Ovulation rate, antral follicle count, and circulating anti-Müllerian hormone in Trio allele carriers, a novel high fecundity bovine genotype.

PubMed

García-Guerra, Alvaro; Motta, Jéssica C L; Melo, Leonardo F; Kirkpatrick, Brian W; Wiltbank, Milo C

2017-10-01

High fecundity genotypes in sheep are a valuable model to study the physiological mechanisms underlying follicle selection and the control of ovulation rate. Similar genotypes in cattle had not been described until the recent identification of a major bovine allele, termed Trio, which had a large effect on ovulation rate. The present study was designed to evaluate ovulation rate, antral follicle count (AFC), circulating ant-müllerian hormone (AMH), and the association among these measures in unstimulated and superstimulated Trio carrier cattle. We hypothesized that AFC and AMH would be variable among individual cows but would be similar between Trio carriers and non-carrier control cows and that there would be no association between these measures of follicle numbers and ovulation rate. In experiment 1, ovulation rate was determined during 4 consecutive estrous cycles in Trio carriers (n = 34) and non-carrier controls (n = 27). Ovulation rate, on average, was greater (P < 0.01) in Trio carriers (3.5 ± 0.2) compared to non-carrier controls (1.1 ± 0.1) with ∼70% of carrier cycles (n = 136) having 3-4 ovulations while only ∼5% had single ovulations. In contrast, non-carrier cycles (n = 108) were mostly single ovulation (89%) with none having more than two ovulations. In experiment 2, AFC, determined at wave emergence, was not different (P = 0.54) between Trio carriers (24.5 ± 1.3; n = 45) and non-carrier controls (23.1 ± 0.9; n = 37), and no correlation was found between AFC and mean ovulation rate in either genotype (r = -0.009 and r = -0.07; P > 0.70, respectively). In Experiment 3, circulating AMH was also not different between genotypes (P = 0.65) while correlations were found between AFC and AMH in Trio carriers (r = 0.43; P = 0.05; n = 27) and non-carrier controls (r = 0.78; P < 0.01; n = 19). In experiment 4, AFC and AMH were determined in Trio-carriers (n = 9) in relation to a synchronized follicular wave

Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2.

PubMed

Mulligan, Anna Marie; Couch, Fergus J; Barrowdale, Daniel; Domchek, Susan M; Eccles, Diana; Nevanlinna, Heli; Ramus, Susan J; Robson, Mark; Sherman, Mark; Spurdle, Amanda B; Wappenschmidt, Barbara; Lee, Andrew; McGuffog, Lesley; Healey, Sue; Sinilnikova, Olga M; Janavicius, Ramunas; Hansen, Thomas vO; Nielsen, Finn C; Ejlertsen, Bent; Osorio, Ana; Muñoz-Repeto, Iván; Durán, Mercedes; Godino, Javier; Pertesi, Maroulio; Benítez, Javier; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Cattaneo, Elisa; Bonanni, Bernardo; Viel, Alessandra; Pasini, Barbara; Papi, Laura; Ottini, Laura; Savarese, Antonella; Bernard, Loris; Radice, Paolo; Hamann, Ute; Verheus, Martijn; Meijers-Heijboer, Hanne E J; Wijnen, Juul; Gómez García, Encarna B; Nelen, Marcel R; Kets, C Marleen; Seynaeve, Caroline; Tilanus-Linthorst, Madeleine M A; van der Luijt, Rob B; van Os, Theo; Rookus, Matti; Frost, Debra; Jones, J Louise; Evans, D Gareth; Lalloo, Fiona; Eeles, Ros; Izatt, Louise; Adlard, Julian; Davidson, Rosemarie; Cook, Jackie; Donaldson, Alan; Dorkins, Huw; Gregory, Helen; Eason, Jacqueline; Houghton, Catherine; Barwell, Julian; Side, Lucy E; McCann, Emma; Murray, Alex; Peock, Susan; Godwin, Andrew K; Schmutzler, Rita K; Rhiem, Kerstin; Engel, Christoph; Meindl, Alfons; Ruehl, Ina; Arnold, Norbert; Niederacher, Dieter; Sutter, Christian; Deissler, Helmut; Gadzicki, Dorothea; Kast, Karin; Preisler-Adams, Sabine; Varon-Mateeva, Raymonda; Schoenbuchner, Ines; Fiebig, Britta; Heinritz, Wolfram; Schäfer, Dieter; Gevensleben, Heidrun; Caux-Moncoutier, Virginie; Fassy-Colcombet, Marion; Cornelis, François; Mazoyer, Sylvie; Léoné, Mélanie; Boutry-Kryza, Nadia; Hardouin, Agnès; Berthet, Pascaline; Muller, Danièle; Fricker, Jean-Pierre; Mortemousque, Isabelle; Pujol, Pascal; Coupier, Isabelle; Lebrun, Marine; Kientz, Caroline; Longy, Michel; Sevenet, Nicolas; Stoppa-Lyonnet, Dominique; Isaacs, Claudine; Caldes, Trinidad; de la Hoya, Miguel; Heikkinen, Tuomas; Aittomäki, Kristiina; Blanco, Ignacio; Lazaro, Conxi; Barkardottir, Rosa B; Soucy, Penny; Dumont, Martine; Simard, Jacques; Montagna, Marco; Tognazzo, Silvia; D'Andrea, Emma; Fox, Stephen; Yan, Max; Rebbeck, Tim; Olopade, Olufunmilayo; Weitzel, Jeffrey N; Lynch, Henry T; Ganz, Patricia A; Tomlinson, Gail E; Wang, Xianshu; Fredericksen, Zachary; Pankratz, Vernon S; Lindor, Noralane M; Szabo, Csilla; Offit, Kenneth; Sakr, Rita; Gaudet, Mia; Bhatia, Jasmine; Kauff, Noah; Singer, Christian F; Tea, Muy-Kheng; Gschwantler-Kaulich, Daphne; Fink-Retter, Anneliese; Mai, Phuong L; Greene, Mark H; Imyanitov, Evgeny; O'Malley, Frances P; Ozcelik, Hilmi; Glendon, Gordon; Toland, Amanda E; Gerdes, Anne-Marie; Thomassen, Mads; Kruse, Torben A; Jensen, Uffe Birk; Skytte, Anne-Bine; Caligo, Maria A; Soller, Maria; Henriksson, Karin; Wachenfeldt, von Anna; Arver, Brita; Stenmark-Askmalm, Marie; Karlsson, Per; Ding, Yuan Chun; Neuhausen, Susan L; Beattie, Mary; Pharoah, Paul D P; Moysich, Kirsten B; Nathanson, Katherine L; Karlan, Beth Y; Gross, Jenny; John, Esther M; Daly, Mary B; Buys, Saundra M; Southey, Melissa C; Hopper, John L; Terry, Mary Beth; Chung, Wendy; Miron, Alexander F; Goldgar, David; Chenevix-Trench, Georgia; Easton, Douglas F; Andrulis, Irene L; Antoniou, Antonis C

2011-01-01

Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for

Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

PubMed Central

2011-01-01

Introduction Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. Methods We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. Results The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. Conclusions The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models

Requirement for the Mitochondrial Pyruvate Carrier in Mammalian Development Revealed by a Hypomorphic Allelic Series

PubMed Central

Bowman, Caitlyn E.; Hartung, Thomas

2016-01-01

Glucose and oxygen are two of the most important molecules transferred from mother to fetus during eutherian pregnancy, and the metabolic fates of these nutrients converge at the transport and metabolism of pyruvate in mitochondria. Pyruvate enters the mitochondrial matrix through the mitochondrial pyruvate carrier (MPC), a complex in the inner mitochondrial membrane that consists of two essential components, MPC1 and MPC2. Here, we define the requirement for mitochondrial pyruvate metabolism during development with a progressive allelic series of Mpc1 deficiency in mouse. Mpc1 deletion was homozygous lethal in midgestation, but Mpc1 hypomorphs and tissue-specific deletion of Mpc1 presented as early perinatal lethality. The allelic series demonstrated that graded suppression of MPC resulted in dose-dependent metabolic and transcriptional changes. Steady-state metabolomics analysis of brain and liver from Mpc1 hypomorphic embryos identified compensatory changes in amino acid and lipid metabolism. Flux assays in Mpc1-deficient embryonic fibroblasts also reflected these changes, including a dramatic increase in mitochondrial alanine utilization. The mitochondrial alanine transaminase GPT2 was found to be necessary and sufficient for increased alanine flux upon MPC inhibition. These data show that impaired mitochondrial pyruvate transport results in biosynthetic deficiencies that can be mitigated in part by alternative anaplerotic substrates in utero. PMID:27215380

No differences in brain microstructure between young KIBRA-C carriers and non-carriers.

PubMed

Hu, Li; Xu, Qunxing; Li, Jizhen; Wang, Feifei; Xu, Xinghua; Sun, Zhiyuan; Ma, Xiangxing; Liu, Yong; Wang, Qing; Wang, Dawei

2018-01-02

KIBRA rs17070145 polymorphism is associated with variations in memory function and the microstructure of related brain areas. Diffusion kurtosis imaging (DKI) as an extension of diffusion tensor imaging that can provide more information about changes in microstructure, based on the idea that water diffusion in biological tissues is heterogeneous due to structural hindrance and restriction. We used DKI to explore the relationship between KIBRA gene polymorphism and brain microstructure in young adults. We recruited 100 healthy young volunteers, including 53 TT carriers and 47 C allele carriers. No differences were detected between the TT homozygotes and C-allele carriers for any diffusion and kurtosis parameter. These results indicate KIBRA rs17070145 polymorphism likely has little or no effect on brain microstructure in young adults.

HLA alleles influence the clinical signature of amoxicillin-clavulanate hepatotoxicity.

PubMed

Stephens, Camilla; López-Nevot, Miguel-Ángel; Ruiz-Cabello, Francisco; Ulzurrun, Eugenia; Soriano, Germán; Romero-Gómez, Manuel; Moreno-Casares, Antonia; Lucena, M Isabel; Andrade, Raúl J

2013-01-01

The genotype-phenotype interaction in drug-induced liver injury (DILI) is a subject of growing interest. Previous studies have linked amoxicillin-clavulanate (AC) hepatotoxicity susceptibility to specific HLA alleles. In this study we aimed to examine potential associations between HLA class I and II alleles and AC DILI with regards to phenotypic characteristics, severity and time to onset in Spanish AC hepatotoxicity cases. High resolution genotyping of HLA loci A, B, C, DRB1 and DQB1 was performed in 75 AC DILI cases and 885 controls. The distributions of class I alleles A*3002 (P/Pc = 2.6E-6/5E-5, OR 6.7) and B*1801 (P/Pc = 0.008/0.22, OR 2.9) were more frequently found in hepatocellular injury cases compared to controls. In addition, the presence of the class II allele combination DRB1*1501-DQB1*0602 (P/Pc = 5.1E-4/0.014, OR 3.0) was significantly increased in cholestatic/mixed cases. The A*3002 and/or B*1801 carriers were found to be younger (54 vs 65 years, P = 0.019) and were more frequently hospitalized than the DRB1*1501-DQB1*0602 carriers. No additional alleles outside those associated with liver injury patterns were found to affect potential severity as measured by Hy's Law criteria. The phenotype frequencies of B*1801 (P/Pc = 0.015/0.42, OR 5.2) and DRB1*0301-DQB1*0201 (P/Pc = 0.0026/0.07, OR 15) were increased in AC DILI cases with delayed onset compared to those corresponding to patients without delayed onset, while the opposite applied to DRB1*1302-DQB1*0604 (P/Pc = 0.005/0.13, OR 0.07). HLA class I and II alleles influence the AC DILI signature with regards to phenotypic expression, latency presentation and severity in Spanish patients.

HLA Alleles Influence the Clinical Signature of Amoxicillin-Clavulanate Hepatotoxicity

PubMed Central

Stephens, Camilla; López-Nevot, Miguel-Ángel; Ruiz-Cabello, Francisco; Ulzurrun, Eugenia; Soriano, Germán; Romero-Gómez, Manuel; Moreno-Casares, Antonia; Lucena, M. Isabel; Andrade, Raúl J.

2013-01-01

Background and Aim The genotype-phenotype interaction in drug-induced liver injury (DILI) is a subject of growing interest. Previous studies have linked amoxicillin-clavulanate (AC) hepatotoxicity susceptibility to specific HLA alleles. In this study we aimed to examine potential associations between HLA class I and II alleles and AC DILI with regards to phenotypic characteristics, severity and time to onset in Spanish AC hepatotoxicity cases. Methods High resolution genotyping of HLA loci A, B, C, DRB1 and DQB1 was performed in 75 AC DILI cases and 885 controls. Results The distributions of class I alleles A*3002 (P/Pc = 2.6E-6/5E-5, OR 6.7) and B*1801 (P/Pc = 0.008/0.22, OR 2.9) were more frequently found in hepatocellular injury cases compared to controls. In addition, the presence of the class II allele combination DRB1*1501-DQB1*0602 (P/Pc = 5.1E-4/0.014, OR 3.0) was significantly increased in cholestatic/mixed cases. The A*3002 and/or B*1801 carriers were found to be younger (54 vs 65 years, P = 0.019) and were more frequently hospitalized than the DRB1*1501-DQB1*0602 carriers. No additional alleles outside those associated with liver injury patterns were found to affect potential severity as measured by Hy’s Law criteria. The phenotype frequencies of B*1801 (P/Pc = 0.015/0.42, OR 5.2) and DRB1*0301-DQB1*0201 (P/Pc = 0.0026/0.07, OR 15) were increased in AC DILI cases with delayed onset compared to those corresponding to patients without delayed onset, while the opposite applied to DRB1*1302-DQB1*0604 (P/Pc = 0.005/0.13, OR 0.07). Conclusions HLA class I and II alleles influence the AC DILI signature with regards to phenotypic expression, latency presentation and severity in Spanish patients. PMID:23874514

Transcriptional regulation differs in affected facioscapulohumeral muscular dystrophy patients compared to asymptomatic related carriers

PubMed Central

Arashiro, Patricia; Eisenberg, Iris; Kho, Alvin T.; Cerqueira, Antonia M. P.; Canovas, Marta; Silva, Helga C. A.; Pavanello, Rita C. M.; Verjovski-Almeida, Sergio; Kunkel, Louis M.; Zatz, Mayana

2009-01-01

Facioscapulohumeral muscular dystrophy (FSHD) is a progressive muscle disorder that has been associated with a contraction of 3.3-kb repeats on chromosome 4q35. FSHD is characterized by a wide clinical inter- and intrafamilial variability, ranging from wheelchair-bound patients to asymptomatic carriers. Our study is unique in comparing the gene expression profiles from related affected, asymptomatic carrier, and control individuals. Our results suggest that the expression of genes on chromosome 4q is altered in affected and asymptomatic individuals. Remarkably, the changes seen in asymptomatic samples are largely in products of genes encoding several chemokines, whereas the changes seen in affected samples are largely in genes governing the synthesis of GPI-linked proteins and histone acetylation. Besides this, the affected patient and related asymptomatic carrier share the 4qA161 haplotype. Thus, these polymorphisms by themselves do not explain the pathogenicity of the contracted allele. Interestingly, our results also suggest that the miRNAs might mediate the regulatory network in FSHD. Together, our results support the previous evidence that FSHD may be caused by transcriptional dysregulation of multiple genes, in cis and in trans, and suggest some factors potentially important for FSHD pathogenesis. The study of the gene expression profiles from asymptomatic carriers and related affected patients is a unique approach to try to enhance our understanding of the missing link between the contraction in D4Z4 repeats and muscle disease, while minimizing the effects of differences resulting from genetic background. PMID:19339494

Allelic Variation in CXCL16 Determines CD3+ T Lymphocyte Susceptibility to Equine Arteritis Virus Infection and Establishment of Long-Term Carrier State in the Stallion.

PubMed

Sarkar, Sanjay; Bailey, Ernest; Go, Yun Young; Cook, R Frank; Kalbfleisch, Ted; Eberth, John; Chelvarajan, R Lakshman; Shuck, Kathleen M; Artiushin, Sergey; Timoney, Peter J; Balasuriya, Udeni B R

2016-12-01

Equine arteritis virus (EAV) is the causative agent of equine viral arteritis (EVA), a respiratory, systemic, and reproductive disease of horses and other equid species. Following natural infection, 10-70% of the infected stallions can become persistently infected and continue to shed EAV in their semen for periods ranging from several months to life. Recently, we reported that some stallions possess a subpopulation(s) of CD3+ T lymphocytes that are susceptible to in vitro EAV infection and that this phenotypic trait is associated with long-term carrier status following exposure to the virus. In contrast, stallions not possessing the CD3+ T lymphocyte susceptible phenotype are at less risk of becoming long-term virus carriers. A genome wide association study (GWAS) using the Illumina Equine SNP50 chip revealed that the ability of EAV to infect CD3+ T lymphocytes and establish long-term carrier status in stallions correlated with a region within equine chromosome 11. Here we identified the gene and mutations responsible for these phenotypes. Specifically, the work implicated three allelic variants of the equine orthologue of CXCL16 (EqCXCL16) that differ by four non-synonymous nucleotide substitutions (XM_00154756; c.715 A → T, c.801 G → C, c.804 T → A/G, c.810 G → A) within exon 1. This resulted in four amino acid changes with EqCXCL16S (XP_001504806.1) having Phe, His, Ile and Lys as compared to EqCXL16R having Tyr, Asp, Phe, and Glu at 40, 49, 50, and 52, respectively. Two alleles (EqCXCL16Sa, EqCXCL16Sb) encoded identical protein products that correlated strongly with long-term EAV persistence in stallions (P<0.000001) and are required for in vitro CD3+ T lymphocyte susceptibility to EAV infection. The third (EqCXCL16R) was associated with in vitro CD3+ T lymphocyte resistance to EAV infection and a significantly lower probability for establishment of the long-term carrier state (viral persistence) in the male reproductive tract. EqCXCL16Sa and EqCXCL16

Allelic Variation in CXCL16 Determines CD3+ T Lymphocyte Susceptibility to Equine Arteritis Virus Infection and Establishment of Long-Term Carrier State in the Stallion

PubMed Central

Cook, R. Frank; Eberth, John; Chelvarajan, R. Lakshman; Artiushin, Sergey; Timoney, Peter J.

2016-01-01

Equine arteritis virus (EAV) is the causative agent of equine viral arteritis (EVA), a respiratory, systemic, and reproductive disease of horses and other equid species. Following natural infection, 10–70% of the infected stallions can become persistently infected and continue to shed EAV in their semen for periods ranging from several months to life. Recently, we reported that some stallions possess a subpopulation(s) of CD3+ T lymphocytes that are susceptible to in vitro EAV infection and that this phenotypic trait is associated with long-term carrier status following exposure to the virus. In contrast, stallions not possessing the CD3+ T lymphocyte susceptible phenotype are at less risk of becoming long-term virus carriers. A genome wide association study (GWAS) using the Illumina Equine SNP50 chip revealed that the ability of EAV to infect CD3+ T lymphocytes and establish long-term carrier status in stallions correlated with a region within equine chromosome 11. Here we identified the gene and mutations responsible for these phenotypes. Specifically, the work implicated three allelic variants of the equine orthologue of CXCL16 (EqCXCL16) that differ by four non-synonymous nucleotide substitutions (XM_00154756; c.715 A → T, c.801 G → C, c.804 T → A/G, c.810 G → A) within exon 1. This resulted in four amino acid changes with EqCXCL16S (XP_001504806.1) having Phe, His, Ile and Lys as compared to EqCXL16R having Tyr, Asp, Phe, and Glu at 40, 49, 50, and 52, respectively. Two alleles (EqCXCL16Sa, EqCXCL16Sb) encoded identical protein products that correlated strongly with long-term EAV persistence in stallions (P<0.000001) and are required for in vitro CD3+ T lymphocyte susceptibility to EAV infection. The third (EqCXCL16R) was associated with in vitro CD3+ T lymphocyte resistance to EAV infection and a significantly lower probability for establishment of the long-term carrier state (viral persistence) in the male reproductive tract. EqCXCL16Sa and Eq

The T-Allele of TCF7L2 rs7903146 Associates With a Reduced Compensation of Insulin Secretion for Insulin Resistance Induced by 9 Days of Bed Rest

PubMed Central

Alibegovic, Amra C.; Sonne, Mette P.; Højbjerre, Lise; Hansen, Torben; Pedersen, Oluf; van Hall, Gerrit; Holst, Jens J.; Stallknecht, Bente; Dela, Flemming; Vaag, Allan

2010-01-01

OBJECTIVE The aim of this study was to determine whether the type 2 diabetes–associated T-allele of transcription factor 7-like 2 (TCF7L2) rs7903146 associates with impaired insulin secretion to compensate for insulin resistance induced by bed rest. RESEARCH DESIGN AND METHODS A total of 38 healthy young Caucasian men were studied before and after bed rest using the hyperinsulinemic-euglycemic clamp technique combined with indirect calorimetry preceded by an intravenous glucose tolerance test. The TCF7L2 rs7903146 was genotyped using allelic discrimination performed with an ABI 7900 system. The genetic analyses were done assuming a dominant model of inheritance. RESULTS The first-phase insulin response (FPIR) was significantly lower in carriers of the T-allele compared with carriers of the CC genotype before bed rest, with and without correction for insulin resistance. The incremental rise of FPIR in response to insulin resistance induced by bed rest was lower in carriers of the T-allele (P < 0.001). Fasting plasma glucagon levels were significantly lower in carriers of the T-allele before and after bed rest. While carriers of the CC genotype developed increased hepatic insulin resistance, the TCF7L2 rs7903146 did not influence peripheral insulin action or the rate of lipolysis before or after bed rest. CONCLUSIONS Healthy carriers of the T-allele of TCF7L2 rs7903146 exhibit a diminished increase of insulin secretion in response to intravenous glucose to compensate for insulin resistance as induced by bed rest. Reduced paracrine glucagon stimulation may contribute to the impairment of β-cell function in the carriers TCF7L2 rs7903146 T-allele associated with increased risk of type 2 diabetes. PMID:20107109

Negative BOLD response and serotonin concentration within rostral subgenual portion of the anterior cingulate cortex for long-allele carriers during perceptual processing of emotional tasks

NASA Astrophysics Data System (ADS)

Hadi, Shamil M.; Siadat, Mohamad R.; Babajani-Feremi, Abbas

2012-03-01

We investigated the effect of synaptic serotonin concentration on hemodynamic responses. The stimuli paradigm involved the presentation of fearful and threatening facial expressions to a set of 24 subjects who were either5HTTLPR long- or short-allele carriers (12 of each type in each group). The BOLD signals of the rACC from subjects of each group were averaged to increase the signal-to-noise ratio. We used a Bayesian approach to estimate the parameters of the underlying hemodynamic model. Our results, during this perceptual processing of emotional task, showed a negative BOLD signal in the rACC in the subjects with long-alleles. In contrast, the subjects with short-alleles showed positive BOLD signals in the rACC. These results suggest that high synaptic serotonin concentration in the rACC inhibits neuronal activity in a fashion similar to GABA, and a consequent negative BOLD signal ensues.

Neural networks underlying trait aggression depend on MAOA gene alleles.

PubMed

Klasen, Martin; Wolf, Dhana; Eisner, Patrick D; Habel, Ute; Repple, Jonathan; Vernaleken, Ingo; Schlüter, Thorben; Eggermann, Thomas; Zerres, Klaus; Zepf, Florian D; Mathiak, Klaus

2018-03-01

Low expressing alleles of the MAOA gene (MAOA-L) have been associated with an increased risk for developing an aggressive personality. This suggests an MAOA-L-specific neurobiological vulnerability associated with trait aggression. The neural networks underlying this vulnerability are unknown. The present study investigated genotype-specific associations between resting state brain networks and trait aggression (Buss-Perry Aggression Questionnaire) in 82 healthy Caucasian males. Genotype influences on aggression-related networks were studied for intrinsic and seed-based brain connectivity. Intrinsic connectivity was higher in the ventromedial prefrontal cortex (VMPFC) of MAOA-L compared to high expressing allele (MAOA-H) carriers. Seed-based connectivity analyses revealed genotype differences in the functional involvement of this region. MAOA genotype modulated the relationship between trait aggression and VMPFC connectivity with supramarginal gyrus (SMG) and areas of the default mode network (DMN). Separate analyses for the two groups were performed to better understand how the genotype modulated the relationship between aggression and brain networks. They revealed a positive correlation between VMPFC connectivity and aggression in right angular gyrus (AG) and a negative correlation in right SMG in the MAOA-L group. No such effect emerged in the MAOA-H carriers. The results indicate a particular relevance of VMPFC for aggression in MAOA-L carriers; in specific, a detachment from the DMN along with a strengthened coupling to the AG seems to go along with lower trait aggression. MAOA-L carriers may thus depend on a synchronization of emotion regulation systems (VMPFC) with core areas of empathy (SMG) to prevent aggression.

Carriers of the Complex Allele HFE c.[187C>G;340+4T>C] Have Increased Risk of Iron Overload in São Miguel Island Population (Azores, Portugal).

PubMed

Branco, Claudia C; Gomes, Cidália T; De Fez, Laura; Bulhões, Sara; Brilhante, Maria José; Pereirinha, Tânia; Cabral, Rita; Rego, Ana Catarina; Fraga, Cristina; Miguel, António G; Brasil, Gracinda; Macedo, Paula; Mota-Vieira, Luisa

2015-01-01

Iron overload is associated with acquired and genetic conditions, the most common being hereditary hemochromatosis (HH) type-I, caused by HFE mutations. Here, we conducted a hospital-based case-control study of 41 patients from the São Miguel Island (Azores, Portugal), six belonging to a family with HH type-I pseudodominant inheritance, and 35 unrelated individuals fulfilling the biochemical criteria of iron overload compatible with HH type-I. For this purpose, we analyzed the most common HFE mutations- c.845G>A [p.Cys282Tyr], c.187C>G [p.His63Asp], and c.193A>T [p.Ser65Cys]. Results revealed that the family's HH pseudodominant pattern is due to consanguineous marriage of HFE-c.845G>A carriers, and to marriage with a genetically unrelated spouse that is a -c.187G carrier. Regarding unrelated patients, six were homozygous for c.845A, and three were c.845A/c.187G compound heterozygous. We then performed sequencing of HFE exons 2, 4, 5 and their intron-flanking regions. No other mutations were observed, but we identified the -c.340+4C [IVS2+4C] splice variant in 26 (74.3%) patients. Functionally, the c.340+4C may generate alternative splicing by HFE exon 2 skipping and consequently, a protein missing the α1-domain essential for HFE/ transferrin receptor-1 interactions. Finally, we investigated HFE mutations configuration with iron overload by determining haplotypes and genotypic profiles. Results evidenced that carriers of HFE-c.187G allele also carry -c.340+4C, suggesting in-cis configuration. This data is corroborated by the association analysis where carriers of the complex allele HFE-c.[187C>G;340+4T>C] have an increased iron overload risk (RR = 2.08, 95% CI = 1.40-2.94, p<0.001). Therefore, homozygous for this complex allele are at risk of having iron overload because they will produce two altered proteins--the p.63Asp [c.187G], and the protein lacking 88 amino acids encoded by exon 2. In summary, we provide evidence that the complex allele HFE-c.[187C>G;340+4T

Carriers of the Complex Allele HFE c.[187C>G;340+4T>C] Have Increased Risk of Iron Overload in São Miguel Island Population (Azores, Portugal)

PubMed Central

Bulhões, Sara; Brilhante, Maria José; Pereirinha, Tânia; Cabral, Rita; Rego, Ana Catarina; Fraga, Cristina; Miguel, António G.; Brasil, Gracinda; Macedo, Paula; Mota-Vieira, Luisa

2015-01-01

Iron overload is associated with acquired and genetic conditions, the most common being hereditary hemochromatosis (HH) type-I, caused by HFE mutations. Here, we conducted a hospital-based case-control study of 41 patients from the São Miguel Island (Azores, Portugal), six belonging to a family with HH type-I pseudodominant inheritance, and 35 unrelated individuals fulfilling the biochemical criteria of iron overload compatible with HH type-I. For this purpose, we analyzed the most common HFE mutations– c.845G>A [p.Cys282Tyr], c.187C>G [p.His63Asp], and c.193A>T [p.Ser65Cys]. Results revealed that the family’s HH pseudodominant pattern is due to consanguineous marriage of HFE-c.845G>A carriers, and to marriage with a genetically unrelated spouse that is a -c.187G carrier. Regarding unrelated patients, six were homozygous for c.845A, and three were c.845A/c.187G compound heterozygous. We then performed sequencing of HFE exons 2, 4, 5 and their intron-flanking regions. No other mutations were observed, but we identified the -c.340+4C [IVS2+4C] splice variant in 26 (74.3%) patients. Functionally, the c.340+4C may generate alternative splicing by HFE exon 2 skipping and consequently, a protein missing the α1-domain essential for HFE/ transferrin receptor-1 interactions. Finally, we investigated HFE mutations configuration with iron overload by determining haplotypes and genotypic profiles. Results evidenced that carriers of HFE-c.187G allele also carry -c.340+4C, suggesting in-cis configuration. This data is corroborated by the association analysis where carriers of the complex allele HFE-c.[187C>G;340+4T>C] have an increased iron overload risk (RR = 2.08, 95% CI = 1.40−2.94, p<0.001). Therefore, homozygous for this complex allele are at risk of having iron overload because they will produce two altered proteins—the p.63Asp [c.187G], and the protein lacking 88 amino acids encoded by exon 2. In summary, we provide evidence that the complex allele HFE-c.[187C

FISH-detected delay in replication timing of mutated FMR1 alleles on both active and inactive X-chromosomes.

PubMed

Yeshaya, J; Shalgi, R; Shohat, M; Avivi, L

1999-01-01

X-chromosome inactivation and the size of the CGG repeat number are assumed to play a role in the clinical, physical, and behavioral phenotype of female carriers of a mutated FMR1 allele. In view of the tight relationship between replication timing and the expression of a given DNA sequence, we have examined the replication timing of FMR1 alleles on active and inactive X-chromosomes in cell samples (lymphocytes or amniocytes) of 25 females: 17 heterozygous for a mutated FMR1 allele with a trinucleotide repeat number varying from 58 to a few hundred, and eight homozygous for a wild-type allele. We have applied two-color fluorescence in situ hybridization (FISH) with FMR1 and X-chromosome alpha-satellite probes to interphase cells of the various genotypes: the alpha-satellite probe was used to distinguish between early replicating (active) and late replicating (inactive) X-chromosomes, and the FMR1 probe revealed the replication pattern of this locus. All samples, except one with a large trinucleotide expansion, showed an early replicating FMR1 allele on the active X-chromosome and a late replicating allele on the inactive X-chromosome. In samples of mutation carriers, both the early and the late alleles showed delayed replication compared with normal alleles, regardless of repeat size. We conclude therefore that: (1) the FMR1 locus is subjected to X-inactivation; (2) mutated FMR1 alleles, regardless of repeat size, replicate later than wild-type alleles on both the active and inactive X-chromosomes; and (3) the delaying effect of the trinucleotide expansion, even with a low repeat size, is superimposed on the delay in replication associated with X-inactivation.

Cognitive and neural correlates of the 5-repeat allele of the dopamine D4 receptor gene in a population lacking the 7-repeat allele.

PubMed

Takeuchi, Hikaru; Tomita, Hiroaki; Taki, Yasuyuki; Kikuchi, Yoshie; Ono, Chiaki; Yu, Zhiqian; Sekiguchi, Atsushi; Nouchi, Rui; Kotozaki, Yuka; Nakagawa, Seishu; Miyauchi, Carlos Makoto; Iizuka, Kunio; Yokoyama, Ryoichi; Shinada, Takamitsu; Yamamoto, Yuki; Hanawa, Sugiko; Araki, Tsuyoshi; Hashizume, Hiroshi; Kunitoki, Keiko; Sassa, Yuko; Kawashima, Ryuta

2015-04-15

The 5-repeat allele of a common length polymorphism in the gene that encodes the dopamine D4 receptor (DRD4) is robustly associated with the risk of attention deficit hyperactivity disorder (ADHD) and substantially exists in Asian populations, which have a lower ADHD prevalence. In this study, we investigated the effect of this allele on microstructural properties of the brain and on its functional activity during externally directed attention-demanding tasks and creative performance in the 765 Asian subjects. For this purpose, we employed diffusion tensor imaging, N-back functional magnetic resonance imaging paradigms, and a test to measure creativity by divergent thinking. The 5-repeat allele was significantly associated with increased originality in the creative performance, increased mean diffusivity (the measure of how the tissue includes water molecules instead of neural and vessel components) in the widespread gray and white matter areas of extensive areas, particularly those where DRD4 is expressed, and reduced task-induced deactivation in the areas that are deactivated during the tasks in the course of both the attention-demanding working memory task and simple sensorimotor task. The observed neural characteristics of 5-repeat allele carriers may lead to an increased risk of ADHD and behavioral deficits. Furthermore, the increased originality of creative thinking observed in the 5-repeat allele carriers may support the notion of the side of adaptivity of the widespread risk allele of psychiatric diseases. Copyright © 2015. Published by Elsevier Inc.

Type 2 Diabetes Risk Alleles Demonstrate Extreme Directional Differentiation among Human Populations, Compared to Other Diseases

PubMed Central

Chen, Rong; Corona, Erik; Sikora, Martin; Dudley, Joel T.; Morgan, Alex A.; Moreno-Estrada, Andres; Nilsen, Geoffrey B.; Ruau, David; Lincoln, Stephen E.; Bustamante, Carlos D.; Butte, Atul J.

2012-01-01

Many disease-susceptible SNPs exhibit significant disparity in ancestral and derived allele frequencies across worldwide populations. While previous studies have examined population differentiation of alleles at specific SNPs, global ethnic patterns of ensembles of disease risk alleles across human diseases are unexamined. To examine these patterns, we manually curated ethnic disease association data from 5,065 papers on human genetic studies representing 1,495 diseases, recording the precise risk alleles and their measured population frequencies and estimated effect sizes. We systematically compared the population frequencies of cross-ethnic risk alleles for each disease across 1,397 individuals from 11 HapMap populations, 1,064 individuals from 53 HGDP populations, and 49 individuals with whole-genome sequences from 10 populations. Type 2 diabetes (T2D) demonstrated extreme directional differentiation of risk allele frequencies across human populations, compared with null distributions of European-frequency matched control genomic alleles and risk alleles for other diseases. Most T2D risk alleles share a consistent pattern of decreasing frequencies along human migration into East Asia. Furthermore, we show that these patterns contribute to disparities in predicted genetic risk across 1,397 HapMap individuals, T2D genetic risk being consistently higher for individuals in the African populations and lower in the Asian populations, irrespective of the ethnicity considered in the initial discovery of risk alleles. We observed a similar pattern in the distribution of T2D Genetic Risk Scores, which are associated with an increased risk of developing diabetes in the Diabetes Prevention Program cohort, for the same individuals. This disparity may be attributable to the promotion of energy storage and usage appropriate to environments and inconsistent energy intake. Our results indicate that the differential frequencies of T2D risk alleles may contribute to the observed

CGG allele size somatic mosaicism and methylation in FMR1 premutation alleles

PubMed Central

Pretto, Dalyir I.; Mendoza-Morales, Guadalupe; Lo, Joyce; Cao, Ru; Hadd, Andrew; Latham, Gary J.; Durbin-Johnson, Blythe; Hagerman, Randi; Tassone, Flora

2014-01-01

Background Greater than 200 CGG repeats in the 5′UTR of the FMR1 gene leads to epigenetic silencing and lack of the FMR1 protein, causing Fragile X Syndrome. Individuals carriers of a premutation (PM) allele with 55–200 CGG repeats are typically unmethylated and can present with clinical features defined as FMR1 associated conditions. Methods Blood samples from 17 male PM carriers were assessed clinically and molecularly by Southern Blot, Western Blot, PCR and QRT-PCR. Blood and brain tissue from additional 18 PM males were also similarly examined. Continuous outcomes were modeled using linear regression and binary outcomes were modeled using logistic regression. Results Methylated alleles were detected in different fractions of blood cells in all PM cases (n= 17). CGG repeat numbers correlated with percent of methylation and mRNA levels and, especially in the upper PM range, with greater number of clinical involvements. Inter/intra- tissue somatic instability and differences in percent methylation were observed between blood and fibroblasts (n=4) and also observed between blood and different brain regions in three of the 18 premutation cases examined. CGG repeat lengths in lymphocytes remained unchanged over a period of time ranging from 2–6 years, three cases for whom multiple samples were available. Conclusion In addition to CGG size instability, individuals with a PM expanded alleles can exhibit methylation and display more clinical features likely due to RNA toxicity and/or FMR1 silencing. The observed association between CGG repeat length and percent of methylation with the severity of the clinical phenotypes underscores the potential value of methylation in affected PM to further understand penetrance, inform diagnosis and to expand treatment options. PMID:24591415

Genetic characterization in symptomatic female DMD carriers: lack of relationship between X-inactivation, transcriptional DMD allele balancing and phenotype

PubMed Central

2012-01-01

Background Although Duchenne and Becker muscular dystrophies, X-linked recessive myopathies, predominantly affect males, a clinically significant proportion of females manifesting symptoms have also been reported. They represent an heterogeneous group characterized by variable degrees of muscle weakness and/or cardiac involvement. Though preferential inactivation of the normal X chromosome has long been considered the principal mechanism behind disease manifestation in these females, supporting evidence is controversial. Methods Eighteen females showing a mosaic pattern of dystrophin expression on muscle biopsy were recruited and classified as symptomatic (7) or asymptomatic (11), based on the presence or absence of muscle weakness. The causative DMD gene mutations were identified in all cases, and the X-inactivation pattern was assessed in muscle DNA. Transcriptional analysis in muscles was performed in all females, and relative quantification of wild-type and mutated transcripts was also performed in 9 carriers. Dystrophin protein was quantified by immunoblotting in 2 females. Results The study highlighted a lack of relationship between dystrophic phenotype and X-inactivation pattern in females; skewed X-inactivation was found in 2 out of 6 symptomatic carriers and in 5 out of 11 asymptomatic carriers. All females were characterized by biallelic transcription, but no association was found between X-inactivation pattern and allele transcriptional balancing. Either a prevalence of wild-type transcript or equal proportions of wild-type and mutated RNAs was observed in both symptomatic and asymptomatic females. Moreover, very similar levels of total and wild-type transcripts were identified in the two groups of carriers. Conclusions This is the first study deeply exploring the DMD transcriptional behaviour in a cohort of female carriers. Notably, no relationship between X-inactivation pattern and transcriptional behaviour of DMD gene was observed, suggesting that the

Dynamic characterization of HLA-B*44 Alleles: A comparative molecular dynamics simulation study.

PubMed

Ozbek, Pemra

2016-06-01

Human Leukocyte Antigens (HLA) are highly polymorphic proteins that play a key role in the immune system. HLA molecule is present on the cell membrane of antigen-presenting cells of the immune system and presents short peptides, originating from the proteins of invading pathogens or self-proteins, to the T-cell Receptor (TCR) molecule of the T-cells. In this study, peptide-binding characteristics of HLA-B*44:02, 44:03, 44:05 alleles bound to three nonameric peptides were studied using molecular dynamics simulations. Polymorphisms among these alleles (Asp116Tyr and Asp156Leu) result in major differences in the allele characteristics. While HLA-B*44:02 (Asp116, Asp156) and HLA-B*44:03 (Asp116, Leu156) depend on tapasin for efficient peptide loading, HLA-B*44:05 (Tyr116, Asp156) is tapasin independent. On the other hand, HLA-B*44:02 and HLA-B*44:03 mismatch is closely related to transplant rejection and acute-graft-versus-host disease. In order to understand the dynamic characteristics, the simulation trajectories were analyzed by applying Root Mean Square Deviation (RMSD) and Root Mean Square Fluctuation (RMSF) calculations and hydrogen bonding analysis. Binding dynamics of the three HLA-B*44 alleles and peptide sequences are comparatively discussed. In general, peptide binding stability is found to depend on the peptide rather than the allele type for HLA-B*44 alleles. Copyright © 2016 Elsevier Ltd. All rights reserved.

Minimal shortening of leukocyte telomere length across age groups in a cross-sectional study for carriers of a longevity-associated FOXO3 allele.

