) and interleukin (IL) 1 seem to play a role in the development of allergic rhinitis, we evaluated the associations between various single-nucleotide polymorphisms (SNPs) of the TNF and IL1 genes in a case-control study. The study population comprised 98 patients with allergic rhinitis. Genotyping was performed using polymerase chain reaction with sequence-specific primers for 2 TNFA promoter variants (rs1800629 and rs361525), 1 variant in the promoter region of IL1A (rs1800587), 2 SNPs in the IL1B gene (rs16944 and rs1 143634), 1 variant in the IL1 receptor (rs2234650), and 1 in IL1RA (rs315952). Patients who were homozygous for the T allele of rs16944 in IL1B had an 8.1-fold greater risk of allergic rhinitis than those with the C allele. In TNFA, a significant relationship was also detected between rs1800629 and rs361525 and allergic rhinitis. Except for rs1800587 in IL1A and rs315952 in IL1RA, significant differences were found between the patient and control groups for all other SNPs. We found that allelic variants in the TNFA and IL1 genes were not only associated with the risk of developing allergic rhinitis, but also affected disease course and severity.

A Functional Variant of SMAD4 Enhances Thoracic Aortic Aneurysm and Dissection Risk through Promoting Smooth Muscle Cell Apoptosis and Proteoglycan Degradation.

PubMed

Wang, Ying; Huang, Hao-Yue; Bian, Guang-Liang; Yu, Yun-Sheng; Ye, Wen-Xue; Hua, Fei; Chen, Yi-Huan; Shen, Zhen-Ya

2017-07-01

Recent studies indicate important roles for SMAD4 in SMCs proliferation, extracellular matrix maintenance, and blood vessel remodeling. However, the genetic effects of SMAD4 in the pathogenesis of thoracic aortic aneurysm and dissection (TAAD) are still largely unknown. Here we identified a functional variant of SMAD4 which might be involved in the pathological progression of TAAD. Five tagging SNPs of SMAD4 were genotyped in 202 TAAD cases and 400 controls using MALDI-TOF. rs12455792 CT or TT variant genotypes was associated with an significantly elevated TAAD risk (adjusted OR=1.58, 95%CI=1.09-2.30) under a dominant genetic model. It was located in the 5'UTR and predicted to influence transcription activity and RNA folding of SMAD4. In luciferase reporter assay, rs12455792 T allele markedly decreased luciferase activities. Accordingly, SMAD4 expression in tissues was lower in patients with CT or TT genotypes, compared with CC. Movat's pentachrome showed that rs12455792 T allele enhanced SMCs loss and fibers accumulation. With angiotensin II induction, rate of Apoptotic SMCs was significantly higher while SMAD4 silenced. Moreover, rs12455792 T allele also increased Versican degradation via ADAMTS-4. In conclusion, this variant might promote SMCs apoptosis and proteoglycans degradation, and further facilitate the progress of TAAD. Our findings identified rs12455792 as a predictor for progression of vascular media pathological changes related thoracic aortic disorders. Copyright © 2017. Published by Elsevier B.V.

Prevalence of glucose-6-phosphate dehydrogenase (G6PD) deficiency among malaria patients in Upper Myanmar.

PubMed

Lee, Jinyoung; Kim, Tae Im; Kang, Jung-Mi; Jun, Hojong; Lê, Hương Giang; Thái, Thị Lam; Sohn, Woon-Mok; Myint, Moe Kyaw; Lin, Khin; Kim, Tong-Soo; Na, Byoung-Kuk

2018-03-16

Glucose-6-phosphate dehydrogenase (G6PD; EC 1.1.1.49) deficiency is one of the most common X-linked recessive hereditary disorders in the world. Primaquine (PQ) has been used for radical cure of P. vivax to prevent relapse. Recently, it is also used to reduce P. falciparum gametocyte carriage to block transmission. However, PQ metabolites oxidize hemoglobin and generate excessive reactive oxygen species which can trigger acute hemolytic anemia in malaria patients with inherited G6PD deficiency. A total of 252 blood samples collected from malaria patients in Myanmar were used in this study. G6PD variant was analysed by a multiplex allele specific PCR kit, DiaPlexC™ G6PD Genotyping Kit [Asian type]. The accuracy of the multiplex allele specific PCR was confirmed by sequencing analysis. Prevalence and distribution of G6PD variants in 252 malaria patients in Myanmar were analysed. Six different types of G6PD allelic variants were identified in 50 (7 females and 43 males) malaria patients. The predominant variant was Mahidol (68%, 34/50), of which 91.2% (31/34) and 8.8% (3/34) were males and females, respectively. Other G6PD variants including Kaiping (18%, 9/50), Viangchan (6%, 3/50), Mediterranean (4%, 2/50), Union (2%, 1/50) and Canton (2%, 1/50) were also observed. Results of this study suggest that more concern for proper and safe use of PQ as a radical cure of malaria in Myanmar is needed by combining G6PD deficiency test before PQ prescription. Establishment of a follow-up system to monitor potential PQ toxicity in malaria patients who are given PQ is also required.

A Loss-of-Function Splice Acceptor Variant in IGF2 Is Protective for Type 2 Diabetes.

PubMed

Mercader, Josep M; Liao, Rachel G; Bell, Avery D; Dymek, Zachary; Estrada, Karol; Tukiainen, Taru; Huerta-Chagoya, Alicia; Moreno-Macías, Hortensia; Jablonski, Kathleen A; Hanson, Robert L; Walford, Geoffrey A; Moran, Ignasi; Chen, Ling; Agarwala, Vineeta; Ordoñez-Sánchez, María Luisa; Rodríguez-Guillen, Rosario; Rodríguez-Torres, Maribel; Segura-Kato, Yayoi; García-Ortiz, Humberto; Centeno-Cruz, Federico; Barajas-Olmos, Francisco; Caulkins, Lizz; Puppala, Sobha; Fontanillas, Pierre; Williams, Amy L; Bonàs-Guarch, Sílvia; Hartl, Chris; Ripke, Stephan; Tooley, Katherine; Lane, Jacqueline; Zerrweck, Carlos; Martínez-Hernández, Angélica; Córdova, Emilio J; Mendoza-Caamal, Elvia; Contreras-Cubas, Cecilia; González-Villalpando, María E; Cruz-Bautista, Ivette; Muñoz-Hernández, Liliana; Gómez-Velasco, Donaji; Alvirde, Ulises; Henderson, Brian E; Wilkens, Lynne R; Le Marchand, Loic; Arellano-Campos, Olimpia; Riba, Laura; Harden, Maegan; Gabriel, Stacey; Abboud, Hanna E; Cortes, Maria L; Revilla-Monsalve, Cristina; Islas-Andrade, Sergio; Soberon, Xavier; Curran, Joanne E; Jenkinson, Christopher P; DeFronzo, Ralph A; Lehman, Donna M; Hanis, Craig L; Bell, Graeme I; Boehnke, Michael; Blangero, John; Duggirala, Ravindranath; Saxena, Richa; MacArthur, Daniel; Ferrer, Jorge; McCarroll, Steven A; Torrents, David; Knowler, William C; Baier, Leslie J; Burtt, Noel; González-Villalpando, Clicerio; Haiman, Christopher A; Aguilar-Salinas, Carlos A; Tusié-Luna, Teresa; Flannick, Jason; Jacobs, Suzanne B R; Orozco, Lorena; Altshuler, David; Florez, Jose C

2017-11-01

Type 2 diabetes (T2D) affects more than 415 million people worldwide, and its costs to the health care system continue to rise. To identify common or rare genetic variation with potential therapeutic implications for T2D, we analyzed and replicated genome-wide protein coding variation in a total of 8,227 individuals with T2D and 12,966 individuals without T2D of Latino descent. We identified a novel genetic variant in the IGF2 gene associated with ∼20% reduced risk for T2D. This variant, which has an allele frequency of 17% in the Mexican population but is rare in Europe, prevents splicing between IGF2 exons 1 and 2. We show in vitro and in human liver and adipose tissue that the variant is associated with a specific, allele-dosage-dependent reduction in the expression of IGF2 isoform 2. In individuals who do not carry the protective allele, expression of IGF2 isoform 2 in adipose is positively correlated with both incidence of T2D and increased plasma glycated hemoglobin in individuals without T2D, providing support that the protective effects are mediated by reductions in IGF2 isoform 2. Broad phenotypic examination of carriers of the protective variant revealed no association with other disease states or impaired reproductive health. These findings suggest that reducing IGF2 isoform 2 expression in relevant tissues has potential as a new therapeutic strategy for T2D, even beyond the Latin American population, with no major adverse effects on health or reproduction. © 2017 by the American Diabetes Association.

I148M variant in PNPLA3 reduces central adiposity and metabolic disease risks while increasing nonalcoholic fatty liver disease.

PubMed

Park, Jin-Ho; Cho, BeLong; Kwon, Hyuktae; Prilutsky, Daria; Yun, Jae Moon; Choi, Ho Chun; Hwang, Kyu-Baek; Lee, In-Hee; Kim, Jong-Il; Kong, Sek Won

2015-12-01

The I148M variant because of the substitution of C to G in PNPLA3 (rs738409) is associated with the increased risk of nonalcoholic fatty liver disease (NAFLD). In liver, I148M variant reduces hydrolytic function of PNPLA3, which results in hepatic steatosis; however, its association with the other clinical phenotype such as adiposity and metabolic diseases is not well established. To identify the impact of I148M variant on clinical risk factors of NAFLD, we recruited 1363 generally healthy Korean males after excluding alcoholic and secondary causes of hepatic steatosis. Central adiposity was assessed by computed tomography, and hepatic steatosis was evaluated by abdominal ultrasonography. The participants were predominantly middle-aged (49.0 ± 7.1 years; range 30-60 years), and the frequency of NAFLD was 44.2%. The rs738409-G allele carriers had a 1.19-fold increased risk for NAFLD (minor allele frequency 0.43; allelic odds ratio 1.38; P = 4.3 × 10(-5) ). Interestingly, the rs738409 GG carriers showed significantly lower levels of visceral and subcutaneous adiposity (P < 0.001 and = 0.015, respectively), BMI (P < 0.001), triglycerides (P < 0.001) and insulin resistance (P = 0.002) compared to CC carriers. These negative associations between clinical risk factors and rs738409-G dosage were more prominent in non-NAFLD group compared to those in NAFLD group. The I148M variant, although increasing the risk of NAFLD, was associated with reduced levels of central adiposity, BMI, serum triglycerides and insulin resistance, suggesting differential roles in fat storage and distribution according to cell types and metabolic status. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Identifying the Deleterious Effect of Rare LHX4 Allelic Variants, a Challenging Issue

PubMed Central

Rochette, Claire; Jullien, Nicolas; Saveanu, Alexandru; Caldagues, Emmanuelle; Bergada, Ignacio; Braslavsky, Debora; Pfeifer, Marija; Reynaud, Rachel; Herman, Jean-Paul; Barlier, Anne; Brue, Thierry; Enjalbert, Alain; Castinetti, Frederic

2015-01-01

LHX4 is a LIM homeodomain transcription factor involved in the early steps of pituitary ontogenesis. To date, 8 heterozygous LHX4 mutations have been reported as responsible of combined pituitary hormone deficiency (CPHD) in Humans. We identified 4 new LHX4 heterozygous allelic variants in patients with congenital hypopituitarism: W204X, delK242, N271S and Q346R. Our objective was to determine the role of LHX4 variants in patients’ phenotypes. Heterologous HEK293T cells were transfected with plasmids encoding for wild-type or mutant LHX4. Protein expression was analysed by Western Blot, and DNA binding by electro-mobility shift assay experiments. Target promoters of LHX4 were cotransfected with wild type or mutant LHX4 to test the transactivating abilities of each variant. Our results show that the W204X mutation was associated with early GH and TSH deficiencies and later onset ACTH deficiency. It led to a truncated protein unable to bind to alpha-Gsu promoter binding consensus sequence. W204X was not able to activate target promoters in vitro. Cotransfection experiments did not favour a dominant negative effect. In contrast, all other mutants were able to bind the promoters and led to an activation similar as that observed with wild type LHX4, suggesting that they were likely polymorphisms. To conclude, our study underlines the need for functional in vitro studies to ascertain the role of rare allelic variants of LHX4 in disease phenotypes. It supports the causative role of the W204X mutation in CPHD and adds up childhood onset ACTH deficiency to the clinical spectrum of the various phenotypes related to LHX4 mutations. PMID:25955177

Association of ITPA polymorphisms rs6051702/rs1127354 instead of rs7270101/rs1127354 as predictor of ribavirin-associated anemia in chronic hepatitis C treated patients.

PubMed

D'Avolio, Antonio; De Nicolò, Amedeo; Cusato, Jessica; Ciancio, Alessia; Boglione, Lucio; Strona, Silvia; Cariti, Giuseppe; Troshina, Giulia; Caviglia, Gian Paolo; Smedile, Antonina; Rizzetto, Mario; Di Perri, Giovanni

2013-10-01

Functional variants rs7270101 and rs1127354 of inosine triphosphatase (ITPA) were recently found to protect against ribavirin (RBV)-induced hemolytic anemia. However, no definitive data are yet available on the role of no functional rs6051702 polymorphism. Since a simultaneous evaluation of the three ITPA SNPs for hemolytic anemia has not yet been investigated, we aimed to understand the contribution of each SNPs and its potential clinical use to predict anemia in HCV treated patients. A retrospective analysis included 379 HCV treated patients. The ITPA variants rs6051702, rs7270101 and rs1127354 were genotyped and tested for association with achieving anemia at week 4. We also investigated, using multivariate logistic regression, the impact of each single and paired associated polymorphism on anemia onset. All SNPs were associated with Hb decrease. The carrier of at least one variant allele in the functional ITPA SNPs was associated with a lower decrement of Hb, as compared to patients without a variant allele. In multivariate logistic regression analyses the carrier of a variant allele in the rs6051702/rs1127354 association (OR=0.11, p=1.75×10(-5)) and Hb at baseline (OR=1.51, p=1.21×10(-4)) were independently associated with protection against clinically significant anemia at week 4. All ITPA polymorphisms considered were shown to be significantly associated with anemia onset. A multivariate regression model based on ITPA genetic polymorphisms was developed for predicting the risk of anemia. Considering the characterization of pre-therapy anemia predictors, rs6051702 SNP in association to rs1127354 is more informative in order to avoid this relevant adverse event. Copyright © 2013 Elsevier B.V. All rights reserved.

FTO gene variants are strongly associated with type 2 diabetes in South Asian Indians.

PubMed

Yajnik, C S; Janipalli, C S; Bhaskar, S; Kulkarni, S R; Freathy, R M; Prakash, S; Mani, K R; Weedon, M N; Kale, S D; Deshpande, J; Krishnaveni, G V; Veena, S R; Fall, C H D; McCarthy, M I; Frayling, T M; Hattersley, A T; Chandak, G R

2009-02-01

Variants of the FTO (fat mass and obesity associated) gene are associated with obesity and type 2 diabetes in white Europeans, but these associations are not consistent in Asians. A recent study in Asian Indian Sikhs showed an association with type 2 diabetes that did not seem to be mediated through BMI. We studied the association of FTO variants with type 2 diabetes and measures of obesity in South Asian Indians in Pune. We genotyped, by sequencing, two single nucleotide polymorphisms, rs9939609 and rs7191344, in the FTO gene in 1,453 type 2 diabetes patients and 1,361 controls from Pune, Western India and a further 961 population-based individuals from Mysore, South India. We observed a strong association of the minor allele A at rs9939609 with type 2 diabetes (OR per allele 1.26; 95% CI 1.13-1.40; p = 3 x 10(-5)). The variant was also associated with BMI but this association appeared to be weaker (0.06 SDs; 95% CI 0.01-0.10) than the previously reported effect in Europeans (0.10 SDs; 95% CI 0.09-0.12; heterogeneity p = 0.06). Unlike in the Europeans, the association with type 2 diabetes remained significant after adjusting for BMI (OR per allele for type 2 diabetes 1.21; 95% CI 1.06-1.37; p = 4.0 x 10(-3)), and also for waist circumference and other anthropometric variables. Our study replicates the strong association of FTO variants with type 2 diabetes and similar to the study in North Indians Sikhs, shows that this association may not be entirely mediated through BMI. This could imply underlying differences between Indians and Europeans in the mechanisms linking body size with type 2 diabetes.

A WFS1 Haplotype Consisting of the Minor Alleles of rs752854, rs10010131, and rs734312 Shows a Protective Role Against Type 2 Diabetes in Russian Patients

PubMed Central

Chistiakov, Dimitry A; Khodyrev, Dmitry S.; Smetanina, Svetlana A.; Bel'chikova, Larisa N.; Suplotova, Lyudmila A.; Nosikov, Valery V.

2010-01-01

BACKGROUND: Rare variants of the WFS1 gene encoding wolframin cause Wolfram syndrome, a monogenic disease associated with diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. In contrast, common variants of WFS1 showed association with type 2 diabetes (T2D) in numerous Caucasian populations. AIM: In this study, we tested whether the markers rs752854, rs10010131, and rs734312, located in the WFS1 gene, are related to the development of T2D in a Russian population. METHODS: The polymorphic markers were genotyped in Russian diabetic (n = 1,112) and non-diabetic (n = 1,097) patients using a Taqman allele discrimination assay. The correlation between the carriage of disease-associated WFS1 variants and the patients' clinical and metabolic characteristics was studied using ANOVA and ANCOVA. Adjustment for confounding variables such as gender, age, body mass index, obesity, HbA1c, and hypertension was made. RESULTS: Haplotype GAG, consisting of the minor alleles of rs752854, rs10010131, and rs734312, respectively, showed association with decreased risk of T2D (OR = 0.44, 95% CI = 0.32-0.61, p = 4.3 x 10-7). Compared to other WFS1 variants, non-diabetic individuals homozygous for GAG/CAG had significantly increased fasting insulin (padjusted = 0.047) and homeostasis model assessment of β-cell function (HOMA-β) index (padjusted = 0.006). Diabetic patients homozygous for GAG/GAG showed significantly elevated levels of 2-h insulin (padjusted = 0.029) and HOMA-β = 0.011. CONCLUSIONS: Disease-associated variants of WFS1 contribute to the pathogenesis of T2D through impaired insulin response to glucose stimulation and altered β-cell function. PMID:21713316

APOL1 nephropathy risk variants are associated with altered high-density lipoprotein profiles in African Americans.

PubMed

Gutiérrez, Orlando M; Judd, Suzanne E; Irvin, Marguerite R; Zhi, Degui; Limdi, Nita; Palmer, Nicholette D; Rich, Stephen S; Sale, Michèle M; Freedman, Barry I

2016-04-01

Two independent coding variants in the apolipoprotein L1 gene (APOL1), G1 and G2, strongly associate with nephropathy in African Americans; associations with cardiovascular disease are more controversial. Although APOL1 binds plasma high-density lipoproteins (HDLs), data on APOL1 risk variant associations with HDL subfractions are sparse. Two APOL1 G1 single nucleotide polymorphisms and the G2 insertion/deletion polymorphism were genotyped in 2010 Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study participants with nuclear magnetic resonance spectroscopy-based lipoprotein subfraction measurements. Linear regression was used to model associations between numbers of APOL1 G1/G2 risk variants and HDL subfractions, adjusting for demographic, clinical and ancestral covariates. Female sex and higher percentage of African ancestry were positively associated with the number of APOL1 G1/G2 risk alleles. In the unadjusted analysis, mean (standard error) small HDL concentrations (μmol/L) for participants with zero, one and two G1/G2 risk alleles were 19.0 (0.2), 19.7 (0.2) and 19.9 (0.4), respectively (P = 0.02). Adjustment for age, sex, diabetes and African ancestry did not change the results but strengthened the statistical significance (P = 0.004). No significant differences in large or medium HDL, very low-density lipoprotein or low-density lipoprotein particle concentrations were observed by APOL1 genotype. Greater numbers of APOL1 G1/G2 risk alleles were associated with higher small HDL particle concentrations in African Americans. These results may suggest novel areas of investigation to uncover reasons for the association between APOL1 risk variants with adverse outcomes in African Americans. © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

APOL1 nephropathy risk variants are associated with altered high-density lipoprotein profiles in African Americans

PubMed Central

Gutiérrez, Orlando M.; Judd, Suzanne E.; Irvin, Marguerite R.; Zhi, Degui; Limdi, Nita; Palmer, Nicholette D.; Rich, Stephen S.; Sale, Michèle M.; Freedman, Barry I.

2016-01-01

Background Two independent coding variants in the apolipoprotein L1 gene (APOL1), G1 and G2, strongly associate with nephropathy in African Americans; associations with cardiovascular disease are more controversial. Although APOL1 binds plasma high-density lipoproteins (HDLs), data on APOL1 risk variant associations with HDL subfractions are sparse. Methods Two APOL1 G1 single nucleotide polymorphisms and the G2 insertion/deletion polymorphism were genotyped in 2010 Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study participants with nuclear magnetic resonance spectroscopy-based lipoprotein subfraction measurements. Linear regression was used to model associations between numbers of APOL1 G1/G2 risk variants and HDL subfractions, adjusting for demographic, clinical and ancestral covariates. Results Female sex and higher percentage of African ancestry were positively associated with the number of APOL1 G1/G2 risk alleles. In the unadjusted analysis, mean (standard error) small HDL concentrations (μmol/L) for participants with zero, one and two G1/G2 risk alleles were 19.0 (0.2), 19.7 (0.2) and 19.9 (0.4), respectively (P = 0.02). Adjustment for age, sex, diabetes and African ancestry did not change the results but strengthened the statistical significance (P = 0.004). No significant differences in large or medium HDL, very low-density lipoprotein or low-density lipoprotein particle concentrations were observed by APOL1 genotype. Conclusions Greater numbers of APOL1 G1/G2 risk alleles were associated with higher small HDL particle concentrations in African Americans. These results may suggest novel areas of investigation to uncover reasons for the association between APOL1 risk variants with adverse outcomes in African Americans. PMID:26152403

MetaSeq: privacy preserving meta-analysis of sequencing-based association studies.

PubMed

Singh, Angad Pal; Zafer, Samreen; Pe'er, Itsik

2013-01-01

Human genetics recently transitioned from GWAS to studies based on NGS data. For GWAS, small effects dictated large sample sizes, typically made possible through meta-analysis by exchanging summary statistics across consortia. NGS studies groupwise-test for association of multiple potentially-causal alleles along each gene. They are subject to similar power constraints and therefore likely to resort to meta-analysis as well. The problem arises when considering privacy of the genetic information during the data-exchange process. Many scoring schemes for NGS association rely on the frequency of each variant thus requiring the exchange of identity of the sequenced variant. As such variants are often rare, potentially revealing the identity of their carriers and jeopardizing privacy. We have thus developed MetaSeq, a protocol for meta-analysis of genome-wide sequencing data by multiple collaborating parties, scoring association for rare variants pooled per gene across all parties. We tackle the challenge of tallying frequency counts of rare, sequenced alleles, for metaanalysis of sequencing data without disclosing the allele identity and counts, thereby protecting sample identity. This apparent paradoxical exchange of information is achieved through cryptographic means. The key idea is that parties encrypt identity of genes and variants. When they transfer information about frequency counts in cases and controls, the exchanged data does not convey the identity of a mutation and therefore does not expose carrier identity. The exchange relies on a 3rd party, trusted to follow the protocol although not trusted to learn about the raw data. We show applicability of this method to publicly available exome-sequencing data from multiple studies, simulating phenotypic information for powerful meta-analysis. The MetaSeq software is publicly available as open source.

A functional ABCA1 gene variant is associated with low HDL-cholesterol levels and shows evidence of positive selection in Native Americans

PubMed Central

Acuña-Alonzo, Víctor; Flores-Dorantes, Teresa; Kruit, Janine K.; Villarreal-Molina, Teresa; Arellano-Campos, Olimpia; Hünemeier, Tábita; Moreno-Estrada, Andrés; Ortiz-López, Ma Guadalupe; Villamil-Ramírez, Hugo; León-Mimila, Paola; Villalobos-Comparan, Marisela; Jacobo-Albavera, Leonor; Ramírez-Jiménez, Salvador; Sikora, Martin; Zhang, Lin-Hua; Pape, Terry D.; de Ángeles Granados-Silvestre, Ma; Montufar-Robles, Isela; Tito-Alvarez, Ana M.; Zurita-Salinas, Camilo; Bustos-Arriaga, José; Cedillo-Barrón, Leticia; Gómez-Trejo, Celta; Barquera-Lozano, Rodrigo; Vieira-Filho, Joao P.; Granados, Julio; Romero-Hidalgo, Sandra; Huertas-Vázquez, Adriana; González-Martín, Antonio; Gorostiza, Amaya; Bonatto, Sandro L.; Rodríguez-Cruz, Maricela; Wang, Li; Tusié-Luna, Teresa; Aguilar-Salinas, Carlos A.; Lisker, Ruben; Moises, Regina S.; Menjivar, Marta; Salzano, Francisco M.; Knowler, William C.; Bortolini, M. Cátira; Hayden, Michael R.; Baier, Leslie J.; Canizales-Quinteros, Samuel

2010-01-01

It has been suggested that the higher susceptibility of Hispanics to metabolic disease is related to their Native American heritage. A frequent cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) gene variant (R230C, rs9282541) apparently exclusive to Native American individuals was associated with low high-density lipoprotein cholesterol (HDL-C) levels, obesity and type 2 diabetes in Mexican Mestizos. We performed a more extensive analysis of this variant in 4405 Native Americans and 863 individuals from other ethnic groups to investigate genetic evidence of positive selection, to assess its functional effect in vitro and to explore associations with HDL-C levels and other metabolic traits. The C230 allele was found in 29 of 36 Native American groups, but not in European, Asian or African individuals. C230 was observed on a single haplotype, and C230-bearing chromosomes showed longer relative haplotype extension compared with other haplotypes in the Americas. Additionally, single-nucleotide polymorphism data from the Human Genome Diversity Panel Native American populations were enriched in significant integrated haplotype score values in the region upstream of the ABCA1 gene. Cells expressing the C230 allele showed a 27% cholesterol efflux reduction (P< 0.001), confirming this variant has a functional effect in vitro. Moreover, the C230 allele was associated with lower HDL-C levels (P = 1.77 × 10−11) and with higher body mass index (P = 0.0001) in the combined analysis of Native American populations. This is the first report of a common functional variant exclusive to Native American and descent populations, which is a major determinant of HDL-C levels and may have contributed to the adaptive evolution of Native American populations. PMID:20418488

Inheritance of allozyme variants in bishop pine (Pinus muricata D.Don)

Treesearch

Constance I. Millar

1985-01-01

Isozyme phenotypes are described for 45 structural loci and I modifier locus in bishop pine (Pinus muricata D. Don,) and segregation data are presented for a subset of 31 polymorphic loci from 19 enzyme systems. All polymorphic loci had alleles that segregated within single-focus Mendelian expectations, although one pair of alleles at each of three...

Identification, Characterisation and Clinical Development of the New Generation of Breast Cancer Susceptibility Alleles

DTIC Science & Technology

2010-03-01

amino acid substitution in this gene has been associated with uric acid nephrolithiasis (32). Recent GWAS have identified another variant within this...Identification of a novel gene and a common variant associated with uric acid nephrolithiasis in a Sardinian genetic isolate. Am J Hum Genet 72

HFE p.C282Y gene variant is associated with varicose veins in Russian population.

PubMed

Sokolova, Ekaterina A; Shadrina, Alexandra S; Sevost'ianova, Kseniya S; Shevela, Andrey I; Soldatsky, Evgenii Yu; Seliverstov, Evgenii I; Demekhova, Marina Yu; Shonov, Oleg A; Ilyukhin, Evgenii A; Smetanina, Mariya A; Voronina, Elena N; Zolotukhin, Igor A; Filipenko, Maxim L

2016-08-01

Recently, the association of polymorphism rs1800562 (p.C282Y) in the hemochromatosis (HFE) gene with the increased risk of venous ulceration was shown. We hypothesized that HFE gene polymorphism might be involved not only in ulceration process, but also in susceptibility to primary varicose veins. We genotyped HFE p.C282Y (rs1800562) and p.H63D (rs1799945) variants in patients with primary varicose veins (n = 463) and in the control group (n = 754). In our study, p.282Y variant (rs1800562 A allele) was significantly associated with the risk of varicose veins (OR 1.79, 95 % CI = 1.11-2.89, P = 0.02). A borderline significant reverse association of p.63D variant (rs1799945 G allele) with venous leg ulcer development was revealed in Russians (OR 0.25, 95 % CI = 0.06-1.00, P = 0.05), but not in the meta-analysis (P = 0.56). We conclude that the HFE gene polymorphism can affect the risk of developing primary varicose veins.

Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African Ancestry Anthropometry Genetics Consortium

PubMed Central

Lu, Yingchang; Justice, Anne E.; Mudgal, Poorva; Liu, Ching-Ti; Young, Kristin; Feitosa, Mary F.; Rand, Kristin; Dimitrov, Latchezar; Duan, Qing; Guo, Xiuqing; Lange, Leslie A.; Nalls, Michael A.; Okut, Hayrettin; Tayo, Bamidele O.; Vedantam, Sailaja; Bradfield, Jonathan P.; Chen, Guanjie; Chesi, Alessandra; Irvin, Marguerite R.; Padhukasahasram, Badri; Zheng, Wei; Allison, Matthew A.; Ambrosone, Christine B.; Bandera, Elisa V.; Berndt, Sonja I.; Blot, William J.; Bottinger, Erwin P.; Carpten, John; Chanock, Stephen J.; Chen, Yii-Der Ida; Conti, David V.; Cooper, Richard S.; Fornage, Myriam; Freedman, Barry I.; Garcia, Melissa; Goodman, Phyllis J.; Hsu, Yu-Han H.; Hu, Jennifer; Huff, Chad D.; Ingles, Sue A.; John, Esther M.; Kittles, Rick; Klein, Eric; Li, Jin; McKnight, Barbara; Nayak, Uma; Nemesure, Barbara; Olshan, Andrew; Salako, Babatunde; Sanderson, Maureen; Shao, Yaming; Siscovick, David S.; Stanford, Janet L.; Strom, Sara S.; Witte, John S.; Yao, Jie; Zhu, Xiaofeng; Ziegler, Regina G.; Zonderman, Alan B.; Ambs, Stefan; Cushman, Mary; Faul, Jessica D.; Hakonarson, Hakon; Levin, Albert M.; Nathanson, Katherine L.; Weir, David R.; Zhi, Degui; Arnett, Donna K.; Kardia, Sharon L. R.; Oloapde, Olufunmilayo I.; Rao, D. C.; Williams, L. Keoki; Becker, Diane M.; Borecki, Ingrid B.; Evans, Michele K.; Harris, Tamara B.; Hirschhorn, Joel N.; Psaty, Bruce M.; Wilson, James G.; Bowden, Donald W.; Cupples, L. Adrienne; Haiman, Christopher A.; Loos, Ruth J. F.; North, Kari E.

2017-01-01

Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10−8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained ≤ 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations. PMID:28430825

Genetic epidemiology of pharmacogenetic variations in CYP2C9, CYP4F2 and VKORC1 genes associated with warfarin dosage in the Indian population.