PubMed

Davy, Philip M C; Willcox, D Craig; Shimabukuro, Michio; Donlon, Timothy A; Torigoe, Trevor; Suzuki, Makoto; Higa, Moritake; Masuzaki, Hiroaki; Sata, Masataka; Chen, Randi; Murkofsky, Rachel; Morris, Brian J; Lim, Eunjung; Allsopp, Richard C; Willcox, Bradley J

2018-04-21

FOXO3 is one of the most prominent genes demonstrating a consistently reproducible genetic association with human longevity. The mechanisms by which these individual gene variants confer greater organismal lifespan are not well understood. We assessed the effect of longevity-associated FOXO3 alleles on age-related leukocyte telomere dynamics in a cross-sectional study comprising of samples from 121 healthy Okinawan-Japanese donors aged 21-95 years. We found that telomere length for carriers of the longevity associated allele of FOXO3 single nucleotide polymorphism rs2802292 displayed no significant correlation with age, an effect that was most pronounced in older (>50) participants. This is the first validated longevity gene variant identified to date showing an association with negligible loss of telomere length with age in humans in a cross sectional study. Reduced telomere attrition may be a key mechanism for the longevity-promoting effect of the FOXO3 genotype studied.

Association between the seven-repeat allele of the dopamine-4 receptor gene (DRD4) and spontaneous food intake in pre-school children.

PubMed

Silveira, Patrícia Pelufo; Portella, André Krumel; Kennedy, James L; Gaudreau, Hélène; Davis, Caroline; Steiner, Meir; Soares, Claudio N; Matthews, Stephen G; Sokolowski, Marla B; Dubé, Laurette; Loucks, Eric B; Hamilton, Jill; Meaney, Michael J; Levitan, Robert D

2014-02-01

Studies in adults show associations between the hypofunctional seven-repeat allele (7R) of the dopamine-4 receptor gene (DRD4), increased eating behaviour and/or obesity, particularly in females. We examined whether 7R is associated with total caloric intake and/or food choices in pre-schoolers. 150 four-year-old children taking part in a birth cohort study in Canada were administered a snack test meal in a laboratory setting. Mothers also filled out a food frequency questionnaire to address childrens' habitual food consumption. Total caloric and individual macronutrient intakes during the snack meal and specific types of foods as reported in the food diaries were compared across 7R allele carriers vs. non-carriers, using current BMI as a co-variate. We found significant sex by genotype interactions for fat and protein intake during the snack test. Post hoc testing revealed that in girls, but not boys, 7R carriers ate more fat and protein than did non-carriers. Based on the food diaries, across both sexes, 7R carriers consumed more portions of ice cream and less vegetables, eggs, nuts and whole bread, suggesting a less healthy pattern of habitual food consumption. The 7R allele of DRD4 influences macronutrient intakes and specific food choices as early as four years of age. The specific pattern of results further suggests that prior associations between the 7R allele and adult overeating/obesity may originate in food choices observable in the preschool years. Longitudinal follow-up of these children will help establish the relevance of these findings for obesity risk and prevention. Copyright © 2013 Elsevier Ltd. All rights reserved.

Angiotensin Converting Enzyme Inhibitors and Alzheimer Disease in the Presence of the Apolipoprotein E4 Allele

PubMed Central

Qiu, Wendy Wei Qiao; Lai, Angela; Mon, Timothy; Mwamburi, Mkaya; Taylor, Warren; Rosenzweig, James; Kowall, Neil; Stern, Robert; Zhu, Haihao; Steffens, David C.

2013-01-01

Objective The effect of angiotensin converting enzyme (ACE) inhibitors on Alzheimer disease (AD) remains unclear, with conflicting results reported. We studied the interaction of the Apolipoprotein E (ApoE) genotype and ACE inhibitors on AD. Methods This was a cross-sectional study of homebound elderly with an AD diagnosis and documentation of medications taken. ApoE genotype was determined. Results A total of 355 subjects with status on ApoE alleles and cognitive diagnoses were studied. The average age (mean ± SD) of this population was 73.3 ± 8.3 years old, and 73% were female. Cross-sectionally, there was no difference in the number of AD cases between ApoE4 carriers and ApoE4 non-carriers or between ACE inhibitor users and non-users in the homebound elderly. ApoE4 carriers treated with ACE inhibitors, however, had more diagnoses of AD compared with those who did not have the treatment (28% versus 6%, p = 0.01) or ApoE4 non-carriers treated with an ACE inhibitor (28% versus 10%, p = 0.03). ACE inhibitor use was associated with AD diagnosis only in the presence of an E4 allele. Using multivariate logistic regression analysis, we found that in diagnosed AD cases there was a significant interaction between ApoE4 and ACE inhibitor use (odds ratio: 20.85; 95% confidence interval: 3.08–140.95; p = 0.002) after adjusting for age, sex, ethnicity, and education. Conclusion The effects of ACE inhibitors on AD may be different depending on ApoE genotype. A prospective study is needed to determine whether ACE inhibitor use accelerates or poorly delays AD development in ApoE4 carriers compared with ApoE4 non-carriers. PMID:23567418

Angiotensin converting enzyme inhibitors and Alzheimer disease in the presence of the apolipoprotein E4 allele.

PubMed

Qiu, Wendy Wei Qiao; Lai, Angela; Mon, Timothy; Mwamburi, Mkaya; Taylor, Warren; Rosenzweig, James; Kowall, Neil; Stern, Robert; Zhu, Haihao; Steffens, David C

2014-02-01

The effect of angiotensin converting enzyme (ACE) inhibitors on Alzheimer disease (AD) remains unclear, with conflicting results reported. We studied the interaction of the Apolipoprotein E (ApoE) genotype and ACE inhibitors on AD. This was a cross-sectional study of homebound elderly with an AD diagnosis and documentation of medications taken. ApoE genotype was determined. A total of 355 subjects with status on ApoE alleles and cognitive diagnoses were studied. The average age (mean ± SD) of this population was 73.3 ± 8.3 years old, and 73% were female. Cross-sectionally, there was no difference in the number of AD cases between ApoE4 carriers and ApoE4 non-carriers or between ACE inhibitor users and non-users in the homebound elderly. ApoE4 carriers treated with ACE inhibitors, however, had more diagnoses of AD compared with those who did not have the treatment (28% versus 6%, p = 0.01) or ApoE4 non-carriers treated with an ACE inhibitor (28% versus 10%, p = 0.03). ACE inhibitor use was associated with AD diagnosis only in the presence of an E4 allele. Using multivariate logistic regression analysis, we found that in diagnosed AD cases there was a significant interaction between ApoE4 and ACE inhibitor use (odds ratio: 20.85; 95% confidence interval: 3.08-140.95; p = 0.002) after adjusting for age, sex, ethnicity, and education. The effects of ACE inhibitors on AD may be different depending on ApoE genotype. A prospective study is needed to determine whether ACE inhibitor use accelerates or poorly delays AD development in ApoE4 carriers compared with ApoE4 non-carriers. Copyright © 2014. Published by Elsevier Inc.

Notable Carrier Risks for Individuals Having Two Copies of SMN1 in Spinal Muscular Atrophy Families with 2-copy Alleles: Estimation Based on Chinese Meta-analysis Data.

PubMed

Wei, Xianda; Tan, Hu; Yang, Pu; Zhang, Rui; Tan, Bo; Zhang, Yue; Mei, Libin; Liang, Desheng; Wu, Lingqian

2017-02-01

Spinal muscular atrophy is an autosomal recessive neuromuscular disease mainly caused by homozygous deletion of SMN1. The 2-copy SMN1 allele may present in the families of SMA patients with homozygous deletion of SMN1, one of whose parents has two SMN1 copies. In such families, individuals having two SMN1 copies still have a chance to be "2 + 0" carriers. In this study, the risks for the parents, fetuses and other siblings having two SMN1 copies to be "2 + 0" carriers were estimated based on Chinese meta-analysis data and turned out to be rather striking. Our findings would help to optimize genetic counseling regarding spinal muscular atrophy.

Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers

PubMed Central

Cox, David G.; Simard, Jacques; Sinnett, Daniel; Hamdi, Yosr; Soucy, Penny; Ouimet, Manon; Barjhoux, Laure; Verny-Pierre, Carole; McGuffog, Lesley; Healey, Sue; Szabo, Csilla; Greene, Mark H.; Mai, Phuong L.; Andrulis, Irene L.; Thomassen, Mads; Gerdes, Anne-Marie; Caligo, Maria A.; Friedman, Eitan; Laitman, Yael; Kaufman, Bella; Paluch, Shani S.; Borg, Åke; Karlsson, Per; Stenmark Askmalm, Marie; Barbany Bustinza, Gisela; Nathanson, Katherine L.; Domchek, Susan M.; Rebbeck, Timothy R.; Benítez, Javier; Hamann, Ute; Rookus, Matti A.; van den Ouweland, Ans M.W.; Ausems, Margreet G.E.M.; Aalfs, Cora M.; van Asperen, Christi J.; Devilee, Peter; Gille, Hans J.J.P.; Peock, Susan; Frost, Debra; Evans, D. Gareth; Eeles, Ros; Izatt, Louise; Adlard, Julian; Paterson, Joan; Eason, Jacqueline; Godwin, Andrew K.; Remon, Marie-Alice; Moncoutier, Virginie; Gauthier-Villars, Marion; Lasset, Christine; Giraud, Sophie; Hardouin, Agnès; Berthet, Pascaline; Sobol, Hagay; Eisinger, François; Bressac de Paillerets, Brigitte; Caron, Olivier; Delnatte, Capucine; Goldgar, David; Miron, Alex; Ozcelik, Hilmi; Buys, Saundra; Southey, Melissa C.; Terry, Mary Beth; Singer, Christian F.; Dressler, Anne-Catharina; Tea, Muy-Kheng; Hansen, Thomas V.O.; Johannsson, Oskar; Piedmonte, Marion; Rodriguez, Gustavo C.; Basil, Jack B.; Blank, Stephanie; Toland, Amanda E.; Montagna, Marco; Isaacs, Claudine; Blanco, Ignacio; Gayther, Simon A.; Moysich, Kirsten B.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Niederacher, Dieter; Sutter, Christian; Gadzicki, Dorothea; Fiebig, Britta; Caldes, Trinidad; Laframboise, Rachel; Nevanlinna, Heli; Chen, Xiaoqing; Beesley, Jonathan; Spurdle, Amanda B.; Neuhausen, Susan L.; Ding, Yuan C.; Couch, Fergus J.; Wang, Xianshu; Peterlongo, Paolo; Manoukian, Siranoush; Bernard, Loris; Radice, Paolo; Easton, Douglas F.; Chenevix-Trench, Georgia; Antoniou, Antonis C.; Stoppa-Lyonnet, Dominique; Mazoyer, Sylvie; Sinilnikova, Olga M.

2011-01-01

Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77–0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription. PMID:21890493

DRD4 long allele carriers show heightened attention to high-priority items relative to low-priority items.

PubMed

Gorlick, Marissa A; Worthy, Darrell A; Knopik, Valerie S; McGeary, John E; Beevers, Christopher G; Maddox, W Todd

2015-03-01

Humans with seven or more repeats in exon III of the DRD4 gene (long DRD4 carriers) sometimes demonstrate impaired attention, as seen in attention-deficit hyperactivity disorder, and at other times demonstrate heightened attention, as seen in addictive behavior. Although the clinical effects of DRD4 are the focus of much work, this gene may not necessarily serve as a "risk" gene for attentional deficits, but as a plasticity gene where attention is heightened for priority items in the environment and impaired for minor items. Here we examine the role of DRD4 in two tasks that benefit from selective attention to high-priority information. We examine a category learning task where performance is supported by focusing on features and updating verbal rules. Here, selective attention to the most salient features is associated with good performance. In addition, we examine the Operation Span (OSPAN) task, a working memory capacity task that relies on selective attention to update and maintain items in memory while also performing a secondary task. Long DRD4 carriers show superior performance relative to short DRD4 homozygotes (six or less tandem repeats) in both the category learning and OSPAN tasks. These results suggest that DRD4 may serve as a "plasticity" gene where individuals with the long allele show heightened selective attention to high-priority items in the environment, which can be beneficial in the appropriate context.

DRD4 Long Allele Carriers Show Heightened Attention to High-Priority Items Relative to Low-Priority Items

PubMed Central

Gorlick, Marissa A.; Worthy, Darrell A.; Knopik, Valerie S.; McGeary, John E.; Beevers, Christopher G.; Maddox, W. Todd

2014-01-01

Humans with 7 or more repeats in exon III of the DRD4 gene (long DRD4 carriers) sometimes demonstrate impaired attention, as seen in ADHD, and at other times demonstrate heightened attention, as seen in addictive behavior. Though the clinical effects of DRD4 are the focus of much work, this gene may not necessarily serve as a ‘risk’ gene for attentional deficits, but as a plasticity gene where attention is heightened for priority items in the environment and impaired for minor items. Here we examine the role of DRD4 in two tasks that benefit from selective attention to high-priority information. We examine a category learning task where performance is supported by focusing on features and updating verbal rules. Here selective attention to the most salient features is associated with good performance. In addition, we examine the Operation Span Task (OSPAN), a working memory capacity task that relies on selective attention to update and maintain items in memory while also performing a secondary task. Long DRD4 carriers show superior performance relative to short DRD4 homozygotes (six or less tandem repeats) in both the category learning and OSPAN tasks. These results suggest that DRD4 may serve as a ‘plasticity’ gene where individuals with the long allele show heightened selective attention to high-priority items in the environment, which can be beneficial in the appropriate context. PMID:25244120

The DRD2 Taq1A A1 Allele May Magnify the Risk of Alzheimer's in Aging African-Americans.

PubMed

Blum, Kenneth; Badgaiyan, Rajendra D; Dunston, Georgia M; Baron, David; Modestino, Edward J; McLaughlin, Thomas; Steinberg, Bruce; Gold, Mark S; Gondré-Lewis, Marjorie C

2017-09-30

Alzheimer's disease is an irreversible, progressive brain disorder that slowly destroys cognitive skills and the ability to perform the simplest tasks. More than 5 million Americans are afflicted with Alzheimer's; a disorder which ranks third, just behind heart disease and cancer, as a cause of death for older people. With no real cure and in spite of enormous efforts worldwide, the disease remains a mystery in terms of treatment. Importantly, African-Americans are two times as likely as Whites to develop late-onset Alzheimer's disease and less likely to receive timely diagnosis and treatment. Dopamine function is linked to normal cognition and memory and carriers of the DRD2 Taq1A A1 allele have significant loss of D2 receptor density in the brain. Recent research has shown that A1 carriers have worse memory performance during long-term memory (LTM) updating, compared to non-carriers or A2-carriers. A1carriers also show less blood oxygen level-dependent (BOLD) activation in the left caudate nucleus which is important for LTM updating. This latter effect was only seen in older adults, suggesting magnification of genetic effects on brain functioning in the elderly. Moreover, the frequency of the A1 allele is 0.40 in African-Americans, with an approximate prevalence of the DRD2 A1 allele in 50% of an African-American subset of individuals. This is higher than what is found in a non-screened American population (≤ 28%) for reward deficiency syndrome (RDS) behaviors. Based on DRD2 known genetic polymorphisms, we hypothesize that the DRD2 Taq1A A1 allele magnifies the risk of Alzheimer's in aging African-Americans. Research linking this high risk for Alzheimer's in the African-American population, with DRD2/ANKK1-TaqIA polymorphism and neurocognitive deficits related to LTM, could pave the way for novel, targeted pro-dopamine homeostatic treatment.

Lack of neural compensatory mechanisms of BDNF val66met met carriers and APOE E4 carriers in healthy aging, mild cognitive impairment, and Alzheimer's disease.

PubMed

Gomar, Jesus J; Conejero-Goldberg, Concepcion; Huey, Edward D; Davies, Peter; Goldberg, Terry E

2016-03-01

Compromises in compensatory neurobiologic mechanisms due to aging and/or genetic factors (i.e., APOE gene) may influence brain-derived neurotrophic factor (BDNF) val66met polymorphism effects on temporal lobe morphometry and memory performance. We studied 2 cohorts from Alzheimer's Disease Neuroimaging Initiative: 175 healthy subjects and 222 with prodromal and established Alzheimer's disease. Yearly structural magnetic resonance imaging and cognitive performance assessments were carried out over 3 years of follow-up. Both cohorts had similar BDNF Val/Val and Met allele carriers' (including both Val/Met and Met/Met individuals) distribution. In healthy subjects, a significant trend for thinner posterior cingulate and precuneus cortices was detected in Met carriers compared to Val homozygotes in APOE E4 carriers, with large and medium effect sizes, respectively. The mild cognitive impairment/Alzheimer's disease cohort showed a longitudinal decline in entorhinal thickness in BDNF Met carriers compared to Val/Val in APOE E4 carriers, with effect sizes ranging from medium to large. In addition, an effect of BDNF genotype was found in APOE E4 carriers for episodic memory (logical memory and ADAS-Cog) and semantic fluency measures, with Met carriers performing worse in all cases. These findings suggest a lack of compensatory mechanisms in BDNF Met carriers and APOE E4 carriers in healthy and pathological aging. Copyright © 2016 Elsevier Inc. All rights reserved.

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

Schizophrenia and neurotrophin-3 alleles.

PubMed

Jŏnsson, E; Brené, S; Zhang, X R; Nimgaonkar, V L; Tylec, A; Schalling, M; Sedvall, G

1997-05-01

Studies of brain anatomy and premorbid functioning indicate that schizophrenia may be of neurodevelopmental origin. In the neurotrophic factor neurotrophin-3 (NT-3) gene, the A3/147-bp allele in a dinucleotide repeat polymorphism located in the promoter region was found to be associated with schizophrenia in a Japanese study. Another NT-3 polymorphism (Glu63Gly) indicated an association with schizophrenic patients with a putative neurodevelopmental form of the disease. We examined Swedish schizophrenic patients (n = 109) and control subjects (n = 78) for the same two NT-3 polymorphisms, as well as a third silent exonic polymorphism (at Pro55). No significant difference was found between the two groups. However, in a meta-analysis including the present and previous studies of Caucasian subjects, the A3/147-bp allele frequency was found to be significantly higher in the schizophrenic patients. In the present study, carriers of the A3/147 bp allele tended to have an earlier age of onset and to display more extrapyramidal symptoms. In the silent exonic polymorphism (at Pro55), female schizophrenic patients had higher adenine and lower guanine allele frequencies than control female subjects. Together with previous studies, the results provide some support for an association between the NT-3 gene and certain forms of schizophrenia. This warrants further investigation of NT-3 and other neurotrophic factors with additional polymorphisms and larger patient samples.

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

DNA transfer-a never ending story. A study on scenarios involving a second person as carrier.

PubMed

Helmus, Janine; Bajanowski, Thomas; Poetsch, Micaela

2016-01-01

The transfer of DNA directly from one item to another has been shown in many studies with elaborate discussions on the nature of the DNA donor as well as material and surface of the items or surrounding features. Every DNA transfer scenario one can imagine seems to be possible. This evokes more and more intricate scenarios proposed by lawyers or attorneys searching for an explanation of the DNA of a certain person on a distinct item with impact on a crime. At court, the forensic genetic scientist has to comment on the probability of these scenarios thus calling for extensive studies on such settings. Here, the possibility of an involvement of a second person as a carrier of the donor's DNA in a variety of different scenarios including three pairs of people and two kinds of items (textiles and plastic bags) was investigated. All transfer settings were executed with and without gloves on the carrier's hands. DNA left on the items was isolated and analyzed using the Powerplex® ESX17 kit. In 21 out of 180 samples, all alleles of the donor DNA could be obtained on the second item (12%), on eight samples, the donor's DNA was dominant compared to all other alleles (38% of samples with complete donor profile). Additionally, 51 samples displayed at least more than half of the donor's alleles (28%). The complete DNA profile of the carrier was found in 47 out of 180 samples (42 partial profiles). In summary, it could be shown that a transfer of donor DNA from epithelial cells through a carrier to a second item is possible, even if the carrier does not wear gloves.

Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3.

PubMed

Hamdi, Yosr; Soucy, Penny; Kuchenbaeker, Karoline B; Pastinen, Tomi; Droit, Arnaud; Lemaçon, Audrey; Adlard, Julian; Aittomäki, Kristiina; Andrulis, Irene L; Arason, Adalgeir; Arnold, Norbert; Arun, Banu K; Azzollini, Jacopo; Bane, Anita; Barjhoux, Laure; Barrowdale, Daniel; Benitez, Javier; Berthet, Pascaline; Blok, Marinus J; Bobolis, Kristie; Bonadona, Valérie; Bonanni, Bernardo; Bradbury, Angela R; Brewer, Carole; Buecher, Bruno; Buys, Saundra S; Caligo, Maria A; Chiquette, Jocelyne; Chung, Wendy K; Claes, Kathleen B M; Daly, Mary B; Damiola, Francesca; Davidson, Rosemarie; De la Hoya, Miguel; De Leeneer, Kim; Diez, Orland; Ding, Yuan Chun; Dolcetti, Riccardo; Domchek, Susan M; Dorfling, Cecilia M; Eccles, Diana; Eeles, Ros; Einbeigi, Zakaria; Ejlertsen, Bent; Engel, Christoph; Gareth Evans, D; Feliubadalo, Lidia; Foretova, Lenka; Fostira, Florentia; Foulkes, William D; Fountzilas, George; Friedman, Eitan; Frost, Debra; Ganschow, Pamela; Ganz, Patricia A; Garber, Judy; Gayther, Simon A; Gerdes, Anne-Marie; Glendon, Gord; Godwin, Andrew K; Goldgar, David E; Greene, Mark H; Gronwald, Jacek; Hahnen, Eric; Hamann, Ute; Hansen, Thomas V O; Hart, Steven; Hays, John L; Hogervorst, Frans B L; Hulick, Peter J; Imyanitov, Evgeny N; Isaacs, Claudine; Izatt, Louise; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Jensen, Uffe Birk; John, Esther M; Joseph, Vijai; Just, Walter; Kaczmarek, Katarzyna; Karlan, Beth Y; Kets, Carolien M; Kirk, Judy; Kriege, Mieke; Laitman, Yael; Laurent, Maïté; Lazaro, Conxi; Leslie, Goska; Lester, Jenny; Lesueur, Fabienne; Liljegren, Annelie; Loman, Niklas; Loud, Jennifer T; Manoukian, Siranoush; Mariani, Milena; Mazoyer, Sylvie; McGuffog, Lesley; Meijers-Heijboer, Hanne E J; Meindl, Alfons; Miller, Austin; Montagna, Marco; Mulligan, Anna Marie; Nathanson, Katherine L; Neuhausen, Susan L; Nevanlinna, Heli; Nussbaum, Robert L; Olah, Edith; Olopade, Olufunmilayo I; Ong, Kai-Ren; Oosterwijk, Jan C; Osorio, Ana; Papi, Laura; Park, Sue Kyung; Pedersen, Inge Sokilde; Peissel, Bernard; Segura, Pedro Perez; Peterlongo, Paolo; Phelan, Catherine M; Radice, Paolo; Rantala, Johanna; Rappaport-Fuerhauser, Christine; Rennert, Gad; Richardson, Andrea; Robson, Mark; Rodriguez, Gustavo C; Rookus, Matti A; Schmutzler, Rita Katharina; Sevenet, Nicolas; Shah, Payal D; Singer, Christian F; Slavin, Thomas P; Snape, Katie; Sokolowska, Johanna; Sønderstrup, Ida Marie Heeholm; Southey, Melissa; Spurdle, Amanda B; Stadler, Zsofia; Stoppa-Lyonnet, Dominique; Sukiennicki, Grzegorz; Sutter, Christian; Tan, Yen; Tea, Muy-Kheng; Teixeira, Manuel R; Teulé, Alex; Teo, Soo-Hwang; Terry, Mary Beth; Thomassen, Mads; Tihomirova, Laima; Tischkowitz, Marc; Tognazzo, Silvia; Toland, Amanda Ewart; Tung, Nadine; van den Ouweland, Ans M W; van der Luijt, Rob B; van Engelen, Klaartje; van Rensburg, Elizabeth J; Varon-Mateeva, Raymonda; Wappenschmidt, Barbara; Wijnen, Juul T; Rebbeck, Timothy; Chenevix-Trench, Georgia; Offit, Kenneth; Couch, Fergus J; Nord, Silje; Easton, Douglas F; Antoniou, Antonis C; Simard, Jacques

2017-01-01

Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10 -6 ). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.

Reduced risk of recurrent myocardial infarction in homozygous carriers of the chromosome 9p21 rs1333049 C risk allele in the contemporary percutaneous coronary intervention era: a prospective observational study

PubMed Central

Hara, Masahiko; Sakata, Yasuhiko; Nakatani, Daisaku; Suna, Shinichiro; Usami, Masaya; Matsumoto, Sen; Ozaki, Kouichi; Nishino, Masami; Sato, Hiroshi; Kitamura, Tetsuhisa; Nanto, Shinsuke; Hamasaki, Toshimitsu; Tanaka, Toshihiro; Hori, Masatsugu; Komuro, Issei

2014-01-01

Objectives Chromosome 9p21 single nucleotide polymorphism (SNP) is a susceptibility variant for acute myocardial infarction (AMI) in the primary prevention setting. However, it is controversial whether this SNP is also associated with recurrent myocardial infarction (ReMI) in the secondary prevention setting. The purpose of this study is to evaluate the impact of chromosome 9p21 SNP on ReMI in patients receiving secondary prevention programmes after AMI. Design A prospective observational study. Setting Osaka Acute Coronary Insufficiency Study (OACIS) in Japan. Participants 2022 patients from the OACIS database. Interventions Genotyping of the 9p21 rs1333049 variant. Primary outcome measures ReMI event after survival discharge for 1 year. Results A total of 43 ReMI occurred during the 1 year follow-up period. Although the rs1333049 C allele had an increased susceptibility to their first AMI in an additive model when compared with 1373 healthy controls (OR 1.20, 95% CI 1.09 to 1.33, p=2.3*10−4), patients with the CC genotype had a lower incidence of ReMI at 1 year after discharge of AMI (log-rank p=0.005). The adjusted HR of the CC genotype as compared with the CG/GG genotypes was 0.20 (0.06 to 0.65, p=0.007). Subgroup analysis demonstrated that the association between the rs1333049 CC genotype and a lower incidence of 1 year ReMI was common to all subgroups. Conclusions Homozygous carriers of the rs1333049 C allele on chromosome 9p21 showed a reduced risk of 1 year ReMI in the contemporary percutaneous coronary intervention era, although the C allele had conferred susceptibility to their first AMI. PMID:25232560

Lunch eating predicts weight-loss effectiveness in carriers of the common allele at PERILIPIN1: the ONTIME (Obesity, Nutrigenetics, Timing, Mediterranean) study.

PubMed

Garaulet, Marta; Vera, Beatriz; Bonnet-Rubio, Gemma; Gómez-Abellán, Purificación; Lee, Yu-Chi; Ordovás, José M

2016-10-01

We propose that eating lunch late impairs the mobilization of fat from adipose tissue, particularly in carriers of PERILIPIN1 (PLIN1) variants. The aim was to test the hypothesis that PLIN1, a circadian lipid-stabilizing protein in the adipocyte, interacts with the timing of food intake to affect weight loss. A total of 1287 overweight and obese subjects [229 men and 1058 women; mean ± SD body mass index (in kg/m 2 ): 31 ± 5] who attended outpatient obesity clinics were enrolled in the ONTIME (Obesity, Nutrigenetics, Timing, Mediterranean) study. Timing of food intake was estimated with a validated questionnaire. Anthropometric variables and PLIN1 genotypes were analyzed, including 6209T>C (rs2289487), 11482G>A (rs894160), 13041A>G (rs2304795), and 14995A>T (rs1052700). The main outcomes were effectiveness of the program and weight-loss progression during 28 wk of treatment. The PLIN1 locus was associated with variability in response to a weight-loss program. Specifically, carrying the minor C allele at the PLIN1 6209T>C was associated with better weight-loss response (P = 0.035). The probability of being a better responder [percentage of weight loss ≥7.5% (median)] was 33% higher among C than among TT carriers (OR: 1.32; 95% CI: 1.05, 1.67; P = 0.017). We found an interaction of PLIN1 × food timing between the 14995A>T variant and timing of lunch eating for total weight loss (P = 0.035). Among AA carriers, eating late was associated with less weight loss (P < 0.001), whereas time of eating did not influence weight loss among TT carriers (P = 0.326). Variability at the PLIN1 locus is associated with variability in weight loss. Moreover, eating late is related to lower weight-loss effectiveness among carriers of the AA genotype at the PLIN1 14995A>T variant. These results contribute to our ability to implement more precise and successful obesity treatments. The ONTIME study was registered at clinicaltrials.gov as NCT02829619. © 2016 American Society for

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.

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

A commonly carried allele of the obesity-related FTO gene is associated with reduced brain volume in the healthy elderly

PubMed Central

Stein, Jason L.; Hua, Xue; Lee, Suh; Hibar, Derrek P.; Leow, Alex D.; Dinov, Ivo D.; Toga, Arthur W.; Saykin, Andrew J.; Shen, Li; Foroud, Tatiana; Pankratz, Nathan; Huentelman, Matthew J.; Craig, David W.; Gerber, Jill D.; Allen, April N.; Corneveaux, Jason J.; Stephan, Dietrich A.; DeCarli, Charles S.; DeChairo, Bryan M.; Potkin, Steven G.; Jack, Clifford R.; Weiner, Michael W.; Raji, Cyrus A.; Lopez, Oscar L.; Becker, James T.; Carmichael, Owen T.; Thompson, Paul M.; Weiner, Michael; Thal, Leon; Petersen, Ronald; Jack, Clifford R.; Jagust, William; Trojanowki, John; Toga, Arthur W.; Beckett, Laurel; Green, Robert C.; Gamst, Anthony; Potter, William Z.; Montine, Tom; Anders, Dale; Bernstein, Matthew; Felmlee, Joel; Fox, Nick; Thompson, Paul; Schuff, Norbert; Alexander, Gene; Bandy, Dan; Koeppe, Robert A.; Foster, Norm; Reiman, Eric M.; Chen, Kewei; Trojanowki, John; Shaw, Les; Lee, Virginia M.-Y.; Korecka, Magdalena; Toga, Arthur W.; Crawford, Karen; Neu, Scott; Harvey, Danielle; Gamst, Anthony; Kornak, John; Kachaturian, Zaven; Frank, Richard; Snyder, Peter J.; Molchan, Susan; Kaye, Jeffrey; Vorobik, Remi; Quinn, Joseph; Schneider, Lon; Pawluczyk, Sonia; Spann, Bryan; Fleisher, Adam S.; Vanderswag, Helen; Heidebrink, Judith L.; Lord, Joanne L.; Johnson, Kris; Doody, Rachelle S.; Villanueva-Meyer, Javier; Chowdhury, Munir; Stern, Yaakov; Honig, Lawrence S.; Bell, Karen L.; Morris, John C.; Mintun, Mark A.; Schneider, Stacy; Marson, Daniel; Griffith, Randall; Badger, Beverly; Grossman, Hillel; Tang, Cheuk; Stern, Jessica; deToledo-Morrell, Leyla; Shah, Raj C.; Bach, Julie; Duara, Ranjan; Isaacson, Richard; Strauman, Silvia; Albert, Marilyn S.; Pedroso, Julia; Toroney, Jaimie; Rusinek, Henry; de Leon, Mony J; De Santi, Susan M; Doraiswamy, P. Murali; Petrella, Jeffrey R.; Aiello, Marilyn; Clark, Christopher M.; Pham, Cassie; Nunez, Jessica; Smith, Charles D.; Given II, Curtis A.; Hardy, Peter; DeKosky, Steven T.; Oakley, MaryAnn; Simpson, Donna M.; Ismail, M. Saleem; Porsteinsson, Anton; McCallum, Colleen; Cramer, Steven C.; Mulnard, Ruth A.; McAdams-Ortiz, Catherine; Diaz-Arrastia, Ramon; Martin-Cook, Kristen; DeVous, Michael; Levey, Allan I.; Lah, James J.; Cellar, Janet S.; Burns, Jeffrey M.; Anderson, Heather S.; Laubinger, Mary M.; Bartzokis, George; Silverman, Daniel H.S.; Lu, Po H.; Fletcher, Rita; Parfitt, Francine; Johnson, Heather; Farlow, Martin; Herring, Scott; Hake, Ann M.; van Dyck, Christopher H.; MacAvoy, Martha G.; Bifano, Laurel A.; Chertkow, Howard; Bergman, Howard; Hosein, Chris; Black, Sandra; Graham, Simon; Caldwell, Curtis; Feldman, Howard; Assaly, Michele; Hsiung, Ging-Yuek R.; Kertesz, Andrew; Rogers, John; Trost, Dick; Bernick, Charles; Gitelman, Darren; Johnson, Nancy; Mesulam, Marsel; Sadowsky, Carl; Villena, Teresa; Mesner, Scott; Aisen, Paul S.; Johnson, Kathleen B.; Behan, Kelly E.; Sperling, Reisa A.; Rentz, Dorene M.; Johnson, Keith A.; Rosen, Allyson; Tinklenberg, Jared; Ashford, Wes; Sabbagh, Marwan; Connor, Donald; Obradov, Sanja; Killiany, Ron; Norbash, Alex; Obisesan, Thomas O.; Jayam-Trouth, Annapurni; Wang, Paul; Auchus, Alexander P.; Huang, Juebin; Friedland, Robert P.; DeCarli, Charles; Fletcher, Evan; Carmichael, Owen; Kittur, Smita; Mirje, Seema; Johnson, Sterling C.; Borrie, Michael; Lee, T-Y; Asthana, Sanjay; Carlsson, Cynthia M.; Potkin, Steven G.; Highum, Diane; Preda, Adrian; Nguyen, Dana; Tariot, Pierre N.; Hendin, Barry A.; Scharre, Douglas W.; Kataki, Maria; Beversdorf, David Q.; Zimmerman, Earl A.; Celmins, Dzintra; Brown, Alice D.; Gandy, Sam; Marenberg, Marjorie E.; Rovner, Barry W.; Pearlson, Godfrey; Blank, Karen; Anderson, Karen; Saykin, Andrew J.; Santulli, Robert B.; Pare, Nadia; Williamson, Jeff D.; Sink, Kaycee M.; Potter, Huntington; Ashok Raj, B.; Giordano, Amy; Ott, Brian R.; Wu, Chuang-Kuo; Cohen, Ronald; Wilks, Kerri L.

2010-01-01

A recently identified variant within the fat mass and obesity-associated (FTO) gene is carried by 46% of Western Europeans and is associated with an ~1.2 kg higher weight, on average, in adults and an ~1 cm greater waist circumference. With >1 billion overweight and 300 million obese persons worldwide, it is crucial to understand the implications of carrying this very common allele for the health of our aging population. FTO is highly expressed in the brain and elevated body mass index (BMI) is associated with brain atrophy, but it is unknown how the obesity-associated risk allele affects human brain structure. We therefore generated 3D maps of regional brain volume differences in 206 healthy elderly subjects scanned with MRI and genotyped as part of the Alzheimer's Disease Neuroimaging Initiative. We found a pattern of systematic brain volume deficits in carriers of the obesity-associated risk allele versus noncarriers. Relative to structure volumes in the mean template, FTO risk allele carriers versus noncarriers had an average brain volume difference of ~8% in the frontal lobes and 12% in the occipital lobes—these regions also showed significant volume deficits in subjects with higher BMI. These brain differences were not attributable to differences in cholesterol levels, hypertension, or the volume of white matter hyperintensities; which were not detectably higher in FTO risk allele carriers versus noncarriers. These brain maps reveal that a commonly carried susceptibility allele for obesity is associated with structural brain atrophy, with implications for the health of the elderly. PMID:20404173

A commonly carried allele of the obesity-related FTO gene is associated with reduced brain volume in the healthy elderly.

PubMed

Ho, April J; Stein, Jason L; Hua, Xue; Lee, Suh; Hibar, Derrek P; Leow, Alex D; Dinov, Ivo D; Toga, Arthur W; Saykin, Andrew J; Shen, Li; Foroud, Tatiana; Pankratz, Nathan; Huentelman, Matthew J; Craig, David W; Gerber, Jill D; Allen, April N; Corneveaux, Jason J; Stephan, Dietrich A; DeCarli, Charles S; DeChairo, Bryan M; Potkin, Steven G; Jack, Clifford R; Weiner, Michael W; Raji, Cyrus A; Lopez, Oscar L; Becker, James T; Carmichael, Owen T; Thompson, Paul M

2010-05-04

A recently identified variant within the fat mass and obesity-associated (FTO) gene is carried by 46% of Western Europeans and is associated with an approximately 1.2 kg higher weight, on average, in adults and an approximately 1 cm greater waist circumference. With >1 billion overweight and 300 million obese persons worldwide, it is crucial to understand the implications of carrying this very common allele for the health of our aging population. FTO is highly expressed in the brain and elevated body mass index (BMI) is associated with brain atrophy, but it is unknown how the obesity-associated risk allele affects human brain structure. We therefore generated 3D maps of regional brain volume differences in 206 healthy elderly subjects scanned with MRI and genotyped as part of the Alzheimer's Disease Neuroimaging Initiative. We found a pattern of systematic brain volume deficits in carriers of the obesity-associated risk allele versus noncarriers. Relative to structure volumes in the mean template, FTO risk allele carriers versus noncarriers had an average brain volume difference of approximately 8% in the frontal lobes and 12% in the occipital lobes-these regions also showed significant volume deficits in subjects with higher BMI. These brain differences were not attributable to differences in cholesterol levels, hypertension, or the volume of white matter hyperintensities; which were not detectably higher in FTO risk allele carriers versus noncarriers. These brain maps reveal that a commonly carried susceptibility allele for obesity is associated with structural brain atrophy, with implications for the health of the elderly.

Connectivity underlying emotion conflict regulation in older adults with 5-HTTLPR short allele: a preliminary investigation.

PubMed

Waring, Jill D; Etkin, Amit; Hallmayer, Joachim F; O'Hara, Ruth

2014-09-01

The serotonin transporter polymorphism short (s) allele is associated with heightened emotional reactivity and reduced emotion regulation, which increases vulnerability to depression and anxiety disorders. We investigated behavioral and neural markers of emotion regulation in community-dwelling older adults, contrasting s allele carriers and long allele homozygotes. Participants (N = 26) completed a face-word emotion conflict task during functional magnetic resonance imaging, in which facilitated regulation of emotion conflict was observed on face-word incongruent trials following another incongruent trial (i.e., emotional conflict adaptation). There were no differences between genetic groups in behavioral task performance or neural activation in postincongruent versus postcongruent trials. By contrast, connectivity between dorsal anterior cingulate cortex (ACC) and pregenual ACC, regions previously implicated in emotion conflict regulation, was impaired in s carriers for emotional conflict adaptation. This is the first demonstration of an association between serotonin transporter polymorphism and functional connectivity in older adults. Poor dorsal ACC-pregenual ACC connectivity in s carriers may be one route by which these individuals experience greater difficulty in implementing effective emotional regulation, which may contribute to their vulnerability for affective disorders. Copyright © 2014 American Association for Geriatric Psychiatry. All rights reserved.

Increased recovery rates of phosphocreatine and inorganic phosphate after isometric contraction in oxidative muscle fibers and elevated hepatic insulin resistance in homozygous carriers of the A-allele of FTO rs9939609.