PubMed

Giri, Anil K; Khan, Nazir M; Grover, Sandeep; Kaur, Ismeet; Basu, Analabha; Tandon, Nikhil; Scaria, Vinod; Kukreti, Ritushree; Brahmachari, Samir K; Bharadwaj, Dwaipayan

2014-07-01

Warfarin, a widely used anticoagulant, exhibits large interindividual variability in dose requirements. CYP2C9 and VKORC1 polymorphisms in various ethnic groups have been extensively studied as genetic markers associated with variable drug response. However, allele frequencies of these variants have not been assessed in major ethnic groups in the Indian population. To study the functional variants known to affect warfarin dosing, we reanalyzed genotype microarray datasets generated as a part of genome-wide association studies as well as data from the Indian Genome Variation database. We examined data from 2680 individuals across 24 ethnically diverse Indian subpopulations. Allelic distribution of VKORC1 (-1639G>A) showed a greater degree of variation across Indian subpopulations, with frequencies as low as 6.5% in an out-group subpopulation to >70% in Tibeto-Burmans. Risk allele frequency of CYP4F2*3 (V433M) was higher in north Indians (0.30-0.44), as compared with other world populations, such as African-American (0.12), Caucasian (0.34) and Hispanic (0.23). TheVKORC1 variant (-1639A) was shown to be prevalent amongst Tibeto-Burmans, whereas CYP2C9 (R144C, I359L) and CYP4F2 (V433M) variants were observed in considerable variability amongst Indo-Europeans. The frequency of CYP2C9*3 (I359L) in north Indians was found to be higher than in most Asian populations. Furthermore, geographical distribution patterns of these variants in north India showed an increased trend of warfarin extensive metabolizers from the Himalayan to Gangetic region. Combined allele frequency (CYP2C9*3 and CYP4F2*3) data suggest that poor metabolizers varied in the range of 0.38-1.85% in Indo-Europeans. Based on genotypic distribution, the majority of the Indian subpopulation might require higher doses for stable anticoagulation, whereas careful assessment is required for Tibeto-Burmans who are expected to have intermediate dose requirement. This is the largest global genetic epidemiological study examining variants associated with warfarin that could potentially be valuable to clinicians in optimizing dosage strategies.

Increased burden of cardiovascular disease in carriers of APOL1 genetic variants.

PubMed

Ito, Kaoru; Bick, Alexander G; Flannick, Jason; Friedman, David J; Genovese, Giulio; Parfenov, Michael G; Depalma, Steven R; Gupta, Namrata; Gabriel, Stacey B; Taylor, Herman A; Fox, Ervin R; Newton-Cheh, Christopher; Kathiresan, Sekar; Hirschhorn, Joel N; Altshuler, David M; Pollak, Martin R; Wilson, James G; Seidman, J G; Seidman, Christine

2014-02-28

Two distinct alleles in the gene encoding apolipoprotein L1 (APOL1), a major component of high-density lipoprotein, confer protection against Trypanosoma brucei rhodesiense infection and also increase risk for chronic kidney disease. Approximately 14% of Americans with African ancestry carry 2 APOL1 risk alleles, accounting for the high chronic kidney disease burden in this population. We tested whether APOL1 risk alleles significantly increase risk for atherosclerotic cardiovascular disease (CVD) in African Americans. We sequenced APOL1 in 1959 randomly selected African American participants in the Jackson Heart Study (JHS) and evaluated associations between APOL1 genotypes and renal and cardiovascular phenotypes. Previously identified association between APOL1 genotypes and chronic kidney disease was confirmed (P=2.4×10(-6)). Among JHS participants with 2 APOL1 risk alleles, we observed increased risk for CVD (50/763 events among participants without versus 37/280 events among participants with 2 risk alleles; odds ratio, 2.17; P=9.4×10(-4)). We replicated this novel association of APOL1 genotype with CVD in Women's Health Initiative (WHI) participants (66/292 events among participants without versus 37/101 events among participants with 2 risk alleles; odds ratio, 1.98; P=8.37×10(-3); JHS and WHI combined, P=8.5×10(-5); odds ratio, 2.12). The increased risk for CVD conferred by APOL1 alleles was robust to correction for both traditional CVD risk factors and chronic kidney disease. APOL1 variants contribute to atherosclerotic CVD risk, indicating a genetic component to cardiovascular health disparities in individuals of African ancestry. The considerable population of African Americans with 2 APOL1 risk alleles may benefit from intensive interventions to reduce CVD.

Complement factor H Y402H variant and risk of age-related macular degeneration in Asians: a systematic review and meta-analysis.

PubMed

Kondo, Naoshi; Bessho, Hiroaki; Honda, Shigeru; Negi, Akira

2011-02-01

To investigate whether the Y402H variant in the complement factor H gene is associated with age-related macular degeneration (AMD) in Asian populations. Meta-analysis of previous publications. Case-control groups of subjects with AMD and controls from 13 association studies. We performed a meta-analysis of the association between Y402H and AMD in Asian populations using data available from 13 case-control studies involving 3973 subjects. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using fixed- and random-effects models. The Q-statistic test was used to assess heterogeneity, and Egger's test was used to evaluate publication bias. Sensitivity analysis, cumulative meta-analysis, and meta-regression analysis were also performed. Allele and genotype frequencies of the Y402H variant. The Y402H variant showed a significant summary OR of 1.97 (95% CI, 1.54-2.52; P<0.001; allelic contrast model) per allele. Possession of at least 1 copy of the C allele increased the disease risk by 1.97-fold (95% CI, 1.63-2.39; P<0.001; dominant model) and accounted for 8.8% of the attributable risk of AMD in Asian populations. Sensitivity analysis indicated the robustness of our findings, and evidence of publication bias was not observed in our meta-analysis. Meta-regression analysis indicated no significant effect of baseline study characteristics on the summary effect size. Cumulative meta-analysis revealed that the summary ORs were stable and the 95% CIs narrowed with the accumulation of data over time. Our analysis provides substantial evidence that the Y402H variant is significantly associated with AMD in Asian populations. Our results expand the number of confirmed AMD susceptibility loci for Asians populations, which provide a better understanding of the genetic architecture underlying disease susceptibility and may advance the potential for preclinical prediction in future genetic tests by a combined evaluation of inherited susceptibility with previously established loci. Copyright © 2011 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Consensus generation and variant detection by Celera Assembler.

PubMed

Denisov, Gennady; Walenz, Brian; Halpern, Aaron L; Miller, Jason; Axelrod, Nelson; Levy, Samuel; Sutton, Granger

2008-04-15

We present an algorithm to identify allelic variation given a Whole Genome Shotgun (WGS) assembly of haploid sequences, and to produce a set of haploid consensus sequences rather than a single consensus sequence. Existing WGS assemblers take a column-by-column approach to consensus generation, and produce a single consensus sequence which can be inconsistent with the underlying haploid alleles, and inconsistent with any of the aligned sequence reads. Our new algorithm uses a dynamic windowing approach. It detects alleles by simultaneously processing the portions of aligned reads spanning a region of sequence variation, assigns reads to their respective alleles, phases adjacent variant alleles and generates a consensus sequence corresponding to each confirmed allele. This algorithm was used to produce the first diploid genome sequence of an individual human. It can also be applied to assemblies of multiple diploid individuals and hybrid assemblies of multiple haploid organisms. Being applied to the individual human genome assembly, the new algorithm detects exactly two confirmed alleles and reports two consensus sequences in 98.98% of the total number 2,033311 detected regions of sequence variation. In 33,269 out of 460,373 detected regions of size >1 bp, it fixes the constructed errors of a mosaic haploid representation of a diploid locus as produced by the original Celera Assembler consensus algorithm. Using an optimized procedure calibrated against 1 506 344 known SNPs, it detects 438 814 new heterozygous SNPs with false positive rate 12%. The open source code is available at: http://wgs-assembler.cvs.sourceforge.net/wgs-assembler/

High prevalence of hemoglobin disorders and glucose-6-phosphate dehydrogenase (G6PD) deficiency in the Republic of Guinea (West Africa).

PubMed

Millimono, Tamba S; Loua, Kovana M; Rath, Silvia L; Relvas, Luis; Bento, Celeste; Diakite, Mandiou; Jarvis, Martin; Daries, Nathalie; Ribeiro, Leticia M; Manco, Licínio; Kaeda, Jaspal S

2012-01-01

Reliable and accurate epidemiological data is a prerequisite for a cost effective screening program for inherited disorders, which however, is lacking in a number of developing countries. Here we report the first detailed population study in the Republic of Guinea, a sub-Saharan West African country, designed to assess the frequency of glucose-6-phosphate dehydrogenase (G6PD) deficiency and hemoglobinopathies, including screening for thalassemia. Peripheral blood samples from 187 Guinean adults were screened for hemoglobin (Hb) variants by standard hematological methods. One hundred and ten samples from males were screened for G6PD deficiency by the fluorescent spot test. Molecular analysis was performed for the most common α-thalassemia (α-thal) deletions, β-globin gene mutations, G6PD variants B (376A), A (376G), A- (376G/202A) and Betica (376G/968C), using polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP) or sequencing. Of the 187 subjects screened, 36 were heterozygous for Hb S [β6(A3)Glu→Val, GAG>GTG] (allele frequency 9.62%). Sixty-four subjects were heterozygous and seven were homozygous for the -α(3.7) kb deletion (allele frequency 20.85%). β-Thalassemia alleles were detected in five subjects, four with the -29 (A>G) mutation (allele frequency 1.07%) and one with codon 15 (TGG>TAG) (allele frequency 0.96%). The G6PD A- and G6PD Betica deficient variants were highly prevalent with a frequency of 5.7 and 3.3%, respectively. While we did not test for ferritin levels or α(0)-thal, four females (5.2%) had red cell indices strongly suggestive of iron deficient anemia: Hb <9.7 g/dL; MCH <19.3 pg; MCV <68.2; MCHC <31.6 g/dl; RDW >19.8%. Our results are consistent with high frequency of alleles such as Hb S, α-thal and G6PD deficient alleles associated with malaria resistance. Finding a 9.6% Hb S allele frequency supports the notion for a proficient neonatal screening to identify the sickle cell patients, who might benefit from early prophylactic treatment for infections. The incidence of significant iron deficient anemia in women is lower than expected in an under developed country.

Biallelic Variants in UBA5 Link Dysfunctional UFM1 Ubiquitin-like Modifier Pathway to Severe Infantile-Onset Encephalopathy.

PubMed

Muona, Mikko; Ishimura, Ryosuke; Laari, Anni; Ichimura, Yoshinobu; Linnankivi, Tarja; Keski-Filppula, Riikka; Herva, Riitta; Rantala, Heikki; Paetau, Anders; Pöyhönen, Minna; Obata, Miki; Uemura, Takefumi; Karhu, Thomas; Bizen, Norihisa; Takebayashi, Hirohide; McKee, Shane; Parker, Michael J; Akawi, Nadia; McRae, Jeremy; Hurles, Matthew E; Kuismin, Outi; Kurki, Mitja I; Anttonen, Anna-Kaisa; Tanaka, Keiji; Palotie, Aarno; Waguri, Satoshi; Lehesjoki, Anna-Elina; Komatsu, Masaaki

2016-09-01

The ubiquitin fold modifier 1 (UFM1) cascade is a recently identified evolutionarily conserved ubiquitin-like modification system whose function and link to human disease have remained largely uncharacterized. By using exome sequencing in Finnish individuals with severe epileptic syndromes, we identified pathogenic compound heterozygous variants in UBA5, encoding an activating enzyme for UFM1, in two unrelated families. Two additional individuals with biallelic UBA5 variants were identified from the UK-based Deciphering Developmental Disorders study and one from the Northern Finland Intellectual Disability cohort. The affected individuals (n = 9) presented in early infancy with severe irritability, followed by dystonia and stagnation of development. Furthermore, the majority of individuals display postnatal microcephaly and epilepsy and develop spasticity. The affected individuals were compound heterozygous for a missense substitution, c.1111G>A (p.Ala371Thr; allele frequency of 0.28% in Europeans), and a nonsense variant or c.164G>A that encodes an amino acid substitution p.Arg55His, but also affects splicing by facilitating exon 2 skipping, thus also being in effect a loss-of-function allele. Using an in vitro thioester formation assay and cellular analyses, we show that the p.Ala371Thr variant is hypomorphic with attenuated ability to transfer the activated UFM1 to UFC1. Finally, we show that the CNS-specific knockout of Ufm1 in mice causes neonatal death accompanied by microcephaly and apoptosis in specific neurons, further suggesting that the UFM1 system is essential for CNS development and function. Taken together, our data imply that the combination of a hypomorphic p.Ala371Thr variant in trans with a loss-of-function allele in UBA5 underlies a severe infantile-onset encephalopathy. Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Common genetic variants associated with thyroid function may be risk alleles for Hashimoto's disease and Graves' disease.

PubMed

Campbell, Purdey; Brix, Thomas H; Wilson, Scott G; Ward, Lynley C; Hui, Jennie; Beilby, John P; Hegedüs, Laszlo; Walsh, John P

2015-02-14

Recent studies have identified common genetic variants associated with TSH, free T4 and thyroid peroxidase antibodies, but it is unclear whether these differ between patients with Hashimoto's disease and Graves' disease. To examine whether 11 common genetic variants differ between Graves' disease and Hashimoto's disease. We genotyped 11 common variants in a discovery cohort of 203 Australian patients with autoimmune thyroid disease (AITD). Two variants with significant or suggestive associations were analysed in a replication cohort of 384 Danish patients. For rs753760 (PDE10A), the minor allele frequency in Graves' disease and Hashimoto's disease was 0·38 vs. 0·23, respectively, (P = 6·42 × 10 -4 ) in the discovery cohort, 0·29 vs. 0·24 (P = 0·147) in the replication cohort and 0·32 vs. 0·24 in combined analysis (P = 0·0021; all analyses adjusted for sex). In healthy controls from Busselton, the frequency was 0·29, significantly different from Hashimoto's disease but not Graves' disease. For rs4889009 (MAF gene region), the frequency of the minor G-allele in Graves' disease and Hashimoto's disease was 0·48 vs. 0·36 (P = 0·0156) in the discovery cohort, 0·48 vs. 0·34 (P = 1·83 × 10 -4 ) in the replication cohort and 0·48 vs. 0·35 in the combined analysis (P = 7·53 × 10 -6 ); in controls, the frequency was 0·38, significantly different from Graves' disease but not Hashimoto's disease. After further adjustment for smoking, associations with rs4889009 remained significant, whereas those with rs753760 were not. Common variants in PDE10A and MAF gene regions may influence whether patients with AITD develop Graves' disease or Hashimoto's disease. © 2015 John Wiley & Sons Ltd.

A detailed clinical and molecular survey of subjects with nonsyndromic USH2A retinopathy reveals an allelic hierarchy of disease-causing variants

PubMed Central

Lenassi, Eva; Vincent, Ajoy; Li, Zheng; Saihan, Zubin; Coffey, Alison J; Steele-Stallard, Heather B; Moore, Anthony T; Steel, Karen P; Luxon, Linda M; Héon, Elise; Bitner-Glindzicz, Maria; Webster, Andrew R

2015-01-01

Defects in USH2A cause both isolated retinal disease and Usher syndrome (ie, retinal disease and deafness). To gain insights into isolated/nonsyndromic USH2A retinopathy, we screened USH2A in 186 probands with recessive retinal disease and no hearing complaint in childhood (discovery cohort) and in 84 probands with recessive retinal disease (replication cohort). Detailed phenotyping, including retinal imaging and audiological assessment, was performed in individuals with two likely disease-causing USH2A variants. Further genetic testing, including screening for a deep-intronic disease-causing variant and large deletions/duplications, was performed in those with one likely disease-causing change. Overall, 23 of 186 probands (discovery cohort) were found to harbour two likely disease-causing variants in USH2A. Some of these variants were predominantly associated with nonsyndromic retinal degeneration (‘retinal disease-specific'); these included the common c.2276 G>T, p.(Cys759Phe) mutation and five additional variants: c.2802 T>G, p.(Cys934Trp); c.10073 G>A, p.(Cys3358Tyr); c.11156 G>A, p.(Arg3719His); c.12295-3 T>A; and c.12575 G>A, p.(Arg4192His). An allelic hierarchy was observed in the discovery cohort and confirmed in the replication cohort. In nonsyndromic USH2A disease, retinopathy was consistent with retinitis pigmentosa and the audiological phenotype was variable. USH2A retinopathy is a common cause of nonsyndromic recessive retinal degeneration and has a different mutational spectrum to that observed in Usher syndrome. The following model is proposed: the presence of at least one ‘retinal disease-specific' USH2A allele in a patient with USH2A-related disease results in the preservation of normal hearing. Careful genotype–phenotype studies such as this will become increasingly important, especially now that high-throughput sequencing is widely used in the clinical setting. PMID:25649381

Association of branched chain amino acids related variant rs1440581 with risk of incident diabetes and longitudinal changes in insulin resistance in Chinese.