PubMed

Grunnet, Louise G; Brøns, Charlotte; Jacobsen, Stine; Nilsson, Emma; Astrup, Arne; Hansen, Torben; Pedersen, Oluf; Poulsen, Pernille; Quistorff, Bjørn; Vaag, Allan

2009-02-01

Recent studies identified the rs9939609 A-allele of the FTO (fat mass and obesity associated) gene as being associated with obesity and type 2 diabetes. We studied the role of the A-allele in the regulation of peripheral organ functions involved in the pathogenesis of obesity and type 2 diabetes. Forty-six young men underwent a hyperinsulinemic euglycemic clamp with excision of skeletal muscle biopsies, an iv glucose tolerance test, 31phosphorous magnetic resonance spectroscopy, and 24-h whole body metabolism was measured in a respiratory chamber. The FTO rs9939609 A-allele was associated with elevated fasting blood glucose and plasma insulin, hepatic insulin resistance, and shorter recovery half-times of phosphocreatine and inorganic phosphate after exercise in a primarily type I muscle. These relationships--except for fasting insulin--remained significant after correction for body fat percentage. The risk allele was not associated with fat distribution, peripheral insulin sensitivity, insulin secretion, 24-h energy expenditure, or glucose and fat oxidation. The FTO genotype did not influence the mRNA expression of FTO or a set of key nuclear or mitochondrially encoded genes in skeletal muscle during rest. Increased energy efficiency--and potentially increased mitochondrial coupling--as suggested by faster recovery rates of phosphocreatine and inorganic phosphate in oxidative muscle fibers may contribute to the increased risk of obesity and type 2 diabetes in homozygous carriers of the FTO A-risk allele. Hepatic insulin resistance may represent the key metabolic defect responsible for mild elevations of fasting blood glucose associated with the FTO phenotype.

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

Association Between CYP2C19 Loss-of-Function Allele Status and Efficacy of Clopidogrel for Risk Reduction Among Patients With Minor Stroke or Transient Ischemic Attack.

PubMed

Wang, Yilong; Zhao, Xingquan; Lin, Jinxi; Li, Hao; Johnston, S Claiborne; Lin, Yi; Pan, Yuesong; Liu, Liping; Wang, David; Wang, Chunxue; Meng, Xia; Xu, Jianfeng; Wang, Yongjun

2016-07-05

effect of treatment assignment on bleeding did not vary significantly between the carriers and the noncarriers of the loss-of-function alleles (2.3% for carriers and 2.5% for noncarriers in the clopidogrel-aspirin group vs 1.4% for carriers and 1.7% for noncarriers in the aspirin only group; P = .78 for interaction). Among patients with minor ischemic stroke or transient ischemic attack, the use of clopidogrel plus aspirin compared with aspirin alone reduced the risk of a new stroke only in the subgroup of patients who were not carriers of the CYP2C19 loss-of-function alleles. These findings support a role of CYP2C19 genotype in the efficacy of this treatment. clinicaltrials.gov Identifier: NCT00979589.

Prediction of striatal D2 receptor binding by DRD2/ANKK1 TaqIA allele status

PubMed Central

Eisenstein, Sarah A.; Bogdan, Ryan; Love-Gregory, Latisha; Corral-Frías, Nadia S.; Koller, Jonathan M.; Black, Kevin J.; Moerlein, Stephen M.; Perlmutter, Joel S.; Barch, Deanna M.; Hershey, Tamara

2016-01-01

In humans, the A1 (T) allele of the dopamine (DA) D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) TaqIA (rs1800497) single nucleotide polymorphism has been associated with reduced striatal DA D2/D3 receptor (D2/D3R) availability. However, radioligands used to estimate D2/D3R are displaceable by endogenous DA and are non-selective for D2R, leaving the relationship between TaqIA genotype and D2R specific binding uncertain. Using the positron emission tomography (PET) radioligand, (N‐[11C]methyl)benperidol ([11C]NMB), which is highly selective for D2R over D3R and is not displaceable by endogenous DA, the current study examined whether DRD2/ANKK1 TaqIA genotype predicts D2R specific binding in 2 independent samples. Sample 1 (n = 39) was composed of obese and non-obese adults; sample 2 (n = 18) was composed of healthy controls, unmedicated individuals with schizophrenia, and siblings of individuals with schizophrenia. Across both samples, A1 allele carriers (A1+) had 5-12% less striatal D2R specific binding relative to individuals homozygous for the A2 allele (A1−), regardless of body mass index or diagnostic group. This reduction is comparable to previous PET studies of D2/D3R availability (10-14%). The pooled effect size for the difference in total striatal D2R binding between A1+ and A1− was large (0.84). In summary, in line with studies using displaceable D2/D3R radioligands, our results indicate that DRD2/ANKK1 TaqIA allele status predicts striatal D2R specific binding as measured by D2R-selective [11C]NMB. These findings support the hypothesis that DRD2/ANKK1 TaqIA allele status may modify D2R, perhaps conferring risk for certain disease states. GRAPHICAL ABSTRACT We investigated the difference in striatal dopamine D2 receptor binding, as measured by PET with (N-[11C]methyl)benperidol ([11C]NMB), between A1 allele carriers (A1+) and individuals homozygous for the A2 allele (A1−) of the DRD2/ANKK1 TaqIA single nucleotide

HLA Alleles are Genetic Markers for Susceptibility and Resistance towards Leprosy in a Mexican Mestizo Population.

PubMed

Aguilar-Medina, Maribel; Escamilla-Tilch, Monica; Frías-Castro, Luis Octavio; Romero-Quintana, Geovanni; Estrada-García, Iris; Estrada-Parra, Sergio; Granados, Julio; Arambula Meraz, Eliakym; Sánchez-Schmitz, Guzman; Khader, Shabaana Abdul; Rangel-Moreno, Javier; Ramos-Payán, Rosalío

2017-01-01

Despite the use of multidrug therapy, leprosy remains endemic in some countries. The association of several human leucocyte antigen (HLA) alleles and gene polymorphisms with leprosy has been demonstrated in many populations, but the major immune contributors associated to the spectrum of leprosy have not been defined yet. In this study, genotyping of HLA-A, -B, -DR, and -DQ alleles was performed in leprosy patients (n = 113) and control subjects (n = 117) from the region with the highest incidence for the disease in México. The odds of developing leprosy and lepromatous subtype were 2.12- and 2.74-fold higher in carriers of HLA-A*28, and 2.48- and 4.14-fold higher for leprosy and dimorphic subtype in carriers of DQB1*06. Interestingly, DQB1*07 was overrepresented in healthy individuals, compared to patients with leprosy (OR = 0.08) and the lepromatous subtype (OR = 0.06). These results suggest that HLA-A*28 is a marker for predisposition to leprosy and the lepromatous subtype and DQB1*06 to leprosy and the dimorphic subtype, while DQB1*07 might be a resistance marker in this Mestizo population. © 2016 John Wiley & Sons Ltd/University College London.

Comparative analysis of conditional reporter alleles in the developing embryo and embryonic nervous system.

PubMed

Ellisor, Debra; Koveal, Dorothy; Hagan, Nellwyn; Brown, Ashly; Zervas, Mark

2009-10-01

A long-standing problem in development is understanding how progenitor cells transiently expressing genes contribute to complex anatomical and functional structures. In the developing nervous system an additional level of complexity arises when considering how cells of distinct lineages relate to newly established neural circuits. To address these problems, we used both cumulative marking with Cre/loxP and Genetic Inducible Fate Mapping (GIFM), which permanently and heritably marks small populations of progenitors and their descendants with fine temporal control using CreER/loxP. A key component used in both approaches is a conditional phenotyping allele that has the potential to be expressed in all cell types, but is quiescent because of a loxP flanked Stop sequence, which precedes a reporter allele. Upon recombination, the resulting phenotyping allele is 'turned on' and then constitutively expressed. Thus, the reporter functions as a high fidelity genetic lineage tracer in vivo. Currently there is an array of reporter alleles that can be used in marking strategies, but their recombination efficiency and applicability to a wide array of tissues has not been thoroughly described. To assess the recombination/marking potential of the reporters, we utilized CreER(T) under the control of a Wnt1 transgene (Wnt1-CreER(T)) as well as a cumulative, non-inducible En1(Cre) knock-in line in combination with three different reporters: R26R (LacZ reporter), Z/EG (EGFP reporter), and Tau-Lox-STOP-Lox-mGFP-IRES-NLS-LacZ (membrane-targeted GFP/nuclear LacZ reporter). We marked the Wnt1 lineage using each of the three reporters at embryonic day (E) 8.5 followed by analysis at E10.0, E12.5, and in the adult. We also compared cumulative marking of cells with a history of En1 expression at the same stages. We evaluated the reporters by whole-mount and section analysis and ascertained the strengths and weaknesses of each of the reporters. Comparative analysis with the reporters

Development of allele-specific multiplex PCR to determine the length of poly-T in intron 8 of CFTR

PubMed Central

Prada, Anne E.

2014-01-01

Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation analysis has been implemented for Cystic Fibrosis (CF) carrier screening, and molecular diagnosis of CF and congenital bilateral absence of the vas deferens (CBAVD). Although poly-T allele analysis in intron 8 of CFTR is required when a patient is positive for R117H, it is not recommended for routine carrier screening. Therefore, commercial kits for CFTR mutation analysis were designed either to mask the poly-T allele results, unless a patient is R117H positive, or to have the poly-T analysis as a standalone reflex test using the same commercial platform. There are other standalone assays developed to detect poly-T alleles, such as heteroduplex analysis, High Resolution Melting (HRM) curve analysis, allele-specific PCR (AS-PCR) and Sanger sequencing. In this report, we developed a simple and easy-to-implement multiplex AS-PCR assay using unlabeled standard length primers, which can be used as a reflex or standalone test for CFTR poly-T track analysis. Out of 115 human gDNA samples tested, results from our new AS-PCR matched to the previous known poly-T results or results from Sanger sequencing. PMID:25071991

A 13-15/21 translocation chromosome in carrier father and mongol son.

PubMed

SERGOVICH, F R; SOLTAN, H C; CARR, D H

1962-10-20

Cytogenetic and dermatoglyphic features were studied in a family in which the mongoloid propositus inherited a 13-15/21 translocation chromosome from his father. Seven other healthy male carriers scattered throughout the pedigree produced nine chromosomally normal children and five carrier children in addition to the mongoloid propositus. These results show that carrier males do not necessarily produce an unusually large proportion of carrier children as previous reports would indicate. Dermatoglyphic studies showed that translocation carriers in this family have neither significantly more centralized nor less centralized palmar axial triradii than non-carrier relatives. No direct evidence was therefore found for the hypothesis that an allele is present on chromosome 21 which influences the height of the triradius.

Genetic Variation at 9p22.2 and Ovarian Cancer Risk for BRCA1 and BRCA2 Mutation Carriers

PubMed Central

Kartsonaki, Christiana; Gayther, Simon A.; Pharoah, Paul D. P.; Sinilnikova, Olga M.; Beesley, Jonathan; Chen, Xiaoqing; McGuffog, Lesley; Healey, Sue; Couch, Fergus J.; Wang, Xianshu; Fredericksen, Zachary; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Roversi, Gaia; Barile, Monica; Viel, Alessandra; Allavena, Anna; Ottini, Laura; Papi, Laura; Gismondi, Viviana; Capra, Fabio; Radice, Paolo; Greene, Mark H.; Mai, Phuong L.; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Thomassen, Mads; Gerdes, Anne-Marie; Kruse, Torben A.; Cruger, Dorthe; Jensen, Uffe Birk; Caligo, Maria Adelaide; Olsson, Håkan; Kristoffersson, Ulf; Lindblom, Annika; Arver, Brita; Karlsson, Per; Stenmark Askmalm, Marie; Borg, Ake; Neuhausen, Susan L.; Ding, Yuan Chun; Nathanson, Katherine L.; Domchek, Susan M.; Jakubowska, Anna; Lubiński, Jan; Huzarski, Tomasz; Byrski, Tomasz; Gronwald, Jacek; Górski, Bohdan; Cybulski, Cezary; Dębniak, Tadeusz; Osorio, Ana; Durán, Mercedes; Tejada, Maria-Isabel; Benítez, Javier; Hamann, Ute; Rookus, Matti A.; Verhoef, Senno; Tilanus-Linthorst, Madeleine A.; Vreeswijk, Maaike P.; Bodmer, Danielle; Ausems, Margreet G. E. M.; van Os, Theo A.; Asperen, Christi J.; Blok, Marinus J.; Meijers-Heijboer, Hanne E. J.; Peock, Susan; Cook, Margaret; Oliver, Clare; Frost, Debra; Dunning, Alison M.; Evans, D. Gareth; Eeles, Ros; Pichert, Gabriella; Cole, Trevor; Hodgson, Shirley; Brewer, Carole; Morrison, Patrick J.; Porteous, Mary; Kennedy, M. John; Rogers, Mark T.; Side, Lucy E.; Donaldson, Alan; Gregory, Helen; Godwin, Andrew; Stoppa-Lyonnet, Dominique; Moncoutier, Virginie; Castera, Laurent; Mazoyer, Sylvie; Barjhoux, Laure; Bonadona, Valérie; Leroux, Dominique; Faivre, Laurence; Lidereau, Rosette; Nogues, Catherine; Bignon, Yves-Jean; Prieur, Fabienne; Collonge-Rame, Marie-Agnès; Venat-Bouvet, Laurence; Fert-Ferrer, Sandra; Miron, Alex; Buys, Saundra S.; Hopper, John L.; Daly, Mary B.; John, Esther M.; Terry, Mary Beth; Goldgar, David; Hansen, Thomas v. O.; Jønson, Lars; Ejlertsen, Bent; Agnarsson, Bjarni A.; Offit, Kenneth; Kirchhoff, Tomas; Vijai, Joseph; Dutra-Clarke, Ana V. C.; Przybylo, Jennifer A.; Montagna, Marco; Casella, Cinzia; Imyanitov, Evgeny N.; Janavicius, Ramunas; Blanco, Ignacio; Lázaro, Conxi; Moysich, Kirsten B.; Karlan, Beth Y.; Gross, Jenny; Beattie, Mary S.; Schmutzler, Rita; Wappenschmidt, Barbara; Meindl, Alfons; Ruehl, Ina; Fiebig, Britta; Sutter, Christian; Arnold, Norbert; Deissler, Helmut; Varon-Mateeva, Raymonda; Kast, Karin; Niederacher, Dieter; Gadzicki, Dorothea; Caldes, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Aittomäki, Kristiina; Simard, Jacques; Soucy, Penny; Spurdle, Amanda B.; Holland, Helene; Chenevix-Trench, Georgia; Easton, Douglas F.; Antoniou, Antonis C.

2011-01-01

Background Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A genome-wide association study recently identified an association between the rare allele of the single-nucleotide polymorphism (SNP) rs3814113 (ie, the C allele) at 9p22.2 and decreased risk of ovarian cancer for women in the general population. We evaluated the association of this SNP with ovarian cancer risk among BRCA1 or BRCA2 mutation carriers by use of data from the Consortium of Investigators of Modifiers of BRCA1/2. Methods We genotyped rs3814113 in 10 029 BRCA1 mutation carriers and 5837 BRCA2 mutation carriers. Associations with ovarian and breast cancer were assessed with a retrospective likelihood approach. All statistical tests were two-sided. Results The minor allele of rs3814113 was associated with a reduced risk of ovarian cancer among BRCA1 mutation carriers (per-allele hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.72 to 0.85; P = 4.8 × 10-9) and BRCA2 mutation carriers (hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.67 to 0.90; P = 5.5 × 10-4). This SNP was not associated with breast cancer risk among either BRCA1 or BRCA2 mutation carriers. BRCA1 mutation carriers with the TT genotype at SNP rs3814113 were predicted to have an ovarian cancer risk to age 80 years of 48%, and those with the CC genotype were predicted to have a risk of 33%. Conclusion Common genetic variation at the 9p22.2 locus was associated with decreased risk of ovarian cancer for carriers of a BRCA1 or BRCA2 mutation. PMID:21169536

Prolactin rs1341239 T allele may have protective role against the brick tea type skeletal fluorosis.

PubMed

Li, Bing-Yun; Yang, Yan-Mei; Liu, Yang; Sun, Jing; Ye, Yan; Liu, Xiao-Na; Liu, Hong-Xu; Sun, Zhen-Qi; Li, Mang; Cui, Jing; Sun, Dian-Jun; Gao, Yan-Hui

2017-01-01

Prolactin (PRL) has been reported to be associated with increased bone turnover, and increased bone turnover is also a feature of skeletal fluorosis (SF). Autocrine/paracrine production of PRL is regulated by the extrapituitary promoter and a polymorphism in the extrapituitary PRL promoter at -1149 (rs1341239) is associated with disturbances of bone metabolism in other diseases. Here, we have investigated the possibility that the rs1341239 polymorphism is associated with SF, which results from the consumption of brick tea. We conducted a cross-sectional study in Sinkiang, Qinghai, Inner Mongolia in China. Demography survey questionnaires were completed and physical examination and X-ray diagnoses were used to diagnose SF. Brick tea water fluoride intake (IF) and urinary fluoride (UF) were tested by an F-ion selective electrode method. A Sequenom MassARRAY system was used to determine PRL gene polymorphisms. Subjects who were younger than 45 years of age and carried the T allele had a significantly decreased risk of SF [OR = 0.279 (95%CI, 0.094-0.824)] compared to those carrying the homozygous G allele. This phenomenon was only observed in Kazakh subjects [OR = 0.127 (95%CI, 0.025-0.646)]. Kazakh females who carried T alleles has a decreased risk of SF [OR = 0.410 (95%CI, 0.199-0.847)]. For Kazakh subjects which IF is less than 3.5 mg/d, a decreased risk of SF was observed among the participants who carried T alleles [OR = 0.118 (95%CI, 0.029-0.472)]. Overall, subjects with 1.6-3.2 mg/L UF and carried T alleles had a significantly decreased risk of SF [OR = 0.476 (95%CI, 0.237-0.955)] compared to homozygous G allele carriers. This phenomenon was only observed in Kazakh subjects [OR = 0.324 (95%CI, 0.114-0.923)]. Our results suggested that the PRL rs1341239 T allele decreases the risk of brick tea SF.

Prolactin rs1341239 T allele may have protective role against the brick tea type skeletal fluorosis

PubMed Central

Li, Bing-Yun; Yang, Yan-Mei; Liu, Yang; Sun, Jing; Ye, Yan; Liu, Xiao-Na; Liu, Hong-Xu; Sun, Zhen-Qi; Li, Mang; Cui, Jing; Sun, Dian-Jun; Gao, Yan-Hui

2017-01-01

Objective Prolactin (PRL) has been reported to be associated with increased bone turnover, and increased bone turnover is also a feature of skeletal fluorosis (SF). Autocrine/paracrine production of PRL is regulated by the extrapituitary promoter and a polymorphism in the extrapituitary PRL promoter at -1149 (rs1341239) is associated with disturbances of bone metabolism in other diseases. Here, we have investigated the possibility that the rs1341239 polymorphism is associated with SF, which results from the consumption of brick tea. Design We conducted a cross-sectional study in Sinkiang, Qinghai, Inner Mongolia in China. Demography survey questionnaires were completed and physical examination and X-ray diagnoses were used to diagnose SF. Brick tea water fluoride intake (IF) and urinary fluoride (UF) were tested by an F-ion selective electrode method. A Sequenom MassARRAY system was used to determine PRL gene polymorphisms. Results Subjects who were younger than 45 years of age and carried the T allele had a significantly decreased risk of SF [OR = 0.279 (95%CI, 0.094–0.824)] compared to those carrying the homozygous G allele. This phenomenon was only observed in Kazakh subjects [OR = 0.127 (95%CI, 0.025–0.646)]. Kazakh females who carried T alleles has a decreased risk of SF [OR = 0.410 (95%CI, 0.199–0.847)]. For Kazakh subjects which IF is less than 3.5 mg/d, a decreased risk of SF was observed among the participants who carried T alleles [OR = 0.118 (95%CI, 0.029–0.472)]. Overall, subjects with 1.6–3.2 mg/L UF and carried T alleles had a significantly decreased risk of SF [OR = 0.476 (95%CI, 0.237–0.955)] compared to homozygous G allele carriers. This phenomenon was only observed in Kazakh subjects [OR = 0.324 (95%CI, 0.114–0.923)]. Conclusions Our results suggested that the PRL rs1341239 T allele decreases the risk of brick tea SF. PMID:28152004

The Relationship Between Apolipoprotein ε4 Carrier Status and Sleep Characteristics in Cognitively Normal Older Adults.

PubMed

Kahya, Melike; Vidoni, Eric; Burns, Jeffrey M; Thompson, Ashley N; Meyer, Kayla; Siengsukon, Catherine F

2017-09-01

The apolipoprotein (APOE) ε4 allele, a well-described genetic risk factor for late-onset Alzheimer disease (AD), is associated with sleep disturbances even in cognitively normal older adults, although it is not clear whether this association is independent of sleep apnea. We sought to extend previous studies by examining whether cognitively normal older adults without self-reported sleep apnea who carry the APOE ε4 allele have altered sleep characteristics compared to noncarriers. Data from N = 36 (APOE ε4 carriers [n = 9], noncarriers [n = 27]) cognitively normal older adults (Clinical Dementia Rating [CDR] scale = 0) without self-reported sleep apnea were used for these analyses. Participants wore an actigraph for 7 days to determine sleep characteristics. The Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) were used to assess sleep quality and daytime sleepiness, respectively. The APOE ε4 carriers had a higher number of awakenings compared to the noncarriers ( P = .02). There was no significant difference in the PSQI global score and the ESS; however, the PSQI subcomponent of daily disturbances was significantly higher in APOE ε4 carriers ( P = .03), indicating increased daytime dysfunction is related to disrupted sleep. This study provides evidence that individuals who are cognitively normal and genetically at risk of AD may have disrupted sleep. These findings are consistent with prior studies and suggest that sleep disruption may be present in the presymptomatic stages of AD.

[Effect of free and polymer carrier encapsulated doxorubicin towards HCT116 cells of human colorectal carcinoma].

PubMed

Sen'kiv, Iu V; Heffeter, P; Riabtseva, A O; Boĭko, N M; Mitina, N Ie; Zaichenko, O S; Berger, W; Stoĭka, R S

2013-01-01

Development of novel nanoscale functionalized carriers is nowadays one of the most urgent problems in cancer treatment. The aim of our study was to compare the antineoplastic effect of free doxorubicin and its complex with a nanoscale polymeric carrier towards HTC116 colorectal carcinoma cells. It was established that application of the complex of poly(5-tret-butylperoxy)-5-methyl-1-hexene-3-in-co-glycydyl metacrylat)-graft-polyethyleneglycol (poly(VEP-GMA-PEG)-graft-PEG), where VEP--5-tret-butylperoxy)-5-methyl-1-hexene-3-in; GMA--glycydyl metacrylat; graft-PEG--graft-polyethyleneglycol accordingly, functionalized with phosphatidylcholine for doxorubicin delivery increased 10 times the efficiency of cytotoxic action of this drug, as compared wich such efficiency in case of the action of free doxorubicin. The encapsulated form of doxorubicin caused more intensive cleavage of the reparation enzyme PARP and longer delay in G2/M cell cycle arrest, compared to such effects of free doxorubicin. The developed carrier itself is non-toxic to the used mammalian cells and does not cause impairment in their cell cycle. A deletion in both alleles of p53 gene did not affect the antineoplastic action of doxorubicin that was immobilized on the nanoscale carrier. Thus, p53-dependent signaling pathways are not involved in the cytotoxic action of doxorubicin-carrier complex. It is suggested that novel nanoscale polymeric carrier poly(VEP-GMA-PEG)-graft-PEG functionalized with phosphatidylcholine could be a promising carrier for targeted delivery of anticancer drugs.

Apolipoprotein E epsilon 2 allele and low serum cholesterol as risk factors for gastric cancer in a Chinese Han population.

PubMed

Kang, Ranran; Li, Ping; Wang, Tingting; Li, Xinxiu; Wei, Zichen; Zhang, Zhenlian; Zhong, Li; Cao, Longlong; Heckman, Michael G; Zhang, Yun-Wu; Xu, Huaxi; Huang, Changming; Bu, Guojun; Chen, Xiao-Fen

2016-01-28

Apolipoprotein E (apoE) mediates lipid metabolism both in peripheral and in the brain. The human APOE gene has three polymorphic alleles that influence the risk for various types of cancer and neurodegenerative diseases. A potential association between APOE allele and the risk for gastric cancer has been implicated, but the specific allele involved and potential associations with the subtype and the grade of cancer malignancy need further clarification. We screened the APOE genotype in 550 gastric cancer patients and 550 non-cancer control individuals and found that the presence of the APOE ε2 and lower serum total cholesterol are associated with an increased risk for gastric cancer (all P ≤ 0.0005). Interestingly, APOE ε2 is also correlated with increased risk for both intestinal and diffuse histotypes but not with TN classification or stage in gastric cancer patients, suggesting that APOE polymorphic alleles are associated with the risk of development but unlikely the progression of gastric cancer. Since ε2 carriers have lower levels of serum total cholesterol than non-ε2 carriers, our findings suggest that the increased risk for gastric cancer by APOE ε2 allele might be mediated through lowered serum total cholesterol levels.

A 13-15/21 Translocation Chromosome in Carrier Father and Mongol Son

PubMed Central

Sergovich, Frederick R.; Soltan, Hubert C.; Carr, David H.

1962-01-01

Cytogenetic and dermatoglyphic features were studied in a family in which the mongoloid propositus inherited a 13-15/21 translocation chromosome from his father. Seven other healthy male carriers scattered throughout the pedigree produced nine chromosomally normal children and five carrier children in addition to the mongoloid propositus. These results show that carrier males do not necessarily produce an unusually large proportion of carrier children as previous reports would indicate. Dermatoglyphic studies showed that translocation carriers in this family have neither significantly more centralized nor less centralized palmar axial triradii than non-carrier relatives. No direct evidence was therefore found for the hypothesis that an allele is present on chromosome 21 which influences the height of the triradius. ImagesFig. 1Fig. 2Fig. 3 PMID:13988069

A comparative analysis of arranging in-flight oxygen aboard commercial air carriers.

PubMed

Stoller, J K; Hoisington, E; Auger, G

1999-04-01

As air travel has become more commonplace in today's society, so too has air travel by oxygen-using individuals. Because there is little oversight or standardization of in-flight oxygen by the Federal Aviation Administration, individual airlines' policies and practices may vary greatly. On the premise that such variation may cause confusion by prospective air travelers, we undertook the current study to describe individual air carriers' policies and practices and to provide guidance to future air travelers. Data were collected by a series of telephone calls placed by the study investigators to all commercial air carriers listed in the 1997 Cleveland Metropolitan Yellow Pages. The callers were registered respiratory therapists who identified themselves as inexperienced oxygen-requiring travelers wishing to arrange in-flight oxygen for an upcoming trip. Standard questions were asked of each carrier that included the following: Did the carrier have a special "help desk" to assist with oxygen arrangements? What oxygen systems, liter flow options, and interface devices were available? What was the charge for oxygen? How was the charged determined? What documentation from the physician was required? How much notification was required by the airline before the actual flight? In addition to recording these responses, the total amount of time spent on the telephone by the caller was logged along with the number of telephone calls and number of people spoken to in arranging in-flight oxygen. To compare oxygen charges between airlines, we calculated charges based on a "standard trip," which was defined as a nonstop, round-trip lasting 6 h in which the traveler used a flow rate of 2 L/min. Of the 33 commercial air carriers listed in the directory, 11 were US-based carriers and 22 were international-based carriers. Seventy-six percent of the airlines offered in-flight oxygen. For the 25 carriers offering in-flight oxygen, mean phone time required to make the arrangements was 9

Increased mental slowing associated with the APOE epsilon4 allele after trihexyphenidyl oral anticholinergic challenge in healthy elderly.

PubMed

Pomara, Nunzio; Belzer, Ken; Hernando, Raymundo; De La Pena, Corazon; Sidtis, John J

2008-02-01

The objectives of this study were to examine the relationship between APOE epsilon4 and subjective effects of trihexyphenidyl on measures reflecting sedation and confusion and to investigate the relationship between trihexyphenidyl-induced subjective effects and objective memory performance. This study comprised 24 cognitively intact, health elderly adults (12 APOE epsilon4 carriers) at an outpatient geriatric psychiatry research clinic. This was a randomized, double blind, placebo-controlled, three-way, crossover experimental design. All participants received 1.0 mg or 2.0 mg trihexyphenidyl or placebo administered in counterbalanced sequences over a period of three consecutive weeks. Bond and Lader's visual analog scales and alternate versions of the Buschke Selective Reminding Test were administered in a repeated measures design at baseline, 1, 2.5, and 5 hours postdrug administration. A 2.0-mg oral dose of trihexyphenidyl resulted in increased subjective ratings of mental slowness in carriers of the APOE epsilon4 allele only. Drug effects as determined by difference scores between 2.0 mg trihexyphenidyl and placebo on ratings of mental slowness significantly correlated with total and delayed recall on the Buschke Selective Reminding Test in carriers of the APOE epsilon4 allele only. However, no significant effects were found with other visual analog scales reflecting subjective sedation and clear-headedness. The epsilon4 allele in healthy elderly was associated with increased subjective mental slowing after trihexyphenidyl anticholinergic challenge.

Cytochrome P450 2D6 variants in a Caucasian population: Allele frequencies and phenotypic consequences

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

Sachse, C.; Brockmoeller, J.; Bauer, S.

Cytochrome P450 2D6 (CYP2D6) metabolizes many important drugs. CYP2D6 activity ranges from complete deficiency to ultrafast metabolism, depending on at least 16 different known alleles. Their frequencies were determined in 589 unrelated German volunteers and correlated with enzyme activity measured by phenotyping with dextromethorphan or debrisoquine. For genotyping, nested PCR-RFLP tests from a PCR amplificate of the entire CYP2D6 gene were developed. The frequency of the CYP2D6*1 allele coding for extensive metabolizer (EM) phenotype was .364. The alleles coding for slightly (CYP2D6*2) or moderately (*9 and *10) reduced activity (intermediate metabolizer phenotype [IM]) showed frequencies of .324, .018, and .015,more » respectively. By use of novel PCR tests for discrimination, CYP2D6 gene duplication alleles were found with frequencies of.005 (*1 x 2), .013 (* 2 x 2), and .001 (*4 x 2). Frequencies of alleles with complete deficiency (poor metabolizer phenotype [PM]) were .207 (*4), .020 (*3 and *5), .009 (*6), and .001 (*7, *15, and *16). The defective CYP2D6 alleles *8, *11, *12, *13, and *14 were not found. All 41 PMs (7.0%) in this sample were explained by five mutations detected by four PCR-RFLP tests, which may suffice, together with the gene duplication test, for clinical prediction of CYP2D6 capacity. Three novel variants of known CYP2D6 alleles were discovered: *1C (T{sub 1957}C), *2B (additional C{sub 2558}T), and *4E (additional C{sub 2938}T). Analysis of variance showed significant differences in enzymatic activity measured by the dextromethorphan metabolic ratio (MR) between carriers of EN/PM (mean MR = .006) and IM/PM (mean MR = .014) alleles and between carriers of one (mean MR = .009) and two (mean MR = .003) functional alleles. The results of this study provide a solid basis for prediction of CYP2D6 capacity, as required in drug research and routine drug treatment. 35 refs., 4 figs., 5 tabs.« less

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

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.

Rapid carrier screening using short tandem repeats in the phenylalanine hydroxylase gene.

PubMed

Shawky, R M; el-Aleem, K A; Rifaat, M M; el-Naggar, R L; Marzouk, G M

2002-01-01

Phenylketonuria (PKU) is an autosomal recessive genetic disorder caused by defects in the phenylalanine hydroxylase (PAH) system. Our work aimed to screen the PAH locus for the presence of potentially useful short tandem repeats (STR) as markers for carrier detection in PKU families in Egypt, and to determine the level of PAH heterozygosity within the Egyptian population. The system contains at least eight independent alleles in the Egyptian population, transmitted in a Mendelian fashion. Variations in the number of STR in the 16 families studied gave rise to polymorphisms that proved to be suitable markers for PKU carrier detection and prenatal diagnosis. The most frequent allelic fragment size in PKU patients was 246 bp (35.7%), which together with a fragment of 254 bp accounted for 60.7% of the mutant chromosomes.

Cosegregation and functional analysis of mutant ABCR (ABCA4) alleles in families that manifest both Stargardt disease and age-related macular degeneration.

PubMed

Shroyer, N F; Lewis, R A; Yatsenko, A N; Wensel, T G; Lupski, J R

2001-11-01

Mutations in ABCR (ABCA4) have been reported to cause a spectrum of autosomal recessively inherited retinopathies, including Stargardt disease (STGD), cone-rod dystrophy and retinitis pigmentosa. Individuals heterozygous for ABCR mutations may be predisposed to develop the multifactorial disorder age-related macular degeneration (AMD). We hypothesized that some carriers of STGD alleles have an increased risk to develop AMD. We tested this hypothesis in a cohort of families that manifest both STGD and AMD. With a direct-sequencing mutation detection strategy, we found that AMD-affected relatives of STGD patients are more likely to be carriers of pathogenic STGD alleles than predicted based on chance alone. We further investigated the role of AMD-associated ABCR mutations by testing for expression and ATP-binding defects in an in vitro biochemical assay. We found that mutations associated with AMD have a range of assayable defects ranging from no detectable defect to apparent null alleles. Of the 21 missense ABCR mutations reported in patients with AMD, 16 (76%) show abnormalities in protein expression, ATP-binding or ATPase activity. We infer that carrier relatives of STGD patients are predisposed to develop AMD.

Preimplantation genetic haplotyping a new application for diagnosis of translocation carrier's embryos- preliminary observations of two robertsonian translocation carrier families.

PubMed

Shamash, Jana; Rienstein, Shlomit; Wolf-Reznik, Haike; Pras, Elon; Dekel, Michal; Litmanovitch, Talia; Brengauz, Masha; Goldman, Boleslav; Yonath, Hagith; Dor, Jehoshua; Levron, Jacob; Aviram-Goldring, Ayala

2011-01-01

Preimplantation genetic diagnosis using fluorescence in-situ hybridization (PGD-FISH) is currently the most common reproductive solution for translocation carriers. However, this technique usually does not differentiate between embryos carrying the balanced form of the translocation and those carrying the homologous normal chromosomes. We developed a new application of preimplantation genetic haplotyping (PGH) that can identify and distinguish between all forms of the translocation status in cleavage stage embryos prior to implantation. Polymorphic markers were used to identify and differentiate between the alleles that carry the translocation and those that are the normal homologous chromosomes. Embryos from two families of robertsonian translocation carriers were successfully analyzed using polymorphic markers haplotyping. Our preliminary results indicate that the PGH is capable of distinguishing between normal, balanced and unbalanced translocation carrier embryos. This method will improve PGD and will enable translocation carriers to avoid transmission of the translocation and the associated medical complications to offspring.

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.

Convergent and divergent effects of apolipoprotein E ε4 and ε2 alleles on amygdala functional networks in nondemented older adults.

PubMed

Gong, Liang; Shu, Hao; He, Cancan; Ye, Qing; Bai, Feng; Xie, Chunming; Zhang, Zhijun

2017-06-01

Traditionally, in the context of Alzheimer's disease, the apolipoprotein E ε2 (APOEε2) allele is a protective factor and the APOEε4 allele is a destructive factor. However, this inverse relationship has recently been challenged, and the neural mechanisms underlying the effects of APOE genotype on Alzheimer's disease remain unclear. A resting-state functional magnetic resonance imaging study was conducted to investigate the effects of APOE genotype and age on amygdala functional connectivity (AFC) networks in 84 patients with amnestic mild cognitive impairment and 124 cognitively normal order adults. The results indicated that the APOEε2 and APOEε4 alleles produced convergent effects in the right AFC network but divergent effects in the left AFC network. As age increased, APOEε2 carriers showed stable AFC, whereas APOEε4 carriers exhibited decreased AFC in all participants. Furthermore, mediation analysis revealed that connectivity strength regulates the effects of APOE genotype and age on cognitive function in amnestic mild cognitive impairment patients. Our findings suggest that the APOEε2 and APOEε4 alleles produce both convergent and divergent topological effects on brain function. Copyright © 2017 Elsevier Inc. All rights reserved.

Anthropometric and lipid profile of individuals with severe obesity carrying the fatty acid-binding protein-2 Thr54 allele.

PubMed

Kops, Natalia Luiza; Correia Horvath, Jaqueline D; de Castro, Mariana L Dias; Friedman, Rogério

2017-09-01

The aim of this study was to evaluate the anthropometric and lipid profiles of individuals being considered for bariatric surgery, taking into account the presence of the Thr54 allele of the fatty acid-binding protein-2 (FABP-2) gene (rs1799883), and dietary intake. In a cross-sectional study, 120 participants being evaluated for bariatric surgery were asked to keep 24-h dietary records (R24 h) for 3 d, and to collect a 24-h urine sample for measurement of urea (as an assessment of the adequacy of food records) during day 3 of the diet record; a fasting blood sample for laboratory and genetic evaluations was collected. When considering the whole sample, no significant differences were found; however, those who complied with the R24 h (n = 43) had more years of schooling and higher saturated fat intake, but lower weight and body mass index (BMI). When analyzing only the completers, the Thr54 allele carriers showed higher body weight (P = 0.02), BMI (P = 0.03), hip circumference (P = 0.02), basal metabolic rate (P = 0.02), and homeostatic model assessment-β (P = 0.04) compared with those who were homozygous for Ala54. When the participants complied with the R24 h, Thr54 carriers were shown to have higher anthropometric parameters and higher homeostatic model assessment-β values than those with the wild genotype, but the lipid profile resulted similar in both carriers and noncarriers. Copyright © 2017 Elsevier Inc. All rights reserved.

Comparison between fluorescent in-situ hybridisation and array comparative genomic hybridisation in preimplantation genetic diagnosis in translocation carriers.

PubMed

Lee, Vivian C Y; Chow, Judy F C; Lau, Estella Y L; Yeung, William S B; Ho, P C; Ng, Ernest H Y

2015-02-01

To compare the pregnancy outcome of the fluorescent in-situ hybridisation and array comparative genomic hybridisation in preimplantation genetic diagnosis of translocation carriers. Historical cohort. A teaching hospital in Hong Kong. All preimplantation genetic diagnosis treatment cycles performed for translocation carriers from 2001 to 2013. Overall, 101 treatment cycles for preimplantation genetic diagnosis in translocation were included: 77 cycles for reciprocal translocation and 24 cycles for Robertsonian translocation. Fluorescent in-situ hybridisation and array comparative genomic hybridisation were used in 78 and 11 cycles, respectively. The ongoing pregnancy rate per initiated cycle after array comparative genomic hybridisation was significantly higher than that after fluorescent in-situ hybridisation in all translocation carriers (36.4% vs 9.0%; P=0.010). The miscarriage rate was comparable with both techniques. The testing method (array comparative genomic hybridisation or fluorescent in-situ hybridisation) was the only significant factor affecting the ongoing pregnancy rate after controlling for the women's age, type of translocation, and clinical information of the preimplantation genetic diagnosis cycles by logistic regression (odds ratio=1.875; P=0.023; 95% confidence interval, 1.090-3.226). This local retrospective study confirmed that comparative genomic hybridisation is associated with significantly higher pregnancy rates versus fluorescent in-situ hybridisation in translocation carriers. Array comparative genomic hybridisation should be the technique of choice in preimplantation genetic diagnosis cycles in translocation carriers.

Human Leukocyte Antigens and Systemic Lupus Erythematosus: A Protective Role for the HLA-DR6 Alleles DRB1*13:02 and *14:03

PubMed Central

Furukawa, Hiroshi; Kawasaki, Aya; Oka, Shomi; Ito, Ikue; Shimada, Kota; Sugii, Shoji; Hashimoto, Atsushi; Komiya, Akiko; Fukui, Naoshi; Kondo, Yuya; Ito, Satoshi; Hayashi, Taichi; Matsumoto, Isao; Kusaoi, Makio; Amano, Hirofumi; Nagai, Tatsuo; Hirohata, Shunsei; Setoguchi, Keigo; Kono, Hajime; Okamoto, Akira; Chiba, Noriyuki; Suematsu, Eiichi; Katayama, Masao; Migita, Kiyoshi; Suda, Akiko; Ohno, Shigeru; Hashimoto, Hiroshi; Takasaki, Yoshinari; Sumida, Takayuki; Nagaoka, Shouhei

2014-01-01

Many studies on associations between human leukocyte antigen (HLA) allele frequencies and susceptibility to systemic lupus erythematosus (SLE) have been performed. However, few protective associations with HLA-DRB1 alleles have been reported. Here, we sought protective, as well as predispositional, alleles of HLA-DRB1 in Japanese SLE patients. An association study was conducted for HLA-DRB1 in Japanese SLE patients. Relative predispositional effects were analyzed by sequential elimination of carriers of each allele with the strongest association. We also explored the association of DRB1 alleles with SLE phenotypes including the presence of autoantibody and clinical manifestations. Significantly different carrier frequencies of certain DRB1 alleles were found to be associated with SLE as follows: increased DRB1*15:01 (P = 5.48×10−10, corrected P (Pc) = 1.59×10−8, odds ratio [OR] 2.17, 95% confidence interval [CI] 1.69–2.79), decreased DRB1*13:02 (P = 7.17×10−5, Pc = 0.0020, OR 0.46, 95% CI 0.34–0.63) and decreased DRB1*14:03 (P = 0.0010, Pc = 0.0272, OR 0.34, 95% CI 0.18–0.63). Additionally, the “*15:01/*13:02 or *14:03” genotype tended to be negatively associated with SLE (P = 0.4209, OR 0.66), despite there being significant positive associations with *15:01 when present together with alleles other than *13:02 or *14:03 (P = 1.79×10−11, OR 2.39, 95% CI 1.84–3.10). This protective effect of *13:02 and *14:03 was also confirmed in SLE patients with different clinical phenotypes. To the best of our knowledge, this is the first report of a protective association between the carrier frequencies of HLA-DRB1*13:02 and *14:03 and SLE in the Japanese population. PMID:24498373

Human leukocyte antigens and systemic lupus erythematosus: a protective role for the HLA-DR6 alleles DRB1*13:02 and *14:03.