PubMed

Xuan, Liping; Hou, Yanan; Wang, Tiange; Li, Mian; Zhao, Zhiyun; Lu, Jieli; Xu, Yu; Chen, Yuhong; Qi, Lu; Wang, Weiqing; Bi, Yufang; Xu, Min

2018-05-31

Previous genome-wide association studies reported rs1440581 was significantly associated with circulating branched chain amino acids (BCAAs) levels in Europeans. We aimed to investigate association of BCAAs related variant rs1440581 with incident T2D risk and longitudinal changes in glucose-related metabolic traits in a community-based prospective cohort of Chinese. 6043 non-diabetic participants aged ≥ 40 years from a community-based population at baseline were included and followed-up for 5 years. The BCAAs related variant rs1440581 was genotyped. Incident T2D was defined as fasting plasma glucose (FPG) ≥ 7.0 mmol/L or taking anti-diabetic therapy. Anthropometry and biochemical measurements were evaluated at both baseline and follow-up. 576 (9.5%) participants developed T2D during the 5-year follow-up. Each C-allele was associated with a 20% higher risk of incident T2D (odds ratio = 1.20, 95% confidence interval [1.05, 1.36]) after adjustments for the confounders. We did not find a main effect of the variant on increase in fasting serum insulin (FSI) level or insulin resistance (IR). However, we found rs1440581 significantly modified effect of weight gain on increase in FSI and HOMA-IR. In the C-allele carriers, body mass index increase was associated with greater increase in Log 10 _FSI (β ± SE 0.027 ± 0.002) and Log 10 _HOMA-IR (0.030 ± 0.003), as compared to T-allele (both P for interaction = 0.003). BCAAs related genetic variant rs1440581 was associated with an increased risk of incident T2D in a Chinese population. This variant might modify effect of weight gain on development in IR.

A Rb1 promoter variant with reduced activity contributes to osteosarcoma susceptibility in irradiated mice

PubMed Central

2014-01-01

Background Syndromic forms of osteosarcoma (OS) account for less than 10% of all recorded cases of this malignancy. An individual OS predisposition is also possible by the inheritance of low penetrance alleles of tumor susceptibility genes, usually without evidence of a syndromic condition. Genetic variants involved in such a non-syndromic form of tumor predisposition are difficult to identify, given the low incidence of osteosarcoma cases and the genetic heterogeneity of patients. We recently mapped a major OS susceptibility QTL to mouse chromosome 14 by comparing alpha-radiation induced osteosarcoma in mouse strains which differ in their tumor susceptibility. Methods Tumor-specific allelic losses in murine osteosacoma were mapped along chromosome 14 using microsatellite markers and SNP allelotyping. Candidate gene search in the mapped interval was refined using PosMed data mining and mRNA expression analysis in normal osteoblasts. A strain-specific promoter variant in Rb1 was tested for its influence on mRNA expression using reporter assay. Results A common Rb1 allele derived from the BALB/cHeNhg strain was identified as the major determinant of radiation-induced OS risk at this locus. Increased OS-risk is linked with a hexanucleotide deletion in the promoter region which is predicted to change WT1 and SP1 transcription factor-binding sites. Both in-vitro reporter and in-vivo expression assays confirmed an approx. 1.5 fold reduced gene expression by this promoter variant. Concordantly, the 50% reduction in Rb1 expression in mice bearing a conditional hemizygous Rb1 deletion causes a significant rise of OS incidence following alpha-irradiation. Conclusion This is the first experimental demonstration of a functional and genetic link between reduced Rb1 expression from a common promoter variant and increased tumor risk after radiation exposure. We propose that a reduced Rb1 expression by common variants in regulatory regions can modify the risk for a malignant transformation of bone cells after radiation exposure. PMID:25092376

From Common to Rare Variants: The Genetic Component of Alzheimer Disease.

PubMed

Nicolas, Gaël; Charbonnier, Camille; Campion, Dominique

2016-01-01

Alzheimer disease (AD) is a remarkable example of genetic heterogeneity. Extremely rare variants in the APP, PSEN1, or PSEN2 genes, or duplications of the APP gene cause autosomal dominant forms, generally with complete penetrance by the age of 65 years. Nonautosomal dominant forms are considered as a complex disorder with a high genetic component, whatever the age of onset. Although genetically heterogeneous, AD is defined by the same neuropathological criteria in all configurations. According to the amyloid cascade hypothesis, the Aβ peptide, which aggregates in AD brains, is a key player. APP, PSEN1, or PSEN2 gene mutations increase the production of more aggregation-prone forms of the Aβ peptide, triggering the pathological process. Several risk factors identified in association studies hit genes involved in Aβ production/secretion, aggregation, clearance, or toxicity. Among them, the APOE ε4 allele is a rare example of a common allele with a large effect size, the ORs ranging from 4 to 11-14 for heterozygous and homozygous carriers, respectively. In addition, genome-wide association studies have identified more than two dozen loci with a weak but significant association, the OR of the at-risk allele ranging from 1.08 to 1.30. Recently, the use of massive parallel sequencing has enabled the analysis of rare variants in a genome-wide manner. Two rare variants have been nominally associated with AD risk or protection (TREM2 p.R47H, MAF approximately 0.002, OR approximately 4 and APP p.A673T, MAF approximately 0.0005, OR approximately 0.2). Association analyses at the gene level identified rare loss-of-function and missense, predicted damaging, variants (MAF <0.01) in the SORL1 and ABCA7 genes associated with a moderate relative risk (OR approximately 5 and approximately 2.8, respectively). Although the latter analyses revealed association signals with moderately rare variants by collapsing them, the power to detect genes hit by extremely rare variants is still limited. An alternative approach is to consider the de novo paradigm, stating that de novo variants may contribute to AD genetics in sporadic patients. Here, we critically review AD genetics reports with a special focus on rare variants. © 2016 S. Karger AG, Basel.

Molecular analysis reveals a high mutation frequency in the first untranslated exon of the PPOX gene and largely excludes variegate porphyria in a subset of clinically affected Afrikaner families.

PubMed

Kotze, M J; De Villiers, J N; Groenewald, J Z; Rooney, R N; Loubser, O; Thiart, R; Oosthuizen, C J; van Niekerk, M M; Groenewald, I M; Retief, A E; Warnich, L

1998-10-01

A subset of probands from 11 South African families with clinical and/or biochemical features of variegate porphyria (VP), but without the known protoporphyrinogen oxidase (PPOX) gene defects identified previously in the South African population, were subjected to mutation analysis. Disease-related mutation(s) could not be identified after screening virtually the entire PPOX gene by heteroduplex single-strand conformation polymorphism analysis (HEX-SSCP), although three new sequence variants were detected in exon 1 of the gene in three normal controls. The presence of these single base changes at nucleotide positions 22 (C/G), 27 (C/A) and 127 (C/A), in addition to the known exon 1 polymorphisms I-26 and I-150, indicates that this untranslated region of the PPOX gene is particularly mutation-prone. Furthermore, microsatellite markers flanking the PPOX and alpha-1 antitrypsin (PI) gene, on chromosomes 1 and 14, respectively, were used to assess the probability of involvement of these loci in disease presentation. Common alleles transmitted from affected parent to affected child were determined where possible in the mutation-negative index cases. Allelic frequencies of these alleles were compared to findings in the normal population, but no predominant disease-associated allele could be identified. Co-segregation of a specific haplotype with the disease phenotype could also not be demonstrated in a large Afrikaner family. It is concluded that further studies are warranted to determine the genetic factor(s) underlying the autosomal dominant pattern of inheritance in molecularly uncharacterized cases showing clinical symptoms of an acute porphyria. Copyright 1998 Academic Press.

Allele-dependent differences in quorum-sensing dynamics result in variant expression of virulence genes in Staphylococcus aureus.

PubMed

Geisinger, Edward; Chen, John; Novick, Richard P

2012-06-01

Agr is an autoinducing, quorum-sensing system that functions in many Gram-positive species and is best characterized in the pathogen Staphylococcus aureus, in which it is a global regulator of virulence gene expression. Allelic variations in the agr genes have resulted in the emergence of four quorum-sensing specificity groups in S. aureus, which correlate with different strain pathotypes. The basis for these predilections is unclear but is hypothesized to involve the phenomenon of quorum-sensing interference between strains of different agr groups, which may drive S. aureus strain isolation and divergence. Whether properties intrinsic to each agr allele directly influence virulence phenotypes within S. aureus is unknown. In this study, we examined group-specific differences in agr autoinduction and virulence gene regulation by utilizing congenic strains, each harboring a unique S. aureus agr allele, enabling a dissection of agr locus-dependent versus genotype-dependent effects on quorum-sensing dynamics and virulence factor production. Employing a reporter fusion to the principal agr promoter, P3, we observed allele-dependent differences in the timing and magnitude of agr activation. These differences were mediated by polymorphisms within the agrBDCA genes and translated to significant variations in the expression of a key transcriptional regulator, Rot, and of several important exoproteins and surface factors involved in pathogenesis. This work uncovers the contribution of divergent quorum-sensing alleles to variant expression of virulence determinants within a bacterial species.

The IL23R A/Gln381 allele promotes IL-23 unresponsiveness in human memory T-helper 17 cells and impairs Th17 responses in psoriasis patients.

PubMed

Di Meglio, Paola; Villanova, Federica; Napolitano, Luca; Tosi, Isabella; Terranova Barberio, Manuela; Mak, Rose K; Nutland, Sarah; Smith, Catherine H; Barker, Jonathan N W N; Todd, John A; Nestle, Frank O

2013-10-01

We and others have shown that the minor, nonconserved allele Gln381 of the Arg381Gln single-nucleotide polymorphism (rs11209026G>A) of the IL-23 receptor gene (IL23R) protects against psoriasis. Moreover, we have recently shown impaired IL-23-induced IL-17A production and STAT-3 phosphorylation in Th17 cells generated in vitro from healthy individuals heterozygous for the protective A allele (GA). However, the biological effect of this variant has not been determined in homozygous carriers of the protective A allele (AA), nor in psoriatic patients. Here we expand our functional investigation of the IL23R Arg381Gln gene variant to include AA homozygous individuals. By using isolated memory CD4+ T cells, we found attenuated IL-23-induced Th17 response in heterozygous individuals. Moreover, we found that AA homozygous individuals were strikingly unresponsive to IL-23, with minimal or no IL-17A and IL-17F production and failure of human memory Th17 cell survival/expansion. Finally, IL-23-induced Th17 response was also attenuated in age- and sex-matched GA versus GG psoriatic patients undergoing systemic treatment. Taken together, our data provide evidence for an allele-dosage effect for IL-23R Gln381 and indicate that common gene alleles associated with complex diseases might have biological effects of considerable magnitude in homozygous carriers.

A Genome-Wide Association Study Reveals Genes Associated with Fusarium Ear Rot Resistance in a Maize Core Diversity Panel

PubMed Central

Zila, Charles T.; Samayoa, L. Fernando; Santiago, Rogelio; Butrón, Ana; Holland, James B.

2013-01-01

Fusarium ear rot is a common disease of maize that affects food and feed quality globally. Resistance to the disease is highly quantitative, and maize breeders have difficulty incorporating polygenic resistance alleles from unadapted donor sources into elite breeding populations without having a negative impact on agronomic performance. Identification of specific allele variants contributing to improved resistance may be useful to breeders by allowing selection of resistance alleles in coupling phase linkage with favorable agronomic characteristics. We report the results of a genome-wide association study to detect allele variants associated with increased resistance to Fusarium ear rot in a maize core diversity panel of 267 inbred lines evaluated in two sets of environments. We performed association tests with 47,445 single-nucleotide polymorphisms (SNPs) while controlling for background genomic relationships with a mixed model and identified three marker loci significantly associated with disease resistance in at least one subset of environments. Each associated SNP locus had relatively small additive effects on disease resistance (±1.1% on a 0–100% scale), but nevertheless were associated with 3 to 12% of the genotypic variation within or across environment subsets. Two of three identified SNPs colocalized with genes that have been implicated with programmed cell death. An analysis of associated allele frequencies within the major maize subpopulations revealed enrichment for resistance alleles in the tropical/subtropical and popcorn subpopulations compared with other temperate breeding pools. PMID:24048647

Lipid and Alzheimer's disease genes associated with healthy aging and longevity in healthy oldest-old.

PubMed

Tindale, Lauren C; Leach, Stephen; Spinelli, John J; Brooks-Wilson, Angela R

2017-03-28

Several studies have found that long-lived individuals do not appear to carry lower numbers of common disease-associated variants than ordinary people; it has been hypothesized that they may instead carry protective variants. An intriguing type of protective variant is buffering variants that protect against variants that have deleterious effects. We genotyped 18 variants in 15 genes related to longevity or healthy aging that had been previously reported as having a gene-gene interaction or buffering effect. We compared a group of 446 healthy oldest-old 'Super-Seniors' (individuals 85 or older who have never been diagnosed with cancer, cardiovascular disease, dementia, diabetes or major pulmonary disease) to 421 random population-based midlife controls. Cases and controls were of European ancestry. Association tests of individual SNPs showed that Super-Seniors were less likely than controls to carry an APOEε4 allele or a haptoglobin HP2 allele. Interactions between APOE/FOXO3, APOE/CRYL1, and LPA/CRYL1 did not remain significant after multiple testing correction. In a network analysis of the candidate genes, lipid and cholesterol metabolism was a common theme. APOE, HP, and CRYL1 have all been associated with Alzheimer's Disease, the pathology of which involves lipid and cholesterol pathways. Age-related changes in lipid and cholesterol maintenance, particularly in the brain, may be central to healthy aging and longevity.

HFE gene variants and iron-induced oxygen radical generation in idiopathic pulmonary fibrosis.

PubMed

Sangiuolo, Federica; Puxeddu, Ermanno; Pezzuto, Gabriella; Cavalli, Francesco; Longo, Giuliana; Comandini, Alessia; Di Pierro, Donato; Pallante, Marco; Sergiacomi, Gianluigi; Simonetti, Giovanni; Zompatori, Maurizio; Orlandi, Augusto; Magrini, Andrea; Amicosante, Massimo; Mariani, Francesca; Losi, Monica; Fraboni, Daniela; Bisetti, Alberto; Saltini, Cesare

2015-02-01

In idiopathic pulmonary fibrosis (IPF), lung accumulation of excessive extracellular iron and macrophage haemosiderin may suggest disordered iron homeostasis leading to recurring microscopic injury and fibrosing damage. The current study population comprised 89 consistent IPF patients and 107 controls. 54 patients and 11 controls underwent bronchoalveolar lavage (BAL). Haemosiderin was assessed by Perls' stain, BAL fluid malondialdehyde (MDA) by high-performance liquid chromatography, BAL cell iron-dependent oxygen radical generation by fluorimetry and the frequency of hereditary haemochromatosis HFE gene variants by reverse dot blot hybridisation. Macrophage haemosiderin, BAL fluid MDA and BAL cell unstimulated iron-dependent oxygen radical generation were all significantly increased above controls (p<0.05). The frequency of C282Y, S65C and H63D HFE allelic variants was markedly higher in IPF compared with controls (40.4% versus 22.4%, OR 2.35, p=0.008) and was associated with higher iron-dependent oxygen radical generation (HFE variant 107.4±56.0, HFE wild type (wt) 59.4±36.4 and controls 16.7±11.8 fluorescence units per 10(5) BAL cells; p=0.028 HFE variant versus HFE wt, p=0.006 HFE wt versus controls). The data suggest iron dysregulation associated with HFE allelic variants may play an important role in increasing susceptibility to environmental exposures, leading to recurring injury and fibrosis in IPF. Copyright ©ERS 2015.