PubMed

Furukawa, Hiroshi; Kawasaki, Aya; Oka, Shomi; Ito, Ikue; Shimada, Kota; Sugii, Shoji; Hashimoto, Atsushi; Komiya, Akiko; Fukui, Naoshi; Kondo, Yuya; Ito, Satoshi; Hayashi, Taichi; Matsumoto, Isao; Kusaoi, Makio; Amano, Hirofumi; Nagai, Tatsuo; Hirohata, Shunsei; Setoguchi, Keigo; Kono, Hajime; Okamoto, Akira; Chiba, Noriyuki; Suematsu, Eiichi; Katayama, Masao; Migita, Kiyoshi; Suda, Akiko; Ohno, Shigeru; Hashimoto, Hiroshi; Takasaki, Yoshinari; Sumida, Takayuki; Nagaoka, Shouhei; Tsuchiya, Naoyuki; Tohma, Shigeto

2014-01-01

Many studies on associations between human leukocyte antigen (HLA) allele frequencies and susceptibility to systemic lupus erythematosus (SLE) have been performed. However, few protective associations with HLA-DRB1 alleles have been reported. Here, we sought protective, as well as predispositional, alleles of HLA-DRB1 in Japanese SLE patients. An association study was conducted for HLA-DRB1 in Japanese SLE patients. Relative predispositional effects were analyzed by sequential elimination of carriers of each allele with the strongest association. We also explored the association of DRB1 alleles with SLE phenotypes including the presence of autoantibody and clinical manifestations. Significantly different carrier frequencies of certain DRB1 alleles were found to be associated with SLE as follows: increased DRB1*15:01 (P = 5.48×10⁻¹⁰, corrected P (Pc) = 1.59×10⁻⁸, odds ratio [OR] 2.17, 95% confidence interval [CI] 1.69-2.79), decreased DRB1*13:02 (P = 7.17×10⁻⁵, Pc = 0.0020, OR 0.46, 95% CI 0.34-0.63) and decreased DRB1*14:03 (P = 0.0010, Pc = 0.0272, OR 0.34, 95% CI 0.18-0.63). Additionally, the "*15:01/*13:02 or *14:03" genotype tended to be negatively associated with SLE (P = 0.4209, OR 0.66), despite there being significant positive associations with *15:01 when present together with alleles other than *13:02 or *14:03 (P = 1.79×10⁻¹¹, OR 2.39, 95% CI 1.84-3.10). This protective effect of *13:02 and *14:03 was also confirmed in SLE patients with different clinical phenotypes. To the best of our knowledge, this is the first report of a protective association between the carrier frequencies of HLA-DRB1*13:02 and *14:03 and SLE in the Japanese population.

Association of HLA-DRB1 alleles with susceptibility to mixed connective tissue disease in Polish patients.

PubMed

Paradowska-Gorycka, A; Stypińska, B; Olesińska, M; Felis-Giemza, A; Mańczak, M; Czuszynska, Z; Zdrojewski, Z; Wojciechowicz, J; Jurkowska, M

2016-01-01

Mixed connective tissue disease (MCTD) is a systemic autoimmune disease, originally defined as a connective tissue inflammatory syndrome with overlapping features of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), polymyositis/dermatomyositis (PM/DM) and systemic sclerosis (SSc), characterized by the presence of antibodies against components of the U1 small nuclear ribonucleoprotein (U1snRNP). The aim of the study was to assess the frequency of (high-resolution-typed) DRB1 alleles in a cohort of Polish patients with MCTD (n = 103). Identification of the variants potentially associated with risk and protection was carried out by comparison with the DKMS Polish Bone Marrow Donor Registry (41306 alleles). DRB1*15:01 (odds ratio (OR): 6.06; 95% confidence interval (CI) 4.55-8.06), DRB1*04 (OR: 3.69; 95% CI 2.69-5.01) and *09:01 (OR: 8.12; 95% CI 2.15-21.75) were identified as risk alleles for MCTD, while HLA-DRB1*07:01 allele was found to be protective (OR: 0.50; 95% CI 0.28-0.83). The carrier frequency of the DRB1*01 was higher in MCTD patients compared with controls, although the differences were not statistically significant. Our results confirm the modulating influence of HLA-DRB1 genotypes on development of connective tissue diseases such as MCTD. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Genetic variations in the human cannabinoid receptor gene are associated with happiness.

PubMed

Matsunaga, Masahiro; Isowa, Tokiko; Yamakawa, Kaori; Fukuyama, Seisuke; Shinoda, Jun; Yamada, Jitsuhiro; Ohira, Hideki

2014-01-01

Happiness has been viewed as a temporary emotional state (e.g., pleasure) and a relatively stable state of being happy (subjective happiness level). As previous studies demonstrated that individuals with high subjective happiness level rated their current affective states more positively when they experience positive events, these two aspects of happiness are interrelated. According to a recent neuroimaging study, the cytosine to thymine single-nucleotide polymorphism of the human cannabinoid receptor 1 gene is associated with sensitivity to positive emotional stimuli. Thus, we hypothesized that our genetic traits, such as the human cannabinoid receptor 1 genotypes, are closely related to the two aspects of happiness. In Experiment 1, 198 healthy volunteers were used to compare the subjective happiness level between cytosine allele carriers and thymine-thymine carriers of the human cannabinoid receptor 1 gene. In Experiment 2, we used positron emission tomography with 20 healthy participants to compare the brain responses to positive emotional stimuli of cytosine allele carriers to that of thymine-thymine carriers. Compared to thymine-thymine carriers, cytosine allele carriers have a higher subjective happiness level. Regression analysis indicated that the cytosine allele is significantly associated with subjective happiness level. The positive mood after watching a positive film was significantly higher for the cytosine allele carriers compared to the thymine-thymine carriers. Positive emotion-related brain region such as the medial prefrontal cortex was significantly activated when the cytosine allele carriers watched the positive film compared to the thymine-thymine carriers. Thus, the human cannabinoid receptor 1 genotypes are closely related to two aspects of happiness. Compared to thymine-thymine carriers, the cytosine allele carriers of the human cannabinoid receptor 1 gene, who are sensitive to positive emotional stimuli, exhibited greater magnitude

Genetic Variations in the Human Cannabinoid Receptor Gene Are Associated with Happiness

PubMed Central

Matsunaga, Masahiro; Isowa, Tokiko; Yamakawa, Kaori; Fukuyama, Seisuke; Shinoda, Jun; Yamada, Jitsuhiro; Ohira, Hideki

2014-01-01

Happiness has been viewed as a temporary emotional state (e.g., pleasure) and a relatively stable state of being happy (subjective happiness level). As previous studies demonstrated that individuals with high subjective happiness level rated their current affective states more positively when they experience positive events, these two aspects of happiness are interrelated. According to a recent neuroimaging study, the cytosine to thymine single-nucleotide polymorphism of the human cannabinoid receptor 1 gene is associated with sensitivity to positive emotional stimuli. Thus, we hypothesized that our genetic traits, such as the human cannabinoid receptor 1 genotypes, are closely related to the two aspects of happiness. In Experiment 1, 198 healthy volunteers were used to compare the subjective happiness level between cytosine allele carriers and thymine-thymine carriers of the human cannabinoid receptor 1 gene. In Experiment 2, we used positron emission tomography with 20 healthy participants to compare the brain responses to positive emotional stimuli of cytosine allele carriers to that of thymine-thymine carriers. Compared to thymine-thymine carriers, cytosine allele carriers have a higher subjective happiness level. Regression analysis indicated that the cytosine allele is significantly associated with subjective happiness level. The positive mood after watching a positive film was significantly higher for the cytosine allele carriers compared to the thymine-thymine carriers. Positive emotion-related brain region such as the medial prefrontal cortex was significantly activated when the cytosine allele carriers watched the positive film compared to the thymine-thymine carriers. Thus, the human cannabinoid receptor 1 genotypes are closely related to two aspects of happiness. Compared to thymine-thymine carriers, the cytosine allele carriers of the human cannabinoid receptor 1 gene, who are sensitive to positive emotional stimuli, exhibited greater magnitude

Compensatory premotor activity during affective face processing in subclinical carriers of a single mutant Parkin allele.

PubMed

Anders, Silke; Sack, Benjamin; Pohl, Anna; Münte, Thomas; Pramstaller, Peter; Klein, Christine; Binkofski, Ferdinand

2012-04-01

Patients with Parkinson's disease suffer from significant motor impairments and accompanying cognitive and affective dysfunction due to progressive disturbances of basal ganglia-cortical gating loops. Parkinson's disease has a long presymptomatic stage, which indicates a substantial capacity of the human brain to compensate for dopaminergic nerve degeneration before clinical manifestation of the disease. Neuroimaging studies provide evidence that increased motor-related cortical activity can compensate for progressive dopaminergic nerve degeneration in carriers of a single mutant Parkin or PINK1 gene, who show a mild but significant reduction of dopamine metabolism in the basal ganglia in the complete absence of clinical motor signs. However, it is currently unknown whether similar compensatory mechanisms are effective in non-motor basal ganglia-cortical gating loops. Here, we ask whether asymptomatic Parkin mutation carriers show altered patterns of brain activity during processing of facial gestures, and whether this might compensate for latent facial emotion recognition deficits. Current theories in social neuroscience assume that execution and perception of facial gestures are linked by a special class of visuomotor neurons ('mirror neurons') in the ventrolateral premotor cortex/pars opercularis of the inferior frontal gyrus (Brodmann area 44/6). We hypothesized that asymptomatic Parkin mutation carriers would show increased activity in this area during processing of affective facial gestures, replicating the compensatory motor effects that have previously been observed in these individuals. Additionally, Parkin mutation carriers might show altered activity in other basal ganglia-cortical gating loops. Eight asymptomatic heterozygous Parkin mutation carriers and eight matched controls underwent functional magnetic resonance imaging and a subsequent facial emotion recognition task. As predicted, Parkin mutation carriers showed significantly stronger activity in

Compensatory premotor activity during affective face processing in subclinical carriers of a single mutant Parkin allele

PubMed Central

Sack, Benjamin; Pohl, Anna; Münte, Thomas; Pramstaller, Peter; Klein, Christine; Binkofski, Ferdinand

2012-01-01

Patients with Parkinson's disease suffer from significant motor impairments and accompanying cognitive and affective dysfunction due to progressive disturbances of basal ganglia–cortical gating loops. Parkinson's disease has a long presymptomatic stage, which indicates a substantial capacity of the human brain to compensate for dopaminergic nerve degeneration before clinical manifestation of the disease. Neuroimaging studies provide evidence that increased motor-related cortical activity can compensate for progressive dopaminergic nerve degeneration in carriers of a single mutant Parkin or PINK1 gene, who show a mild but significant reduction of dopamine metabolism in the basal ganglia in the complete absence of clinical motor signs. However, it is currently unknown whether similar compensatory mechanisms are effective in non-motor basal ganglia–cortical gating loops. Here, we ask whether asymptomatic Parkin mutation carriers show altered patterns of brain activity during processing of facial gestures, and whether this might compensate for latent facial emotion recognition deficits. Current theories in social neuroscience assume that execution and perception of facial gestures are linked by a special class of visuomotor neurons (‘mirror neurons’) in the ventrolateral premotor cortex/pars opercularis of the inferior frontal gyrus (Brodmann area 44/6). We hypothesized that asymptomatic Parkin mutation carriers would show increased activity in this area during processing of affective facial gestures, replicating the compensatory motor effects that have previously been observed in these individuals. Additionally, Parkin mutation carriers might show altered activity in other basal ganglia–cortical gating loops. Eight asymptomatic heterozygous Parkin mutation carriers and eight matched controls underwent functional magnetic resonance imaging and a subsequent facial emotion recognition task. As predicted, Parkin mutation carriers showed significantly stronger

Diversity of alleles encoding HLA-B40: relative frequencies in united states populations and description of five novel alleles.

PubMed

Pimtanothai, N; Rizzuto, G A; Slack, R; Steiner, N K; Kosman, C A; Jones, P F; Koester, R; Ng, J; Hartzman, R J; Katovich Hurley, C

2000-08-01

The frequency of each B*40 allele was determined by DNA sequencing in four major United States populations: Caucasians, African Americans, Asians/Pacific Islanders, and Hispanics. Thirty-two individuals from each ethnic group, who were previously described serologically as B40, B60, or B61, were randomly selected out of a pool of 82,979 unrelated individuals for allele characterization. Out of nine different B*40 alleles identified in this study, B*4001 and B*4002 were the two most frequent B*40 alleles in all the population groups. B*4001 was the primary B*40 allele seen in Caucasians (83%) and African Americans (76%), while B*4002 was found in the majority of Hispanics (62%). The distributions of both alleles were comparable in the Asian/Pacific Islander population. These two alleles were the only B*40 alleles detected in Caucasians while four to five additional B*40 alleles were seen in the other population groups. The other B*40 alleles detected in this study included: B*4003 and B*4010 in Asian/Pacific Islanders; B*4012 and B*4016 in African Americans; and B*4004, B*4006, and B*4027 in Hispanics. Analysis revealed significant differences between Hispanics and all other groups as well as between African Americans and Asian/Pacific Islanders. This report also describes five novel B*40 alleles: B*4019, B*4020, B*4024, B*4027, and B*4028.

Identification of fragile X pre-mutation carriers in the Chinese obstetric population using a robust FMR1 polymerase chain reaction assay: implications for screening and prenatal diagnosis.

PubMed

Cheng, Y Ky; Lin, C Sw; Kwok, Y Ky; Chan, Y M; Lau, T K; Leung, T Y; Choy, K W

2017-04-01

There is significant morbidity associated with fragile X syndrome. Unfortunately, most maternal carriers are clinically silent during their reproductive years. Because of this, many experts have put forward the notion of preconception or prenatal fragile X carrier screening for females. This study aimed to determine the prevalence of fragile X syndrome pre-mutation and asymptomatic full-mutation carriers in a Chinese pregnant population, and the distribution of cytosine-guanine-guanine (CGG) repeat numbers using a robust fragile X mental retardation 1 (FMR1) polymerase chain reaction assay. This was a cross-sectional survey in prospectively recruited pregnant women from a university hospital in Hong Kong. Chinese pregnant women without a family history of fragile X syndrome were recruited between April 2013 and May 2015. A specific FMR1 polymerase chain reaction assay was performed on peripheral blood to determine the CGG repeat number of the FMR1 gene. Prenatal counselling was offered to full-mutation and pre-mutation carriers. In 2650 Chinese pregnant women, two individuals with pre-mutation alleles (0.08%, one in 1325) and one asymptomatic woman with full-mutation (0.04%, one in 2650) alleles were identified. The overall prevalence of pre-mutation and full-mutation alleles was 0.11% (1 in 883). Furthermore, 30 (1.1%) individuals with intermediate alleles were detected. In the 2617 women with normal CGG repeats, the most common CGG repeat allele was 30. The overall prevalence of pre-mutation and asymptomatic full-mutation carriers in the Chinese pregnant population was one in 883, detected by a new FMR1 polymerase chain reaction assay.

High Frequency of Human Leukocyte Antigen-B*57:01 Allele Carriers among HIV-Infected Patients in Serbia.

PubMed

Siljic, Marina; Salemovic, Dubravka; Cirkovic, Valentina; Pesic-Pavlovic, Ivana; Todorovic, Marija; Ranin, Jovan; Dragovic, Gordana; Jevtovic, Djordje; Stanojevic, Maja

2017-01-01

Abacavir is an effective antiretroviral drug and one of the most commonly used nucleoside reverse transcriptase inhibitors in Serbia. А percentage of the treated patients experience a potentially life-threatening hypersensitivity reaction, which was shown to be associated with the presence of the class I MHC allele, HLA-B*57:01; hence genotyping for HLA-B*57:01 prior to starting abacavir is nowadays recommended in international HIV treatment guidelines. In Serbia, this testing became available in 2013. This study was designed to estimate the prevalence of the HLA-B*57:01 allele in Serbian HIV-1-infected patients. The presence of the HLA-B*57:01 allele was analyzed in 273 HIV-1-infected patients aged 18 years or more, who were abacavir naïve. Buccal swab samples were obtained from all participants and assayed for the presence of HLA-B*57:01 using a commercially available HLA-B*57:01 real-time PCR kit. The presence of the HLA-B*57:01 allele was found in 22 of 273 tested individuals (8%; 95% CI 5.4-11.9%). This is the first study that estimated the HLA-B*57:01 prevalence among HIV-infected patients in Serbia. The very high prevalence of HLA-B*57:01 found in our study strongly supports HLA-B*57:01 genotyping, which should be implemented prior to the initiation of an abacavir-containing therapy to reduce the risk of potentially life-threatening hypersensitivity reactions. © 2017 S. Karger AG, Basel.

Association between the DRD2 A1 allele and response to methadone and buprenorphine maintenance treatments.

PubMed

Barratt, Daniel T; Coller, Janet K; Somogyi, Andrew A

2006-06-05

The TaqI A polymorphism (A(1)) of the dopamine D(2) receptor gene (DRD2), although not a specific predictor of opioid dependence, has been strongly associated with high levels of prior heroin use and poor treatment outcomes among methadone maintenance patients. The aims of this study were to confirm these findings via a retrospective analysis of A(1) allele frequency in methadone (n = 46) and buprenorphine (n = 25) patients, and non-opioid-dependent controls (n = 95). Subjects were genotyped at the DRD2 TaqI A locus using PCR amplification followed by TaqI restriction enzyme digestion and gel electrophoresis. For methadone and buprenorphine subjects, heroin use (prior to treatment), treatment outcomes, and withdrawal occurrence were determined from comprehensive case notes. No significant differences in A(1) allele frequency (%) were observed between: methadone (19.6%), buprenorphine (18.0%), and control (17.9%) groups (P > 0.7); successful and poor treatment outcome groups, methadone: 20.0% and 19.2%, respectively (P = 1.0); buprenorphine: 18.4% and 20.0%, respectively (P = 1.0). Also, there were no significant relationships between TaqI A genotype and prior heroin use (P = 0.47). However, among the successful methadone subjects, significantly fewer A(1) allele carriers experienced withdrawal than non-A(1) carriers (P = 0.04). In conclusion, the DRD2 genotype effects did not affect opioid maintenance treatment outcomes. This suggests the need for a further prospective investigation into the role of the DRD2 A(1) allele in heroin use and response to maintenance pharmacotherapies for opioid dependence.

Craving for alcohol and food during treatment for alcohol dependence: modulation by T allele of 1519T>C GABAAalpha6.

PubMed

Han, Doug Hyun; Bolo, Nicholas; Daniels, Melissa A; Lyoo, In Kyoon; Min, Kyung Joon; Kim, Chang Hyun; Renshaw, Perry F

2008-09-01

Craving for alcohol and food has been studied in association with alcohol dependence and eating disorders, respectively. One subclass of the gamma-aminobutyric acid (GABA) receptor, 1519T>C GABA(A)alpha6 has been reported to be associated with both alcohol dependence and weight gain. In this study, we hypothesized that patients being treated for alcohol dependence would report decreased craving for alcohol, but an increased craving for food during a 4-week treatment period. We further hypothesized that the T allele of the 1519T>C GABA(A)alpha6 gene would modulate the extent of changes in craving for alcohol and food. This study included 98 male inpatients being treated for alcohol dependence. A 7-point visual analog scale was applied to evaluate relative levels of alcohol and food craving at baseline and again 4 weeks later. Body weight was also checked at the same periods. Genotyping of the 1519T>C SNP in GABA(A)alpha6 was carried out by restriction fragment length polymorphism. There were significant changes in craving for alcohol and food in all patients with alcohol dependence. During the treatment period, body weight increased in all patients with alcohol dependence. Changes in alcohol and food craving in T-allele carriers (CT + TT) of 1519T>C GABA(A)alpha6 were greater than those observed in CC homozygotes. In T-allele carriers, body weight significantly increased and the changes in weight showed a negative correlation with the change in the craving for alcohol and a positive correlation with the changes in craving for food. The current results suggest that in T-allele carriers the change in craving for alcohol during treatment for alcohol dependence is negatively associated with changes in craving for food. The T allele of the 1519T>C GABA(A)alpha6 gene may be one of the modulating factors associated with changes in craving for alcohol and food during treatment of patients with alcohol dependence.

Glutathione-S-transferase M1, T1 and P1 polymorphisms, and breast cancer risk, in BRCA1/2 mutation carriers

PubMed Central

Kadouri, L; Kote-Jarai, Z; Hubert, A; Baras, M; Abeliovich, D; Hamburger, T; Peretz, T; Eeles, R A

2008-01-01

Variation in penetrance estimates for BRCA1/2 carriers suggests that other environmental and genetic factors may modify cancer risk in carriers. The GSTM1, T1 and P1 isoenzymes are involved in metabolism of environmental carcinogens. The GSTM1 and GSTT1 gene is absent in a substantial proportion of the population. In GSTP1, a single-nucleotide polymorphism that translates to Ile112Val was associated with lower activity. We studied the effect of these polymorphisms on breast cancer (BC) risk in BRCA1/2 carriers. A population of 320 BRCA1/2 carriers were genotyped; of them 262 were carriers of one of the three Ashkenazi founder mutations. Two hundred and eleven were affected with BC (20 also with ovarian cancer (OC)) and 109 were unaffected with BC (39 of them had OC). Risk analyses were conducted using Cox proportional hazard models adjusted for origin (Ashkenazi vs non-Ashkenazi). We found an estimated BC HR of 0.89 (95% CI 0.65–1.12, P=0.25) and 1.11 (95% CI 0.81–1.52, P=0.53) for the null alleles of GSTM1 and GSTT1, respectively. For GSTP1, HR for BC was 1.36 (95% CI 1.02–1.81, P=0.04) for individuals with Ile/Val, and 2.00 (95% CI 1.18–3.38) for carriers of the Val/Val genotype (P=0.01). An HR of 3.20 (95% CI 1.26–8.09, P=0.01), and younger age at BC onset (P=0.2), were found among Val/Val, BRCA2 carriers, but not among BRCA1 carriers. In conclusion, our results indicate significantly elevated risk for BC in carriers of BRCA2 mutations with GSTP1-Val allele with dosage effect, as implicated by higher risk in homozygous Val carriers. The GSTM1- and GSTT1-null allele did not seem to have a major effect. PMID:18542066

The GLO1 C332 (Ala111) allele confers autism vulnerability: family-based genetic association and functional correlates.

PubMed

Gabriele, Stefano; Lombardi, Federica; Sacco, Roberto; Napolioni, Valerio; Altieri, Laura; Tirindelli, Maria Cristina; Gregorj, Chiara; Bravaccio, Carmela; Rousseau, Francis; Persico, Antonio M

2014-12-01

Glyoxalase I (GLO1) is a homodimeric Zn(2+)-dependent isomerase involved in the detoxification of methylglyoxal and in limiting the formation of advanced glycation end-products (AGE). We previously found the rs4746 A332 (Glu111) allele of the GLO1 gene, which encodes for glyoxalase I, associated with "unaffected sibling" status in families with one or more children affected by Autism Spectrum Disorder (ASD). To identify and characterize this protective allele, we sequenced GLO1 exons and exon-intron junctions, detecting two additional SNPs (rs1049346, rs1130534) in linkage disequilibrium with rs4746. A family-based association study involving 385 simplex and 20 multiplex Italian families yielded a significant association with autism driven only by the rs4746 C332 (Ala111) allele itself (P < 0.05 and P < 0.001 under additive and dominant/recessive models, respectively). Glyoxalase enzymatic activity was significantly reduced both in leukocytes and in post-mortem temporocortical tissue (N = 38 and 13, respectively) of typically developing C332 allele carriers (P < 0.05 and <0.01), with no difference in Glo1 protein levels. Conversely, AGE amounts were significantly higher in the same C332 post-mortem brains (P = 0.001), with a strong negative correlation between glyoxalase activity and AGE levels (τ = -0.588, P < 0.01). Instead, 19 autistic brains show a dysregulation of the glyoxalase-AGE axis (τ = -0.209, P = 0.260), with significant blunting of glyoxalase activity and AGE amounts compared to controls (P < 0.05), and loss of rs4746 genotype effects. In summary, the GLO1 C332 (Ala111) allele confers autism vulnerability by reducing brain glyoxalase activity and enhancing AGE formation, but years after an autism diagnosis the glyoxalase-AGE axis appears profoundly disrupted, with loss of C332 allelic effects. Copyright © 2014 Elsevier Ltd. All rights reserved.

The C allele of ATM rs11212617 does not associate with metformin response in the Diabetes Prevention Program.

PubMed

Florez, Jose C; Jablonski, Kathleen A; Taylor, Andrew; Mather, Kieren; Horton, Edward; White, Neil H; Barrett-Connor, Elizabeth; Knowler, William C; Shuldiner, Alan R; Pollin, Toni I

2012-09-01

The C allele at the rs11212617 polymorphism in the ataxia-telangiectasia-mutated (ATM) gene has been associated with greater clinical response to metformin in people with type 2 diabetes. We tested whether this variant modified the effect of metformin in the Diabetes Prevention Program (DPP), in which metformin reduced diabetes incidence by 31% in volunteers with impaired glucose tolerance. We genotyped rs11212617 in 2,994 DPP participants and analyzed its effects on diabetes incidence and related traits. Contrary to expectations, C carriers enjoyed no preventive advantage on metformin; their hazard ratio, compared with A carriers, was 1.17 ([95% CI 0.96-1.42], P = 0.13) under metformin. There were no significant differences by genotype in metformin's effects on insulin sensitivity, fasting glucose, glycated hemoglobin, or disposition index. The reported association of rs11212617 with metformin response was not confirmed for diabetes prevention or for effects on relevant physiologic parameters in the DPP.

Incidence of bovine leukocyte adhesion deficiency, complex vertebral malformation, and deficiency of uridine-5-monophosphate synthase carriers in Brazilian Girolando cattle.

PubMed

Paiva, D S; Fonseca, I; Pinto, I S B; Ianella, P; Campos, T A; Caetano, A R; Paiva, S R; Silva, M V G B; Martins, M F

2013-08-29

Among the various hereditary diseases that have been widely studied in dairy cattle, bovine leukocyte adhesion deficiency (BLAD), deficiency of uridine-5-monophosphate synthase (DUMPS), and complex vertebral malformation (CVM) are noteworthy because of their high impact on overall herd productivity as a consequence of increased calf mortality. The aim of this study was to verify the frequency of carriers of BLAD, CVM, and DUMPS mutant alleles in cows and bulls from the National Girolando Progeny Test carried out in Brazil by using polymerase chain reaction (PCR)-restriction fragment length polymorphism and allele-specific PCR assays. A total of 777 animals were genotyped for BLAD, 783 for CVM, and 122 for DUMPS. The frequencies of carriers for BLAD and CVM were 0.77 and 1.53%, respectively, whereas no carriers of DUMPS were observed.

Delimiting Allelic Imbalance of TYMS by Allele-Specific Analysis.

PubMed

Balboa-Beltrán, Emilia; Cruz, Raquel; Carracedo, Angel; Barros, Francisco

2015-07-01

Allelic imbalance of thymidylate synthase (TYMS) is attributed to polymorphisms in the 5'- and 3'-untranslated region (UTR). These polymorphisms have been related to the risk of suffering different cancers, for example leukemia, breast or gastric cancer, and response to different drugs, among which are methotrexate glutamates, stavudine, and specifically 5-fluorouracil (5-FU), as TYMS is its direct target. A vast literature has been published in relation to 5-FU, even suggesting the sole use of these polymorphisms to effectively manage 5-FU dosage. Estimates of the extent to which these polymorphisms influence in TYMS expression have in the past been based on functional analysis by luciferase assays and quantification of TYMS mRNA, but both these studies, as the association studies with cancer risk or with toxicity or response to 5-FU, are very contradictory. Regarding functional assays, the artificial genetic environment created in luciferase assay and the problems derived from quantitative polymerase chain reactions (qPCRs), for example the use of a reference gene, may have distorted the results. To avoid these sources of interference, we have analyzed the allelic imbalance of TYMS by allelic-specific analysis in peripheral blood mononuclear cells (PBMCs) from patients.Allelic imbalance in PBMCs, taken from 40 patients with suspected myeloproliferative haematological diseases, was determined by fluorescent fragment analysis (for the 3'-UTR polymorphism), Sanger sequencing and allelic-specific qPCR in multiplex (for the 5'-UTR polymorphisms).For neither the 3'- nor the 5'-UTR polymorphisms did the observed allelic imbalance exceed 1.5 fold. None of the TYMS polymorphisms is statistically associated with allelic imbalance.The results acquired allow us to deny the previously established assertion of an influence of 2 to 4 fold of the rs45445694 and rs2853542 polymorphisms in the expression of TYMS and narrow its allelic imbalance to 1.5 fold, in our population

Genetic characterization of an alloalbumin, albumin Kashmir, using gene amplification and allele-specific oligonucleotides.

PubMed Central

Savva, D; Tárnoky, A L; Vickers, M F

1990-01-01

The molecular basis for albumin Kashmir was studied using the polymerase chain reaction to amplify a DNA fragment containing codon 501 in exon 12 of the human albumin gene. Southern blots of the amplified DNA were hybridized to oligonucleotide probes specific either for the normal allele of albumin or for albumin Kashmir. The results provide strong evidence that codon 501 in albumin Kashmir is AAG (lysine) instead of GAG (glutamic acid), thus confirming the protein sequences reported. This approach was used to characterize a bisalbuminaemic individual as a carrier for albumin Kashmir. Similar strategies may be devised to study the molecular basis and to identify carriers of other alloalbumins. Images Fig. 1. Fig. 2. PMID:2317208

Human minisatellite alleles detectable only after PCR amplification.

PubMed

Armour, J A; Crosier, M; Jeffreys, A J

1992-01-01

We present evidence that a proportion of alleles at two human minisatellite loci is undetected by standard Southern blot hybridization. In each case the missing allele(s) can be identified after PCR amplification and correspond to tandem arrays too short to detect by hybridization. At one locus, there is only one undetected allele (population frequency 0.3), which contains just three repeat units. At the second locus, there are at least five undetected alleles (total population frequency 0.9) containing 60-120 repeats; they are not detected because these tandem repeats give very poor signals when used as a probe in standard Southern blot hybridization, and also cross-hybridize with other sequences in the genome. Under these circumstances only signals from the longest tandemly repeated alleles are detectable above the nonspecific background. The structures of these loci have been compared in human and primate DNA, and at one locus the short human allele containing three repeat units is shown to be an intermediate state in the expansion of a monomeric precursor allele in primates to high copy number in the longer human arrays. We discuss the implications of such loci for studies of human populations, minisatellite isolation by cloning, and the evolution of highly variable tandem arrays.

A pseudodeficiency allele (D152N) of the human {beta}-glucuronidase gene

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

Vervoort, R.; Liebaers, I.; Lissens, W.

1995-10-01

We present evidence that a 480G{r_arrow}A transition in the coding region of the {Beta}glucuronidase gene, which results in an aspartic-acid-to-asparagine substitution at amino acid position 152 (D152N), produces a pseudodeficiency allele (GUSBp) that leads to greatly reduced levels of {Beta}-glucuronidase activity without apparent deleterious consequences. The 48OG{r_arrow}A mutation was found initially in the pseudodeficient mother of a child with mucopolysaccharidosis VII (MPSVII), but it was not on her disease-causing allele, which carried the L176F mutation. The 480G{r_arrow}A change was also present in an unrelated individual with another MPSVII allele who had unusually low {Beta}-glucuronidase activity, but whose clinical symptoms weremore » probably unrelated to {Beta}-glucuronidase deficiency. This individual also had an R357X mutation, probably on his second allele. We screened 100 unrelated normal individuals for the 480G{r_arrow}A mutation with a PCR method and detected one carrier. Reduced {Beta}-glucuronidase activity following transfection of COS cells with the D152N cDNA supported the causal relationship between the D152N allele and pseudodeficiency. The mutation reduced the fraction of expressed enzyme that was secreted. Pulse-chase experiments indicated that the reduced activity in COS cells was due to accelerated intracellular turnover of the D152N enzyme. They also suggested that a potential glycosylation site created by the mutation is utilized in {approximately}50% of the enzyme expressed. 25 refs., 3 figs., 3 tabs.« less

Common Atrial Fibrillation Risk Alleles at 4q25 Predict Recurrence after Catheter-based Atrial Fibrillation Ablation

PubMed Central

Shoemaker, M. Benjamin; Muhammad, Raafia; Parvez, Babar; White, Brenda W.; Streur, Megan; Song, Yanna; Stubblefield, Tanya; Kucera, Gayle; Blair, Marcia; Rytlewski, Jason; Parvathaneni, Sunthosh; Nagarakanti, Rangadham; Saavedra, Pablo; Ellis, Christopher; Whalen, S. Patrick; Roden, Dan M; Darbar, Dawood

2012-01-01

Background Common single nucleotide polymorphisms (SNPs) at chromosome 4q25 (rs2200733, rs10033464) are associated with both lone and typical AF. Risk alleles at 4q25 have recently been shown to predict recurrence of AF after ablation in a population of predominately lone AF, but lone AF represents only 5–30% of AF cases. Objective To test the hypothesis that 4q25 AF risk alleles can predict response to AF ablation in the majority of AF cases. Methods Patients enrolled in the Vanderbilt AF Registry underwent 378 catheter-based AF ablations (median age 60 years, 71% male, 89% typical AF) between 2004 and 2011. The primary endpoint was time to recurrence of any non-sinus atrial tachyarrhythmia (atrial tachycardia, atrial flutter, or AF; [AT/AF]). Results Two-hundred AT/AF recurrences (53%) were observed. In multivariable analysis, the rs2200733 risk allele predicted a 24% shorter recurrence-free time (survival time ratio 0.76 95% confidence interval [CI] 0.6–0.95, P=0.016) compared with wild-type. The heterozygous haplotype demonstrated a 21% shorter recurrence-free time (survival time ratio = 0.79, 95% CI 0.62–0.99) and the homozygous risk allele carriers a 39% shorter recurrence-free time (survival time ratio = 0.61, 95% CI 0.37–1.0) (P=0.037). Conclusion Risk alleles at the 4q25 loci predict impaired clinical response to AF ablation in a population of predominately typical AF patients. Our findings suggest the rs2200733 polymorphism may hold promise as an as an objectively measured patient characteristic that can used as a clinical tool for selection of patients for AF ablation. PMID:23178686

Increased hippocampal activation in ApoE-4 carriers and non-carriers with amnestic mild cognitive impairment.

PubMed

Tran, Tammy T; Speck, Caroline L; Pisupati, Aparna; Gallagher, Michela; Bakker, Arnold

2017-01-01

Increased fMRI activation in the hippocampus is recognized as a signature characteristic of the amnestic mild cognitive impairment (aMCI) stage of Alzheimer's disease (AD). Previous work has localized this increased activation to the dentate gyrus/CA3 subregion of the hippocampus and showed a correlation with memory impairments in those patients. Increased hippocampal activation has also been reported in carriers of the ApoE-4 allelic variation independently of mild cognitive impairment although these findings were not localized to a hippocampal subregion. To assess the ApoE-4 contribution to increased hippocampal fMRI activation, patients with aMCI genotyped for ApoE-4 status and healthy age-matched control participants completed a high-resolution fMRI scan while performing a memory task designed to tax hippocampal subregion specific functions. Consistent with previous reports, patients with aMCI showed increased hippocampal activation in the left dentate gyrus/CA3 region of the hippocampus as well as memory task errors attributable to this subregion. However, this increased fMRI activation in the hippocampus did not differ between ApoE-4 carriers and ApoE-4 non-carriers and the proportion of memory errors attributable to dentate gyrus/CA3 function did not differ between ApoE-4 carriers and ApoE-4 non-carriers. These results indicate that increased fMRI activation of the hippocampus observed in patients with aMCI is independent of ApoE-4 status and that ApoE-4 does not contribute to the dysfunctional hippocampal activation or the memory errors attributable to this subregion in these patients.

Comparative effects of carrier proteins on vaccine-induced immune response.

PubMed

Knuf, Markus; Kowalzik, Frank; Kieninger, Dorothee

2011-07-12

The efficacy of vaccines against major encapsulated bacterial pathogens -Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae type b (Hib) - has been significantly enhanced by conjugating the respective polysaccharides with different carrier proteins: diphtheria toxoid; non-toxic cross-reactive material of diphtheria toxin(197), tetanus toxoid, N. meningitidis outer membrane protein, and non-typeable H. influenzae-derived protein D. Hib, meningococcal, and pneumococcal conjugate vaccines have shown good safety and immunogenicity profiles regardless of the carrier protein used, although data are conflicting as to which carrier protein is the most immunogenic. Coadministration of conjugate vaccines bearing the same carrier protein has the potential for inducing either positive or negative effects on vaccine immunogenicity (immune interference). Clinical studies on the coadministration of conjugate vaccines reveal conflicting data with respect to immune interference and vaccine efficacy. Copyright © 2011 Elsevier Ltd. All rights reserved.

Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction.

PubMed

Do, Ron; Stitziel, Nathan O; Won, Hong-Hee; Jørgensen, Anders Berg; Duga, Stefano; Angelica Merlini, Pier; Kiezun, Adam; Farrall, Martin; Goel, Anuj; Zuk, Or; Guella, Illaria; Asselta, Rosanna; Lange, Leslie A; Peloso, Gina M; Auer, Paul L; Girelli, Domenico; Martinelli, Nicola; Farlow, Deborah N; DePristo, Mark A; Roberts, Robert; Stewart, Alexander F R; Saleheen, Danish; Danesh, John; Epstein, Stephen E; Sivapalaratnam, Suthesh; Hovingh, G Kees; Kastelein, John J; Samani, Nilesh J; Schunkert, Heribert; Erdmann, Jeanette; Shah, Svati H; Kraus, William E; Davies, Robert; Nikpay, Majid; Johansen, Christopher T; Wang, Jian; Hegele, Robert A; Hechter, Eliana; Marz, Winfried; Kleber, Marcus E; Huang, Jie; Johnson, Andrew D; Li, Mingyao; Burke, Greg L; Gross, Myron; Liu, Yongmei; Assimes, Themistocles L; Heiss, Gerardo; Lange, Ethan M; Folsom, Aaron R; Taylor, Herman A; Olivieri, Oliviero; Hamsten, Anders; Clarke, Robert; Reilly, Dermot F; Yin, Wu; Rivas, Manuel A; Donnelly, Peter; Rossouw, Jacques E; Psaty, Bruce M; Herrington, David M; Wilson, James G; Rich, Stephen S; Bamshad, Michael J; Tracy, Russell P; Cupples, L Adrienne; Rader, Daniel J; Reilly, Muredach P; Spertus, John A; Cresci, Sharon; Hartiala, Jaana; Tang, W H Wilson; Hazen, Stanley L; Allayee, Hooman; Reiner, Alex P; Carlson, Christopher S; Kooperberg, Charles; Jackson, Rebecca D; Boerwinkle, Eric; Lander, Eric S; Schwartz, Stephen M; Siscovick, David S; McPherson, Ruth; Tybjaerg-Hansen, Anne; Abecasis, Goncalo R; Watkins, Hugh; Nickerson, Deborah A; Ardissino, Diego; Sunyaev, Shamil R; O'Donnell, Christopher J; Altshuler, David; Gabriel, Stacey; Kathiresan, Sekar

2015-02-05

Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl(-1). At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.

High allele frequency of CYP2C9*3 (rs1057910) in a Negrito's subtribe population in Malaysia; Aboriginal people of Jahai.

PubMed

Rosdi, Rasmaizatul Akma; Mohd Yusoff, Narazah; Ismail, Rusli; Soo Choon, Tan; Saleem, Mohamed; Musa, Nurfadhlina; Yusoff, Surini

2016-09-01

CYP2C9 gene polymorphisms modulate inter-individual variations in the human body's responses to various endogenous and exogenous drug substrates. To date, little is known about the CYP2C9 gene polymorphisms among the aboriginal populations of the world, including those in Malaysia. To characterise and compare the CYP2C9 polymorphisms (CYP2C9*2, CYP2C9*3, CYP2C9*4 and CYP2C9*5) between one of Malaysia's aboriginal populations, Jahai, with the national major ethnic, Malay. To also compare the allele frequencies from these two populations with available data of other aboriginal populations around the world. The extracted DNA of 155 Jahais and 183 Malays was genotyped for CYP2C9 polymorphisms using a nested multiplex allele-specific polymerase chain reaction technique. The results were confirmed by DNA direct sequencing. Genotyping results revealed that CYP2C9*2, CYP2C9*4 and CYP2C9*5 were absent in Jahais, while only the latter two were absent in Malays. The CYP2C9*3 allelic frequency in Jahais was 36.2%, making them the most frequent carriers of the allele thus far reported in any ethnic group from Southeast Asia. The high frequency of CYP2C9*3 and the absence of CYP2C9*2 in Jahais suggest that genetic drift may be occurring in this ethnic group. This is the first study to determine the CYP2C9 polymorphisms in an aboriginal population in Malaysia.

Conscientiousness is Negatively Associated with Grey Matter Volume in Young APOE ɛ4-Carriers.

PubMed

Kunz, Lukas; Reuter, Martin; Axmacher, Nikolai; Montag, Christian

2017-01-01

The etiology of late onset Alzheimer's disease (LOAD) depends on multiple factors, among which the APOE ɛ4 allele is the most adverse genetic determinant and conscientiousness represents an influential personality trait. A potential association of both factors with brain structure in young adulthood may constitute a constellation that sets the course toward or against the subtle disease progression of LOAD that starts decades before clinical manifestation. Hence, in the present study, we examined the modulating effects of APOE ɛ4 on the relation between personality dimensions, including conscientiousness, and total grey matter volume (GMV) in young healthy adults using an a priori genotyping design. 105 participants completed an inventory assessing the Five Factor Model of Personality (NEO-FFI) and a structural MRI scan. Total GMV was estimated using both Freesurfer as well as VBM8. Across all participants, total GMV was positively associated with extraversion and negatively related to age. In APOE ɛ4-carriers- but not in APOE ɛ4-non-carriers- conscientiousness was negatively associated with total GMV. In line with the hypothesis of antagonistic pleiotropy of the APOE ɛ4 allele, this result suggests that young APOE ɛ4-carriers with increased total GMV may particularly benefit from cognitive advantages and thus have a lower need to engage in conscientious behavior. In this subset of young APOE ɛ4-carriers, the reduction in conscientiousness could then bring along adverse health behavior in the long run, potentiating the risk for LOAD. Hence, young APOE ɛ4-carriers with increased total GMV may be at a particularly high risk for LOAD.

Comparative anatomy of chromosomal domains with imprinted and non-imprinted allele-specific DNA methylation.

PubMed

Paliwal, Anupam; Temkin, Alexis M; Kerkel, Kristi; Yale, Alexander; Yotova, Iveta; Drost, Natalia; Lax, Simon; Nhan-Chang, Chia-Ling; Powell, Charles; Borczuk, Alain; Aviv, Abraham; Wapner, Ronald; Chen, Xiaowei; Nagy, Peter L; Schork, Nicholas; Do, Catherine; Torkamani, Ali; Tycko, Benjamin

2013-08-01

Allele-specific DNA methylation (ASM) is well studied in imprinted domains, but this type of epigenetic asymmetry is actually found more commonly at non-imprinted loci, where the ASM is dictated not by parent-of-origin but instead by the local haplotype. We identified loci with strong ASM in human tissues from methylation-sensitive SNP array data. Two index regions (bisulfite PCR amplicons), one between the C3orf27 and RPN1 genes in chromosome band 3q21 and the other near the VTRNA2-1 vault RNA in band 5q31, proved to be new examples of imprinted DMRs (maternal alleles methylated) while a third, between STEAP3 and C2orf76 in chromosome band 2q14, showed non-imprinted haplotype-dependent ASM. Using long-read bisulfite sequencing (bis-seq) in 8 human tissues we found that in all 3 domains the ASM is restricted to single differentially methylated regions (DMRs), each less than 2kb. The ASM in the C3orf27-RPN1 intergenic region was placenta-specific and associated with allele-specific expression of a long non-coding RNA. Strikingly, the discrete DMRs in all 3 regions overlap with binding sites for the insulator protein CTCF, which we found selectively bound to the unmethylated allele of the STEAP3-C2orf76 DMR. Methylation mapping in two additional genes with non-imprinted haplotype-dependent ASM, ELK3 and CYP2A7, showed that the CYP2A7 DMR also overlaps a CTCF site. Thus, two features of imprinted domains, highly localized DMRs and allele-specific insulator occupancy by CTCF, can also be found in chromosomal domains with non-imprinted ASM. Arguing for biological importance, our analysis of published whole genome bis-seq data from hES cells revealed multiple genome-wide association study (GWAS) peaks near CTCF binding sites with ASM.

Comparative Anatomy of Chromosomal Domains with Imprinted and Non-Imprinted Allele-Specific DNA Methylation

PubMed Central

Kerkel, Kristi; Yale, Alexander; Yotova, Iveta; Drost, Natalia; Lax, Simon; Nhan-Chang, Chia-Ling; Powell, Charles; Borczuk, Alain; Aviv, Abraham; Wapner, Ronald; Chen, Xiaowei; Nagy, Peter L.; Schork, Nicholas; Do, Catherine; Torkamani, Ali; Tycko, Benjamin

2013-01-01

Allele-specific DNA methylation (ASM) is well studied in imprinted domains, but this type of epigenetic asymmetry is actually found more commonly at non-imprinted loci, where the ASM is dictated not by parent-of-origin but instead by the local haplotype. We identified loci with strong ASM in human tissues from methylation-sensitive SNP array data. Two index regions (bisulfite PCR amplicons), one between the C3orf27 and RPN1 genes in chromosome band 3q21 and the other near the VTRNA2-1 vault RNA in band 5q31, proved to be new examples of imprinted DMRs (maternal alleles methylated) while a third, between STEAP3 and C2orf76 in chromosome band 2q14, showed non-imprinted haplotype-dependent ASM. Using long-read bisulfite sequencing (bis-seq) in 8 human tissues we found that in all 3 domains the ASM is restricted to single differentially methylated regions (DMRs), each less than 2kb. The ASM in the C3orf27-RPN1 intergenic region was placenta-specific and associated with allele-specific expression of a long non-coding RNA. Strikingly, the discrete DMRs in all 3 regions overlap with binding sites for the insulator protein CTCF, which we found selectively bound to the unmethylated allele of the STEAP3-C2orf76 DMR. Methylation mapping in two additional genes with non-imprinted haplotype-dependent ASM, ELK3 and CYP2A7, showed that the CYP2A7 DMR also overlaps a CTCF site. Thus, two features of imprinted domains, highly localized DMRs and allele-specific insulator occupancy by CTCF, can also be found in chromosomal domains with non-imprinted ASM. Arguing for biological importance, our analysis of published whole genome bis-seq data from hES cells revealed multiple genome-wide association study (GWAS) peaks near CTCF binding sites with ASM. PMID:24009515

Age at cancer onset in germline TP53 mutation carriers: association with polymorphisms in predicted G-quadruplex structures

PubMed Central

Hainaut, Pierre

2014-01-01

Germline TP53 mutations predispose to multiple cancers defining Li-Fraumeni/Li-Fraumeni-like syndrome (LFS/LFL), a disease with large individual disparities in cancer profiles and age of onset. G-quadruplexes (G4s) are secondary structural motifs occurring in guanine tracks, with regulatory effects on DNA and RNA. We analyzed 85 polymorphisms within or near five predicted G4s in TP53 in search of modifiers of penetrance of LFS/LFL in Brazilian cancer families with (n = 35) or without (n = 110) TP53 mutations. Statistical analyses stratified on family structure showed that cancer tended to occur ~15 years later in mutation carriers who also carried the variant alleles of two polymorphisms within predicted G4-forming regions, rs17878362 (TP53 PIN3, 16 bp duplication in intron 3; P = 0.082) and rs17880560 (6 bp duplication in 3′ flanking region; P = 0.067). Haplotype analysis showed that this inverse association was driven by the polymorphic status of the remaining wild-type (WT) haplotype in mutation carriers: in carriers with a WT haplotype containing at least one variant allele of rs17878362 or rs17880560, cancer occurred ~15 years later than in carriers with other WT haplotypes (P = 0.019). No effect on age of cancer onset was observed in subjects without a TP53 mutation. The G4 in intron 3 has been shown to regulate alternative p53 messenger RNA splicing, whereas the biological roles of predicted G4s in the 3′ flanking region remain to be elucidated. In conclusion, this study demonstrates that G4 polymorphisms in haplotypes of the WT TP53 allele have an impact on LFS/LFL penetrance in germline TP53 mutation carriers. PMID:24336192

Efficient computation of the joint probability of multiple inherited risk alleles from pedigree data.

PubMed

Madsen, Thomas; Braun, Danielle; Peng, Gang; Parmigiani, Giovanni; Trippa, Lorenzo

2018-06-25

The Elston-Stewart peeling algorithm enables estimation of an individual's probability of harboring germline risk alleles based on pedigree data, and serves as the computational backbone of important genetic counseling tools. However, it remains limited to the analysis of risk alleles at a small number of genetic loci because its computing time grows exponentially with the number of loci considered. We propose a novel, approximate version of this algorithm, dubbed the peeling and paring algorithm, which scales polynomially in the number of loci. This allows extending peeling-based models to include many genetic loci. The algorithm creates a trade-off between accuracy and speed, and allows the user to control this trade-off. We provide exact bounds on the approximation error and evaluate it in realistic simulations. Results show that the loss of accuracy due to the approximation is negligible in important applications. This algorithm will improve genetic counseling tools by increasing the number of pathogenic risk alleles that can be addressed. To illustrate we create an extended five genes version of BRCAPRO, a widely used model for estimating the carrier probabilities of BRCA1 and BRCA2 risk alleles and assess its computational properties. © 2018 WILEY PERIODICALS, INC.

Allele-Specific Silencing of Mutant mRNA Rescues Ultrastructural and Arrhythmic Phenotype in Mice Carriers of the R4496C Mutation in the Ryanodine Receptor Gene (RYR2).

PubMed

Bongianino, Rossana; Denegri, Marco; Mazzanti, Andrea; Lodola, Francesco; Vollero, Alessandra; Boncompagni, Simona; Fasciano, Silvia; Rizzo, Giulia; Mangione, Damiano; Barbaro, Serena; Di Fonso, Alessia; Napolitano, Carlo; Auricchio, Alberto; Protasi, Feliciano; Priori, Silvia G

2017-08-18

Mutations in the cardiac Ryanodine Receptor gene ( RYR2 ) cause dominant catecholaminergic polymorphic ventricular tachycardia (CPVT), a leading cause of sudden death in apparently healthy individuals exposed to emotions or physical exercise. We investigated the efficacy of allele-specific silencing by RNA interference to prevent CPVT phenotypic manifestations in our dominant CPVT mice model carriers of the heterozygous mutation R4496C in RYR2 . We developed an in vitro mRNA and protein-based assays to screen multiple siRNAs for their ability to selectively silence mutant RYR2 -R4496C mRNA over the corresponding wild-type allele. For the most performant of these siRNAs (siRYR2-U10), we evaluated the efficacy of an adeno-associated serotype 9 viral vector (AAV9) expressing miRYR2-U10 in correcting RyR2 (Ryanodine Receptor type 2 protein) function after in vivo delivery by intraperitoneal injection in neonatal and adult RyR2 R4496C/+ (mice heterozygous for the R4496C mutation in the RyR2) heterozygous CPVT mice. Transcriptional analysis showed that after treatment with miRYR2-U10, the ratio between wild-type and mutant RYR2 mRNA was doubled (from 1:1 to 2:1) confirming the ability of miRYR2-U10 to selectively inhibit RYR2 -R4496C mRNA, whereas protein quantification showed that total RyR2 was reduced by 15% in the heart of treated mice. Furthermore, AAV9-miRYR2-U10 effectively (1) reduced isoproterenol-induced delayed afterdepolarizations and triggered activity in infected cells, (2) reduced adrenergically mediated ventricular tachycardia in treated mice, (3) reverted ultrastructural abnormalities of junctional sarcoplasmic reticulum and transverse tubules, and (4) attenuated mitochondrial abnormalities. The study demonstrates that allele-specific silencing with miRYR2-U10 prevents life-threatening arrhythmias in CPVT mice, suggesting that the reduction of mutant RyR2 may be a novel therapeutic approach for CPVT. © 2017 American Heart Association, Inc.

Lipid Oxidation in Carriers of Lecithin:Cholesterol Acyltransferase Gene Mutations

PubMed Central

Holleboom, Adriaan G.; Daniil, Georgios; Fu, Xiaoming; Zhang, Renliang; Hovingh, G. Kees; Schimmel, Alinda W.; Kastelein, John J.P.; Stroes, Erik S.G.; Witztum, Joseph L.; Hutten, Barbara A.; Tsimikas, Sotirios; Hazen, Stanley L.; Chroni, Angeliki; Kuivenhoven, Jan Albert

2013-01-01

Objective Lecithin:cholesterol acyltransferase (LCAT) has been shown to play a role in the depletion of lipid oxidation products, but this has so far not been studied in humans. In this study, we investigated processes and parameters relevant to lipid oxidation in carriers of functional LCAT mutations. Methods and Results In 4 carriers of 2 mutant LCAT alleles, 63 heterozygotes, and 63 family controls, we measured activities of LCAT, paraoxonase 1, and platelet-activating factor-acetylhydrolase; levels of lysophosphatidylcholine molecular species, arachidonic and linoleic acids, and their oxidized derivatives; immunodetectable oxidized phospholipids on apolipoprotein (apo) B–containing and apo(a)-containing lipoproteins; IgM and IgG autoantibodies to malondialdehyde-low-density lipoprotein and IgG and IgM apoB-immune complexes; and the antioxidant capacity of high-density lipoprotein (HDL). In individuals with LCAT mutations, plasma LCAT activity, HDL cholesterol, apoA-I, arachidonic acid, and its oxidized derivatives, oxidized phospholipids on apo(a)-containing lipoproteins, HDL-associated platelet-activating factor-acetylhydrolase activity, and the antioxidative capacity of HDL were gene-dose–dependently decreased. Oxidized phospholipids on apoB-containing lipoproteins was increased in heterozygotes (17%; P<0.001) but not in carriers of 2 defective LCAT alleles. Conclusion Carriers of LCAT mutations present with significant reductions in LCAT activity, HDL cholesterol, apoA-I, platelet-activating factor-acetylhydrolase activity, and antioxidative potential of HDL, but this is not associated with parameters of increased lipid peroxidation; we did not observe significant changes in the oxidation products of arachidonic acid and linoleic acid, immunoreactive oxidized phospholipids on apo(a)-containing lipoproteins, and IgM and IgG autoantibodies against malondialdehyde-low-density lipoprotein. These data indicate that plasma LCAT activity, HDL

Heightened amygdala responsiveness in s-carriers of 5-HTTLPR genetic polymorphism reflects enhanced cortical rather than subcortical inputs: An MEG study.

PubMed

Luo, Qian; Holroyd, Tom; Mitchell, Derek; Yu, Henry; Cheng, Xi; Hodgkinson, Colin; Chen, Gang; McCaffrey, Daniel; Goldman, David; Blair, R James

2017-09-01

Short allele carriers (S-carriers) of the serotonin transporter gene (5-HTTLPR) show an elevated amygdala response to emotional stimuli relative to long allele carriers (LL-homozygous). However, whether this reflects increased responsiveness of the amygdala generally or interactions between the amygdala and the specific input systems remains unknown. It is argued that the amygdala receives input via a quick subcortical and a slower cortical pathway. If the elevated amygdala response in S-carriers reflects generally increased amygdala responding, then group differences in amygdala should be seen across the amygdala response time course. However, if the difference is a secondary consequence of enhanced amygdala-cortical interactions, then group differences might only be present later in the amygdala response. Using magnetoencephalography (MEG), we found an enhanced amygdala response to fearful expressions starting 40-50 ms poststimulus. However, group differences in the amygdala were only seen 190-200 ms poststimulus, preceded by increased superior temporal sulcus (STS) responses in S-carriers from 130 to 140 ms poststimulus. An enhanced amygdala response to angry expressions started 260-270 ms poststimulus with group differences in the amygdala starting at 160-170 ms poststimulus onset, preceded by increased STS responses in S-carriers from 150 to 160 ms poststimulus. These suggest that enhanced amygdala responses in S-carriers might reflect enhanced STS-amygdala connectivity in S-carriers. Hum Brain Mapp 38:4313-4321, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

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.

An Enhanced Polymerase Chain Reaction Assay to Detect Pre- and Full Mutation Alleles of the Fragile X Mental Retardation 1 Gene

PubMed Central

Saluto, Alessandro; Brussino, Alessandro; Tassone, Flora; Arduino, Carlo; Cagnoli, Claudia; Pappi, Patrizia; Hagerman, Paul; Migone, Nicola; Brusco, Alfredo

2005-01-01

Several diagnostic strategies have been applied to the detection of FMR1 gene repeat expansions in fragile X syndrome. Here, we report a novel polymerase chain reaction-based strategy using the Expand Long Template PCR System (Roche Diagnostics, Mannheim, Germany) and the osmolyte betaine. Repeat expansions up to ∼330 CGGs in males and up to at least ∼160 CGGs in carrier women could be easily visualized on ethidium bromide agarose gels. We also demonstrated that fluorescence analysis of polymerase chain reaction products was a reliable tool to verify the presence of premutation and full mutation alleles both in males and in females. This technique, primarily designed to detect premutation alleles, can be used as a routine first screen for expanded FMR1 alleles. PMID:16258159

The interleukin-10-1082 'A' allele and abdominal aortic aneurysms.

PubMed

Bown, Matthew J; Lloyd, Geraint M; Sandford, Rebecca M; Thompson, John R; London, Nicholas J M; Samani, Nilesh J; Sayers, Robert D

2007-10-01

Abdominal aortic aneurysms (AAA) are caused by inflammatory processes in the wall of the aorta resulting in degradation of structural proteins. This inflammatory process is mediated, in part, by cytokines, and interleukin-10 (IL-10) is a predominantly anti-inflammatory cytokine. A single nucleotide polymorphism in the promoter region of the IL-10 gene that affects transcription has been associated with AAA in a small study. The aim of this study was to determine whether this polymorphism is associated with AAA and also examine its effect on the growth of small AAA. A case control study was performed. A total of 389 patients with AAA and 404 healthy controls were recruited. IL-10-1082 polymorphisms were determined by polymerase chain reaction-based methods. In the case of patients with small AAA (<5.5 cm), serial size measurements were recorded to determine mean growth rate. There was a statistically significant difference both in allele and genotype frequencies between the case and control groups with the IL-10-1082 'A' allele being more common in the AAA group (P = .006). In the AAA group, genotype frequencies were as follows: GG 84, GA 201, and AA 104. In the control group, the genotype frequencies were GG 118, GA 205, and AA 81. The odds ratio for the 'A' allele as a risk factor for AAA was 1.50 (95% confidence interval 1.09 to 2.07). Regression modeling revealed that the IL-10-1082 genotype was, however, not independently associated with AAA if age, tobacco use, hypertension, and history of coronary or peripheral artery disease was taken into account. There was a trend towards lower plasma IL-10 level in IL-10 AA carriers, but the IL-10 'A' allele did not have any discernible effect on the growth of small AAA. This study demonstrates that the IL-10-1082 'A' allele is associated with AAA, although this association is likely to be secondary to an association between IL-10-1082 genotype and other markers of cardiovascular disease rather than AAA per se.

Erasure and reestablishment of random allelic expression imbalance after epigenetic reprogramming

PubMed Central

Jeffries, Aaron Richard; Uwanogho, Dafe Aghogho; Cocks, Graham; Perfect, Leo William; Dempster, Emma; Mill, Jonathan; Price, Jack

2016-01-01

Clonal level random allelic expression imbalance and random monoallelic expression provides cellular heterogeneity within tissues by modulating allelic dosage. Although such expression patterns have been observed in multiple cell types, little is known about when in development these stochastic allelic choices are made. We examine allelic expression patterns in human neural progenitor cells before and after epigenetic reprogramming to induced pluripotency, observing that loci previously characterized by random allelic expression imbalance (0.63% of expressed genes) are generally reset to a biallelic state in induced pluripotent stem cells (iPSCs). We subsequently neuralized the iPSCs and profiled isolated clonal neural stem cells, observing that significant random allelic expression imbalance is reestablished at 0.65% of expressed genes, including novel loci not found to show allelic expression imbalance in the original parental neural progenitor cells. Allelic expression imbalance was associated with altered DNA methylation across promoter regulatory regions, with clones characterized by skewed allelic expression being hypermethylated compared to their biallelic sister clones. Our results suggest that random allelic expression imbalance is established during lineage commitment and is associated with increased DNA methylation at the gene promoter. PMID:27539784

Skewed X-chromosome inactivation plays a crucial role in the onset of symptoms in carriers of Becker muscular dystrophy.

PubMed

Viggiano, Emanuela; Picillo, Esther; Ergoli, Manuela; Cirillo, Alessandra; Del Gaudio, Stefania; Politano, Luisa

2017-04-01

Becker muscular dystrophy (BMD) is an X-linked recessive disorder affecting approximately 1: 18.000 male births. Female carriers are usually asymptomatic, although 2.5-18% may present muscle or heart symptoms. In the present study, the role of the X chromosome inactivation (XCI) on the onset of symptoms in BMD carriers was analysed and compared with the pattern observed in Duchenne muscular dystrophy (DMD) carriers. XCI was determined on the lymphocytes of 36 BMD carriers (both symptomatic and not symptomatic) from 11 families requiring genetic advice at the Cardiomyology and Medical Genetics of the Second University of Naples, using the AR methylation-based assay. Carriers were subdivided into two groups, according to age above or below 50 years. Seven females from the same families known as noncarriers were used as controls. A Student's t-test for nonpaired data was performed to evaluate the differences observed in the XCI values between asymptomatic and symptomatic carriers, and carriers aged above or below 50 years. A Pearson correlation test was used to evaluate the inheritance of the XCI pattern in 19 mother-daughter pairs. The results showed that symptomatic BMD carriers had a skewed XCI with a preferential inactivation of the X chromosome carrying the normal allele, whereas the asymptomatic carriers and controls showed a random XCI. No concordance concerning the XCI pattern was observed between mothers and related daughters. The data obtained in the present study suggest that the onset of symptoms in BMD carriers is related to a skewed XCI, as observed in DMD carriers. Furthermore, they showed no concordance in the XCI pattern inheritance. Copyright © 2017 John Wiley & Sons, Ltd.

Identification of the third/extra allele for forensic application in cases with TPOX tri-allelic pattern.

PubMed

Picanço, Juliane Bentes; Raimann, Paulo Eduardo; Motta, Carlos Henrique Ares Silveira da; Rodenbusch, Rodrigo; Gusmão, Leonor; Alho, Clarice Sampaio

2015-05-01

Genotyping of polymorphic short tandem repeats (STRs) loci is widely used in forensic DNA analysis. STR loci eventually present tri-allelic pattern as a genotyping irregularity and, in that situation, the doubt about the tri-allele locus frequency calculation can reduce the analysis strength. In the TPOX human STR locus, tri-allelic genotypes have been reported with a widely varied frequency among human populations. We investigate whether there is a single extra allele (the third allele) in the TPOX tri-allelic pattern, what it is, and where it is, aiming to understand its genomic anatomy and to propose the knowledge of this TPOX extra allele from genetic profile, thus preserving the two standard TPOX alleles in forensic analyses. We looked for TPOX tri-allelic subjects in 75,113 Brazilian families. Considering only the parental generation (mother+father) we had 150,226 unrelated subjects evaluated. From this total, we found 88 unrelated subjects with tri-allelic pattern in the TPOX locus (0.06%; 88/150,226). Seventy three of these 88 subjects (73/88; 83%) had the Clayton's original Type 2 tri-allelic pattern (three peaks of even intensity). The remaining 17% (15/88) show a new Type 2 derived category with heterozygote peak imbalance (one double dose peak plus one regular sized peak). In this paper we present detailed data from 66 trios (mother+father+child) with true biological relationships. In 39 of these families (39/66; 59%) the extra TPOX allele was transmitted either from the mother or from the father to the child. Evidences indicated the allele 10 as the extra TPOX allele, and it is on the X chromosome. The present data, which support the previous Lane hypothesis, improve the knowledge about tri-allelic pattern of TPOX CODIS' locus allowing the use of TPOX profile in forensic analyses even when with tri-allelic pattern. This evaluation is now available for different forensic applications. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Hydrocortisone fails to abolish NF-κB1 protein nuclear translocation in deletion allele carriers of the NFKB1 promoter polymorphism (-94ins/delATTG) and is associated with increased 30-day mortality in septic shock.

PubMed

Schäfer, Simon T; Gessner, Sophia; Scherag, André; Rump, Katharina; Frey, Ulrich H; Siffert, Winfried; Westendorf, Astrid M; Steinmann, Jörg; Peters, Jürgen; Adamzik, Michael

2014-01-01

Previous investigations and meta-analyses on the effect of glucocorticoids on mortality in septic shock revealed mixed results. This heterogeneity might be evoked by genetic variations. Such candidate is a promoter polymorphism (-94ins/delATTG) of the gene encoding the ubiquitous transcription-factor nuclear-factor-κB (NF-κB) which binds to recognition elements in the promoter of several genes encoding for the innate immune-system. In turn, hydrocortisone inhibits NF-κB nuclear translocation and thus transcription of key immune-response regulators. Accordingly, we tested the hypotheses that hydrocortisone has a NFKB1 genotype dependent effect on 1) NF-κB1 nuclear translocation evoked by lipopolysaccharide (LPS) in monocytes in vitro, and 2) mortality in septic shock. Monocytes of volunteers with the homozygous insertion (II; n = 5) or deletion (DD; n = 6) NFKB1 genotype were incubated with 10 µgml-1 LPS ± hydrocortisone (10-5M), and NF-κB1 nuclear translocation was assessed (immunofluorescence). Furthermore, we analyzed 30-day-mortality in 160 patients with septic shock stratified for both genotype and hydrocortisone therapy. Hydrocortisone inhibited LPS induced nuclear translocation of NF-κB1 in II (25%±11;p = 0.0001) but not in DD genotypes (51%±15;p = n.s.). Onehundredandfour of 160 patients with septic shock received hydrocortisone, at the discretion of the intensivist. NFKB1 deletion allele carriers (ID/DD) receiving hydrocortisone had a much greater 30-day-mortality (57.6%) than II genotypes (24.4%; HR:3.18, 95%-CI:1.61-6.28;p = 0.001). In contrast, 30-day mortality was 22.2% in ID/DD and 25.0% in II genotypes without hydrocortisone therapy. Results were similar when using propensity score matching to account for possible bias in the intensivists' decision to administer hydrocortisone. Hydrocortisone fails to inhibit LPS induced nuclear NF-κB1 translocation in deletion allele carriers of the NFKB1 promoter polymorphism (-94ins

Assigning breed origin to alleles in crossbred animals.

PubMed

Vandenplas, Jérémie; Calus, Mario P L; Sevillano, Claudia A; Windig, Jack J; Bastiaansen, John W M

2016-08-22

For some species, animal production systems are based on the use of crossbreeding to take advantage of the increased performance of crossbred compared to purebred animals. Effects of single nucleotide polymorphisms (SNPs) may differ between purebred and crossbred animals for several reasons: (1) differences in linkage disequilibrium between SNP alleles and a quantitative trait locus; (2) differences in genetic backgrounds (e.g., dominance and epistatic interactions); and (3) differences in environmental conditions, which result in genotype-by-environment interactions. Thus, SNP effects may be breed-specific, which has led to the development of genomic evaluations for crossbred performance that take such effects into account. However, to estimate breed-specific effects, it is necessary to know breed origin of alleles in crossbred animals. Therefore, our aim was to develop an approach for assigning breed origin to alleles of crossbred animals (termed BOA) without information on pedigree and to study its accuracy by considering various factors, including distance between breeds. The BOA approach consists of: (1) phasing genotypes of purebred and crossbred animals; (2) assigning breed origin to phased haplotypes; and (3) assigning breed origin to alleles of crossbred animals based on a library of assigned haplotypes, the breed composition of crossbred animals, and their SNP genotypes. The accuracy of allele assignments was determined for simulated datasets that include crosses between closely-related, distantly-related and unrelated breeds. Across these scenarios, the percentage of alleles of a crossbred animal that were correctly assigned to their breed origin was greater than 90 %, and increased with increasing distance between breeds, while the percentage of incorrectly assigned alleles was always less than 2 %. For the remaining alleles, i.e. 0 to 10 % of all alleles of a crossbred animal, breed origin could not be assigned. The BOA approach accurately assigns

Robust Identification of Local Adaptation from Allele Frequencies

PubMed Central

Günther, Torsten; Coop, Graham

2013-01-01

Comparing allele frequencies among populations that differ in environment has long been a tool for detecting loci involved in local adaptation. However, such analyses are complicated by an imperfect knowledge of population allele frequencies and neutral correlations of allele frequencies among populations due to shared population history and gene flow. Here we develop a set of methods to robustly test for unusual allele frequency patterns and correlations between environmental variables and allele frequencies while accounting for these complications based on a Bayesian model previously implemented in the software Bayenv. Using this model, we calculate a set of “standardized allele frequencies” that allows investigators to apply tests of their choice to multiple populations while accounting for sampling and covariance due to population history. We illustrate this first by showing that these standardized frequencies can be used to detect nonparametric correlations with environmental variables; these correlations are also less prone to spurious results due to outlier populations. We then demonstrate how these standardized allele frequencies can be used to construct a test to detect SNPs that deviate strongly from neutral population structure. This test is conceptually related to FST and is shown to be more powerful, as we account for population history. We also extend the model to next-generation sequencing of population pools—a cost-efficient way to estimate population allele frequencies, but one that introduces an additional level of sampling noise. The utility of these methods is demonstrated in simulations and by reanalyzing human SNP data from the Human Genome Diversity Panel populations and pooled next-generation sequencing data from Atlantic herring. An implementation of our method is available from http://gcbias.org. PMID:23821598

Polymorphisms of the OXTR gene explain why sales professionals love to help customers

PubMed Central

Verbeke, Willem; Bagozzi, Richard P.; van den Berg, Wouter E.; Lemmens, Aurelie

2013-01-01

Polymorphisms of the OXTR gene affect people's social interaction styles in various social encounters: carriers of the OXTR GG, compared to the OXTR AA/AG in general, are more motivated to interact socially and detect social salience. We focus on sales professionals operating in knowledge intensive organizations. Study 1, with a sample of 141 sales people, shows that carriers of the OXTR GG allele, compared to the OXTR AA/AG allele, are more motivated to help customers than to manipulatively impose goods/services on them. Study 2, using genomic functional magnetic resonance imaging (fMRI) on a sample of 21 sales professionals processing facial pictures with different emotional valences, investigates key nuclei of social brain regions (SBRs). Compared to OXTR AA/AG carriers, OXTR GG carriers experience greater effective connectivity between SBRs of interest measured by Granger causality tests using univariate Haugh tests. In addition, the multivariate El-Himdi and Roy tests demonstrate that the amygdala, prefrontal cortex, and pars opercularis (inferior frontal gyrus) play key roles when processing emotional expressions. The bilateral amygdala and medial prefrontal cortex (mPFC) show significantly greater clout—influence on other brain regions—for GG allele carriers than non-carriers; likewise, the bilateral pars opercularis, left amygdala, and left mPFC are more receptive to activity in other brain regions among GG allele carriers than AG/AA allele carriers are. Thus, carriers of the OXTR GG allele are more sensitive to changes in emotional cues, enhancing social salience. To our knowledge, this is the first study on how insights from imaging genetics help understanding of the social motivation of people operating in a professional setting. PMID:24348351

Polymorphisms of the OXTR gene explain why sales professionals love to help customers.

PubMed

Verbeke, Willem; Bagozzi, Richard P; van den Berg, Wouter E; Lemmens, Aurelie

2013-01-01

Polymorphisms of the OXTR gene affect people's social interaction styles in various social encounters: carriers of the OXTR GG, compared to the OXTR AA/AG in general, are more motivated to interact socially and detect social salience. We focus on sales professionals operating in knowledge intensive organizations. Study 1, with a sample of 141 sales people, shows that carriers of the OXTR GG allele, compared to the OXTR AA/AG allele, are more motivated to help customers than to manipulatively impose goods/services on them. Study 2, using genomic functional magnetic resonance imaging (fMRI) on a sample of 21 sales professionals processing facial pictures with different emotional valences, investigates key nuclei of social brain regions (SBRs). Compared to OXTR AA/AG carriers, OXTR GG carriers experience greater effective connectivity between SBRs of interest measured by Granger causality tests using univariate Haugh tests. In addition, the multivariate El-Himdi and Roy tests demonstrate that the amygdala, prefrontal cortex, and pars opercularis (inferior frontal gyrus) play key roles when processing emotional expressions. The bilateral amygdala and medial prefrontal cortex (mPFC) show significantly greater clout-influence on other brain regions-for GG allele carriers than non-carriers; likewise, the bilateral pars opercularis, left amygdala, and left mPFC are more receptive to activity in other brain regions among GG allele carriers than AG/AA allele carriers are. Thus, carriers of the OXTR GG allele are more sensitive to changes in emotional cues, enhancing social salience. To our knowledge, this is the first study on how insights from imaging genetics help understanding of the social motivation of people operating in a professional setting.

Cervical cancer in Indian women reveals contrasting association among common sub-family of HLA class I alleles.

PubMed

Gokhale, Priyanka; Mania-Pramanik, Jayanti; Sonawani, Archana; Idicula-Thomas, Susan; Kerkar, Shilpa; Tongaonkar, Hemant; Chaudhari, Hemangi; Warke, Himangi; Salvi, Vinita

2014-12-01

We studied the relationship between human leukocyte antigen (HLA) class I alleles and cervical cancer among Indian women. Seventy-five cervical cancer cases were compared with 175 noncancer controls. Cervical biopsy tissue specimen from cancer cases and cervical swab specimen from controls were collected for HPV detection and typing. Blood was taken for HLA typing by PCR-SSOP method. The impact of HLA class I alleles on cervical cancer risk was evaluated using StatCalc program (Epi Info version 6.0.4. CDC Atlanta, GA, USA), and confirmed with Bonferroni correction. Results revealed HLA-B*37, HLA-B*58 were associated significantly with increased risk while HLA-B*40 with decreased risk for cervical cancer. At high-resolution analysis after Bonferroni correction, HLA-B*37:01 allele was associated with increased risk, whereas HLA-B*40:06 was with decreased risk for cervical cancer. HLA-B*37:01 and HLA-B*40:06 belong to the same superfamily of HLA-B44. In silico analysis revealed different binding affinities of HLA-B*37:01 and HLA-B*40:06 for the epitopes predicted for E6 and L1 proteins of HPV16. The higher binding affinity of epitopes to B*40:06, as revealed by docking studies, supports the hypothesis that this allele is able to present the antigenic peptides more efficiently than B*37:01 and thereby can protect the carriers from the risk of cervical cancer. Thus, there is a clear indication that HLA plays an important role in the development of cervical cancer in HPV-infected women. Identification of these factors in high-risk HPV-infected women may help in reducing the cervical cancer burden in India.

Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE.

PubMed

Mavaddat, Nasim; Peock, Susan; Frost, Debra; Ellis, Steve; Platte, Radka; Fineberg, Elena; Evans, D Gareth; Izatt, Louise; Eeles, Rosalind A; Adlard, Julian; Davidson, Rosemarie; Eccles, Diana; Cole, Trevor; Cook, Jackie; Brewer, Carole; Tischkowitz, Marc; Douglas, Fiona; Hodgson, Shirley; Walker, Lisa; Porteous, Mary E; Morrison, Patrick J; Side, Lucy E; Kennedy, M John; Houghton, Catherine; Donaldson, Alan; Rogers, Mark T; Dorkins, Huw; Miedzybrodzka, Zosia; Gregory, Helen; Eason, Jacqueline; Barwell, Julian; McCann, Emma; Murray, Alex; Antoniou, Antonis C; Easton, Douglas F

2013-06-05

Reliable estimates of cancer risk are critical for guiding management of BRCA1 and BRCA2 mutation carriers. The aims of this study were to derive penetrance estimates for breast cancer, ovarian cancer, and contralateral breast cancer in a prospective series of mutation carriers and to assess how these risks are modified by common breast cancer susceptibility alleles. Prospective cancer risks were estimated using a cohort of 978 BRCA1 and 909 BRCA2 carriers from the United Kingdom. Nine hundred eighty-eight women had no breast or ovarian cancer diagnosis at baseline, 1509 women were unaffected by ovarian cancer, and 651 had been diagnosed with unilateral breast cancer. Cumulative risks were obtained using Kaplan-Meier estimates. Associations between cancer risk and covariables of interest were evaluated using Cox regression. All statistical tests were two-sided. The average cumulative risks by age 70 years for BRCA1 carriers were estimated to be 60% (95% confidence interval [CI] = 44% to 75%) for breast cancer, 59% (95% CI = 43% to 76%) for ovarian cancer, and 83% (95% CI = 69% to 94%) for contralateral breast cancer. For BRCA2 carriers, the corresponding risks were 55% (95% CI = 41% to 70%) for breast cancer, 16.5% (95% CI = 7.5% to 34%) for ovarian cancer, and 62% (95% CI = 44% to 79.5%) for contralateral breast cancer. BRCA2 carriers in the highest tertile of risk, defined by the joint genotype distribution of seven single nucleotide polymorphisms associated with breast cancer risk, were at statistically significantly higher risk of developing breast cancer than those in the lowest tertile (hazard ratio = 4.1, 95% CI = 1.2 to 14.5; P = .02). Prospective risk estimates confirm that BRCA1 and BRCA2 carriers are at high risk of developing breast, ovarian, and contralateral breast cancer. Our results confirm findings from retrospective studies that common breast cancer susceptibility alleles in combination are predictive of breast cancer risk for BRCA2 carriers.

Erasure and reestablishment of random allelic expression imbalance after epigenetic reprogramming.