Allele-Specific Methylation Occurs at Genetic Variants Associated with Complex Disease

PubMed Central

Hutchinson, John N.; Raj, Towfique; Fagerness, Jes; Stahl, Eli; Viloria, Fernando T.; Gimelbrant, Alexander; Seddon, Johanna; Daly, Mark; Chess, Andrew; Plenge, Robert

2014-01-01

We hypothesize that the phenomenon of allele-specific methylation (ASM) may underlie the phenotypic effects of multiple variants identified by Genome-Wide Association studies (GWAS). We evaluate ASM in a human population and document its genome-wide patterns in an initial screen at up to 380,678 sites within the genome, or up to 5% of the total genomic CpGs. We show that while substantial inter-individual variation exists, 5% of assessed sites show evidence of ASM in at least six samples; the majority of these events (81%) are under genetic influence. Many of these cis-regulated ASM variants are also eQTLs in peripheral blood mononuclear cells and monocytes and/or in high linkage-disequilibrium with variants linked to complex disease. Finally, focusing on autoimmune phenotypes, we extend this initial screen to confirm the association of cis-regulated ASM with multiple complex disease-associated variants in an independent population using next-generation bisulfite sequencing. These four variants are implicated in complex phenotypes such as ulcerative colitis and AIDS progression disease (rs10491434), Celiac disease (rs2762051), Crohn's disease, IgA nephropathy and early-onset inflammatory bowel disease (rs713875) and height (rs6569648). Our results suggest cis-regulated ASM may provide a mechanistic link between the non-coding genetic changes and phenotypic variation observed in these diseases and further suggests a route to integrating DNA methylation status with GWAS results. PMID:24911414

Human longevity is influenced by many genetic variants: evidence from 75,000 UK Biobank participants

PubMed Central

Pilling, Luke C.; Atkins, Janice L.; Bowman, Kirsty; Jones, Samuel E.; Tyrrell, Jessica; Beaumont, Robin N.; Ruth, Katherine S.; Tuke, Marcus A.; Yaghootkar, Hanieh; Wood, Andrew R.; Freathy, Rachel M.; Murray, Anna; Weedon, Michael N.; Xue, Luting; Lunetta, Kathryn; Murabito, Joanne M.; Harries, Lorna W.; Robine, Jean-Marie; Brayne, Carol; Kuchel, George A.; Ferrucci, Luigi; Frayling, Timothy M.; Melzer, David

2016-01-01

Variation in human lifespan is 20 to 30% heritable in twins but few genetic variants have been identified. We undertook a Genome Wide Association Study (GWAS) using age at death of parents of middle-aged UK Biobank participants of European decent (n=75,244 with father's and/or mother's data, excluding early deaths). Genetic risk scores for 19 phenotypes (n=777 proven variants) were also tested. In GWAS, a nicotine receptor locus (CHRNA3, previously associated with increased smoking and lung cancer) was associated with fathers' survival. Less common variants requiring further confirmation were also identified. Offspring of longer lived parents had more protective alleles for coronary artery disease, systolic blood pressure, body mass index, cholesterol and triglyceride levels, type-1 diabetes, inflammatory bowel disease and Alzheimer's disease. In candidate analyses, variants in the TOMM40/APOE locus were associated with longevity, but FOXO variants were not. Associations between extreme longevity (mother >=98 years, fathers >=95 years, n=1,339) and disease alleles were similar, with an additional association with HDL cholesterol (p=5.7×10-3). These results support a multiple protective factors model influencing lifespan and longevity (top 1% survival) in humans, with prominent roles for cardiovascular-related pathways. Several of these genetically influenced risks, including blood pressure and tobacco exposure, are potentially modifiable. PMID:27015805

Elevated Proportions of Deleterious Genetic Variation in Domestic Animals and Plants

PubMed Central

Rubin, Carl-Johan; Carneiro, Miguel; Axelsson, Erik; Andersson, Leif

2018-01-01

Abstract A fraction of genetic variants segregating in any population are deleterious, which negatively impacts individual fitness. The domestication of animals and plants is associated with population bottlenecks and artificial selection, which are predicted to increase the proportion of deleterious variants. However, the extent to which this is a general feature of domestic species is unclear. Here, we examine the effects of domestication on the prevalence of deleterious variation using pooled whole-genome resequencing data from five domestic animal species (dog, pig, rabbit, chicken, and silkworm) and two domestic plant species (rice and soybean) compared with their wild ancestors. We find significantly reduced genetic variation and increased proportion of nonsynonymous amino acid changes in all but one of the domestic species. These differences are observable across a range of allele frequencies, both common and rare. We find proportionally more single nucleotide polymorphisms in highly conserved elements in domestic species and a tendency for domestic species to harbor a higher proportion of changes classified as damaging. Our findings most likely reflect an increased incidence of deleterious variants in domestic species, which is most likely attributable to population bottlenecks that lead to a reduction in the efficacy of selection. An exception to this pattern is displayed by European domestic pigs, which do not show traces of a strong population bottleneck and probably continued to exchange genes with wild boar populations after domestication. The results presented here indicate that an elevated proportion of deleterious variants is a common, but not ubiquitous, feature of domestic species. PMID:29325102

Genome-wide association study of chemotherapeutic agent-induced severe neutropenia/leucopenia for patients in Biobank Japan.

PubMed

Low, Siew-Kee; Chung, Suyoun; Takahashi, Atsushi; Zembutsu, Hitoshi; Mushiroda, Taisei; Kubo, Michiaki; Nakamura, Yusuke

2013-08-01

Chemotherapeutic agents are notoriously known to have a narrow therapeutic range that often results in life-threatening toxicity. Hence, it is clinically important to identify the patients who are at high risk for severe toxicity to certain chemotherapy through a pharmacogenomics approach. In this study, we carried out multiple genome-wide association studies (GWAS) of 13 122 cancer patients who received different chemotherapy regimens, including cyclophosphamide- and platinum-based (cisplatin and carboplatin), anthracycline-based (doxorubicin and epirubicin), and antimetabolite-based (5-fluorouracil and gemcitabine) treatment, antimicrotubule agents (paclitaxel and docetaxel), and topoisomerase inhibitors (camptothecin and etoposide), as well as combination therapy with paclitaxel and carboplatin, to identify genetic variants that are associated with the risk of severe neutropenia/leucopenia in the Japanese population. In addition, we used a weighted genetic risk scoring system to evaluate the cumulative effects of the suggestive genetic variants identified from GWAS in order to predict the risk levels of individuals who carry multiple risk alleles. Although we failed to identify genetic variants that surpassed the genome-wide significance level (P < 5.0 × 10(-8) ) through GWAS, probably due to insufficient statistical power and complex clinical features, we were able to shortlist some of the suggestive associated loci. The current study is at the relatively preliminary stage, but does highlight the complexity and problematic issues associated with retrospective pharmacogenomics studies. However, we hope that verification of these genetic variants through local and international collaborations could improve the clinical outcome for cancer patients. © 2013 Japanese Cancer Association.

Cluster B personality disorders are associated with allelic variation of monoamine oxidase A activity.

PubMed

Jacob, Christian P; Müller, Johannes; Schmidt, Michael; Hohenberger, Katrin; Gutknecht, Lise; Reif, Andreas; Schmidtke, Armin; Mössner, Rainald; Lesch, Klaus Peter

2005-09-01

Genetic variants of the monoamine oxidase A (MAOA) have been associated with aggression-, anxiety-, and addiction-related behavior in several nonclinical and clinical populations. Here, we investigated the influence of allelic variation of MAOA activity on aggression-related personality traits and disease risk in patients with personality disorders. Personality disorders were diagnosed with the Structured Clinical Interview of DSM-IV and were allocated to cluster A, B, and C. Personality features were assessed by the revised NEO Personality Inventory and the Tridimensional Personality Questionnaire. The genotype of the MAOA gene-linked polymorphic region (MAOA-LPR) was determined in 566 patients with personality disorders and in 281 healthy controls. MAOA genotype was significantly associated with cluster B personality disorders (chi2=7.77, p=0.005, df=1) but not with cluster C personality disorders. In total, 26.0% of cluster B patients were hemi- or homozygous for the low-activity variant of the MAOA genotype, compared to 16.4% in the control group. Associations between MAOA variants and personality domains related to impulsivity and aggressiveness were inconsistent. Our findings further support the notion that allelic variation of MAOA activity contributes modestly to the balance of hyper- (impulsive-aggressive) and hyporeactive (anxious-depressive) traits.

A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor–negative breast cancer

PubMed Central

Haiman, Christopher A; Chen, Gary K; Vachon, Celine M; Canzian, Federico; Dunning, Alison; Millikan, Robert C; Wang, Xianshu; Ademuyiwa, Foluso; Ahmed, Shahana; Ambrosone, Christine B; Baglietto, Laura; Balleine, Rosemary; Bandera, Elisa V; Beckmann, Matthias W; Berg, Christine D; Bernstein, Leslie; Blomqvist, Carl; Blot, William J; Brauch, Hiltrud; Buring, Julie E; Carey, Lisa A; Carpenter, Jane E; Chang-Claude, Jenny; Chanock, Stephen J; Chasman, Daniel I; Clarke, Christine L; Cox, Angela; Cross, Simon S; Deming, Sandra L; Diasio, Robert B; Dimopoulos, Athanasios M; Driver, W Ryan; Dünnebier, Thomas; Durcan, Lorraine; Eccles, Diana; Edlund, Christopher K; Ekici, Arif B; Fasching, Peter A; Feigelson, Heather S; Flesch-Janys, Dieter; Fostira, Florentia; Försti, Asta; Fountzilas, George; Gerty, Susan M; Giles, Graham G; Godwin, Andrew K; Goodfellow, Paul; Graham, Nikki; Greco, Dario; Hamann, Ute; Hankinson, Susan E; Hartmann, Arndt; Hein, Rebecca; Heinz, Judith; Holbrook, Andrea; Hoover, Robert N; Hu, Jennifer J; Hunter, David J; Ingles, Sue A; Irwanto, Astrid; Ivanovich, Jennifer; John, Esther M; Johnson, Nicola; Jukkola-Vuorinen, Arja; Kaaks, Rudolf; Ko, Yon-Dschun; Kolonel, Laurence N; Konstantopoulou, Irene; Kosma, Veli-Matti; Kulkarni, Swati; Lambrechts, Diether; Lee, Adam M; Le Marchand, Loïc; Lesnick, Timothy; Liu, Jianjun; Lindstrom, Sara; Mannermaa, Arto; Margolin, Sara; Martin, Nicholas G; Miron, Penelope; Montgomery, Grant W; Nevanlinna, Heli; Nickels, Stephan; Nyante, Sarah; Olswold, Curtis; Palmer, Julie; Pathak, Harsh; Pectasides, Dimitrios; Perou, Charles M; Peto, Julian; Pharoah, Paul D P; Pooler, Loreall C; Press, Michael F; Pylkäs, Katri; Rebbeck, Timothy R; Rodriguez-Gil, Jorge L; Rosenberg, Lynn; Ross, Eric; Rüdiger, Thomas; Silva, Isabel dos Santos; Sawyer, Elinor; Schmidt, Marjanka K; Schulz-Wendtland, Rüdiger; Schumacher, Fredrick; Severi, Gianluca; Sheng, Xin; Signorello, Lisa B; Sinn, Hans-Peter; Stevens, Kristen N; Southey, Melissa C; Tapper, William J; Tomlinson, Ian; Hogervorst, Frans B L; Wauters, Els; Weaver, JoEllen; Wildiers, Hans; Winqvist, Robert; Van Den Berg, David; Wan, Peggy; Xia, Lucy Y; Yannoukakos, Drakoulis; Zheng, Wei; Ziegler, Regina G; Siddiq, Afshan; Slager, Susan L; Stram, Daniel O; Easton, Douglas; Kraft, Peter; Henderson, Brian E; Couch, Fergus J

2012-01-01

Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 × 10−10). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 × 10−9), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 × 10−9). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations. PMID:22037553

Evidence for a founder effect for pseudoxanthoma elasticum in the Afrikaner population of South Africa.

PubMed

Le Saux, Olivier; Beck, Konstanze; Sachsinger, Christine; Treiber, Carina; Göring, Harald H H; Curry, Katie; Johnson, Eric W; Bercovitch, Lionel; Marais, Anna-Susan; Terry, Sharon F; Viljoen, Denis L; Boyd, Charles D

2002-10-01

Pseudoxanthoma elasticum (PXE) is a heritable elastic tissue disorder recently shown to be attributable to mutations in the ABCC6 ( MRP6) gene. Whereas PXE has been identified in all ethnic groups studied to date, the prevalence of this disease in various populations is uncertain, although often assumed to be similar. A notable exception however is the prevalence of PXE among South African Afrikaners. A previous report has suggested that a founder effect may explain the higher prevalence of PXE in Afrikaners, a European-derived population that first settled in South Africa in the 17th century. To investigate this hypothesis, we performed haplotype and mutational analysis of DNA from 24 South African families of Afrikaner, British and Indian descent. Among the 17 Afrikaner families studied, three common haplotypes and six different disease-causing variants were identified. Three of these mutant alleles were missense variants, two were nonsense mutations and one was a single base-pair insertion. The most common variant accounted for 53% of the PXE alleles, whereas other mutant alleles appeared at lower frequencies ranging from 3% to 12%. Haplotype analysis of the Afrikaner families showed that the three most frequent mutations were identical-by-descent, indicating a founder origin of PXE in this population.

Variants in MTNR1B influence fasting glucose levels

PubMed Central

Prokopenko, Inga; Langenberg, Claudia; Florez, Jose C; Saxena, Richa; Soranzo, Nicole; Thorleifsson, Gudmar; Loos, Ruth J F; Manning, Alisa K; Jackson, Anne U; Aulchenko, Yurii; Potter, Simon C; Erdos, Michael R; Sanna, Serena; Hottenga, Jouke-Jan; Wheeler, Eleanor; Kaakinen, Marika; Lyssenko, Valeriya; Chen, Wei-Min; Ahmadi, Kourosh; Beckmann, Jacques S; Bergman, Richard N; Bochud, Murielle; Bonnycastle, Lori L; Buchanan, Thomas A; Cao, Antonio; Cervino, Alessandra; Coin, Lachlan; Collins, Francis S; Crisponi, Laura; de Geus, Eco J C; Dehghan, Abbas; Deloukas, Panos; Doney, Alex S F; Elliott, Paul; Freimer, Nelson; Gateva, Vesela; Herder, Christian; Hofman, Albert; Hughes, Thomas E; Hunt, Sarah; Illig, Thomas; Inouye, Michael; Isomaa, Bo; Johnson, Toby; Kong, Augustine; Krestyaninova, Maria; Kuusisto, Johanna; Laakso, Markku; Lim, Noha; Lindblad, Ulf; Lindgren, Cecilia M; McCann, Owen T; Mohlke, Karen L; Morris, Andrew D; Naitza, Silvia; Orrù, Marco; Palmer, Colin N A; Pouta, Anneli; Randall, Joshua; Rathmann, Wolfgang; Saramies, Jouko; Scheet, Paul; Scott, Laura J; Scuteri, Angelo; Sharp, Stephen; Sijbrands, Eric; Smit, Jan H; Song, Kijoung; Steinthorsdottir, Valgerdur; Stringham, Heather M; Tuomi, Tiinamaija; Tuomilehto, Jaakko; Uitterlinden, André G; Voight, Benjamin F; Waterworth, Dawn; Wichmann, H-Erich; Willemsen, Gonneke; Witteman, Jacqueline C M; Yuan, Xin; Zhao, Jing Hua; Zeggini, Eleftheria; Schlessinger, David; Sandhu, Manjinder; Boomsma, Dorret I; Uda, Manuela; Spector, Tim D; Penninx, Brenda WJH; Altshuler, David; Vollenweider, Peter; Jarvelin, Marjo Riitta; Lakatta, Edward; Waeber, Gerard; Fox, Caroline S; Peltonen, Leena; Groop, Leif C; Mooser, Vincent; Cupples, L Adrienne; Thorsteinsdottir, Unnur; Boehnke, Michael; Barroso, Inês; Van Duijn, Cornelia; Dupuis, Josée; Watanabe, Richard M; Stefansson, Kari; McCarthy, Mark I; Wareham, Nicholas J; Meigs, James B; Abecasis, Gonçalo R

2009-01-01

To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 = × 10−50) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 × 10−15). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 × 10−7) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 × 10−57) and GCK (rs4607517, P = 1.0 × 10−25) loci. PMID:19060907

CACNA1C risk variant affects facial emotion recognition in healthy individuals.