PubMed

Jeffries, Aaron Richard; Uwanogho, Dafe Aghogho; Cocks, Graham; Perfect, Leo William; Dempster, Emma; Mill, Jonathan; Price, Jack

2016-10-01

Clonal level random allelic expression imbalance and random monoallelic expression provides cellular heterogeneity within tissues by modulating allelic dosage. Although such expression patterns have been observed in multiple cell types, little is known about when in development these stochastic allelic choices are made. We examine allelic expression patterns in human neural progenitor cells before and after epigenetic reprogramming to induced pluripotency, observing that loci previously characterized by random allelic expression imbalance (0.63% of expressed genes) are generally reset to a biallelic state in induced pluripotent stem cells (iPSCs). We subsequently neuralized the iPSCs and profiled isolated clonal neural stem cells, observing that significant random allelic expression imbalance is reestablished at 0.65% of expressed genes, including novel loci not found to show allelic expression imbalance in the original parental neural progenitor cells. Allelic expression imbalance was associated with altered DNA methylation across promoter regulatory regions, with clones characterized by skewed allelic expression being hypermethylated compared to their biallelic sister clones. Our results suggest that random allelic expression imbalance is established during lineage commitment and is associated with increased DNA methylation at the gene promoter. © 2016 Jeffries et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

Association between the APOE ε4 Allele and Late-Onset Alzheimer's Disease in an Ecuadorian Mestizo Population

PubMed Central

Calero, Cristian; Vinueza, Rodrigo; Correa, Patricio; Carrera-Gonzalez, Andrea; Villegas, Franklin; Moreta, Germania; Paredes, Rosario

2017-01-01

Alzheimer's disease (AD) is the most common neurodegenerative disease. It has two main pathological hallmarks: amyloid plaques and neurofibrillary tangles. The APOE ε4 allele has been recognized as the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD) in several populations worldwide, yet the risk varies by region and ethnicity. The aims of this study were to describe APOE allele and genotype frequencies and examine the relationship between the APOE ε4 allele and LOAD risk in an Ecuadorian Mestizo population. We carried out a case-control study comprising 56 individuals clinically diagnosed with probable AD (≥65 years of age) and 58 unrelated healthy control subjects (≥65 years of age). Genotyping was performed using the real-time PCR method. Our data showed that allelic and genotypic frequencies follow the trends observed in most worldwide populations. We also found a high-risk association between APOE ε4 allele carriers and LOAD (OR = 7.286; 95% CI = 2.824–18.799; p < 0.001). Therefore, we concluded that APOE ε4 must be considered an important genetic risk factor for LOAD in the Ecuadorian Mestizo population. Additionally, we suggest that in mixed populations the effects of admixture and ethnic identity should be differentiated when evaluating genetic contributions to Alzheimer's disease risk. PMID:29348964

Is RNASEL:p.Glu265* a modifier of early-onset breast cancer risk for carriers of high-risk mutations?

PubMed

Nguyen-Dumont, Tú; Teo, Zhi L; Hammet, Fleur; Roberge, Alexis; Mahmoodi, Maryam; Tsimiklis, Helen; Park, Daniel J; Pope, Bernard J; Lonie, Andrew; Kapuscinski, Miroslav K; Mahmood, Khalid; Goldgar, David E; Giles, Graham G; Winship, Ingrid; Hopper, John L; Southey, Melissa C

2018-02-08

Breast cancer risk for BRCA1 and BRCA2 pathogenic mutation carriers is modified by risk factors that cluster in families, including genetic modifiers of risk. We considered genetic modifiers of risk for carriers of high-risk mutations in other breast cancer susceptibility genes. In a family known to carry the high-risk mutation PALB2:c.3113G>A (p.Trp1038*), whole-exome sequencing was performed on germline DNA from four affected women, three of whom were mutation carriers. RNASEL:p.Glu265* was identified in one of the PALB2 carriers who had two primary invasive breast cancer diagnoses before 50 years. Gene-panel testing of BRCA1, BRCA2, PALB2 and RNASEL in the Australian Breast Cancer Family Registry identified five carriers of RNASEL:p.Glu265* in 591 early onset breast cancer cases. Three of the five women (60%) carrying RNASEL:p.Glu265* also carried a pathogenic mutation in a breast cancer susceptibility gene compared with 30 carriers of pathogenic mutations in the 586 non-carriers of RNASEL:p.Glu265* (5%) (p < 0.002). Taqman genotyping demonstrated that the allele frequency of RNASEL:p.Glu265* was similar in affected and unaffected Australian women, consistent with other populations. Our study suggests that RNASEL:p.Glu265* may be a genetic modifier of risk for early-onset breast cancer predisposition in carriers of high-risk mutations. Much larger case-case and case-control studies are warranted to test the association observed in this report.

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

Distribution of apolipoprotein E alleles in a Scottish healthy newborn population.

PubMed

Becher, J-C; Bell, J E; McIntosh, N; Keeling, J W

2005-01-01

The different alleles of the human apolipoprotein E polymorphism, ApoE epsilon2, epsilon3, epsilon4, have important implications for systemic lipid metabolism, immunological function and for the brain in maintenance and in response to injury. Few studies have focussed on their role in early life. The ApoE alleles and genotypes were ascertained in the cord blood of 371 full-term and normal Scottish newborn infants using PCR methodology. The results were compared to previously published data for Scottish adults in late middle age. There was a marginally significant over-representation of epsilon4 and under-representation of epsilon3 alleles in healthy infants as compared with adults. Inspection of the individual genotypes confirms the over-representation of ApoE 4/4 and 2/4 with a reduction in ApoE 2/3 and 3/3 when compared with Scottish adults. Although these results may have occurred by chance, the ApoE epsilon4 allele may confer an increased risk of premature death. Copyright (c) 2005 S. Karger AG, Basel.

Forensic Loci Allele Database (FLAD): Automatically generated, permanent identifiers for sequenced forensic alleles.

PubMed

Van Neste, Christophe; Van Criekinge, Wim; Deforce, Dieter; Van Nieuwerburgh, Filip

2016-01-01

It is difficult to predict if and when massively parallel sequencing of forensic STR loci will replace capillary electrophoresis as the new standard technology in forensic genetics. The main benefits of sequencing are increased multiplexing scales and SNP detection. There is not yet a consensus on how sequenced profiles should be reported. We present the Forensic Loci Allele Database (FLAD) service, made freely available on http://forensic.ugent.be/FLAD/. It offers permanent identifiers for sequenced forensic alleles (STR or SNP) and their microvariants for use in forensic allele nomenclature. Analogous to Genbank, its aim is to provide permanent identifiers for forensically relevant allele sequences. Researchers that are developing forensic sequencing kits or are performing population studies, can register on http://forensic.ugent.be/FLAD/ and add loci and allele sequences with a short and simple application interface (API). Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Effects of the BDNF Val66Met polymorphism and met allele load on declarative memory related neural networks.

PubMed

Dodds, Chris M; Henson, Richard N; Suckling, John; Miskowiak, Kamilla W; Ooi, Cinly; Tait, Roger; Soltesz, Fruzsina; Lawrence, Phil; Bentley, Graham; Maltby, Kay; Skeggs, Andrew; Miller, Sam R; McHugh, Simon; Bullmore, Edward T; Nathan, Pradeep J

2013-01-01

It has been suggested that the BDNF Val66Met polymorphism modulates episodic memory performance via effects on hippocampal neural circuitry. However, fMRI studies have yielded inconsistent results in this respect. Moreover, very few studies have examined the effect of met allele load on activation of memory circuitry. In the present study, we carried out a comprehensive analysis of the effects of the BDNF polymorphism on brain responses during episodic memory encoding and retrieval, including an investigation of the effect of met allele load on memory related activation in the medial temporal lobe. In contrast to previous studies, we found no evidence for an effect of BDNF genotype or met load during episodic memory encoding. Met allele carriers showed increased activation during successful retrieval in right hippocampus but this was contrast-specific and unaffected by met allele load. These results suggest that the BDNF Val66Met polymorphism does not, as previously claimed, exert an observable effect on neural systems underlying encoding of new information into episodic memory but may exert a subtle effect on the efficiency with which such information can be retrieved.

Allelic variation in Salmonella: an underappreciated driver of adaptation and virulence

PubMed Central

Yue, Min; Schifferli, Dieter M.

2014-01-01

Salmonella enterica causes substantial morbidity and mortality in humans and animals. Infection and intestinal colonization by S. enterica require virulence factors that mediate bacterial binding and invasion of enterocytes and innate immune cells. Some S. enterica colonization factors and their alleles are host restricted, suggesting a potential role in regulation of host specificity. Recent data also suggest that colonization factors promote horizontal gene transfer of antimicrobial resistance genes by increasing the local density of Salmonella in colonized intestines. Although a profusion of genes are involved in Salmonella pathogenesis, the relative importance of their allelic variation has only been studied intensely in the type 1 fimbrial adhesin FimH. Although other Salmonella virulence factors demonstrate allelic variation, their association with specific metadata (e.g., host species, disease or carrier state, time and geographic place of isolation, antibiotic resistance profile, etc.) remains to be interrogated. To date, genome-wide association studies (GWAS) in bacteriology have been limited by the paucity of relevant metadata. In addition, due to the many variables amid metadata categories, a very large number of strains must be assessed to attain statistically significant results. However, targeted approaches in which genes of interest (e.g., virulence factors) are specifically sequenced alleviates the time-consuming and costly statistical GWAS analysis and increases statistical power, as larger numbers of strains can be screened for non-synonymous single nucleotide polymorphisms (SNPs) that are associated with available metadata. Congruence of specific allelic variants with specific metadata from strains that have a relevant clinical and epidemiological history will help to prioritize functional wet-lab and animal studies aimed at determining cause-effect relationships. Such an approach should be applicable to other pathogens that are being collected

Association between the TNFRII 196R allele and diagnosis of rheumatoid arthritis

PubMed Central

Goëb, Vincent; Dieudé, Philippe; Vittecoq, Olivier; Mejjad, Othmane; Ménard, Jean-François; Thomas, Marlène; Gilbert, Danièle; Boumier, Patrick; Pouplin, Sophie; Daragon, Alain; Fardellone, Patrice; Tron, François; Cornélis, François; Le Loët, Xavier

2005-01-01

Tumour necrosis factor (TNF)-α plays a key role in the pathogenesis of rheumatoid arthritis (RA). It binds to two receptors, namely TNF receptor (TNFR)I and TNFRII. Several studies have suggested an association between TNFRII 196R/R genotype and RA. The objective of the present study was to evaluate the predictive value of the TNFRII 196R allele for RA diagnosis and prognosis in a cohort of patients with very early arthritis. We followed up a total of 278 patients recruited from the community, who had swelling of at least two joints that had persisted for longer than 4 weeks but had been evolving for less than 6 months, and who had not received disease-modifying antirheumatic drugs or steroid therapy. At 2 years, patients were classified according to the American College of Rheumatology criteria. All patients were genotyped with respect to TNFRII 196M/R polymorphism. Radiographs of hands and feet (read according to the modified Sharp method) and the Health Assessment Questionnaire were used to quantify structural and functional severity. The cohort of 278 patients was found to include 156 and 122 RA and non-RA patients, respectively. The TNFRII 196R allele was found to be associated with RA (P = 0.002). However, progression of radiographic severity and Health Assessment Questionnaire scores over 1 year did not differ between carriers of the 196R allele and noncarriers. Our findings suggest that the TNFRII 196R allele may be associated with RA diagnosis but that it does not predict early radiographic progression or functional severity in patients with very early, unclassified arthritis. PMID:16207322

Characterization and Early Detection of Balance Deficits in Fragile X Premutation Carriers With and Without Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS).

PubMed

O'Keefe, Joan A; Robertson-Dick, Erin; Dunn, Emily J; Li, Yan; Deng, Youping; Fiutko, Amber N; Berry-Kravis, Elizabeth; Hall, Deborah A

2015-12-01

Fragile X-associated tremor/ataxia syndrome (FXTAS) results from a "premutation" size 55-200 CGG repeat expansion in the fragile X mental retardation 1 (FMR1) gene. Core motor features include cerebellar gait ataxia and kinetic tremor, resulting in progressive mobility disability. There are no published studies characterizing balance deficits in FMR1 premutation carriers with and without FXTAS using a battery of quantitative measures to test the sensory integration underlying postural control, automatic postural reflexes, and dynamic postural stability limits. Computerized dynamic posturography (CDP) and two performance-based balance measures were administered in 44 premutation carriers, 21 with FXTAS and 23 without FXTAS, and 42 healthy controls to compare balance and functional mobility between these groups. Relationships between FMR1 molecular variables, age, and sex and CDP scores were explored. FXTAS subjects demonstrated significantly lower scores on the sensory organization test (with greatest reductions in the vestibular control of balance), longer response latencies to balance perturbations, and reduced stability limits compared to controls. Premutation carriers without FXTAS also demonstrated significantly delayed response latencies and disrupted sensory weighting for balance control. Advancing age, male sex, increased CGG repeat size, and reduced X activation of the normal allele in premutation carrier women predicted balance dysfunction. These postural control deficits in carriers with and without FXTAS implicate dysfunctional cerebellar neural networks and may provide valuable outcome markers for tailored rehabilitative interventions. Our findings suggest that CDP may provide sensitive measures for early detection of postural control impairments in at-risk carriers and better characterize balance dysfunction and progression in FXTAS.

Ewes carrying the Booroola and Vacaria prolificacy alleles respond differently to ovulation induction with equine chorionic gonadotrophin.

PubMed

Moraes, J C F; Souza, C J H

2017-09-21

The magnitude of ovulation rate (OR) after hormonal induction in sheep should be considered when prolific genotypes are used. We investigated for the first time the effect of the Vacaria allele and its combined effect with the Booroola prolificacy mutation on OR after hormonal treatment during breeding and anoestrous season. A hundred forty-nine Ile de France crossbred ewes, raised in natural pastures in South Brazil, were used to evaluate the OR after treatment with progestagen (MAP) followed or not by equine chorionic gonadotrophin (eCG) treatment (MAP + eCG). During the breeding season, 96% MAP-treated ewes ovulated in comparison to 97% of MAP + eCG-treated females. The double heterozygous carriers (BNVN) presented the higher OR, followed by the single Vacaria (NNVN) and Booroola (BNNN) heterozygous females and least the wild-type (NNNN) ewes. During anoestrus, 96% eCG-treated ewes ovulated, in contrast to 6% treated with MAP alone. The OR of the gonadotrophin-treated females was higher in BNVN and BNNN than NNVN and NNNN ewes. An additive effect in the OR of the two mutations was observed since OR in double heterozygous ewes was similar to the sum of the effects of the alleles of the single heterozygous carrier ewes.

Analysis of Thiopurine S-Methyltransferase Deficient Alleles in Acute Lymphoblastic Leukemia Patients in Mexican Patients.

PubMed

Jiménez-Morales, Silvia; Ramírez-Florencio, Mireya; Mejía-Aranguré, Juan Manuel; Núñez-Enríquez, Juan Carlos; Bekker-Mendez, Carolina; Torres-Escalante, José Luis; Flores-Lujano, Janet; Jiménez-Hernández, Elva; Del Carmen Rodríguez-Zepeda, María; Leal, Yelda A; González-Montalvo, Pablo Miguel; Pantoja-Guillen, Francisco; Peñaloza-Gonzalez, José Gabriel; Gutiérrez-Juárez, Erick Israel; Núñez-Villegas, Nora Nancy; Pérez-Saldivar, Maria Luisa; Guerra-Castillo, Francisco Xavier; Flores-Villegas, Luz Victoria; Ramos-Cervantes, María Teresa; Fragoso, José Manuel; García-Escalante, María Guadalupe; Del Carmen Pinto-Escalante, Doris; Ramírez-Bello, Julián; Hidalgo-Miranda, Alfredo

2016-11-01

It has been demonstrated that heterozygote and homozygote thiopurine S-methyltransferase (TPMT) mutant allele carriers are at high risk to develop severe and potentially fatal hematopoietic toxicity after treatment with standard doses of 6-mercaptopurine (6-MP) and methotrexate (MX). Those drugs are the backbone of acute lymphoblastic leukemia (ALL) and several autoimmune disease treatments. We undertook this study to determine the frequency of the TPMT deficient alleles in children with ALL and non-ALL subjects from Mexico City and Yucatan, Mexico. We included 849 unrelated subjects, of which 368 ALL children and 342 non-ALL subjects were from Mexico City, and 60 ALL cases and 79 non-ALL individuals were from Yucatan. Genotyping of the rs1800462, rs1800460 and rs1142345 SNPs was performed by 5'exonuclease technique using TaqMan probes (Life Technologies Foster City, CA). The mutant TPMT alleles were present in 4.8% (81/1698 chromosomes) and only 0.2% were homozygote TPMT*3A/TPMT*3A. We did not find statistically significant differences in the distribution of the mutant alleles between patients from Mexico City and Yucatan in either ALL cases or non-ALL. Nonetheless, the TPMT*3C frequency in ALL patients was higher than non-ALL subjects (p = 0.03). To note, the null homozygous TPMT*3A/TPMT*3A genotype was found in 2.5% of the non-ALL subjects. TPMT mutant alleles did not exhibit differential distribution between both evaluated populations; however, TPMT*3C is overrepresented in ALL cases in comparison with non-ALL group. Assessing the TPMT mutant alleles could benefit the ALL children and those undergoing 6-MP and MX treatment. Copyright © 2016 IMSS. Published by Elsevier Inc. All rights reserved.

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

Wide allelic heterogeneity with predominance of large IDS gene complex rearrangements in a sample of Mexican patients with Hunter syndrome.

PubMed

Alcántara-Ortigoza, M A; García-de Teresa, B; González-Del Angel, A; Berumen, J; Guardado-Estrada, M; Fernández-Hernández, L; Navarrete-Martínez, J I; Maza-Morales, M; Rius-Domínguez, R

2016-05-01

Hunter syndrome or mucopolysaccharidosis type II (MPSII) is caused by pathogenic variants in the IDS gene. This is the first study that examines the mutational spectrum in 25 unrelated Mexican MPSII families. The responsible genotype was identified in 96% of the families (24/25) with 10 novel pathogenic variants: c.133G>C, c.1003C>T, c.1025A>C, c.463_464delinsCCGTATAGCTGG, c.754_767del, c.1132_1133del, c.1463del, c.508-1G>C, c.1006+1G>T and c.(-217_103del). Extensive IDS gene deletions were identified in four patients; using DNA microarray analysis two patients showed the loss of the entire AFF2 gene, and epilepsy developed in only one of them. Wide allelic heterogeneity was noted, with large gene alterations (e.g. IDS/IDSP1 gene inversions, partial to extensive IDS deletions, and one chimeric IDS-IDSP1 allele) that occurred at higher frequencies than previously reported (36% vs 18.9-29%). The frequency of carrier mothers (80%) is consistent with previous descriptions (>70%). Carrier assignment allowed molecular prenatal diagnoses. Notably, somatic and germline mosaicism was identified in one family, and two patients presented thrombocytopenic purpura and pancytopenia after idursulfase enzyme replacement treatment. Our findings suggest a wide allelic heterogeneity in Mexican MPSII patients; DNA microarray analysis contributes to further delineation of the resulting phenotype for IDS and neighboring loci deletions. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Allelic inhibition of displacement activity: a simplified one tube allele-specific PCR for evaluation of ITPA polymorphisms.

PubMed

Galmozzi, E; Facchetti, F; Degasperi, E; Aghemo, A; Lampertico, P

2013-02-01

Recently, genome-wide association studies (GWAS) in patients with chronic hepatitis C virus (HCV) infection have identified two functional single nucleotide polymorphisms (SNPs) in the inosine triphosphatase (ITPA) gene, that are associated strongly and independently with hemolytic anemia in patients exposed to pegylated-interferon (Peg-IFN) plus ribavirin (RBV) combined therapy. Here has been developed a simplified allele discrimination polymerase chain reaction (PCR) assay named allelic inhibition of displacement activity (AIDA) for evaluation of ITPA polymorphisms. AIDA system relies on three unlabeled primers only, two outer common primers and one inner primer with allele-specific 3' terminus mismatch. DNA samples from 192 patients with chronic HCV infection were used to validate the AIDA system and results were compared with the gold standard TaqMan(®) SNP genotyping assay. Concordant data were obtained for all samples, granting for high specificity of the method. In conclusion, AIDA is a practical one-tube method to reproducibly and to assess accurately rs7270101 and rs1127354 ITPA SNPs. Copyright © 2012 Elsevier B.V. All rights reserved.

Comparison of Prion Allele Frequency found in Suffolk and Targhee Sheep

USDA-ARS?s Scientific Manuscript database

Scrapie is a class of Transmissible Spongiform Encephalopathy that affects sheep and goats. The objective of this study was to compare genotypic and allelic frequencies among USSES Targhee and Suffolk sheep. A total of 122 sheep were genotyped for codon 171 with allele specific primers in 2 separate...

Role of APOE ε4 Allele and Incident Stroke on Cognitive Decline and Mortality.

PubMed

Rajan, Kumar B; Aggarwal, Neelum T; Schneider, Julie A; Wilson, Robert S; Everson-Rose, Susan A; Evans, Denis A

2016-01-01

The apolipoprotein E (APOE) ε4 allele and stroke increase the risk of cognitive decline. However, the association of the APOE ε4 allele before and after stroke is not well understood. Using a prospective sample of 3444 (66% African Americans, 61% females, mean age=71.9 y) participants, we examined cognitive decline relative to stroke among those with and without the APOE ε4 allele. In our sample, 505 (15%) had incident stroke. Among participants without stroke, the ε4 allele was associated with increased cognitive decline compared to noncarriers (0.080 vs. 0.036 units/year; P<0.0001). Among participants without the ε4 allele, cognitive decline increased significantly after stroke compared to before stroke (0.115 vs. 0.039 units/year; P<0.0001). Interestingly, cognitive decline before and after stroke was not significantly different among those with the ε4 allele (0.091 vs. 0.102 units/year; P=0.32). Poor cognitive function was associated with higher risk of stroke (hazard ratio=1.41, 95% confidence interval, 1.25-1.58), but the APOE ε4 allele was not (P=0.66). The APOE ε4 allele, cognitive function, and incident stroke were associated with mortality. The association of stroke with cognitive decline appears to differ by the presence of the APOE ε4 allele, but no such interaction was observed for mortality.

Global distribution of malaria-resistant MHC-HLA alleles: the number and frequencies of alleles and malaria risk.

PubMed

Garamszegi, László Zsolt

2014-09-03

The major histocompatibility complex (MHC) is the most polymorphic genetic region in vertebrates, but the origin of such genetic diversity remains unresolved. Several studies have demonstrated at the within-population level that individuals harbouring particular alleles can be less or more susceptible to malaria, but these do not allow strong generalization. Here worldwide data on the frequencies of several hundred MHC alleles of the human leucocyte antigen (HLA) system in relation to malaria risk at the between-population level were analysed in a phylogenetic framework, and results for different alleles were quantitatively summarized in a meta-analysis. There was an overall positive relationship between malaria pressure and the frequency of several HLA alleles indicating that allele frequencies increase in countries with strong malaria pressure. Nevertheless, considerable heterogeneity was observed across alleles, and some alleles showed a remarkable negative relationship with malaria risk. When heterogeneities were partitioned into different organization groups of the MHC, the strongest positive relationships were detected for alleles of the HLA-A and HLA-B loci, but there were also differences between MHC supertypes that constitute functionally distinct nucleotide sequences. Finally, the number of MHC alleles that are maintained within countries was also related to malaria risk. Therefore, malaria represents a key selection pressure for the human MHC and has left clear evolutionary footprints on both the frequencies and the number of alleles observed in different countries.

Hydrocortisone Fails to Abolish NF-κB1 Protein Nuclear Translocation in Deletion Allele Carriers of the NFKB1 Promoter Polymorphism (-94ins/delATTG) and Is Associated with Increased 30-Day Mortality in Septic Shock

PubMed Central

Schäfer, Simon T.; Gessner, Sophia; Scherag, André; Rump, Katharina; Frey, Ulrich H.; Siffert, Winfried; Westendorf, Astrid M.; Steinmann, Jörg; Peters, Jürgen; Adamzik, Michael

2014-01-01

Background Previous investigations and meta-analyses on the effect of glucocorticoids on mortality in septic shock revealed mixed results. This heterogeneity might be evoked by genetic variations. Such candidate is a promoter polymorphism (-94ins/delATTG) of the gene encoding the ubiquitous transcription-factor nuclear-factor-κB (NF-κB) which binds to recognition elements in the promoter of several genes encoding for the innate immune-system. In turn, hydrocortisone inhibits NF-κB nuclear translocation and thus transcription of key immune-response regulators. Accordingly, we tested the hypotheses that hydrocortisone has a NFKB1 genotype dependent effect on 1) NF-κB1 nuclear translocation evoked by lipopolysaccharide (LPS) in monocytes in vitro, and 2) mortality in septic shock. Methods Monocytes of volunteers with the homozygous insertion (II; n = 5) or deletion (DD; n = 6) NFKB1 genotype were incubated with 10 µgml-1 LPS ± hydrocortisone (10-5M), and NF-κB1 nuclear translocation was assessed (immunofluorescence). Furthermore, we analyzed 30-day-mortality in 160 patients with septic shock stratified for both genotype and hydrocortisone therapy. Results Hydrocortisone inhibited LPS induced nuclear translocation of NF-κB1 in II (25%±11;p = 0.0001) but not in DD genotypes (51%±15;p = n.s.). Onehundredandfour of 160 patients with septic shock received hydrocortisone, at the discretion of the intensivist. NFKB1 deletion allele carriers (ID/DD) receiving hydrocortisone had a much greater 30-day-mortality (57.6%) than II genotypes (24.4%; HR:3.18, 95%-CI:1.61-6.28;p = 0.001). In contrast, 30-day mortality was 22.2% in ID/DD and 25.0% in II genotypes without hydrocortisone therapy. Results were similar when using propensity score matching to account for possible bias in the intensivists' decision to administer hydrocortisone. Conclusion Hydrocortisone fails to inhibit LPS induced nuclear NF-κB1 translocation in deletion allele carriers of the

Disentangling the effects of serotonin on risk perception: S-carriers of 5-HTTLPR are primarily concerned with the magnitude of the outcomes, not the uncertainty.

PubMed

Millroth, Philip; Juslin, Peter; Eriksson, Elias; Agren, Thomas

2017-10-01

Serotonin signaling is vital for reward processing, and hence, also for decision-making. The serotonin transporter gene linked polymorphic region (5-HTTLPR) has been connected to decision making, suggesting that short-allele carriers (s) are more risk averse than long-allele homozygotes (ll). However, previous research has not identified if this occurs because s-carriers (i) are more sensitive to the uncertainty of the outcomes or (ii) are more sensitive to the magnitude of the outcomes. This issue was disentangled using a willingness-to-pay task, where the participants evaluated prospects involving certain gains, uncertain gains, and ambiguous gains. The results clearly favored the hypothesis that s-carriers react more to the magnitude of the outcomes. Self-reported measures of everyday risk-taking behavior also favored this hypothesis. We discuss how these results are in line with recent research on the serotonergic impact on reward processing. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Allelic clustering and ancestry-dependent frequencies of rs6232, rs6234, and rs6235 PCSK1 SNPs in a Northern Ontario population sample.

PubMed

Sirois, Francine; Kaefer, Nadine; Currie, Krista A; Chrétien, Michel; Nkongolo, Kabwe K; Mbikay, Majambu

2012-10-01

The PCSK1 (proprotein convertase subtilisin/kexin type 1) locus encodes proprotein convertase 1/3, an endoprotease that converts prohormones and proneuropeptides to their active forms. Spontaneous loss-of-function mutations in the coding sequence of its gene have been linked to obesity in humans. Minor alleles of two common non-synonymous single-nucleotide polymorphisms (SNPs), rs6232 (T > C, N221D) and rs6235 (C > G, S690T), have been associated with increased risk of obesity in European populations. In this study, we compared the frequencies of the rs6232 and rs6234 (G > C, Q665E) SNPs in Aboriginal and Caucasian populations of Northern Ontario. The two SNPs were all relatively less frequent in Aboriginals: The minor allele frequency of the rs6232 SNP was 0.01 in Aboriginals and 0.08 in Caucasians (P < 4.10(-6)); for the rs6234 SNP, it was 0.20 and 0.32, respectively (P < 0.001). Resequencing revealed that the rs6234 SNP variation was tightly linked to that of the rs6235 SNP, as previously reported. Most interestingly, all carriers of the rs6232 SNP variation also carried the rs6234/rs6235 SNP clustered variations, but not the reverse, suggesting the former occurred later on an allele already carrying the latter. These data indicate that, in Northern Ontario Aboriginals, the triple-variant PCSK1 allele is relatively rare and might be of lesser significance for obesity risk in this population.

A Simple, High-Throughput Assay for Fragile X Expanded Alleles Using Triple Repeat Primed PCR and Capillary Electrophoresis

PubMed Central

Lyon, Elaine; Laver, Thomas; Yu, Ping; Jama, Mohamed; Young, Keith; Zoccoli, Michael; Marlowe, Natalia

2010-01-01

Population screening has been proposed for Fragile X syndrome to identify premutation carrier females and affected newborns. We developed a PCR-based assay capable of quickly detecting the presence or absence of an expanded FMR1 allele with high sensitivity and specificity. This assay combines a triplet repeat primed PCR with high-throughput automated capillary electrophoresis. We evaluated assay performance using archived samples sent for Fragile X diagnostic testing representing a range of Fragile X CGG-repeat expansions. Two hundred five previously genotyped samples were tested with the new assay. Data were analyzed for the presence of a trinucleotide “ladder” extending beyond 55 repeats, which was set as a cut-off to identify expanded FMR1 alleles. We identified expanded FMR1 alleles in 132 samples (59 premutation, 71 full mutation, 2 mosaics) and normal FMR1 alleles in 73 samples. We found 100% concordance with previous results from PCR and Southern blot analyses. In addition, we show feasibility of using this assay with DNA extracted from dried-blood spots. Using a single PCR combined with high-throughput fragment analysis on the automated capillary electrophoresis instrument, we developed a rapid and reproducible PCR-based laboratory assay that meets many of the requirements for a first-tier test for population screening. PMID:20431035

Clinically significant psychiatric symptoms among male carriers of the fragile X premutation, with and without FXTAS, and the mediating influence of executive functioning.

PubMed

Grigsby, Jim; Brega, Angela G; Bennett, Rachael E; Bourgeois, James A; Seritan, Andreea L; Goodrich, Glenn K; Hagerman, Randi J

2016-08-01

To clarify the neuropsychiatric phenotype of fragile X-associated tremor/ataxia syndrome (FXTAS), and assess the extent to which it is mediated by the dysexecutive syndrome that is a major feature of the disorder. We examined the prevalence of clinically meaningful psychiatric symptoms among male carriers of the fragile X premutation, with and without FXTAS, in comparison with men with a normal allele. Measures included the Neuropsychiatric Inventory (NPI), Symptom Checklist-90-R (SCL-90-R), and the Behavioral Dyscontrol Scale, a measure of executive functioning. Between-group differences were evaluated using logistic regression, followed by a mediation analysis with ordinary least squares regression to assess the contribution of dysexecutive syndrome to the observed psychiatric domains. Men with FXTAS showed higher rates of clinically significant symptoms overall and in specific domains: somatization, obsessive compulsive, depression, anxiety, psychoticism, agitation/aggression, apathy/indifference, irritability, and nighttime behavior problems. Post hoc analyses suggested that findings of psychoticism among men with FXTAS may be associated with participants' accurate acknowledgment of cognitive and physical dysfunction, rather than reflecting psychosis. Asymptomatic carriers showed no evidence of clinically significant psychiatric symptoms, but when all carriers were compared with men having a normal FMR1 allele, executive function deficits were found to mediate scores in several domains on both NPI and SCL-90-R. Building on prior research, the results provide evidence that the psychiatric phenotype for men includes clinically meaningful depression, hostility, and irritability, in association with behavioral and attentional disinhibition. It is likely that these problems reflect the effects of impaired executive functioning.

47 CFR 54.316 - Rate comparability review and certification for areas served by non-rural carriers.

Code of Federal Regulations, 2010 CFR

2010-10-01

... Rates, Price Indices, and Expenditures for Telephone Service published by the Wireline Competition... areas served by non-rural carriers. 54.316 Section 54.316 Telecommunication FEDERAL COMMUNICATIONS... High Cost Areas § 54.316 Rate comparability review and certification for areas served by non-rural...

Determination of frequencies of alleles, associated with the pseudodeficiency of lysosomal hydrolases, in population of Ukraine.

PubMed

Olkhovych, N V; Gorovenko, N G

2016-01-01

The pseudodeficiency of lysosomal hydrolases described as a significant reduction in enzyme activi­ty in vitro in clinically healthy individuals, can lead to diagnostic errors in the process of biochemical analysis of lysosomal storage disease in case of its combination with pathology of another origin. Pseudodeficiency is mostly caused by some non-pathogenic changes in the corresponding gene. These changes lead to the in vitro lability of the enzyme molecule, whereas in vivo the enzyme retains its functional activity. To assess the prevalence of the most common lysosomal hydrolases pseudodeficiency alleles in Ukraine, we have determined the frequency of alleles c.1055A>G and c.* 96A>G in the ARSA gene, substitutions c.739C>T (R247W) and c.745C>T (R249W) in the HEXA gene, c.1726G>A (G576S) and c.2065G>A (E689K) in the GAA gene, c.937G>T (D313Y) in the GLA1 gene and c.898G>A (A300T) in the IDUA gene in a group of 117 healthy individuals from different regions of the country and 14 heterozygous carriers of pathogenic mutations in the HEXA gene (parents of children with confirmed diagnosis of Tay-Sachs disease). The total frequency of haplotypes, associated with arylsulfatase A pseudodeficiency, in healthy people in Ukraine (c.1055G/c.*96G and c.1055G/c.*96A haplotypes) was 10.3%. The frequency of c.739C>T (R247W) allele, associated with hexo­saminidase A pseudodeficiency, among Tay-Sachs carriers from Ukraine was 7.1%. The total frequency of α-glucosidase pseudodeficiency haplotypes in healthy individuals in Ukraine (c.1726A/c.2065A and c.1726G/c.2065A haplotypes) was 2.6%. No person among examined individuals with the substitution c.937G>T (D313Y) in the GLA1 gene and c.898G>A (A300T) in the IDUA gene was found. The differential diagnostics of lysosomal storage diseases requires obligatory determination of the presence of the pseudodeficiency alleles, particularly the ones with high incidence in the total population. Ignoring phenomenon of pseudodeficiency may

Phenotype-Genotype Correlations and Estimated Carrier Frequencies of Primary Hyperoxaluria

PubMed Central

Hopp, Katharina; Cogal, Andrea G.; Bergstralh, Eric J.; Seide, Barbara M.; Olson, Julie B.; Meek, Alicia M.; Lieske, John C.; Milliner, Dawn S.

2015-01-01

Primary hyperoxaluria (PH) is a rare autosomal recessive disease characterized by oxalate accumulation in the kidneys and other organs. Three loci have been identified: AGXT (PH1), GRHPR (PH2), and HOGA1 (PH3). Here, we compared genotype to phenotype in 355 patients in the Rare Kidney Stone Consortium PH registry and calculated prevalence using publicly available whole-exome data. PH1 (68.4% of families) was the most severe PH type, whereas PH3 (11.0% of families) showed the slowest decline in renal function but the earliest symptoms. A group of patients with disease progression similar to that of PH3, but for whom no mutation was detected (11.3% of families), suggested further genetic heterogeneity. We confirmed that the AGXT p.G170R mistargeting allele resulted in a milder PH1 phenotype; however, other potential AGXT mistargeting alleles caused more severe (fully penetrant) disease. We identified the first PH3 patient with ESRD; a homozygote for two linked, novel missense mutations. Population analysis suggested that PH is an order of magnitude more common than determined from clinical cohorts (prevalence, approximately 1:58,000; carrier frequency, approximately 1:70). We estimated PH to be approximately three times less prevalent among African Americans than among European Americans because of a limited number of common European origin alleles. PH3 was predicted to be as prevalent as PH1 and twice as common as PH2, indicating that PH3 (and PH2) cases are underdiagnosed and/or incompletely penetrant. These results highlight a role for molecular analyses in PH diagnostics and prognostics and suggest that wider analysis of the idiopathic stone-forming population may be beneficial. PMID:25644115

Phenotype-Genotype Correlations and Estimated Carrier Frequencies of Primary Hyperoxaluria.

PubMed

Hopp, Katharina; Cogal, Andrea G; Bergstralh, Eric J; Seide, Barbara M; Olson, Julie B; Meek, Alicia M; Lieske, John C; Milliner, Dawn S; Harris, Peter C

2015-10-01

Primary hyperoxaluria (PH) is a rare autosomal recessive disease characterized by oxalate accumulation in the kidneys and other organs. Three loci have been identified: AGXT (PH1), GRHPR (PH2), and HOGA1 (PH3). Here, we compared genotype to phenotype in 355 patients in the Rare Kidney Stone Consortium PH registry and calculated prevalence using publicly available whole-exome data. PH1 (68.4% of families) was the most severe PH type, whereas PH3 (11.0% of families) showed the slowest decline in renal function but the earliest symptoms. A group of patients with disease progression similar to that of PH3, but for whom no mutation was detected (11.3% of families), suggested further genetic heterogeneity. We confirmed that the AGXT p.G170R mistargeting allele resulted in a milder PH1 phenotype; however, other potential AGXT mistargeting alleles caused more severe (fully penetrant) disease. We identified the first PH3 patient with ESRD; a homozygote for two linked, novel missense mutations. Population analysis suggested that PH is an order of magnitude more common than determined from clinical cohorts (prevalence, approximately 1:58,000; carrier frequency, approximately 1:70). We estimated PH to be approximately three times less prevalent among African Americans than among European Americans because of a limited number of common European origin alleles. PH3 was predicted to be as prevalent as PH1 and twice as common as PH2, indicating that PH3 (and PH2) cases are underdiagnosed and/or incompletely penetrant. These results highlight a role for molecular analyses in PH diagnostics and prognostics and suggest that wider analysis of the idiopathic stone-forming population may be beneficial. Copyright © 2015 by the American Society of Nephrology.

Prevalence of Huntington's disease gene CAG trinucleotide repeat alleles in patients with bipolar disorder.

PubMed

Ramos, Eliana Marisa; Gillis, Tammy; Mysore, Jayalakshmi S; Lee, Jong-Min; Alonso, Isabel; Gusella, James F; Smoller, Jordan W; Sklar, Pamela; MacDonald, Marcy E; Perlis, Roy H

2015-06-01

Huntington's disease is a neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms that are caused by huntingtin gene (HTT) CAG trinucleotide repeat alleles of 36 or more units. A greater than expected prevalence of incompletely penetrant HTT CAG repeat alleles observed among individuals diagnosed with major depressive disorder raises the possibility that another mood disorder, bipolar disorder, could likewise be associated with Huntington's disease. We assessed the distribution of HTT CAG repeat alleles in a cohort of individuals with bipolar disorder. HTT CAG allele sizes from 2,229 Caucasian individuals diagnosed with DSM-IV bipolar disorder were compared to allele sizes in 1,828 control individuals from multiple cohorts. We found that HTT CAG repeat alleles > 35 units were observed in only one of 4,458 chromosomes from individuals with bipolar disorder, compared to three of 3,656 chromosomes from control subjects. These findings do not support an association between bipolar disorder and Huntington's disease. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

HLA-B27 allele frequency in Sri Lankan patients with spondyloarthritides.

PubMed

Kidnapillai, S; Sirisena, N D; Dissanayake, V H

2016-06-01

This preliminary study aims to describe the HLA-B27 allele frequency in Sri Lankan patients with spondyloarthritides (SA). An anonymised database of 373 Sri Lankan patients with SA referred for HLA-B27 testing was retrospectively analysed. Eighty five (22.8%) patients were positive for the HLA-B27 allele. A male preponderance was observed among the positives. The HLA-B27 allele frequency in this sample of patients with SA was relatively low compared to published studies in other populations. Further research is needed to identify the predominant subtypes of the allele to determine which subtypes are the most prevalent in a larger sample of Sri Lankan patients with SA, and to define their association with the specific types of SA.

Ancient DNA Investigation of a Medieval German Cemetery Confirms Long-Term Stability of CCR5-Δ32 Allele Frequencies in Central Europe.

PubMed

Bouwman, Abigail; Shved, Natallia; Akgül, Gülfirde; Rühli, Frank; Warinner, Christina

2017-04-01

The CCR5-Δ32 mutation present in European populations is among the most prominently debated cases of recent positive selection in humans. This allele, a 32-bp deletion that renders the T-cell CCR5 receptor nonfunctional, has important epidemiological and public health significance, as homozygous carriers are resistant to several HIV strains. However, although the function of this allele in preventing HIV infection is now well described, its human evolutionary origin is poorly understood. Initial attempts to determine the emergence of the CCR5-Δ32 allele pointed to selection during the 14th-century Black Death pandemic; however, subsequent analyses suggest that the allele rose in frequency more than 5,000 years ago, possibly through drift. Recently, three studies have identified populations predating the 14th century CE that are positive for the CCR5-Δ32 allele, supporting the claim for a more ancient origin. However, these studies also suggest poorly understood regional differences in the recent evolutionary history of the CCR5-Δ32 allele. Here a new hydrolysis-probe-based real-time PCR assay was designed to ascertain CCR5 allele frequency in 53 individuals from a 10th- to 12th-century CE church and convent complex in central Germany that predates outbreaks of the Black Death pandemic. High-confidence genotypes were obtained for 32 individuals, and results show that CCR5-Δ32 allele frequency has remained unchanged in this region of Central Europe over the last millennium, suggesting that there has been no strong positive selective pressure over this time period and confirming a more ancient origin for the allele.

Brain function in carriers of a genome-wide supported bipolar disorder variant.

PubMed

Erk, Susanne; Meyer-Lindenberg, Andreas; Schnell, Knut; Opitz von Boberfeld, Carola; Esslinger, Christine; Kirsch, Peter; Grimm, Oliver; Arnold, Claudia; Haddad, Leila; Witt, Stephanie H; Cichon, Sven; Nöthen, Markus M; Rietschel, Marcella; Walter, Henrik

2010-08-01

The neural abnormalities underlying genetic risk for bipolar disorder, a severe, common, and highly heritable psychiatric condition, are largely unknown. An opportunity to define these mechanisms is provided by the recent discovery, through genome-wide association, of a single-nucleotide polymorphism (rs1006737) strongly associated with bipolar disorder within the CACNA1C gene, encoding the alpha subunit of the L-type voltage-dependent calcium channel Ca(v)1.2. To determine whether the genetic risk associated with rs1006737 is mediated through hippocampal function. Functional magnetic resonance imaging study. University hospital. A total of 110 healthy volunteers of both sexes and of German descent in the Hardy-Weinberg equilibrium for rs1006737. Blood oxygen level-dependent signal during an episodic memory task and behavioral and psychopathological measures. Using an intermediate phenotype approach, we show that healthy carriers of the CACNA1C risk variant exhibit a pronounced reduction of bilateral hippocampal activation during episodic memory recall and diminished functional coupling between left and right hippocampal regions. Furthermore, risk allele carriers exhibit activation deficits of the subgenual anterior cingulate cortex, a region repeatedly associated with affective disorders and the mediation of adaptive stress-related responses. The relevance of these findings for affective disorders is supported by significantly higher psychopathology scores for depression, anxiety, obsessive-compulsive thoughts, interpersonal sensitivity, and neuroticism in risk allele carriers, correlating negatively with the observed regional brain activation. Our data demonstrate that rs1006737 or genetic variants in linkage disequilibrium with it are functional in the human brain and provide a neurogenetic risk mechanism for bipolar disorder backed by genome-wide evidence.

A 15-year-long Southern blotting analysis of FMR1 to detect female carriers and for prenatal diagnosis of fragile X syndrome in Taiwan.

PubMed

Tzeng, C-C; Tsai, L-P; Chang, Y-K; Hung, Y-J; Chang, Y-Y; Su, Y-P; Jiang, J-J; Liang, H-M

2017-08-01

Here, we review the results of Southern blotting analyses of the FMR1 gene performed in our reference laboratory in Taiwan over a 15-year period. In total, 725 high-risk women with a family history of fragile X syndrome (FXS) or idiopathic intellectual disability, 3911 low-risk pregnant women without such family history, and prenatal diagnosis data for 32 foetuses from 24 carrier mothers were included. Only 2 carriers were in the low-risk group, which indicated a prevalence of 1 of 1955 women (95% confidence interval: 1/7156-1/539). A total of 100 carriers were found to be in the high-risk group, thus revealing a significantly higher frequency than the low-risk group (100/725 vs 2/3911, P<0.0001). Eight of the 14 foetuses that inherited the maternal mutant allele were verified to have a full mutation, with the smallest maternal pre-mutation allele carrying 56 CGG repeats. The overall findings confirmed that the carrier prevalence among low-risk women in Taiwan is significantly lower than that reported in western countries. Therefore, the most important step for preventing FXS in Taiwan would be to focus on high-risk women by promoting general awareness of this disease and spreading knowledge regarding the benefits of carrier screening and prenatal testing. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The distribution of apolipoprotein E alleles in Scottish perinatal deaths

PubMed Central

Becher, J‐C; Keeling, J W; McIntosh, N; Wyatt, B; Bell, J

2006-01-01

Background The apolipoprotein E (ApoE) polymorphism has been well studied in the adult human population, in part because the e4 allele is a known risk factor for Alzheimer's disease. Little is known of the distribution of ApoE alleles in newborns, and their association with perinatal brain damage has not been investigated. Methods ApoE genotyping was undertaken in a Scottish cohort of perinatal deaths (n = 261), some of whom had prenatal brain damage. The distribution of ApoE alleles in perinatal deaths was compared with that in healthy liveborn infants and in adults in Scotland. Results ApoE e2 was over‐represented in 251 perinatal deaths (13% v 8% in healthy newborns, odds ratio (OR) = 1.63, 95% confidence interval (CI) 1.13 to 2.36 and 13% v 8% in adults, OR = 1.67, 95% CI 1.16 to 2.41), both in liveborn and stillborn perinatal deaths. In contrast, the prevalence of ApoE e4 was raised in healthy liveborn infants (19%) compared with stillbirths (13%, OR = 1.59, 95% CI 1.11 to 2.26) and with adults (15%, OR = 1.35, 95% CI 1.04 to 1.76). However, no correlation was found between ApoE genotype and the presence or absence of perinatal brain damage. Conclusions This study shows a shift in ApoE allelic distribution in early life compared with adults. The raised prevalence of ApoE e2 associated with perinatal death suggests that this allele is detrimental to pregnancy outcome, whereas ApoE e4 may be less so. However, ApoE genotype did not appear to influence the vulnerability for perinatal hypoxic/ischaemic brain damage, in agreement with findings in adult brains and in animal models. PMID:16183800

[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.

Tremor-Ataxia syndrome and primary ovarian insufficiency in anFMR1 premutation carrier

PubMed Central

Rodriguez-Guerrero, Tatiana; Fandiño-Losada, Andres; Ramirez-Cheyne, Julian

2017-01-01

Abstract Introduction: The FMR1 gene has four allelic variants according to the number of repeats of the CGG triplet. Premutation carriers with between 55 and 200 repeats are susceptible to developing pathologies such as tremor and ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI) syndrome. Case description: The patient was a 53-year-old female farmer with severe tremor in the upper limbs at rest that worsens with movement, tremor in the jaw and tongue, and generalized cerebral atrophy. She is a carrier of the FMR1 premutation diagnosed by PCR and Southern Blot, complying with the clinical and radiological criteria of FXTAS, and in addition, has a history of vagal symptoms suggestive of ovarian failure and menstrual cycle disorders that led to hysterectomy at age 33 and was subsequently diagnosed with FXPOI. Conclusion: An unusual case of FXTAS and FXPOI complying with clinical and radiological criteria is reported in a premutation carrier of the FMR1 gene. PMID:29299012

Rapid genotyping assays for the 4-base pair deletion of canine MDR1/ABCB1 gene and low frequency of the mutant allele in Border Collie dogs.

PubMed

Mizukami, Keijiro; Chang, Hye-Sook; Yabuki, Akira; Kawamichi, Takuji; Hossain, Mohammad A; Rahman, Mohammad M; Uddin, Mohammad M; Yamato, Osamu

2012-01-01

P-glycoprotein, encoded by the MDR1 or ABCB1 gene, is an integral component of the blood-brain barrier as an efflux pump for xenobiotics crucial in limiting drug uptake into the central nervous system. Dogs homozygous for a 4-base pair deletion of the canine MDR1 gene show altered expression or function of P-glycoprotein, resulting in neurotoxicosis after administration of the substrate drugs. In the present study, the usefulness of microchip electrophoresis for genotyping assays detecting this deletion mutation was evaluated. Mutagenically separated polymerase chain reaction (MS-PCR) and real-time PCR assays were newly developed and evaluated. Furthermore, a genotyping survey was carried out in a population of Border Collies dogs in Japan to determine the allele frequency in this breed. Microchip electrophoresis showed advantages in detection sensitivity and time saving over other modes of electrophoresis. The MS-PCR assay clearly discriminated all genotypes. Real-time PCR assay was most suitable for a large-scale survey due to its high throughput and rapidity. The genotyping survey demonstrated that the carrier and mutant allele frequencies were 0.49% and 0.25%, respectively, suggesting that the mutant allele frequency in Border Collies is markedly low compared to that in the susceptible dog breeds such as rough and smooth Collies.

Haplotypic Background of a Private Allele at High Frequency in the Americas

PubMed Central

Schroeder, Kari B.; Jakobsson, Mattias; Crawford, Michael H.; Schurr, Theodore G.; Boca, Simina M.; Conrad, Donald F.; Tito, Raul Y.; Osipova, Ludmilla P.; Tarskaia, Larissa A.; Zhadanov, Sergey I.; Wall, Jeffrey D.; Pritchard, Jonathan K.; Malhi, Ripan S.; Smith, David G.; Rosenberg, Noah A.

2009-01-01

Recently, the observation of a high-frequency private allele, the 9-repeat allele at microsatellite D9S1120, in all sampled Native American and Western Beringian populations has been interpreted as evidence that all modern Native Americans descend primarily from a single founding population. However, this inference assumed that all copies of the 9-repeat allele were identical by descent and that the geographic distribution of this allele had not been influenced by natural selection. To investigate whether these assumptions are satisfied, we genotyped 34 single nucleotide polymorphisms across ∼500 kilobases (kb) around D9S1120 in 21 Native American and Western Beringian populations and 54 other worldwide populations. All chromosomes with the 9-repeat allele share the same haplotypic background in the vicinity of D9S1120, suggesting that all sampled copies of the 9-repeat allele are identical by descent. Ninety-one percent of these chromosomes share the same 76.26 kb haplotype, which we call the “American Modal Haplotype” (AMH). Three observations lead us to conclude that the high frequency and widespread distribution of the 9-repeat allele are unlikely to be the result of positive selection: 1) aside from its association with the 9-repeat allele, the AMH does not have a high frequency in the Americas, 2) the AMH is not unusually long for its frequency compared with other haplotypes in the Americas, and 3) in Latin American mestizo populations, the proportion of Native American ancestry at D9S1120 is not unusual compared with that observed at other genomewide microsatellites. Using a new method for estimating the time to the most recent common ancestor (MRCA) of all sampled copies of an allele on the basis of an estimate of the length of the genealogy descended from the MRCA, we calculate the mean time to the MRCA of the 9-repeat allele to be between 7,325 and 39,900 years, depending on the demographic model used. The results support the hypothesis that all

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

Genome-wide association study in discordant sibships identifies multiple inherited susceptibility alleles linked to lung cancer.

PubMed

Galvan, Antonella; Falvella, Felicia S; Frullanti, Elisa; Spinola, Monica; Incarbone, Matteo; Nosotti, Mario; Santambrogio, Luigi; Conti, Barbara; Pastorino, Ugo; Gonzalez-Neira, Anna; Dragani, Tommaso A

2010-03-01

We analyzed a series of young (median age = 52 years) non-smoker lung cancer patients and their unaffected siblings as controls, using a genome-wide 620 901 single-nucleotide polymorphism (SNP) array analysis and a case-control DNA pooling approach. We identified 82 putatively associated SNPs that were retested by individual genotyping followed by use of the sib transmission disequilibrium test, pointing to 36 SNPs associated with lung cancer risk in the discordant sibs series. Analysis of these 36 SNPs in a polygenic model characterized by additive and interchangeable effects of rare alleles revealed a highly statistically significant dosage-dependent association between risk allele carrier status and proportion of cancer cases. Replication of the same 36 SNPs in a population-based series confirmed the association with lung cancer for three SNPs, suggesting that phenocopies and genetic heterogeneity can play a major role in the complex genetics of lung cancer risk in the general population.

Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers

PubMed Central

Blanco, Ignacio; Kuchenbaecker, Karoline; Cuadras, Daniel; Wang, Xianshu; Barrowdale, Daniel; de Garibay, Gorka Ruiz; Librado, Pablo; Sánchez-Gracia, Alejandro; Rozas, Julio; Bonifaci, Núria; McGuffog, Lesley; Pankratz, Vernon S.; Islam, Abul; Mateo, Francesca; Berenguer, Antoni; Petit, Anna; Català, Isabel; Brunet, Joan; Feliubadaló, Lidia; Tornero, Eva; Benítez, Javier; Osorio, Ana; Cajal, Teresa Ramón y; Nevanlinna, Heli; Aittomäki, Kristiina; Arun, Banu K.; Toland, Amanda E.; Karlan, Beth Y.; Walsh, Christine; Lester, Jenny; Greene, Mark H.; Mai, Phuong L.; Nussbaum, Robert L.; Andrulis, Irene L.; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Timothy R.; Barkardottir, Rosa B.; Jakubowska, Anna; Lubinski, Jan; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Claes, Kathleen; Van Maerken, Tom; Díez, Orland; Hansen, Thomas V.; Jønson, Lars; Gerdes, Anne-Marie; Ejlertsen, Bent; de la Hoya, Miguel; Caldés, Trinidad; Dunning, Alison M.; Oliver, Clare; Fineberg, Elena; Cook, Margaret; Peock, Susan; McCann, Emma; Murray, Alex; Jacobs, Chris; Pichert, Gabriella; Lalloo, Fiona; Chu, Carol; Dorkins, Huw; Paterson, Joan; Ong, Kai-Ren; Teixeira, Manuel R.; Hogervorst, Frans B. L.; van der Hout, Annemarie H.; Seynaeve, Caroline; van der Luijt, Rob B.; Ligtenberg, Marjolijn J. L.; Devilee, Peter; Wijnen, Juul T.; Rookus, Matti A.; Meijers-Heijboer, Hanne E. J.; Blok, Marinus J.; van den Ouweland, Ans M. W.; Aalfs, Cora M.; Rodriguez, Gustavo C.; Phillips, Kelly-Anne A.; Piedmonte, Marion; Nerenstone, Stacy R.; Bae-Jump, Victoria L.; O'Malley, David M.; Ratner, Elena S.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Rhiem, Kerstin; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Plendl, Hansjoerg J.; Niederacher, Dieter; Sutter, Christian; Wang-Gohrke, Shan; Steinemann, Doris; Preisler-Adams, Sabine; Kast, Karin; Varon-Mateeva, Raymonda; Gehrig, Andrea; Bojesen, Anders; Pedersen, Inge Sokilde; Sunde, Lone; Jensen, Uffe Birk; Thomassen, Mads; Kruse, Torben A.; Foretova, Lenka; Peterlongo, Paolo; Bernard, Loris; Peissel, Bernard; Scuvera, Giulietta; Manoukian, Siranoush; Radice, Paolo; Ottini, Laura; Montagna, Marco; Agata, Simona; Maugard, Christine; Simard, Jacques; Soucy, Penny; Berger, Andreas; Fink-Retter, Anneliese; Singer, Christian F.; Rappaport, Christine; Geschwantler-Kaulich, Daphne; Tea, Muy-Kheng; Pfeiler, Georg; John, Esther M.; Miron, Alex; Neuhausen, Susan L.; Terry, Mary Beth; Chung, Wendy K.; Daly, Mary B.; Goldgar, David E.; Janavicius, Ramunas; Dorfling, Cecilia M.; van Rensburg, Elisabeth J.; Fostira, Florentia; Konstantopoulou, Irene; Garber, Judy; Godwin, Andrew K.; Olah, Edith; Narod, Steven A.; Rennert, Gad; Paluch, Shani Shimon; Laitman, Yael; Friedman, Eitan; Liljegren, Annelie; Rantala, Johanna; Stenmark-Askmalm, Marie; Loman, Niklas; Imyanitov, Evgeny N.; Hamann, Ute; Spurdle, Amanda B.; Healey, Sue; Weitzel, Jeffrey N.; Herzog, Josef; Margileth, David; Gorrini, Chiara; Esteller, Manel; Gómez, Antonio; Sayols, Sergi; Vidal, Enrique; Heyn, Holger; Stoppa-Lyonnet, Dominique; Léoné, Melanie; Barjhoux, Laure; Fassy-Colcombet, Marion; de Pauw, Antoine; Lasset, Christine; Ferrer, Sandra Fert; Castera, Laurent; Berthet, Pascaline; Cornelis, François; Bignon, Yves-Jean; Damiola, Francesca; Mazoyer, Sylvie; Maxwell, Christopher A.; Vijai, Joseph; Robson, Mark; Kauff, Noah; Corines, Marina J.; Villano, Danylko; Cunningham, Julie; Lee, Adam; Lindor, Noralane; Lázaro, Conxi; Easton, Douglas F.; Offit, Kenneth; Chenevix-Trench, Georgia; Couch, Fergus J.; Antoniou, Antonis C.; Pujana, Miguel Angel

2015-01-01

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04 – 1.15, p = 1.9 x 10−4 (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03 – 1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients’ survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers. PMID:25830658

Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers.

PubMed

Blanco, Ignacio; Kuchenbaecker, Karoline; Cuadras, Daniel; Wang, Xianshu; Barrowdale, Daniel; de Garibay, Gorka Ruiz; Librado, Pablo; Sánchez-Gracia, Alejandro; Rozas, Julio; Bonifaci, Núria; McGuffog, Lesley; Pankratz, Vernon S; Islam, Abul; Mateo, Francesca; Berenguer, Antoni; Petit, Anna; Català, Isabel; Brunet, Joan; Feliubadaló, Lidia; Tornero, Eva; Benítez, Javier; Osorio, Ana; Ramón y Cajal, Teresa; Nevanlinna, Heli; Aittomäki, Kristiina; Arun, Banu K; Toland, Amanda E; Karlan, Beth Y; Walsh, Christine; Lester, Jenny; Greene, Mark H; Mai, Phuong L; Nussbaum, Robert L; Andrulis, Irene L; Domchek, Susan M; Nathanson, Katherine L; Rebbeck, Timothy R; Barkardottir, Rosa B; Jakubowska, Anna; Lubinski, Jan; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Claes, Kathleen; Van Maerken, Tom; Díez, Orland; Hansen, Thomas V; Jønson, Lars; Gerdes, Anne-Marie; Ejlertsen, Bent; de la Hoya, Miguel; Caldés, Trinidad; Dunning, Alison M; Oliver, Clare; Fineberg, Elena; Cook, Margaret; Peock, Susan; McCann, Emma; Murray, Alex; Jacobs, Chris; Pichert, Gabriella; Lalloo, Fiona; Chu, Carol; Dorkins, Huw; Paterson, Joan; Ong, Kai-Ren; Teixeira, Manuel R; Hogervorst, Frans B L; van der Hout, Annemarie H; Seynaeve, Caroline; van der Luijt, Rob B; Ligtenberg, Marjolijn J L; Devilee, Peter; Wijnen, Juul T; Rookus, Matti A; Meijers-Heijboer, Hanne E J; Blok, Marinus J; van den Ouweland, Ans M W; Aalfs, Cora M; Rodriguez, Gustavo C; Phillips, Kelly-Anne A; Piedmonte, Marion; Nerenstone, Stacy R; Bae-Jump, Victoria L; O'Malley, David M; Ratner, Elena S; Schmutzler, Rita K; Wappenschmidt, Barbara; Rhiem, Kerstin; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Plendl, Hansjoerg J; Niederacher, Dieter; Sutter, Christian; Wang-Gohrke, Shan; Steinemann, Doris; Preisler-Adams, Sabine; Kast, Karin; Varon-Mateeva, Raymonda; Gehrig, Andrea; Bojesen, Anders; Pedersen, Inge Sokilde; Sunde, Lone; Jensen, Uffe Birk; Thomassen, Mads; Kruse, Torben A; Foretova, Lenka; Peterlongo, Paolo; Bernard, Loris; Peissel, Bernard; Scuvera, Giulietta; Manoukian, Siranoush; Radice, Paolo; Ottini, Laura; Montagna, Marco; Agata, Simona; Maugard, Christine; Simard, Jacques; Soucy, Penny; Berger, Andreas; Fink-Retter, Anneliese; Singer, Christian F; Rappaport, Christine; Geschwantler-Kaulich, Daphne; Tea, Muy-Kheng; Pfeiler, Georg; John, Esther M; Miron, Alex; Neuhausen, Susan L; Terry, Mary Beth; Chung, Wendy K; Daly, Mary B; Goldgar, David E; Janavicius, Ramunas; Dorfling, Cecilia M; van Rensburg, Elisabeth J; Fostira, Florentia; Konstantopoulou, Irene; Garber, Judy; Godwin, Andrew K; Olah, Edith; Narod, Steven A; Rennert, Gad; Paluch, Shani Shimon; Laitman, Yael; Friedman, Eitan; Liljegren, Annelie; Rantala, Johanna; Stenmark-Askmalm, Marie; Loman, Niklas; Imyanitov, Evgeny N; Hamann, Ute; Spurdle, Amanda B; Healey, Sue; Weitzel, Jeffrey N; Herzog, Josef; Margileth, David; Gorrini, Chiara; Esteller, Manel; Gómez, Antonio; Sayols, Sergi; Vidal, Enrique; Heyn, Holger; Stoppa-Lyonnet, Dominique; Léoné, Melanie; Barjhoux, Laure; Fassy-Colcombet, Marion; de Pauw, Antoine; Lasset, Christine; Ferrer, Sandra Fert; Castera, Laurent; Berthet, Pascaline; Cornelis, François; Bignon, Yves-Jean; Damiola, Francesca; Mazoyer, Sylvie; Sinilnikova, Olga M; Maxwell, Christopher A; Vijai, Joseph; Robson, Mark; Kauff, Noah; Corines, Marina J; Villano, Danylko; Cunningham, Julie; Lee, Adam; Lindor, Noralane; Lázaro, Conxi; Easton, Douglas F; Offit, Kenneth; Chenevix-Trench, Georgia; Couch, Fergus J; Antoniou, Antonis C; Pujana, Miguel Angel

2015-01-01

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.

Lipooligosaccharide Structures of Invasive and Carrier Isolates of Neisseria meningitidis Are Correlated with Pathogenicity and Carriage*

PubMed Central

John, Constance M.; Phillips, Nancy J.; Din, Richard; Liu, Mingfeng; Rosenqvist, Einar; Høiby, E. Arne; Stein, Daniel C.; Jarvis, Gary A.

2016-01-01

The degree of phosphorylation and phosphoethanolaminylation of lipid A on neisserial lipooligosaccharide (LOS), a major cell-surface antigen, can be correlated with inflammatory potential and the ability to induce immune tolerance in vitro. On the oligosaccharide of the LOS, the presence of phosphoethanolamine and sialic acid substituents can be correlated with in vitro serum resistance. In this study, we analyzed the structure of the LOS from 40 invasive isolates and 25 isolates from carriers of Neisseria meningitidis without disease. Invasive strains were classified as groups 1–3 that caused meningitis, septicemia without meningitis, and septicemia with meningitis, respectively. Intact LOS was analyzed by high resolution matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Prominent peaks for lipid A fragment ions with three phosphates and one phosphoethanolamine were detected in all LOS analyzed. LOS from groups 2 and 3 had less abundant ions for highly phosphorylated lipid A forms and induced less TNF-α in THP-1 monocytic cells compared with LOS from group 1. Lipid A from all invasive strains was hexaacylated, whereas lipid A of 6/25 carrier strains was pentaacylated. There were fewer O-acetyl groups and more phosphoethanolamine and sialic acid substitutions on the oligosaccharide from invasive compared with carrier isolates. Bioinformatic and genomic analysis of LOS biosynthetic genes indicated significant skewing to specific alleles, dependent on the disease outcome. Our results suggest that variable LOS structures have multifaceted effects on homeostatic innate immune responses that have critical impact on the pathophysiology of meningococcal infections. PMID:26655715

Comparative In Vivo Effects of Hemoglobin-Based Oxygen Carriers (HBOC) with Varying Prooxidant and Physiological Reactivity.

PubMed

Toma, Vlad Al; Farcaș, Anca D; Roman, Ioana; Sevastre, Bogdan; Hathazi, Denisa; Scurtu, Florina; Damian, Grigore; Silaghi-Dumitrescu, Radu

2016-01-01

A series of hemoglobin-based oxygen carrier candidates (HBOC), previously noted for their differences in prooxidative and physiological reactivity, were compared in terms of the negative effects displayed upon injection in Wistar rats. At the concentrations tested, antioxidant strategies based on albumin as well as based on rubrerythrin appear to offer observable physiological advantages.

Disrupted topology of the resting state structural connectome in middle-aged APOE ε4 carriers.

PubMed

Korthauer, L E; Zhan, L; Ajilore, O; Leow, A; Driscoll, I

2018-05-24

The apolipoprotein E (APOE) ε4 allele is the best characterized genetic risk factor for Alzheimer's disease to date. Older APOE ε4 carriers (aged 60 + years) are known to have disrupted structural and functional connectivity, but less is known about APOE-associated network integrity in middle age. The goal of this study was to characterize APOE-related differences in network topology in middle age, as disentangling the early effects of healthy versus pathological aging may aid early detection of Alzheimer's disease and inform treatments. We performed resting state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor imaging (DTI) in healthy, cognitively normal, middle-aged adults (age 40-60; N = 76, 38 APOE ε4 carriers). Graph theoretical analysis was used to calculate local and global efficiency of 1) a whole brain rs-fMRI network; 2) a whole brain DTI network; and 3) the resting state structural connectome (rsSC), an integrated functional-structural network derived using functional-by-structural hierarchical (FSH) mapping. Our results indicated no APOE ε4-associated differences in network topology of the rs-fMRI or DTI networks alone. However, ε4 carriers had significantly lower global and local efficiency of the integrated rsSC compared to non-carriers. Furthermore, ε4 carriers were less resilient to targeted node failure of the rsSC, which mimics the neuropathological process of Alzheimer's disease. Collectively, these findings suggest that integrating multiple neuroimaging modalities and employing graph theoretical analysis may reveal network-level vulnerabilities that may serve as biomarkers of age-related cognitive decline in middle age, decades before the onset of overt cognitive impairment. Copyright © 2018. Published by Elsevier Inc.

Phenotypic characterization of nevus and tumor patterns in MITF E318K mutation carrier melanoma patients.

PubMed

Sturm, Richard A; Fox, Carly; McClenahan, Phil; Jagirdar, Kasturee; Ibarrola-Villava, Maider; Banan, Parastoo; Abbott, Nicola C; Ribas, Gloria; Gabrielli, Brian; Duffy, David L; Peter Soyer, H

2014-01-01

A germline polymorphism of the microphthalmia transcription factor (MITF) gene encoding a SUMOylation-deficient E318K-mutated protein has recently been described as a medium-penetrance melanoma gene. In a clinical assessment of nevi from 301 volunteers taken from Queensland, we identified six individuals as MITF E318K mutation carriers. The phenotype for 5 of these individuals showed a commonality of fair skin, body freckling that varied over a wide range, and total nevus count between 46 and 430; in addition, all were multiple primary melanoma patients. The predominant dermoscopic signature pattern of nevi was reticular, and the frequency of globular nevi in carriers varied, which does not suggest that the MITF E318K mutation acts to force the continuous growth of nevi. Excised melanocytic lesions were available for four MITF E318K carrier patients and were compared with a matched range of wild-type (WT) melanocytic lesions. The MITF staining pattern showed a predominant nuclear signal in all sections, with no significant difference in the nuclear/cytoplasmic ratio between mutation-positive or -negative samples. A high incidence of amelanotic melanomas was found within the group, with three of the five melanomas from one patient suggesting a genetic interaction between the MITF E318K allele and an MC1R homozygous red hair color (RHC) variant genotype.

Both hemophilia health care providers and hemophilia a carriers report that carriers have excessive bleeding.

PubMed

Paroskie, Allison; Oso, Olatunde; Almassi, Benjamin; DeBaun, Michael R; Sidonio, Robert F

2014-05-01

Hemophilia A, the result of reduced factor VIII activity, is an X-linked recessive bleeding disorder. Previous reports of hemophilia A carriers suggest an increased bleeding tendency. Our objective was to determine the attitudes and understanding of the hemophilia A carrier bleeding phenotype, and opinions regarding timing of carrier testing from the perspective of both medical providers and affected patients. Data from this survey were used as preliminary data for an ongoing prospective study. An electronic survey was distributed to physicians and nurses employed at Hemophilia Treatment Centers, and hemophilia A carriers who were members of Hemophilia Federation of America. The questions focused on the clinical understanding of bleeding symptoms and management of hemophilia A carriers, and the timing and intensity of carrier testing. Our survey indicates that 51% (36/51) of providers compared with 78% (36/46) of carriers believe that hemophilia A carriers with normal factor VIII activity have an increased bleeding tendency (P<0.001); 72% (33/36) of hemophilia A carriers report a high frequency of bleeding symptoms. Regarding carrier testing, 72% (50/69) of medical providers recommend testing after 14 years of age, conversely 65% (29/45) of hemophilia A carriers prefer testing to be done before this age (P<0.001). Hemophilia A carriers self-report a higher frequency of bleeding than previously acknowledged, and have a preference for earlier testing to confirm carrier status.

Neurological Dysfunction in Early Maturity of a Model for Niemann-Pick C1 Carrier Status.

PubMed

Hung, Ya Hui; Walterfang, Mark; Churilov, Leonid; Bray, Lisa; Jacobson, Laura H; Barnham, Kevin J; Jones, Nigel C; O'Brien, Terence J; Velakoulis, Dennis; Bush, Ashley I

2016-07-01

Autosomal recessive inheritance of NPC1 with loss-of-function mutations underlies Niemann-Pick disease, type C1 (NP-C1), a lysosomal storage disorder with progressive neurodegeneration. It is uncertain from limited biochemical studies and patient case reports whether NPC1 haploinsufficiency can cause a partial NP-C1 phenotype in carriers. In the present study, we examined this possibility in heterozygotes of a natural loss-of-function mutant Npc1 mouse model. We found partial motor dysfunction and increased anxiety-like behavior in Npc1 (+/-) mice by 9 weeks of age. Relative to Npc1 (+/+) mice, Npc1 (+/-) mice failed to show neurodevelopmental improvements in motor coordination and balance on an accelerating Rotarod. In the open-field test, Npc1 (+/-) mice showed an intermediate phenotype in spontaneous locomotor activity compared with Npc1 (+/+) and Npc1 (-/-) mice, as well as decreased center tendency. Together with increased stride length under anxiogenic conditions on the DigiGait treadmill, these findings are consistent with heightened anxiety. Our findings indicate that pathogenic NPC1 allele carriers, who represent about 0.66 % of humans, could be vulnerable to motor and anxiety disorders.

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

Peripheral subnuclear positioning suppresses Tcrb recombination and segregates Tcrb alleles from RAG2.

PubMed

Chan, Elizabeth A W; Teng, Grace; Corbett, Elizabeth; Choudhury, Kingshuk Roy; Bassing, Craig H; Schatz, David G; Krangel, Michael S

2013-11-26

Allelic exclusion requires that the two alleles at antigen-receptor loci attempt to recombine variable (V), diversity (D), and joining (J) gene segments [V(D)J recombination] asynchronously in nuclei of developing lymphocytes. It previously was shown that T-cell receptor β (Tcrb) alleles frequently and stochastically associate with the nuclear lamina and pericentromeric heterochromatin in CD4(-)CD8(-) thymocytes. Moreover, rearranged alleles were underrepresented at these locations. Here we used 3D immunofluorescence in situ hybridization to identify recently rearranged Tcrb alleles based on the accumulation of the DNA-repair protein 53BP1. We found that Tcrb alleles recombine asynchronously in double-negative thymocytes and that V(D)J recombination is suppressed on peripheral as compared with central Tcrb alleles. Moreover, the recombination events that did take place at the nuclear periphery preferentially occurred on Tcrb alleles that were partially dissociated from the nuclear lamina. To understand better the mechanism by which V(D)J recombination is suppressed at the nuclear periphery, we evaluated the subnuclear distribution of recombination-activating gene 2 (RAG2) protein. We found that RAG2 abundance was reduced at the nuclear periphery. Moreover, RAG2 was distributed differently from RNA polymerase II and histone H3K4 trimethylation. Our data suggest that the nuclear periphery suppresses V(D)J recombination, at least in part, by segregating Tcrb alleles from RAG proteins.

Disrupted functional and structural networks in cognitively normal elderly subjects with the APOE ɛ4 allele.

PubMed

Chen, Yaojing; Chen, Kewei; Zhang, Junying; Li, Xin; Shu, Ni; Wang, Jun; Zhang, Zhanjun; Reiman, Eric M

2015-03-13

As the Apolipoprotein E (APOE) ɛ4 allele is a major genetic risk factor for sporadic Alzheimer's disease (AD), which has been suggested as a disconnection syndrome manifested by the disruption of white matter (WM) integrity and functional connectivity (FC), elucidating the subtle brain structural and functional network changes in cognitively normal ɛ4 carriers is essential for identifying sensitive neuroimaging based biomarkers and understanding the preclinical AD-related abnormality development. We first constructed functional network on the basis of resting-state functional magnetic resonance imaging and a structural network on the basis of diffusion tensor image. Using global, local and nodal efficiencies of these two networks, we then examined (i) the differences of functional and WM structural network between cognitively normal ɛ4 carriers and non-carriers simultaneously, (ii) the sensitivity of these indices as biomarkers, and (iii) their relationship to behavior measurements, as well as to cholesterol level. For ɛ4 carriers, we found reduced global efficiency significantly in WM and marginally in FC, regional FC dysfunctions mainly in medial temporal areas, and more widespread for WM network. Importantly, the right parahippocampal gyrus (PHG.R) was the only region with simultaneous functional and structural damage, and the nodal efficiency of PHG.R in WM network mediates the APOE ɛ4 effect on memory function. Finally, the cholesterol level correlated with WM network differently than with the functional network in ɛ4 carriers. Our results demonstrated ɛ4-specific abnormal structural and functional patterns, which may potentially serve as biomarkers for early detection before the onset of the disease.

Apolipoprotein E polymorphism and low density lipoprotein (LDL) oxidation in patients with dementia.

PubMed

Wehr, Hanna; Bednarska-Makaruk, Małgorzata; Graban, Ałła; Kunicki, Paweł K; Lojkowska, Wanda; Rodo, Maria; Ryglewicz, Danuta

2003-01-01

In patients with dementia, 29 diagnosed as probably suffering from Alzheimer's disease and 46 subjects with dementia of vascular origin, and in 41 non demented control subjects LDL oxidation in vitro was compared in carriers of various apolipoprotein E alleles. Restriction isotyping was performed by gene amplification and cleavage with Hhal, LDL oxidation was investigated by determination of conjugated dienes and vitamin E (alpha tocopherol) plasma level was measured by HPLC. In subjects with dementia oxidation of LDL was shown to be higher in carriers of epsilon4 allele as compared with non-carriers of this allele. It was especially observed in the propagation phase, which illustrates oxidation intensity after the exhaustion of the antioxidant reserve in LDL. Vitamin E level did not show differences between carriers of different alleles. It is concluded that the differences in oxidation susceptibility of LDL between demented subjects possessing particular apolipoprotein E forms can result partially from differing antioxidant properties of apolipoprotein E isoforms and, in a substantial degree, from the size and quality of LDL.

The apolipoprotein E epsilon4 allele and memory performance in HIV-1 seropositive subjects: differences at baseline but not after acute oral lorazepam challenge.

PubMed

Pomara, Nunzio; Belzer, Kenneth D; Silva, Raul; Cooper, Thomas B; Sidtis, John J

2008-11-01

The APOE epsilon4 allele, an established genetic risk factor for late-onset Alzheimer's disease, has been linked to an increased risk for dementia especially in older individuals with HIV-1 infection. This allele has also been associated with increased memory impairment following oral lorazepam challenge in healthy elderly. Lorazepam and other benzodiazepines are widely prescribed in individuals with HIV-1 infection who are at increased risk for cognitive impairment. The aim of this study was to examine if the epsilon4 allele influences lorazepam-induced memory deficits in this population. Forty-one non-demented, HIV-1 seropositive adults (15 epsilon4 carriers, mean age = 43.47 +/- 8.25; 26 epsilon4 non-carriers, mean age = 46.77 +/- 8.56) participated in a double-blind, placebo-controlled crossover design, receiving single acute oral doses of lorazepam 0.5, 1.0 mg, or placebo over three sessions, each 1 week apart. Standardized neuropsychological assessments, including measures of immediate and delayed verbal recall, were conducted at baseline and at 1, 2.5, and 5 h post-drug administration in each condition. Acute lorazepam administration produced dose- and time-dependent impairments in measures of verbal recall. However, the e4 allele did not modulate these adverse effects. An APOE epsilon4 group by time interaction was also found such that the APOE-epsilon4-positive subjects had significantly better immediate and delayed verbal recall than the negative subjects at baseline assessment, but the groups did not significantly differ at any subsequent time point. Future studies should clarify the role of epsilon4 in the modulation of drug-induced cognitive toxicity and baseline performance and their relationship to progressive decline, especially in older individuals with HIV-1 infection, a group at increased risk for dementia.

Both Hemophilia Health Care Providers and Hemophilia A Carriers Report that Carriers have Excessive Bleeding

PubMed Central

Paroskie, Allison; Oso, Olatunde; DeBaun, Michael R.; Sidonio, Robert F

2014-01-01

Introduction Hemophilia A, the result of reduced factor VIII (FVIII) activity, is an X-linked recessive bleeding disorder. Previous reports of Hemophilia A carriers suggest an increased bleeding tendency. Our objective was to determine the attitudes and understanding of the Hemophilia A carrier bleeding phenotype, and opinions regarding timing of carrier testing from the perspective of both medical providers and affected patients. Data from this survey was used as preliminary data for an ongoing prospective study. Material and Methods An electronic survey was distributed to physicians and nurses employed at Hemophilia Treatment Centers (HTC), and Hemophilia A carriers who were members of Hemophilia Federation of America. Questions focused on the clinical understanding of bleeding symptoms and management of Hemophilia A carriers, and the timing and intensity of carrier testing. Results Our survey indicates that 51% (36/51) of providers compared to 78% (36/46) of carriers believe that Hemophilia A carriers with normal FVIII activity have an increased bleeding tendency (p<0.001); 72% (33/36) of Hemophilia A carriers report a high frequency of bleeding symptoms. Regarding carrier testing, 72% (50/69) of medical providers recommend testing after 14 years of age, conversely 65% (29/45) of Hemophilia A carriers prefer testing to be done prior to this age (p<0.001). Discussion Hemophilia A carriers self-report a higher frequency of bleeding than previously acknowledged, and have a preference for earlier testing to confirm carrier status. PMID:24309601

The Predicted Cross Value for Genetic Introgression of Multiple Alleles

PubMed Central

Han, Ye; Cameron, John N.; Wang, Lizhi; Beavis, William D.

2017-01-01

We consider the plant genetic improvement challenge of introgressing multiple alleles from a homozygous donor to a recipient. First, we frame the project as an algorithmic process that can be mathematically formulated. We then introduce a novel metric for selecting breeding parents that we refer to as the predicted cross value (PCV). Unlike estimated breeding values, which represent predictions of general combining ability, the PCV predicts specific combining ability. The PCV takes estimates of recombination frequencies as an input vector and calculates the probability that a pair of parents will produce a gamete with desirable alleles at all specified loci. We compared the PCV approach with existing estimated-breeding-value approaches in two simulation experiments, in which 7 and 20 desirable alleles were to be introgressed from a donor line into a recipient line. Results suggest that the PCV is more efficient and effective for multi-allelic trait introgression. We also discuss how operations research can be used for other crop genetic improvement projects and suggest several future research directions. PMID:28122824

eSensor®: A Microarray Technology Based on Electrochemical Detection of Nucleic Acids and Its Application to Cystic Fibrosis Carrier Screening

NASA Astrophysics Data System (ADS)

Reed, Michael R.; Coty, William A.