PubMed

Nieratschker, Vanessa; Brückmann, Christof; Plewnia, Christian

2015-11-27

Recognition and correct interpretation of facial emotion is essential for social interaction and communication. Previous studies have shown that impairments in this cognitive domain are common features of several psychiatric disorders. Recent association studies identified CACNA1C as one of the most promising genetic risk factors for psychiatric disorders and previous evidence suggests that the most replicated risk variant in CACNA1C (rs1006737) is affecting emotion recognition and processing. However, studies investigating the influence of rs1006737 on this intermediate phenotype in healthy subjects at the behavioral level are largely missing to date. Here, we applied the "Reading the Mind in the Eyes" test, a facial emotion recognition paradigm in a cohort of 92 healthy individuals to address this question. Whereas accuracy was not affected by genotype, CACNA1C rs1006737 risk-allele carries (AA/AG) showed significantly slower mean response times compared to individuals homozygous for the G-allele, indicating that healthy risk-allele carriers require more information to correctly identify a facial emotion. Our study is the first to provide evidence for an impairing behavioral effect of the CACNA1C risk variant rs1006737 on facial emotion recognition in healthy individuals and adds to the growing number of studies pointing towards CACNA1C as affecting intermediate phenotypes of psychiatric disorders.

A variant of the endothelial nitric oxide synthase gene (NOS3) associated with AMS susceptibility is less common in the Quechua, a high altitude Native population.

PubMed

Wang, Pei; Ha, Alice Y N; Kidd, Kenneth K; Koehle, Michael S; Rupert, Jim L

2010-01-01

Endothelial nitric oxide synthase (eNOS) is a vascular enzyme that produces nitric oxide, a transient signaling molecule that by vasodilatation regulates blood flow and pressure. Nitric oxide is believed to play roles in both short-term acclimatization and long-term evolutionary adaptation to environmental hypoxia. Several laboratories, including ours, have shown that variants in NOS3 (the gene encoding eNOS) are overrepresented in individuals with altitude-related illnesses such as high altitude pulmonary edema (HAPE) and acute mountain sickness (AMS), suggesting that NOS3 genotypes contribute to altitude tolerance. To further test our hypothesis that the G allele at the G894T polymorphism in NOS3 (dbSNP number: rs1799983; protein polymorphism Glu298Asp) is beneficial in hypoxic environments, we compared frequencies of this allele in an altitude-adapted Amerindian population, Quechua of the Andean altiplano, with those in a lowland Amerindian population, Maya of the Yucatan Peninsula. While common in both populations, the G allele was significantly more frequent in the highlanders. Taken together, our data suggest that this variant in NOS3, which has been previously associated with higher levels of nitric oxide, contributes to both acclimatization and adaptation to altitude.

Mechanistic insights into the link between visfatin gene C-1535T polymorphism and coronary artery disease: an in vitro study.

PubMed

Wang, Yong-Sheng; Gao, Wei; Li, Hong-Fen; Wang, Ze-Mu; Zhu, Jun; Zhao, Huan; Yan, Jian-Jun; Jia, En-Zhi; Yang, Zhi-Jian; Wang, Lian-Sheng

2012-04-01

Visfatin, a pro-inflammatory cytokine predominantly released from leucocytes, is correlated with coronary artery disease (CAD). We have previously reported that the -1535C>T polymorphism (rs1330082), which located on the promoter region of visfatin, was associated with decreased risk of CAD. Here, we investigated the underlying mechanism by which this polymorphism affects the genetic susceptibility to CAD. The difference of the promoter activities between -1535T variant and -1535C allele was tested by luciferase reporter gene assay. The difference of transcription factor binding activities between T and C allele was evaluated by electrophoretic mobility shift assay. In reporter gene assay, we showed that the T variant had a significantly reduced transcriptional activity compared with the C allele. The T-variant significantly attenuated the promoter binding affinity to nuclear transcription factors and this effect became much obvious after treatment with TNF-α. Moreover, competition experiment revealed that the retarded complex formed by T-1535- or C-1535-probe binding to nuclear extracts was nearly completely inhibited by unlabeled activator protein-1 (AP-1) specific probe, indicating that AP-1 might be the target nuclear effector. Taken together, our data provided potential mechanistic link between the visfatin -1535C>T polymorphism and reduced CAD risk.

Exploiting induced variation to dissect quantitative traits in barley.

PubMed

Druka, Arnis; Franckowiak, Jerome; Lundqvist, Udda; Bonar, Nicola; Alexander, Jill; Guzy-Wrobelska, Justyna; Ramsay, Luke; Druka, Ilze; Grant, Iain; Macaulay, Malcolm; Vendramin, Vera; Shahinnia, Fahimeh; Radovic, Slobodanka; Houston, Kelly; Harrap, David; Cardle, Linda; Marshall, David; Morgante, Michele; Stein, Nils; Waugh, Robbie

2010-04-01

The identification of genes underlying complex quantitative traits such as grain yield by means of conventional genetic analysis (positional cloning) requires the development of several large mapping populations. However, it is possible that phenotypically related, but more extreme, allelic variants generated by mutational studies could provide a means for more efficient cloning of QTLs (quantitative trait loci). In barley (Hordeum vulgare), with the development of high-throughput genome analysis tools, efficient genome-wide identification of genetic loci harbouring mutant alleles has recently become possible. Genotypic data from NILs (near-isogenic lines) that carry induced or natural variants of genes that control aspects of plant development can be compared with the location of QTLs to potentially identify candidate genes for development--related traits such as grain yield. As yield itself can be divided into a number of allometric component traits such as tillers per plant, kernels per spike and kernel size, mutant alleles that both affect these traits and are located within the confidence intervals for major yield QTLs may represent extreme variants of the underlying genes. In addition, the development of detailed comparative genomic models based on the alignment of a high-density barley gene map with the rice and sorghum physical maps, has enabled an informed prioritization of 'known function' genes as candidates for both QTLs and induced mutant genes.

Genetic determinants of financial risk taking.

PubMed

Kuhnen, Camelia M; Chiao, Joan Y

2009-01-01

Individuals vary in their willingness to take financial risks. Here we show that variants of two genes that regulate dopamine and serotonin neurotransmission and have been previously linked to emotional behavior, anxiety and addiction (5-HTTLPR and DRD4) are significant determinants of risk taking in investment decisions. We find that the 5-HTTLPR s/s allele carriers take 28% less risk than those carrying the s/l or l/l alleles of the gene. DRD4 7-repeat allele carriers take 25% more risk than individuals without the 7-repeat allele. These findings contribute to the emerging literature on the genetic determinants of economic behavior.

KIR Diversity in Māori and Polynesians: Populations in which HLA-B is not a Significant KIR Ligand

PubMed Central

Nemat-Gorgani, Neda; Edinur, Hisham A.; Hollenbach, Jill A.; Traherne, James A.; Dunn, Paul P. J.; Chambers, Geoffrey K.; Parham, Peter; Norman, Paul J.

2014-01-01

HLA class I molecules and killer cell immunoglobulin-like receptors (KIR) form a diverse system of ligands and receptors that individualize human immune systems in ways that improve the survival of individuals and populations. Human settlement of Oceania by island-hopping East and Southeast Asian migrants started ~3,500 years ago. Subsequently, New Zealand was reached ~750 years ago by ancestral Māori. To examine how this history impacted KIR and HLA diversity, and their functional interaction, we defined at high resolution the allelic and haplotype diversity of the 13 expressed KIR genes in 49 Māori and 34 Polynesians. Eighty KIR variants, including four ‘new’ alleles, were defined; as were 35 centromeric and 22 telomeric KIR region haplotypes, which combine to give >50 full-length KIR haplotypes. Two new and divergent variant KIR form part of a telomeric KIR haplotype, which appears derived from Papua New Guinea and was probably obtained by the Asian migrants en route to Polynesia. Māori and Polynesian KIR are very similar, but differ significantly from African, European, Japanese and Amerindian KIR. Māori and Polynesians have high KIR haplotype diversity with corresponding allotype diversity being maintained throughout the KIR locus. Within the population each individual has a unique combination of HLA class I and KIR. Characterizing Māori and Polynesians is a paucity of HLA-B allotypes recognized by KIR. Compensating for this deficiency are high frequencies (>50%) of HLA-A allotypes recognized by KIR. These HLA-A allotypes are ones that modern humans likely acquired from archaic humans at a much earlier time. PMID:25139336

Meta-Analyses of ALDH2 and ADH1B with Alcohol Dependence in Asians

ERIC Educational Resources Information Center

Luczak, Susan E.; Glatt, Stephen J.; Wall, Tamara J.

2006-01-01

Meta-analyses were conducted to determine the magnitude of relationships between polymorphisms in 2 genes, ALDH2 and ADH1B, with alcohol dependence in Asians. For each gene, possession of 1 variant [asterisk]2 allele was protective against alcohol dependence, and possession of a 2nd [asterisk]2 allele did not offer significant additional…

Association of autoimmune Addison's disease with alleles of STAT4 and GATA3 in European cohorts.

PubMed

Mitchell, Anna L; Macarthur, Katie D R; Gan, Earn H; Baggott, Lucy E; Wolff, Anette S B; Skinningsrud, Beate; Platt, Hazel; Short, Andrea; Lobell, Anna; Kämpe, Olle; Bensing, Sophie; Betterle, Corrado; Kasperlik-Zaluska, Anna; Zurawek, Magdalena; Fichna, Marta; Kockum, Ingrid; Nordling Eriksson, Gabriel; Ekwall, Olov; Wahlberg, Jeanette; Dahlqvist, Per; Hulting, Anna-Lena; Penna-Martinez, Marissa; Meyer, Gesine; Kahles, Heinrich; Badenhoop, Klaus; Hahner, Stephanie; Quinkler, Marcus; Falorni, Alberto; Phipps-Green, Amanda; Merriman, Tony R; Ollier, William; Cordell, Heather J; Undlien, Dag; Czarnocka, Barbara; Husebye, Eystein; Pearce, Simon H S

2014-01-01

Gene variants known to contribute to Autoimmune Addison's disease (AAD) susceptibility include those at the MHC, MICA, CIITA, CTLA4, PTPN22, CYP27B1, NLRP-1 and CD274 loci. The majority of the genetic component to disease susceptibility has yet to be accounted for. To investigate the role of 19 candidate genes in AAD susceptibility in six European case-control cohorts. A sequential association study design was employed with genotyping using Sequenom iPlex technology. In phase one, 85 SNPs in 19 genes were genotyped in UK and Norwegian AAD cohorts (691 AAD, 715 controls). In phase two, 21 SNPs in 11 genes were genotyped in German, Swedish, Italian and Polish cohorts (1264 AAD, 1221 controls). In phase three, to explore association of GATA3 polymorphisms with AAD and to determine if this association extended to other autoimmune conditions, 15 SNPs in GATA3 were studied in UK and Norwegian AAD cohorts, 1195 type 1 diabetes patients from Norway, 650 rheumatoid arthritis patients from New Zealand and in 283 UK Graves' disease patients. Meta-analysis was used to compare genotype frequencies between the participating centres, allowing for heterogeneity. We report significant association with alleles of two STAT4 markers in AAD cohorts (rs4274624: P = 0.00016; rs10931481: P = 0.0007). In addition, nominal association of AAD with alleles at GATA3 was found in 3 patient cohorts and supported by meta-analysis. Association of AAD with CYP27B1 alleles was also confirmed, which replicates previous published data. Finally, nominal association was found at SNPs in both the NF-κB1 and IL23A genes in the UK and Italian cohorts respectively. Variants in the STAT4 gene, previously associated with other autoimmune conditions, confer susceptibility to AAD. Additionally, we report association of GATA3 variants with AAD: this adds to the recent report of association of GATA3 variants with rheumatoid arthritis.

Validation of Type 2 Diabetes Risk Variants Identified by Genome-Wide Association Studies in Northern Han Chinese

PubMed Central

Rao, Ping; Zhou, Yong; Ge, Si-Qi; Wang, An-Xin; Yu, Xin-Wei; Alzain, Mohamed Ali; Veronica, Andrea Katherine; Qiu, Jing; Song, Man-Shu; Zhang, Jie; Wang, Hao; Fang, Hong-Hong; Gao, Qing; Wang, You-Xin; Wang, Wei

2016-01-01

Background: More than 60 genetic susceptibility loci associated with type 2 diabetes mellitus (T2DM) have been established in populations of Asian and European ancestry. Given ethnic differences and environmental factors, validation of the effects of genetic risk variants with reported associations identified by Genome-Wide Association Studies (GWASs) is essential. The study aims at evaluating the associations of T2DM with 29 single nucleotide polymorphisms (SNPs) from 19 candidate genes derived from GWASs in a northern Han Chinese population. Method: In this case-control study, 461 T2DM-diagnosed patients and 434 controls were recruited at the Jidong oil field hospital (Hebei, China) from January 2009 to October 2013. A cumulative genetic risk score (cGRS) was calculated by summation of the number of risk alleles, and a weight GRS (wGRS) was calculated as the sum of risk alleles at each locus multiplied by their effect sizes for T2DM, using the independent variants selected. Result: The allelic frequency of the “A” allele at rs17106184 (Fas-associated factor 1, FAF1) was significantly higher in the T2DM patients than that of the healthy controls (11.7% vs. 6.4%, p < 0.001). Individuals in the highestquartile of wGRS had an over three-fold increased risk for developing T2DM compared with those in the lowest quartile (odds ratio = 3.06, 95% CI = 1.92–4.88, p < 0.001) adjusted for age, sex, BMI, total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), systolic blood pressure (SBP) and diastolic blood pressure (DBP). The results were similar when analyzed with the cGRS. Conclusions: We confirmed the association between rs17106184 (FAF1) and T2DM in a northern Han Chinese population. The GRS calculated based on T2DM susceptibility variants may be a useful tool for predicting the T2DM susceptibility. PMID:27589775

Ghrelin gene: identification of missense variants and a frameshift mutation in extremely obese children and adolescents and healthy normal weight students.

PubMed

Hinney, Anke; Hoch, Anne; Geller, Frank; Schäfer, Helmut; Siegfried, Wolfgang; Goldschmidt, Hanspeter; Remschmidt, Helmut; Hebebrand, Johannes

2002-06-01

Ghrelin induces obesity via central and peripheral mechanisms. Administration of ghrelin leads to increased food intake and decreased fat utilisation in rodents. Ghrelin levels are decreased in obese individuals. Recently, a polymorphism (Arg-51-Gln) within the ghrelin gene (GHRL) was described to be associated with obesity. We screened the GHRL coding region in 215 extremely obese German Children and adolescents (study group 1) and 93 normal weight students (study group 2) by single strand conformation polymorphism analysis (SSCP). We found the two previously described single nucleotide polymorphisms (SNP: Arg-51-Gln and Leu-72-Met) in similar frequencies in study groups 1 and 2 (allele frequencies were: 0.019 and 0.016 for the 51-Gln allele and 0.091 and 0.086 for the 72-Met allele, respectively). Hence, we could not confirm the previous finding. Additionally, two novel variants were identified within the coding region: (1) We detected one healthy normal weight individual with a frameshift mutation (2bp deletion at codon 34). This frameshift mutation affects the coding region of the mature ghrelin. Hence, it is highly likely that the normal weight student is haplo-insufficient for ghrelin. (2) An A to T transversion leads to an amino acid exchange from Gln to Leu at amino acid position 90. The frequency of the 90-Leu allele was significantly higher in the extremely obese children and adolescents (0.063) than in the normal weight students (0.016; nominal p = 0.011). Additionally, we genotyped 134 underweight students and 44 normal weight adults for this SNP. Genotype frequencies were similar in extremely obese children and adolescents, underweight students and normal weight adults (p > 0.8). In conclusion, we identified four sequence variants in the coding region of the ghrelin gene in individuals belonging to different weight extremes. A frameshift mutation was detected in a normal weight individual. None of the variants seem to influence weight regulation.

Common CYP2D6 polymorphisms affecting alternative splicing and transcription: long-range haplotypes with two regulatory variants modulate CYP2D6 activity

PubMed Central

Wang, Danxin; Poi, Ming J.; Sun, Xiaochun; Gaedigk, Andrea; Leeder, J. Steven; Sadee, Wolfgang

2014-01-01

Cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of 25% of clinically used drugs. Genetic polymorphisms cause substantial variation in CYP2D6 activity and serve as biomarkers guiding drug therapy. However, genotype–phenotype relationships remain ambiguous except for poor metabolizers carrying null alleles, suggesting the presence of yet unknown genetic variants. Searching for regulatory CYP2D6 polymorphisms, we find that a SNP defining the CYP2D6*2 allele, rs16947 [R296C, 17–60% minor allele frequency (MAF)], previously thought to convey normal activity, alters exon 6 splicing, thereby reducing CYP2D6 expression at least 2-fold. In addition, two completely linked SNPs (rs5758550/rs133333, MAF 13–42%) increase CYP2D6 transcription more than 2-fold, located in a distant downstream enhancer region (>100 kb) that interacts with the CYP2D6 promoter. In high linkage disequilibrium (LD) with each other, rs16947 and the enhancer SNPs form haplotypes that affect CYP2D6 enzyme activity in vivo. In a pediatric cohort of 164 individuals, rs16947 alone (minor haplotype frequency 28%) was associated with reduced CYP2D6 metabolic activity (measured as dextromethorphan/metabolite ratios), whereas rs5758550/rs133333 alone (frequency 3%) resulted in increased CYP2D6 activity, while haplotypes containing both rs16947 and rs5758550/rs133333 were similar to the wild-type. Other alleles used in biomarker panels carrying these variants such as CYP2D6*41 require re-evaluation of independent effects on CYP2D6 activity. The occurrence of two regulatory variants of high frequency and in high LD, residing on a long haplotype, highlights the importance of gene architecture, likely shaped by evolutionary selection pressures, in determining activity of encoded proteins. PMID:23985325

TREM2 R47H variant and risk of essential tremor: A cross-sectional international multicenter study

PubMed Central

Ortega-Cubero, Sara; Lorenzo-Betancor, Oswaldo; Lorenzo, Elena; Agúndez, José A.G.; Jiménez-Jiménez, Félix J.; Ross, Owen A.; Wurster, Isabel; Mielke, Carina; Lin, Juei-Jueng; Coria, Francisco; Clarimon, Jordi; Ezquerra, Mario; Brighina, Laura; Annesi, Grazia; Alonso-Navarro, Hortensia; García-Martin, Elena; Gironell, Alex; Marti, Maria J.; Yueh, Kuo-Chu; Wszolek, Zbigniew K.; Sharma, Manu; Berg, Daniela; Krüger, Rejko; Pastor, Maria A.; Pastor, Pau

2015-01-01

Introduction Essential tremor (ET) is the most frequent movement disorder in adults. Its pathophysiology is not clearly understood, however there is growing evidence showing common etiologic factors with other neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases (AD, PD). Recently, a rare p.R47H substitution (rs75932628) in the TREM2 protein (triggering receptor expressed on myeloid cells 2; OMIM: *605086) has been proposed as a risk factor for AD, PD and amyotrophic lateral sclerosis (ALS). The objective of the study was to determine whether TREM2 p.R47H allele is also a risk factor for developing ET. Methods This was a cross-sectional multicenter international study. An initial case-control cohort from Spain (n = 456 ET, n = 2715 controls) was genotyped. In a replication phase, a case-control series (n = 897 ET, n = 1449 controls) from different populations (Italy, Germany, North-America and Taiwan) was studied. Owed to the rarity of the variant, published results on p.R47H allele frequency from 14777 healthy controls from European, North American or Chinese descent were additionally considered. The main outcome measure was p.R47H (rs75932628) allelic frequency. Results There was a significant association between TREM2 p.R47H variant and ET in the Spanish cohort (odds ratio [OR], 5.97; 95% CI, 1.203–29.626; p = 0.042), but it was not replicated in other populations. Conclusions These results argue in favor of population-specific differences in the allelic distribution and suggest that p.R47H (rs75932628) variant may contribute to the susceptibility of ET in Spanish population. However, taking into account the very low frequency of p.R47H, further confirmatory analyses of larger ET series are needed. PMID:25585992

TREM2 R47H variant and risk of essential tremor: a cross-sectional international multicenter study.

PubMed

Ortega-Cubero, Sara; Lorenzo-Betancor, Oswaldo; Lorenzo, Elena; Agúndez, José A G; Jiménez-Jiménez, Félix J; Ross, Owen A; Wurster, Isabel; Mielke, Carina; Lin, Juei-Jueng; Coria, Francisco; Clarimon, Jordi; Ezquerra, Mario; Brighina, Laura; Annesi, Grazia; Alonso-Navarro, Hortensia; García-Martin, Elena; Gironell, Alex; Marti, Maria J; Yueh, Kuo-Chu; Wszolek, Zbigniew K; Sharma, Manu; Berg, Daniela; Krüger, Rejko; Pastor, Maria A; Pastor, Pau

2015-03-01

Essential tremor (ET) is the most frequent movement disorder in adults. Its pathophysiology is not clearly understood, however there is growing evidence showing common etiologic factors with other neurodegenerative disorders such as Alzheimer's and Parkinson's diseases (AD, PD). Recently, a rare p.R47H substitution (rs75932628) in the TREM2 protein (triggering receptor expressed on myeloid cells 2; OMIM: *605086) has been proposed as a risk factor for AD, PD and amyotrophic lateral sclerosis (ALS). The objective of the study was to determine whether TREM2 p.R47H allele is also a risk factor for developing ET. This was a cross-sectional multicenter international study. An initial case-control cohort from Spain (n = 456 ET, n = 2715 controls) was genotyped. In a replication phase, a case-control series (n = 897 ET, n = 1449 controls) from different populations (Italy, Germany, North-America and Taiwan) was studied. Owed to the rarity of the variant, published results on p.R47H allele frequency from 14777 healthy controls from European, North American or Chinese descent were additionally considered. The main outcome measure was p.R47H (rs75932628) allelic frequency. There was a significant association between TREM2 p.R47H variant and ET in the Spanish cohort (odds ratio [OR], 5.97; 95% CI, 1.203-29.626; p = 0.042), but it was not replicated in other populations. These results argue in favor of population-specific differences in the allelic distribution and suggest that p.R47H (rs75932628) variant may contribute to the susceptibility of ET in Spanish population. However, taking into account the very low frequency of p.R47H, further confirmatory analyses of larger ET series are needed. Copyright © 2014 Elsevier Ltd. All rights reserved.

The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants

PubMed Central

Reuter, Miriam S.; Walker, Susan; Thiruvahindrapuram, Bhooma; Whitney, Joe; Cohn, Iris; Sondheimer, Neal; Yuen, Ryan K.C.; Trost, Brett; Paton, Tara A.; Pereira, Sergio L.; Herbrick, Jo-Anne; Wintle, Richard F.; Merico, Daniele; Howe, Jennifer; MacDonald, Jeffrey R.; Lu, Chao; Nalpathamkalam, Thomas; Sung, Wilson W.L.; Wang, Zhuozhi; Patel, Rohan V.; Pellecchia, Giovanna; Wei, John; Strug, Lisa J.; Bell, Sherilyn; Kellam, Barbara; Mahtani, Melanie M.; Bassett, Anne S.; Bombard, Yvonne; Weksberg, Rosanna; Shuman, Cheryl; Cohn, Ronald D.; Stavropoulos, Dimitri J.; Bowdin, Sarah; Hildebrandt, Matthew R.; Wei, Wei; Romm, Asli; Pasceri, Peter; Ellis, James; Ray, Peter; Meyn, M. Stephen; Monfared, Nasim; Hosseini, S. Mohsen; Joseph-George, Ann M.; Keeley, Fred W.; Cook, Ryan A.; Fiume, Marc; Lee, Hin C.; Marshall, Christian R.; Davies, Jill; Hazell, Allison; Buchanan, Janet A.; Szego, Michael J.; Scherer, Stephen W.

2018-01-01

BACKGROUND: The Personal Genome Project Canada is a comprehensive public data resource that integrates whole genome sequencing data and health information. We describe genomic variation identified in the initial recruitment cohort of 56 volunteers. METHODS: Volunteers were screened for eligibility and provided informed consent for open data sharing. Using blood DNA, we performed whole genome sequencing and identified all possible classes of DNA variants. A genetic counsellor explained the implication of the results to each participant. RESULTS: Whole genome sequencing of the first 56 participants identified 207 662 805 sequence variants and 27 494 copy number variations. We analyzed a prioritized disease-associated data set (n = 1606 variants) according to standardized guidelines, and interpreted 19 variants in 14 participants (25%) as having obvious health implications. Six of these variants (e.g., in BRCA1 or mosaic loss of an X chromosome) were pathogenic or likely pathogenic. Seven were risk factors for cancer, cardiovascular or neurobehavioural conditions. Four other variants — associated with cancer, cardiac or neurodegenerative phenotypes — remained of uncertain significance because of discrepancies among databases. We also identified a large structural chromosome aberration and a likely pathogenic mitochondrial variant. There were 172 recessive disease alleles (e.g., 5 individuals carried mutations for cystic fibrosis). Pharmacogenomics analyses revealed another 3.9 potentially relevant genotypes per individual. INTERPRETATION: Our analyses identified a spectrum of genetic variants with potential health impact in 25% of participants. When also considering recessive alleles and variants with potential pharmacologic relevance, all 56 participants had medically relevant findings. Although access is mostly limited to research, whole genome sequencing can provide specific and novel information with the potential of major impact for health care. PMID:29431110

Utilizing population controls in rare-variant case-parent association tests.

PubMed

Jiang, Yu; Satten, Glen A; Han, Yujun; Epstein, Michael P; Heinzen, Erin L; Goldstein, David B; Allen, Andrew S

2014-06-05

There is great interest in detecting associations between human traits and rare genetic variation. To address the low power implicit in single-locus tests of rare genetic variants, many rare-variant association approaches attempt to accumulate information across a gene, often by taking linear combinations of single-locus contributions to a statistic. Using the right linear combination is key-an optimal test will up-weight true causal variants, down-weight neutral variants, and correctly assign the direction of effect for causal variants. Here, we propose a procedure that exploits data from population controls to estimate the linear combination to be used in an case-parent trio rare-variant association test. Specifically, we estimate the linear combination by comparing population control allele frequencies with allele frequencies in the parents of affected offspring. These estimates are then used to construct a rare-variant transmission disequilibrium test (rvTDT) in the case-parent data. Because the rvTDT is conditional on the parents' data, using parental data in estimating the linear combination does not affect the validity or asymptotic distribution of the rvTDT. By using simulation, we show that our new population-control-based rvTDT can dramatically improve power over rvTDTs that do not use population control information across a wide variety of genetic architectures. It also remains valid under population stratification. We apply the approach to a cohort of epileptic encephalopathy (EE) trios and find that dominant (or additive) inherited rare variants are unlikely to play a substantial role within EE genes previously identified through de novo mutation studies. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Relation of genomic variants for Alzheimer disease dementia to common neuropathologies

PubMed Central

Yu, Lei; Buchman, Aron S.; Schneider, Julie A.; De Jager, Philip L.; Bennett, David A.

2016-01-01

Objective: To investigate the associations of previously reported Alzheimer disease (AD) dementia genomic variants with common neuropathologies. Methods: This is a postmortem study including 1,017 autopsied participants from 2 clinicopathologic cohorts. Analyses focused on 22 genomic variants associated with AD dementia in large-scale case-control genome-wide association study (GWAS) meta-analyses. The neuropathologic traits of interest were a pathologic diagnosis of AD according to NIA-Reagan criteria, macroscopic and microscopic infarcts, Lewy bodies (LB), and hippocampal sclerosis. For each variant, multiple logistic regression was used to investigate its association with neuropathologic traits, adjusting for age, sex, and subpopulation structure. We also conducted power analyses to estimate the sample sizes required to detect genome-wide significance (p < 5 × 10−8) for pathologic AD for all variants. Results: APOE ε4 allele was associated with greater odds of pathologic AD (odds ratio [OR] 3.82, 95% confidence interval [CI] 2.67–5.46, p = 1.9 × 10−13), while ε2 allele was associated with lower odds of pathologic AD (OR 0.42, 95% CI 0.30–0.61, p = 3.1 × 10−6). Four additional genomic variants including rs6656401 (CR1), rs1476679 (ZCWPW1), rs35349669 (INPP5D), and rs17125944 (FERMT2) had p values less than 0.05. Remarkably, half of the previously reported AD dementia variants are not likely to be detected for association with pathologic AD with a sample size in excess of the largest GWAS meta-analyses of AD dementia. Conclusions: Many recently discovered genomic variants for AD dementia are not associated with the pathology of AD. Some genomic variants for AD dementia appear to be associated with other common neuropathologies. PMID:27371493

Relation of genomic variants for Alzheimer disease dementia to common neuropathologies.

PubMed

Farfel, Jose M; Yu, Lei; Buchman, Aron S; Schneider, Julie A; De Jager, Philip L; Bennett, David A

2016-08-02

To investigate the associations of previously reported Alzheimer disease (AD) dementia genomic variants with common neuropathologies. This is a postmortem study including 1,017 autopsied participants from 2 clinicopathologic cohorts. Analyses focused on 22 genomic variants associated with AD dementia in large-scale case-control genome-wide association study (GWAS) meta-analyses. The neuropathologic traits of interest were a pathologic diagnosis of AD according to NIA-Reagan criteria, macroscopic and microscopic infarcts, Lewy bodies (LB), and hippocampal sclerosis. For each variant, multiple logistic regression was used to investigate its association with neuropathologic traits, adjusting for age, sex, and subpopulation structure. We also conducted power analyses to estimate the sample sizes required to detect genome-wide significance (p < 5 × 10(-8)) for pathologic AD for all variants. APOE ε4 allele was associated with greater odds of pathologic AD (odds ratio [OR] 3.82, 95% confidence interval [CI] 2.67-5.46, p = 1.9 × 10(-13)), while ε2 allele was associated with lower odds of pathologic AD (OR 0.42, 95% CI 0.30-0.61, p = 3.1 × 10(-6)). Four additional genomic variants including rs6656401 (CR1), rs1476679 (ZCWPW1), rs35349669 (INPP5D), and rs17125944 (FERMT2) had p values less than 0.05. Remarkably, half of the previously reported AD dementia variants are not likely to be detected for association with pathologic AD with a sample size in excess of the largest GWAS meta-analyses of AD dementia. Many recently discovered genomic variants for AD dementia are not associated with the pathology of AD. Some genomic variants for AD dementia appear to be associated with other common neuropathologies. © 2016 American Academy of Neurology.

Association Between Coronary Artery Disease Genetic Variants and Subclinical Atherosclerosis: An Association Study and Meta-analysis.

PubMed

Zabalza, Michel; Subirana, Isaac; Lluis-Ganella, Carla; Sayols-Baixeras, Sergi; de Groot, Eric; Arnold, Roman; Cenarro, Ana; Ramos, Rafel; Marrugat, Jaume; Elosua, Roberto

2015-10-01

Recent studies have identified several genetic variants associated with coronary artery disease. Some of these genetic variants are not associated with classical cardiovascular risk factors and the mechanism of such associations is unclear. The aim of the study was to determine whether these genetic variants are related to subclinical atherosclerosis measured by carotid intima media thickness, carotid stiffness, and ankle brachial index. A cross-sectional study nested in the follow-up of the REGICOR cohort was undertaken. The study included 2667 individuals. Subclinical atherosclerosis measurements were performed with standardized methods. Nine genetic variants were genotyped to assess associations with subclinical atherosclerosis, individually and in a weighted genetic risk score. A systematic review and meta-analysis of previous studies that analyzed these associations was undertaken. Neither the selected genetic variants nor the genetic risk score were significantly associated with subclinical atherosclerosis. In the meta-analysis, the rs1746048 (CXCL12; n = 10581) risk allele was directly associated with carotid intima-media thickness (β = 0.008; 95% confidence interval, 0.001-0.015), whereas the rs6725887 (WDR12; n = 7801) risk allele was inversely associated with this thickness (β = -0.013; 95% confidence interval, -0.024 to -0.003). The analyzed genetic variants seem to mediate their association with coronary artery disease through different mechanisms. Our results generate the hypothesis that the CXCL12 variant appears to influence coronary artery disease risk through arterial remodeling and thickening, whereas the WDR12 risk variant could be related to higher plaque vulnerability. Copyright © 2014 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

TREM2 Variants in Alzheimer's Disease

PubMed Central

Guerreiro, Rita; Wojtas, Aleksandra; Bras, Jose; Carrasquillo, Minerva; Rogaeva, Ekaterina; Majounie, Elisa; Cruchaga, Carlos; Sassi, Celeste; Kauwe, John S.K.; Younkin, Steven; Hazrati, Lilinaz; Collinge, John; Pocock, Jennifer; Lashley, Tammaryn; Williams, Julie; Lambert, Jean-Charles; Amouyel, Philippe; Goate, Alison; Rademakers, Rosa; Morgan, Kevin; Powell, John; St. George-Hyslop, Peter; Singleton, Andrew; Hardy, John

2013-01-01

BACKGROUND Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia. METHODS We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice. RESULTS We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set (P = 0.02). There were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant alleles in 1107 controls (P<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimer's disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P = 0.002), as did direct genotyping of an additional series of 1887 patients with Alzheimer's disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alzheimer's disease. CONCLUSIONS Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease. (Funded by Alzheimer's Research UK and others.) PMID:23150934

Involvement of genetic variants associated with primary open-angle glaucoma in pathogenic mechanisms and family history of glaucoma.

PubMed

Mabuchi, Fumihiko; Sakurada, Yoichi; Kashiwagi, Kenji; Yamagata, Zentaro; Iijima, Hiroyuki; Tsukahara, Shigeo

2015-03-01

To investigate the associations between the non-intraocular pressure (IOP)-related genetic variants (genetic variants associated with vulnerability of the optic nerve independent of IOP) and primary open-angle glaucoma (POAG), including normal-tension glaucoma (NTG) and high-tension glaucoma (HTG), and between the non-IOP-related genetic variants and a family history of glaucoma. Case-control study. Japanese patients with NTG (n = 213) and HTG (n = 212) and 191 control subjects were genotyped for 5 non-IOP-related genetic variants predisposing to POAG near the SRBD1, ELOVL5, CDKN2B/CDKN2B-AS1, SIX1/SIX6, and ATOH7 genes. The load of these genetic variants was compared between the control subjects and patients with NTG or HTG and between the POAG patients with and without a family history of glaucoma. The total number of POAG risk alleles and the product of the odds ratios (POAG risk) of these genetic variants were significantly larger (P < .0025) in patients with both NTG and HTG than in the control subjects, and were significantly larger (P = .0042 and P = .023, respectively) in POAG patients with a family history of glaucoma than in those without. As the number of relatives with glaucoma increased, the total number of risk alleles and the product of the odds ratios increased (P = .012 and P = .047, respectively). Non-IOP-related genetic variants contribute to the pathogenesis of HTG as well as NTG. A positive family history of glaucoma in cases of POAG is thought to reflect the influence of genetic variants predisposing to POAG. Copyright © 2015 Elsevier Inc. All rights reserved.

The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants.

PubMed

Reuter, Miriam S; Walker, Susan; Thiruvahindrapuram, Bhooma; Whitney, Joe; Cohn, Iris; Sondheimer, Neal; Yuen, Ryan K C; Trost, Brett; Paton, Tara A; Pereira, Sergio L; Herbrick, Jo-Anne; Wintle, Richard F; Merico, Daniele; Howe, Jennifer; MacDonald, Jeffrey R; Lu, Chao; Nalpathamkalam, Thomas; Sung, Wilson W L; Wang, Zhuozhi; Patel, Rohan V; Pellecchia, Giovanna; Wei, John; Strug, Lisa J; Bell, Sherilyn; Kellam, Barbara; Mahtani, Melanie M; Bassett, Anne S; Bombard, Yvonne; Weksberg, Rosanna; Shuman, Cheryl; Cohn, Ronald D; Stavropoulos, Dimitri J; Bowdin, Sarah; Hildebrandt, Matthew R; Wei, Wei; Romm, Asli; Pasceri, Peter; Ellis, James; Ray, Peter; Meyn, M Stephen; Monfared, Nasim; Hosseini, S Mohsen; Joseph-George, Ann M; Keeley, Fred W; Cook, Ryan A; Fiume, Marc; Lee, Hin C; Marshall, Christian R; Davies, Jill; Hazell, Allison; Buchanan, Janet A; Szego, Michael J; Scherer, Stephen W

2018-02-05

The Personal Genome Project Canada is a comprehensive public data resource that integrates whole genome sequencing data and health information. We describe genomic variation identified in the initial recruitment cohort of 56 volunteers. Volunteers were screened for eligibility and provided informed consent for open data sharing. Using blood DNA, we performed whole genome sequencing and identified all possible classes of DNA variants. A genetic counsellor explained the implication of the results to each participant. Whole genome sequencing of the first 56 participants identified 207 662 805 sequence variants and 27 494 copy number variations. We analyzed a prioritized disease-associated data set ( n = 1606 variants) according to standardized guidelines, and interpreted 19 variants in 14 participants (25%) as having obvious health implications. Six of these variants (e.g., in BRCA1 or mosaic loss of an X chromosome) were pathogenic or likely pathogenic. Seven were risk factors for cancer, cardiovascular or neurobehavioural conditions. Four other variants - associated with cancer, cardiac or neurodegenerative phenotypes - remained of uncertain significance because of discrepancies among databases. We also identified a large structural chromosome aberration and a likely pathogenic mitochondrial variant. There were 172 recessive disease alleles (e.g., 5 individuals carried mutations for cystic fibrosis). Pharmacogenomics analyses revealed another 3.9 potentially relevant genotypes per individual. Our analyses identified a spectrum of genetic variants with potential health impact in 25% of participants. When also considering recessive alleles and variants with potential pharmacologic relevance, all 56 participants had medically relevant findings. Although access is mostly limited to research, whole genome sequencing can provide specific and novel information with the potential of major impact for health care. © 2018 Joule Inc. or its licensors.

Comprehensive analysis of the MLH1 promoter region in 480 patients with colorectal cancer and 1150 controls reveals new variants including one with a heritable constitutional MLH1 epimutation.

PubMed

Morak, Monika; Ibisler, Ayseguel; Keller, Gisela; Jessen, Ellen; Laner, Andreas; Gonzales-Fassrainer, Daniela; Locher, Melanie; Massdorf, Trisari; Nissen, Anke M; Benet-Pagès, Anna; Holinski-Feder, Elke

2018-04-01

Germline defects in MLH1 , MSH2 , MSH6 and PMS2 predisposing for Lynch syndrome (LS) are mainly based on sequence changes, whereas a constitutional epimutation of MLH1 (CEM) is exceptionally rare. This abnormal MLH1 promoter methylation is not hereditary when arising de novo, whereas a stably heritable and variant-induced CEM was described for one single allele. We searched for MLH1 promoter variants causing a germline or somatic methylation induction or transcriptional repression. We analysed the MLH1 promoter sequence in five different patient groups with colorectal cancer (CRC) (n=480) composed of patients with i) CEM (n=16), ii) unsolved loss of MLH1 expression in CRC (n=37), iii) CpG-island methylator-phenotype CRC (n=102), iv) patients with LS (n=83) and v) MLH1-proficient CRC (n=242) as controls. 1150 patients with non-LS tumours also served as controls to correctly judge the results. We detected 10 rare MLH1 promoter variants. One novel, complex MLH1 variant c.-63_-58delins18 is present in a patient with CRC with CEM and his sister, both showing a complete allele-specific promoter methylation and transcriptional silencing. The other nine promoter variants detected in 17 individuals were not associated with methylation. For four of these, a normal, biallelic MLH1 expression was found in the patients' cDNA. We report the second promoter variant stably inducing a hereditary CEM. Concerning the classification of promoter variants, we discuss contradictory results from the literature for two variants, describe classification discrepancies between existing rules for five variants, suggest the (re-)classification of five promoter variants to (likely) benign and regard four variants as functionally unclear. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

αIIbβ3 variants defined by next-generation sequencing: Predicting variants likely to cause Glanzmann thrombasthenia

PubMed Central

Buitrago, Lorena; Rendon, Augusto; Liang, Yupu; Simeoni, Ilenia; Negri, Ana; Filizola, Marta; Ouwehand, Willem H.; Coller, Barry S.; Alessi, Marie-Christine; Ballmaier, Matthias; Bariana, Tadbir; Bellissimo, Daniel; Bertoli, Marta; Bray, Paul; Bury, Loredana; Carrell, Robin; Cattaneo, Marco; Collins, Peter; French, Deborah; Favier, Remi; Freson, Kathleen; Furie, Bruce; Germeshausen, Manuela; Ghevaert, Cedric; Gomez, Keith; Goodeve, Anne; Gresele, Paolo; Guerrero, Jose; Hampshire, Dan J.; Hadinnapola, Charaka; Heemskerk, Johan; Henskens, Yvonne; Hill, Marian; Hogg, Nancy; Johnsen, Jill; Kahr, Walter; Kerr, Ron; Kunishima, Shinji; Laffan, Michael; Natwani, Amit; Neerman-Arbez, Marguerite; Nurden, Paquita; Nurden, Alan; Ormiston, Mark; Othman, Maha; Ouwehand, Willem; Perry, David; Vilk, Shoshana Ravel; Reitsma, Pieter; Rondina, Matthew; Simeoni, Ilenia; Smethurst, Peter; Stephens, Jonathan; Stevenson, William; Szkotak, Artur; Turro, Ernest; Van Geet, Christel; Vries, Minka; Ward, June; Waye, John; Westbury, Sarah; Whiteheart, Sidney; Wilcox, David; Zhang, Bi

2015-01-01

Next-generation sequencing is transforming our understanding of human genetic variation but assessing the functional impact of novel variants presents challenges. We analyzed missense variants in the integrin αIIbβ3 receptor subunit genes ITGA2B and ITGB3 identified by whole-exome or -genome sequencing in the ThromboGenomics project, comprising ∼32,000 alleles from 16,108 individuals. We analyzed the results in comparison with 111 missense variants in these genes previously reported as being associated with Glanzmann thrombasthenia (GT), 20 associated with alloimmune thrombocytopenia, and 5 associated with aniso/macrothrombocytopenia. We identified 114 novel missense variants in ITGA2B (affecting ∼11% of the amino acids) and 68 novel missense variants in ITGB3 (affecting ∼9% of the amino acids). Of the variants, 96% had minor allele frequencies (MAF) < 0.1%, indicating their rarity. Based on sequence conservation, MAF, and location on a complete model of αIIbβ3, we selected three novel variants that affect amino acids previously associated with GT for expression in HEK293 cells. αIIb P176H and β3 C547G severely reduced αIIbβ3 expression, whereas αIIb P943A partially reduced αIIbβ3 expression and had no effect on fibrinogen binding. We used receiver operating characteristic curves of combined annotation-dependent depletion, Polyphen 2-HDIV, and sorting intolerant from tolerant to estimate the percentage of novel variants likely to be deleterious. At optimal cut-off values, which had 69–98% sensitivity in detecting GT mutations, between 27% and 71% of the novel αIIb or β3 missense variants were predicted to be deleterious. Our data have implications for understanding the evolutionary pressure on αIIbβ3 and highlight the challenges in predicting the clinical significance of novel missense variants. PMID:25827233

Psoriasis Patients Are Enriched for Genetic Variants That Protect against HIV-1 Disease

PubMed Central

Chen, Haoyan; Hayashi, Genki; Lai, Olivia Y.; Dilthey, Alexander; Kuebler, Peter J.; Wong, Tami V.; Martin, Maureen P.; Fernandez Vina, Marcelo A.; McVean, Gil; Wabl, Matthias; Leslie, Kieron S.; Maurer, Toby; Martin, Jeffrey N.; Deeks, Steven G.; Carrington, Mary; Bowcock, Anne M.; Nixon, Douglas F.; Liao, Wilson

2012-01-01

An important paradigm in evolutionary genetics is that of a delicate balance between genetic variants that favorably boost host control of infection but which may unfavorably increase susceptibility to autoimmune disease. Here, we investigated whether patients with psoriasis, a common immune-mediated disease of the skin, are enriched for genetic variants that limit the ability of HIV-1 virus to replicate after infection. We analyzed the HLA class I and class II alleles of 1,727 Caucasian psoriasis cases and 3,581 controls and found that psoriasis patients are significantly more likely than controls to have gene variants that are protective against HIV-1 disease. This includes several HLA class I alleles associated with HIV-1 control; amino acid residues at HLA-B positions 67, 70, and 97 that mediate HIV-1 peptide binding; and the deletion polymorphism rs67384697 associated with high surface expression of HLA-C. We also found that the compound genotype KIR3DS1 plus HLA-B Bw4-80I, which respectively encode a natural killer cell activating receptor and its putative ligand, significantly increased psoriasis susceptibility. This compound genotype has also been associated with delay of progression to AIDS. Together, our results suggest that genetic variants that contribute to anti-viral immunity may predispose to the development of psoriasis. PMID:22577363

ERASE-Seq: Leveraging replicate measurements to enhance ultralow frequency variant detection in NGS data

PubMed Central

Kamps-Hughes, Nick; McUsic, Andrew; Kurihara, Laurie; Harkins, Timothy T.; Pal, Prithwish; Ray, Claire

2018-01-01

The accurate detection of ultralow allele frequency variants in DNA samples is of interest in both research and medical settings, particularly in liquid biopsies where cancer mutational status is monitored from circulating DNA. Next-generation sequencing (NGS) technologies employing molecular barcoding have shown promise but significant sensitivity and specificity improvements are still needed to detect mutations in a majority of patients before the metastatic stage. To address this we present analytical validation data for ERASE-Seq (Elimination of Recurrent Artifacts and Stochastic Errors), a method for accurate and sensitive detection of ultralow frequency DNA variants in NGS data. ERASE-Seq differs from previous methods by creating a robust statistical framework to utilize technical replicates in conjunction with background error modeling, providing a 10 to 100-fold reduction in false positive rates compared to published molecular barcoding methods. ERASE-Seq was tested using spiked human DNA mixtures with clinically realistic DNA input quantities to detect SNVs and indels between 0.05% and 1% allele frequency, the range commonly found in liquid biopsy samples. Variants were detected with greater than 90% sensitivity and a false positive rate below 0.1 calls per 10,000 possible variants. The approach represents a significant performance improvement compared to molecular barcoding methods and does not require changing molecular reagents. PMID:29630678