We have developed a test for identification of carriers for cystic fibrosis using the eSensor® DNA detection technology. Oligonucleotide probes are deposited within self-assembled monolayers on gold electrodes arrayed upon printed circuit boards. These probes allow sequence-specific capture of amplicons containing a panel of mutation sites associated with cystic fibrosis. DNA targets are detected and mutations genotyped using a “sandwich” assay methodology employing electrochemical detection of ferrocene-labeled oligonucleotides for discrimination of carrier and non-carrier alleles. Performance of the cystic fibrosis application demonstrates sufficient accuracy and reliability for clinical diagnostic use, and the procedure can be performed by trained medical technologists available in the hospital laboratory.

Evolutionary dynamics of sporophytic self-incompatibility alleles in plants.

PubMed

Schierup, M H; Vekemans, X; Christiansen, F B

1997-10-01

The stationary frequency distribution and allelic dynamics in finite populations are analyzed through stochastic simulations in three models of single-locus, multi-allelic sporophytic self-incompatibility. The models differ in the dominance relationships among alleles. In one model, alleles act codominantly in both pollen and style (SSIcod), in the second, alleles form a dominance hierarchy in pollen and style (SSIdom). In the third model, alleles interact codominantly in the style and form a dominance hierarchy in the pollen (SSIdomcod). The SSIcod model behaves similarly to the model of gametophytic self-incompatibility, but the selection intensity is stronger. With dominance, dominant alleles invade the population more easily than recessive alleles and have a lower frequency at equilibrium. In the SSIdom model, recessive alleles have both a higher allele frequency and higher expected life span. In the SSIdomcod model, however, loss due to drift occurs more easily for pollen-recessive than for pollen-dominant alleles, and therefore, dominant alleles have a higher expected life span than the more recessive alleles. The process of allelic turnover in the SSIdomcod and SSIdom models is closely approximated by a random walk on a dominance ladder. Implications of the results for experimental studies of sporophytic self-incompatibility in natural populations are discussed.

Simulation of introgression of the polled allele into the Holstein breed via conventional breeding versus gene editing

USDA-ARS?s Scientific Manuscript database

The objective of this study was to simulate the introgression of the polled allele into a dairy cattle population and compare the impact of using the methods of conventional breeding versus gene editing to increase the frequency of the polled allele. The rate of minor allele frequency (MAF) change, ...

Peripheral subnuclear positioning suppresses Tcrb recombination and segregates Tcrb alleles from RAG2

PubMed Central

Chan, Elizabeth A. W.; Teng, Grace; Corbett, Elizabeth; Choudhury, Kingshuk Roy; Bassing, Craig H.; Schatz, David G.; Krangel, Michael S.

2013-01-01

Allelic exclusion requires that the two alleles at antigen-receptor loci attempt to recombine variable (V), diversity (D), and joining (J) gene segments [V(D)J recombination] asynchronously in nuclei of developing lymphocytes. It previously was shown that T-cell receptor β (Tcrb) alleles frequently and stochastically associate with the nuclear lamina and pericentromeric heterochromatin in CD4−CD8− thymocytes. Moreover, rearranged alleles were underrepresented at these locations. Here we used 3D immunofluorescence in situ hybridization to identify recently rearranged Tcrb alleles based on the accumulation of the DNA-repair protein 53BP1. We found that Tcrb alleles recombine asynchronously in double-negative thymocytes and that V(D)J recombination is suppressed on peripheral as compared with central Tcrb alleles. Moreover, the recombination events that did take place at the nuclear periphery preferentially occurred on Tcrb alleles that were partially dissociated from the nuclear lamina. To understand better the mechanism by which V(D)J recombination is suppressed at the nuclear periphery, we evaluated the subnuclear distribution of recombination-activating gene 2 (RAG2) protein. We found that RAG2 abundance was reduced at the nuclear periphery. Moreover, RAG2 was distributed differently from RNA polymerase II and histone H3K4 trimethylation. Our data suggest that the nuclear periphery suppresses V(D)J recombination, at least in part, by segregating Tcrb alleles from RAG proteins. PMID:24218622

Pyramiding of transgenic Pm3 alleles in wheat results in improved powdery mildew resistance in the field.

PubMed

Koller, Teresa; Brunner, Susanne; Herren, Gerhard; Hurni, Severine; Keller, Beat

2018-04-01

The combined effects of enhanced total transgene expression level and allele-specificity combination in transgenic allele-pyramided Pm3 wheat lines result in improved powdery mildew field resistance without negative pleiotropic effects. Allelic Pm3 resistance genes of wheat confer race-specific resistance to powdery mildew (Blumeria graminis f. sp. tritici, Bgt) and encode nucleotide-binding domain, leucine-rich repeat (NLR) receptors. Transgenic wheat lines overexpressing alleles Pm3a, b, c, d, f, and g have previously been generated by transformation of cultivar Bobwhite and tested in field trials, revealing varying degrees of powdery mildew resistance conferred by the transgenes. Here, we tested four transgenic lines each carrying two pyramided Pm3 alleles, which were generated by crossbreeding of lines transformed with single Pm3 alleles. All four allele-pyramided lines showed strongly improved powdery mildew resistance in the field compared to their parental lines. The improved resistance results from the two effects of enhanced total transgene expression levels and allele-specificity combinations. In contrast to leaf segment tests on greenhouse-grown seedlings, no allelic suppression was observed in the field. Plant development and yield scores of the pyramided lines were similar to the mean scores of the corresponding parental lines, and thus, the allele pyramiding did not cause any negative effects. On the contrary, in pyramided line, Pm3b × Pm3f normal plant development was restored compared to the delayed development and reduced seed set of parental line Pm3f. Allele-specific RT qPCR revealed additive transgene expression levels of the two Pm3 alleles in the pyramided lines. A positive correlation between total transgene expression level and powdery mildew field resistance was observed. In summary, allele pyramiding of Pm3 transgenes proved to be successful in enhancing powdery mildew field resistance.

Cardiac involvement in female Duchenne and Becker muscular dystrophy carriers in comparison to their first-degree male relatives: a comparative cardiovascular magnetic resonance study.

PubMed

Florian, Anca; Rösch, Sabine; Bietenbeck, Michael; Engelen, Markus; Stypmann, Jörg; Waltenberger, Johannes; Sechtem, Udo; Yilmaz, Ali

2016-03-01

Duchenne (DMD) and Becker (BMD) muscular dystrophies are X-linked recessive disorders associated with both skeletal myopathy and progressive cardiomyopathy in males. Female DMD/BMD carriers (DMDc/BMDc) are mostly free of skeletal muscle symptoms, but they are also prone to cardiomyopathy. The aim of the current study was to characterize the frequency, pattern, and extent of cardiomyopathy in female DMD/BMD carriers (DMDc/BMDc) in comparison to their first-degree male MD relatives. Thirty-six (age 44 ± 14 years) female MD carriers (20 DMDc and 16 BMDc) constituted the 'MD carrier group' and were prospectively enrolled. All MD carriers underwent a complete CMR study comprising cine- and late gadolinium enhancement (LGE) imaging. In 22 of these women ('female MD carrier comparison group', 7 DMD and 15 BMD), at least one first-degree male relative with a previously established diagnosis of MD underwent the same CMR protocol and was assigned to the 'male MD comparison group' (n = 24, 6 DMD and 18 BMD). In the total MD carrier group, 17 (47%) MD carriers had at least one pathological CMR finding [5 (14%) with a reduced left ventricular ejection fraction (LV-EF) and 16 (44%) with the presence of LGE]. All LGE-positive patients (n = 16) showed non-ischaemic LGE with subepicardial involvement of the LV lateral free wall being the most frequent pattern (13/16, 81%). Compared with BMDc, DMDc demonstrated more frequently a pathological CMR result (65 vs. 19%; P = 0.008)--in spite of being significantly younger (40 ± 11 vs. 50 ± 16 years, P = 0.038). In the male MD comparison group, the same LGE pattern as in female carriers was seen, but with a significantly higher prevalence of cardiac abnormalities compared with their female carrier relatives constituting the female MD comparison group (75 vs. 27%; P = 0.003). Cardiac involvement is a frequent finding in female carriers of DMD, but less frequently observed in carriers of BMD. Those DMDc and BMDc with cardiac involvement

Association of primary biliary cirrhosis with the allele HLA-DPB1*0301 in a German population.

PubMed

Mella, J G; Roschmann, E; Maier, K P; Volk, B A

1995-02-01

The major histocompatibility complex class II alleles at the HLA-DPB1 locus were investigated in 32 German Caucasoid patients with primary biliary cirrhosis (PBC) and compared with those from 47 normal control patients using molecular genotyping techniques. The second exon of the HLA-DPB1 gene was amplified by polymerase chain reaction (PCR) and hybridized with 25 sequence-specific oligonucleotides (SSOs) to assign the HLA-DPB1 alleles on the basis of known sequence variations, according to the protocols of the Eleventh International Histocompatibility Workshop. A strong association of PBC was found with the allele HLA-DPB1*0301. The allele HLA DPB1*0301 was present in 50% (16 of 32) of the patients with PBC compared with 13% (6 of 47) of normal controls (P corrected < .015), whereas the other HLA-DPB1 alleles showed no significant differences in both groups. The relative risk (RR) estimate for the allele HLA-DPB1*0301 was 6.8 (95% confidence limits: 2.27 to 20.57). In summary, this study clearly demonstrates an association of PBC with the HLA-DPB1*0301 allele in German Caucasoids and may add new data to the immunogenetic background of PBC, suggesting a contribution of the HLA-DPB1 gene to the genetic susceptibility of the disease.

Tyrosine hydroxylase and dopamine D4 receptor allelic distribution in Scandinavian chronic alcoholics.

PubMed

Geijer, T; Jönsson, E; Neiman, J; Persson, M L; Brené, S; Gyllander, A; Sedvall, G; Rydberg, U; Wasserman, D; Terenius, L

1997-02-01

Associations of polymorphic genetic markers at the tyrosine hydroxylase (TH) and dopamine D4 receptor (DRD4) loci were examined in Scandinavian chronic alcoholics (n = 72) and control subjects (n = 67). Patients were divided into subgroups with regard to the presence of parental alcoholism and age of onset. Neither the TH nor the DRD4 allele distributions were significantly different when alcoholic samples were compared with control subjects. However, a tendency to high prevalence for 1 of the 5 TH alleles assayed (TH-K3) was observed in a subsample of 44 alcoholics characterized by late onset when compared with control subjects (27.3% vs. 10.6%, p = 0.041). Results suggest that no major influence on alcoholism is exerted through genes associated with the DRD4 or TH allelic markers examined.

Reduced carriership of 4G allele of plasminogen activator inhibitor-1 4G/5G polymorphism in very young survivors of myocardial infarction.

PubMed

Rallidis, Loukianos S; Gialeraki, Argyri; Merkouri, Efrosyni; Liakos, George; Dagres, Nikolaos; Sionis, Dimitrios; Travlou, Anthi; Lekakis, John; Kremastinos, Dimitrios T

2010-05-01

There are limited and controversial data regarding the impact of 4G/5G polymorphism of the plasminogen activator inhibitor-1 (PAI-1) gene in the pathogenesis of premature myocardial infarction (MI). We explored whether 4G/5G polymorphism of the PAI-1 gene is associated with the development of MI allele carriers (4G/4G and 4G/5G genotypes) of PAI-1 were less frequent in patients than in controls (69.6 vs. 83.6%, P = 0.007). 4G carriership of the polymorphism of PAI-1 was associated with lower risk for acute MI (odds ratio 0.45, 95% confidence interval 0.23-0.88, P = 0.02) after adjusting for major cardiovascular risk factors. Patients possessing the 4G allele had higher PAI-1 plasma levels (32.2 +/- 25 vs. 22.2 +/- 11.3 ng/ml, P = 0.006) but lower lipoprotein(a) levels (10.1 [2.1-29.9] vs. 15.3 [8.2-57.1] mg/dl, P = 0.03) compared to 5G/5G homozygotes. Our data indicate that the 4G allele of the PAI-1 4G/5G polymorphism is less frequent among survivors of MI at very young age compared with matched controls.

Intrinsic MYH7 expression regulation contributes to tissue level allelic imbalance in hypertrophic cardiomyopathy.

PubMed

Montag, Judith; Syring, Mandy; Rose, Julia; Weber, Anna-Lena; Ernstberger, Pia; Mayer, Anne-Kathrin; Becker, Edgar; Keyser, Britta; Dos Remedios, Cristobal; Perrot, Andreas; van der Velden, Jolanda; Francino, Antonio; Navarro-Lopez, Francesco; Ho, Carolyn Yung; Brenner, Bernhard; Kraft, Theresia

2017-08-01

HCM, the most common inherited cardiac disease, is mainly caused by mutations in sarcomeric genes. More than a third of the patients are heterozygous for mutations in the MYH7 gene encoding for the β-myosin heavy chain. In HCM-patients, expression of the mutant and the wildtype allele can be unequal, thus leading to fractions of mutant and wildtype mRNA and protein which deviate from 1:1. This so-called allelic imbalance was detected in whole tissue samples but also in individual cells. There is evidence that the severity of HCM not only depends on the functional effect of the mutation itself, but also on the fraction of mutant protein in the myocardial tissue. Allelic imbalance has been shown to occur in a broad range of genes. Therefore, we aimed to examine whether the MYH7-alleles are intrinsically expressed imbalanced or whether the allelic imbalance is solely associated with the disease. We compared the expression of MYH7-alleles in non-HCM donors and in HCM-patients with different MYH7-missense mutations. In the HCM-patients, we identified imbalanced as well as equal expression of both alleles. Also at the protein level, allelic imbalance was determined. Most interestingly, we also discovered allelic imbalance and balance in non-HCM donors. Our findings therefore strongly indicate that apart from mutation-specific mechanisms, also non-HCM associated allelic-mRNA expression regulation may account for the allelic imbalance of the MYH7 gene in HCM-patients. Since the relative amount of mutant mRNA and protein or the extent of allelic imbalance has been associated with the severity of HCM, individual analysis of the MYH7-allelic expression may provide valuable information for the prognosis of each patient.

Colorectal cancer risk variants at 8q23.3 and 11q23.1 are associated with disease phenotype in APC mutation carriers.

PubMed

Ghorbanoghli, Z; Nieuwenhuis, M H; Houwing-Duistermaat, J J; Jagmohan-Changur, S; Hes, F J; Tops, C M; Wagner, A; Aalfs, C M; Verhoef, S; Gómez García, E B; Sijmons, R H; Menko, F H; Letteboer, T G; Hoogerbrugge, N; van Wezel, T; Vasen, H F A; Wijnen, J T

2016-10-01

Familial adenomatous polyposis (FAP) is a dominantly inherited syndrome caused by germline mutations in the APC gene and characterized by the development of multiple colorectal adenomas and a high risk of developing colorectal cancer (CRC). The severity of polyposis is correlated with the site of the APC mutation. However, there is also phenotypic variability within families with the same underlying APC mutation, suggesting that additional factors influence the severity of polyposis. Genome-wide association studies identified several single nucleotide polymorphisms (SNPs) that are associated with CRC. We assessed whether these SNPs are associated with polyp multiplicity in proven APC mutation carriers. Sixteen CRC-associated SNPs were analysed in a cohort of 419 APC germline mutation carriers from 182 families. Clinical data were retrieved from the Dutch Polyposis Registry. Allele frequencies of the SNPs were compared for patients with <100 colorectal adenomas versus patients with ≥100 adenomas, using generalized estimating equations with the APC genotype as a covariate. We found a trend of association of two of the tested SNPs with the ≥100 adenoma phenotype: the C alleles of rs16892766 at 8q23.3 (OR 1.71, 95 % CI 1.05-2.76, p = 0.03, dominant model) and rs3802842 at 11q23.1 (OR 1.51, 95 % CI 1.03-2.22, p = 0.04, dominant model). We identified two risk variants that are associated with a more severe phenotype in APC mutation carriers. These risk variants may partly explain the phenotypic variability in families with the same APC gene defect. Further studies with a larger sample size are recommended to evaluate and confirm the phenotypic effect of these SNPs in FAP.

Histidine-lysine peptides as carriers of nucleic acids.

PubMed

Leng, Qixin; Goldgeier, Lisa; Zhu, Jingsong; Cambell, Patricia; Ambulos, Nicholas; Mixson, A James

2007-03-01

With their biodegradability and diversity of permutations, peptides have significant potential as carriers of nucleic acids. This review will focus on the sequence and branching patterns of peptide carriers composed primarily of histidines and lysines. While lysines within peptides are important for binding to the negatively charged phosphates, histidines are critical for endosomal lysis enabling nucleic acids to reach the cytosol. Histidine-lysine (HK) polymers by either covalent or ionic bonds with liposomes augment transfection compared to liposome carriers alone. More recently, we have examined peptides as sole carriers of nucleic acids because of their intrinsic advantages compared to the bipartite HK/liposome carriers. With a protocol change and addition of a histidine-rich tail, HK peptides as sole carriers were more effective than liposomes alone in several cell lines. While four-branched polymers with a primary repeating sequence pattern of -HHK- were more effective as carriers of plasmids, eight-branched polymers with a sequence pattern of -HHHK- were more effective as carriers of siRNA. Compared to polyethylenimine, HK carriers of siRNA and plasmids had reduced toxicity. When injected intravenously, HK polymers in complex with plasmids encoding antiangiogenic proteins significantly decreased tumor growth. Furthermore, modification of HK polymers with polyethylene glycol and vascular-specific ligands increased specificity of the polyplex to the tumor by more than 40-fold. Together with further development and insight on the structure of HK polyplexes, HK peptides may prove to be useful as carriers of different forms of nucleic acids both in vitro and in vivo.

Huntington disease reduced penetrance alleles occur at high frequency in the general population

PubMed Central

Kay, Chris; Collins, Jennifer A.; Miedzybrodzka, Zosia; Madore, Steven J.; Gordon, Erynn S.; Gerry, Norman; Davidson, Mark; Slama, Ramy A.

2016-01-01

Objective: To directly estimate the frequency and penetrance of CAG repeat alleles associated with Huntington disease (HD) in the general population. Methods: CAG repeat length was evaluated in 7,315 individuals from 3 population-based cohorts from British Columbia, the United States, and Scotland. The frequency of ≥36 CAG alleles was assessed out of a total of 14,630 alleles. The general population frequency of reduced penetrance alleles (36–39 CAG) was compared to the prevalence of patients with HD with genetically confirmed 36–39 CAG from a multisource clinical ascertainment in British Columbia, Canada. The penetrance of 36–38 CAG repeat alleles for HD was estimated for individuals ≥65 years of age and compared against previously reported clinical penetrance estimates. Results: A total of 18 of 7,315 individuals had ≥36 CAG, revealing that approximately 1 in 400 individuals from the general population have an expanded CAG repeat associated with HD (0.246%). Individuals with CAG 36–37 genotypes are the most common (36, 0.096%; 37, 0.082%; 38, 0.027%; 39, 0.000%; ≥40, 0.041%). General population CAG 36–38 penetrance rates are lower than penetrance rates extrapolated from clinical cohorts. Conclusion: HD alleles with a CAG repeat length of 36–38 occur at high frequency in the general population. The infrequent diagnosis of HD at this CAG length is likely due to low penetrance. Another important contributing factor may be reduced ascertainment of HD in those of older age. PMID:27335115

BRCA1 allele-specific expression in genetic predisposed breast/ovarian cancer.

PubMed

Jamard, Estelle; Volard, Bertrand; Dugué, Audrey Emmanuelle; Legros, Angelina; Leconte, Alexandra; Clarisse, Bénédicte; Davy, Grégoire; Polycarpe, Florence; Dugast, Catherine; Abadie, Caroline; Frebourg, Thierry; Tinat, Julie; Tennevet, Isabelle; Layet, Valérie; Joly, Florence; Castéra, Laurent; Berthet, Pascaline; Vaur, Dominique; Krieger, Sophie

2017-04-01

Germline allele specific expression (ASE), resulting in a lowered expression of one of the BRCA1 alleles, has been described as a possible predisposition marker in Hereditary Breast or Ovarian Cancer (HBOC), usable for molecular diagnosis in HBOC. The main objective of this prospective case-control study was to compare the proportion of ASE between controls without familial history of breast or ovarian cancer, and HBOC cases without BRCA1 or BRCA2 deleterious mutation. BRCA1 ASE evaluated on three SNPs among controls and HBOC patients without deleterious mutation were assessed by pyrosequencing. The allelic ratios and the proportion of ASE were compared between controls and cases using a Student's t test and a Fisher exact test, respectively. The linearity and reproducibility of the ASE dosage was demonstrated with R 2  > 0.99 and a coefficient of variation below 10 %, and ASE was detected in two positive controls harbouring BRCA1 truncated mutations. In the heterozygote population, composed of 99/264 controls (37.5 %) and 96/227 patients (42.3 %), we detected a 5 % ASE without truncated mutations, in each population. We failed to detect any significant difference of ASE between controls and patients. So far, BRCA1 Allelic specific expression is not usable in routine diagnosis as a possible predisposition marker in HBOC patients except for the detection of truncated mutations.

Allelic genealogies in sporophytic self-incompatibility systems in plants.

PubMed

Schierup, M H; Vekemans, X; Christiansen, F B

1998-11-01

Expectations for the time scale and structure of allelic genealogies in finite populations are formed under three models of sporophytic self-incompatibility. The models differ in the dominance interactions among the alleles that determine the self-incompatibility phenotype: In the SSIcod model, alleles act codominantly in both pollen and style, in the SSIdom model, alleles form a dominance hierarchy, and in SSIdomcod, alleles are codominant in the style and show a dominance hierarchy in the pollen. Coalescence times of alleles rarely differ more than threefold from those under gametophytic self-incompatibility, and transspecific polymorphism is therefore expected to be equally common. The previously reported directional turnover process of alleles in the SSIdomcod model results in coalescence times lower and substitution rates higher than those in the other models. The SSIdom model assumes strong asymmetries in allelic action, and the most recessive extant allele is likely to be the most recent common ancestor. Despite these asymmetries, the expected shape of the allele genealogies does not deviate markedly from the shape of a neutral gene genealogy. The application of the results to sequence surveys of alleles, including interspecific comparisons, is discussed.

Identification of a new defective SERPINA1 allele (PI*Zla palma) encoding an alpha-1-antitrypsin with altered glycosylation pattern.

PubMed

Hernández-Pérez, José M; Ramos-Díaz, Ruth; Pérez, José A

2017-10-01

Alpha-1-antitrypsin (AAT) deficiency is a genetic condition that arises from mutations in the SERPINA1 gene and predisposes to develop pulmonary emphysema and, less frequently, liver disease. Occasionally, new defective SERPINA1 alleles are detected as an outcome of targeted-screening programs or case-findings. This study began with a female patient showing bronchial hyperreactivity. Serum level and phenotype for AAT was analysed by immunonephelometry and isoelectric focusing electrophoresis. The SERPINA1 gene of the proband was genotyped by PCR amplification and DNA sequencing. Analysis of AAT deficiency was extended to the proband's family. An abnormal AAT variant that migrated to a more cathodal position than PiZ AAT was detected in the proband's serum. Genetic analysis demonstrated that proband is heterozygous for a new defective SERPINA1 allele (PI*Z la palma ) characterized by the c.321C > A (p.Asn83Lys) mutation in the M1Val213 background. This mutation abolishes the N-glycosylation site in position 83 of the mature AAT. Eight relatives of the proband are carriers of the PI*Z la palma allele and four of them have shown symptoms of bronchial asthma or bronchial hyperreactivity. The mean α1AT level in the serum of PI*MZ la palma individuals was 87.1 mg/dl. The reduction in circulating AAT levels associated to the PI*Z la palma allele was similar to that of PI*Z allele, representing a risk of impairment in lung function. Copyright © 2017 Elsevier Ltd. All rights reserved.

Association of Docosahexaenoic Acid Supplementation With Alzheimer Disease Stage in Apolipoprotein E ε4 Carriers: A Review.

PubMed

Yassine, Hussein N; Braskie, Meredith N; Mack, Wendy J; Castor, Katherine J; Fonteh, Alfred N; Schneider, Lon S; Harrington, Michael G; Chui, Helena C

2017-03-01

The apolipoprotein E ε4 (APOE4) allele identifies a unique population that is at significant risk for developing Alzheimer disease (AD). Docosahexaenoic acid (DHA) is an essential ω-3 fatty acid that is critical to the formation of neuronal synapses and membrane fluidity. Observational studies have associated ω-3 intake, including DHA, with a reduced risk for incident AD. In contrast, randomized clinical trials of ω-3 fatty acids have yielded mixed and inconsistent results. Interactions among DHA, APOE genotype, and stage of AD pathologic changes may explain the mixed results of DHA supplementation reported in the literature. Although randomized clinical trials of ω-3 in symptomatic AD have had negative findings, several observational and clinical trials of ω-3 in the predementia stage of AD suggest that ω-3 supplementation may slow early memory decline in APOE4 carriers. Several mechanisms by which the APOE4 allele could alter the delivery of DHA to the brain may be amenable to DHA supplementation in predementia stages of AD. Evidence of accelerated DHA catabolism (eg, activation of phospholipases and oxidation pathways) could explain the lack of efficacy of ω-3 supplementation in AD dementia. The association of cognitive benefit with DHA supplementation in predementia but not AD dementia suggests that early ω-3 supplementation may reduce the risk for or delay the onset of AD symptoms in APOE4 carriers. Recent advances in brain imaging may help to identify the optimal timing for future DHA clinical trials. High-dose DHA supplementation in APOE4 carriers before the onset of AD dementia can be a promising approach to decrease the incidence of AD. Given the safety profile, availability, and affordability of DHA supplements, refining an ω-3 intervention in APOE4 carriers is warranted.

Are ‘Endurance’ Alleles ‘Survival’ Alleles? Insights from the ACTN3 R577X Polymorphism

PubMed Central

Fiuza-Luces, Carmen; Ruiz, Jonatan R.; Rodríguez-Romo, Gabriel; Santiago, Catalina; Gómez-Gallego, Félix; Yvert, Thomas; Cano-Nieto, Amalia; Garatachea, Nuria

2011-01-01

Exercise phenotypes have played a key role for ensuring survival over human evolution. We speculated that some genetic variants that influence exercise phenotypes could be associated with exceptional survival (i.e. reaching ≥100years of age). Owing to its effects on muscle structure/function, a potential candidate is the Arg(R)577Ter(X) polymorphism (rs1815739) in ACTN3, the structural gene encoding the skeletal muscle protein α-actinin-3. We compared the ACTN3 R577X genotype/allele frequencies between the following groups of ethnically-matched (Spanish) individuals: centenarians (cases, n = 64; 57 female; age range: 100–108 years), young healthy controls (n = 283, 67 females, 216 males; 21±2 years), and humans who are at the two end-points of exercise capacity phenotypes, i.e. muscle endurance (50 male professional road cyclists) and muscle power (63 male jumpers/sprinters). Although there were no differences in genotype/allele frequencies between centenarians (RR:28.8%; RX:47.5%; XX:23.7%), and controls (RR:31.8%; RX:49.8%; XX:18.4%) or endurance athletes (RR:28.0%; RX:46%; XX:26.0%), we observed a significantly higher frequency of the X allele (P = 0.019) and XX genotype (P = 0.011) in centenarians compared with power athletes (RR:47.6%; RX:36.5%;XX:15.9%). Notably, the frequency of the null XX (α-actinin-3 deficient) genotype in centenarians was the highest ever reported in non-athletic Caucasian populations. In conclusion, despite there were no significant differences with the younger, control population, overall the ACTN3 genotype of centenarians resembles that of world-class elite endurance athletes and differs from that of elite power athletes. Our preliminary data would suggest a certain ‘survival’ advantage brought about by α-actinin-3 deficiency and the ‘endurance’/oxidative muscle phenotype that is commonly associated with this condition. PMID:21407828

Preconceptional identification of cystic fibrosis carriers in the Sardinian population: A pilot screening program.

PubMed

Coiana, Alessandra; Faa', Valeria; Carta, Daniela; Puddu, Rosalba; Cao, Antonio; Rosatelli, Maria Cristina

2011-05-01

In Sardinia the mutational spectrum of CFTR gene is well defined. A mutation detection rate of 94% can be achieved by screening for 15 CFTR mutations with a frequency higher than 0.5%. The efficiency of this molecular test suggests that Sardinians may represent a suitable population for a preconceptional screening. Five hundred couples of Sardinia descent were screened for 38 mutations using a semi-automated reverse-dot blot and PCR-gel electrophoresis assays. This mutation panel included the 15 most frequent CF alleles in Sardinia. We identified 38 CF carriers, revealing an overall frequency of 1/25 (4%). The most common CF allele was the p.Thr338Ile (T338I) (65%), followed by the p.Phe508del (F508del) (22.5%). We also identified one couple at risk and an asymptomatic female homozygote for the p.Thr338Ile allele. In spite of the low number of the couples tested, the results herein reported demonstrate the efficacy and efficiency of the preconceptional screening program and the high participation rate of the Sardinian population (99%). Copyright © 2010 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Persistent HPV16/18 infection in Indian women with the A-allele (rs6457617) of HLA-DQB1 and T-allele (rs16944) of IL-1β -511 is associated with development of cervical carcinoma.

PubMed

Dutta, Sankhadeep; Chakraborty, Chandraditya; Mandal, Ranajit Kumar; Basu, Partha; Biswas, Jaydip; Roychoudhury, Susanta; Panda, Chinmay Kumar

2015-07-01

The aim of this study was to understand the association of human papillomavirus (HPV) type 16/18 infection and polymorphisms in the HLA-DQB1 (rs6457617) and IL-1β -511 (rs16944) loci with the development of uterine cervical cancer (CaCx). The distribution of HLA-DQB1 G > A and IL-1β -511 C/T polymorphisms was determined in HPV-negative cervical swabs from normal women (N = 111) and compared with cervical swabs of HPV-cleared normal women (once HPV infected followed by natural clearance of the infection, N = 86), HPV16/18-positive cervical intraepithelial neoplasia (CIN, N = 41) and CaCx biopsies (N = 107). The A-allele containing genotypes (i.e. G/A and A/A) of HLA-DQB1 was significantly associated with CaCx compared with HPV-negative [OR = 2.56(1.42-4.62), p = 0.001] or HPV-cleared [OR = 2.07(1.12-3.87), p = 0.01] normal women, whereas the T-allele containing genotypes (i.e. C/T and T/T) of IL-1β showed increased risk of CIN [OR = 3.68(0.97-16.35), p = 0.03; OR = 3.59(0.92-16.38), p = 0.03] and CaCx development [OR = 2.03(1.03-5.2), p = 0.02; OR = 2.25(0.96-5.31), p = 0.04] compared with HPV-negative or HPV-cleared normal women. Considering these two loci together, it was evident that the T- and A-alleles rendered significantly increased susceptibility for development of CIN and CaCx compared with HPV-negative and HPV-cleared normal women. Moreover, the T-allele of IL-1β showed increased susceptibility for CIN [OR = 3.62(0.85-17.95), p = 0.04] and CaCx [OR = 2.39(0.91-6.37), p = 0.05] development compared with the HPV-cleared women, even in the presence of the HLA-DQB1 G-allele. Thus, our data suggest that persistent HPV16/18 infection in the cervix due to the presence of the HLA-DQB1 A-allele and chronic inflammation due to the presence of the IL-1β -511 T-allele might predispose women to CaCx development.

Plasma metabolomics reveal alterations of sphingo- and glycerophospholipid levels in non-diabetic carriers of the transcription factor 7-like 2 polymorphism rs7903146.

PubMed

Then, Cornelia; Wahl, Simone; Kirchhofer, Anna; Grallert, Harald; Krug, Susanne; Kastenmüller, Gabi; Römisch-Margl, Werner; Claussnitzer, Melina; Illig, Thomas; Heier, Margit; Meisinger, Christa; Adamski, Jerzy; Thorand, Barbara; Huth, Cornelia; Peters, Annette; Prehn, Cornelia; Heukamp, Ina; Laumen, Helmut; Lechner, Andreas; Hauner, Hans; Seissler, Jochen

2013-01-01

Polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene have been shown to display a powerful association with type 2 diabetes. The aim of the present study was to evaluate metabolic alterations in carriers of a common TCF7L2 risk variant. Seventeen non-diabetic subjects carrying the T risk allele at the rs7903146 TCF7L2 locus and 24 subjects carrying no risk allele were submitted to intravenous glucose tolerance test and euglycemic-hyperinsulinemic clamp. Plasma samples were analysed for concentrations of 163 metabolites through targeted mass spectrometry. TCF7L2 risk allele carriers had a reduced first-phase insulin response and normal insulin sensitivity. Under fasting conditions, carriers of TCF7L2 rs7903146 exhibited a non-significant increase of plasma sphingomyelins (SMs), phosphatidylcholines (PCs) and lysophosphatidylcholines (lysoPCs) species. A significant genotype effect was detected in response to challenge tests in 6 SMs (C16:0, C16:1, C18:0, C18:1, C24:0, C24:1), 5 hydroxy-SMs (C14:1, C16:1, C22:1, C22:2, C24:1), 4 lysoPCs (C14:0, C16:0, C16:1, C17:0), 3 diacyl-PCs (C28:1, C36:6, C40:4) and 4 long-chain acyl-alkyl-PCs (C40:2, C40:5, C44:5, C44:6). Plasma metabolomic profiling identified alterations of phospholipid metabolism in response to challenge tests in subjects with TCF7L2 rs7903146 genotype. This may reflect a genotype-mediated link to early metabolic abnormalities prior to the development of disturbed glucose tolerance.

Altered Episodic Memory in Introverted Young Adults Carrying the BDNFMet Allele

PubMed Central

Bombardier, Andreanne; Beauchemin, Maude; Gosselin, Nadia; Poirier, Judes; De Beaumont, Louis

2016-01-01

While most studies have been interested in the distinct, predisposing roles of the common BDNF Val66Met variant and extraversion personality traits on episodic memory, very few studies have looked at the synergistic effects of genetic and personality factors to account for cognitive variance. This is surprising considering recent reports challenging the long-held belief that the BDNFMet variant negatively impacts cognitive function. A total of 75 young healthy adults (26 of them carried at least one copy of the BDNFMet allele) took part in this study consisting of genetic profiling from saliva, personality assessment using the Revised NEO Personality Inventory (NEO PI-R) and a short battery of neuropsychological tests. An ANOVA revealed that BDNFMet carriers were significantly less extraverted than BDNFVal carriers (F1,73 = 9.54; p < 0.01; ηp2 = 0.126). Moreover, extraversion was found to significantly moderate the relationship between the BDNF genotype and episodic memory performance (p = 0.03). Subsequent correlational analyses yielded a strong and significant correlation (r = 0.542; p < 0.005) between introversion and delayed episodic memory specific to BDNFMet individuals. The present study suggests that introversion and the BDNFMet variant synergistically interact to reduce episodic memory performance in healthy, young adults. These findings reaffirm that a more accurate explanation of cognitive variance can be achieved by looking at the synergistic effects of genotype and phenotype factors. PMID:27845759

Genotype-phenotype correlation and functional studies in patients with cystic fibrosis bearing CFTR complex alleles.

PubMed

Terlizzi, Vito; Castaldo, Giuseppe; Salvatore, Donatello; Lucarelli, Marco; Raia, Valeria; Angioni, Adriano; Carnovale, Vincenzo; Cirilli, Natalia; Casciaro, Rosaria; Colombo, Carla; Di Lullo, Antonella Miriam; Elce, Ausilia; Iacotucci, Paola; Comegna, Marika; Scorza, Manuela; Lucidi, Vincenzina; Perfetti, Anna; Cimino, Roberta; Quattrucci, Serena; Seia, Manuela; Sofia, Valentina Maria; Zarrilli, Federica; Amato, Felice

2017-04-01

The effect of complex alleles in cystic fibrosis (CF) is poorly defined for the lack of functional studies. To describe the genotype-phenotype correlation and the results of either in vitro and ex vivo studies performed on nasal epithelial cells (NEC) in a cohort of patients with CF carrying cystic fibrosis transmembrane conductance regulator ( CFTR ) complex alleles. We studied 70 homozygous, compound heterozygous or heterozygous for CFTR mutations: p.[Arg74Trp;Val201Met;Asp1270Asn], n=8; p.[Ile148Thr;Ile1023_Val1024del], n=5; p.[Arg117Leu;Leu997Phe], n=6; c.[1210-34TG[12];1210-12T[5];2930C>T], n=3; p.[Arg74Trp;Asp1270Asn], n=4; p.Asp1270Asn, n=2; p.Ile148Thr, n=6; p.Leu997Phe, n=36. In 39 patients, we analysed the CFTR gating activity on NEC in comparison with patients with CF (n=8) and carriers (n=4). Finally, we analysed in vitro the p.[Arg74Trp;Val201Met;Asp1270Asn] complex allele. The p.[Ile148Thr;Ile1023_Val1024del] caused severe CF in five compound heterozygous with a class I-II mutation. Their CFTR activity on NEC was comparable with patients with two class I-II mutations (mean 7.3% vs 6.9%). The p.[Arg74Trp;Asp1270Asn] and the p.Asp1270Asn have scarce functional effects, while p.[Arg74Trp;Val201Met;Asp1270Asn] caused mild CF in four of five subjects carrying a class I-II mutation in trans , or CFTR-related disorders (CFTR-RD) in three having in trans a class IV-V mutation. The p.[Arg74Trp;Val201Met;Asp1270Asn] causes significantly (p<0.001) higher CFTR activity compared with compound heterozygous for class I-II mutations. Furthermore, five of six compounds heterozygous with the p.[Arg117Leu;Leu997Phe] had mild CF, whereas the p.Leu997Phe, in trans with a class I-II CFTR mutation, caused CFTR-RD or a healthy status (CFTR activity: 21.3-36.9%). Finally, compounds heterozygous for the c.[1210-34TG[12];1210-12T[5];2930C>T] and a class I-II mutation had mild CF or CFTR-RD (gating activity: 18.5-19.0%). The effect of complex alleles partially depends on the

Comparative efficacy of several disinfectants in suspension and carrier tests against Haemophilus parasuis serovars 1 and 5.

PubMed

Rodríguez Ferri, E F; Martínez, S; Frandoloso, R; Yubero, S; Gutiérrez Martín, C B

2010-06-01

The comparative efficacy of 16 active compounds (including the most commonly used chemical groups) and 10 commercial formulations against Haemophilus parasuis serovars 1 and 5 was studied. These organisms were tested in suspension and carrier tests in the presence and absence of serum as representative of organic matter. Chloramine-T and half of the formulations from commercial sources (most of them including quaternary ammonium compounds) were effective in both in vitro tests, regardless of the presence or absence of organic load. All 26 disinfectants except for an iodophor (0.1% available iodine) resulted in at least 3-log(10) reduction in colony-forming units in suspension test, and most of them resulted in the maximal level of detection (>6-log(10) reduction). On the other hand, disinfectants were not as effective in carrier test as in suspension test, and the presence of serum considerably reduced the activities of most of the compounds tested, especially in carrier test. These results suggest the importance of selecting suitable disinfection for routine use on surfaces contaminated with H. parasuis, particularly when organic matter is present. Chloramine-T and formulations 2 and 7-10 are recommended for a complete inactivation of H. parasuis in swine herds. Copyright 2009 Elsevier Ltd. All rights reserved.

Detection of 549 new HLA alleles in potential stem cell donors from the United States, Poland and Germany.

PubMed

Hernández-Frederick, C J; Cereb, N; Giani, A S; Ruppel, J; Maraszek, A; Pingel, J; Sauter, J; Schmidt, A H; Yang, S Y

2016-01-01

We characterized 549 new human leukocyte antigen (HLA) class I and class II alleles found in newly registered stem cell donors as a result of high-throughput HLA typing. New alleles include 101 HLA-A, 132 HLA-B, 105 HLA-C, 2 HLA-DRB1, 89 HLA-DQB1 and 120 HLA-DPB1 alleles. Mainly, new alleles comprised single nucleotide variations when compared with homologous sequences. We identified nonsynonymous nucleotide mutations in 70.7% of all new alleles, synonymous variations in 26.4% and nonsense substitutions in 2.9% (null alleles). Some new alleles (55, 10.0%) were found multiple times, HLA-DPB1 alleles being the most frequent among these. Furthermore, as several new alleles were identified in individuals from ethnic minority groups, the relevance of recruiting donors belonging to such groups and the importance of ethnicity data collection in donor centers and registries is highlighted. © 2015 The Authors. HLA published by John Wiley & Sons Ltd.

Recent Advances in Subunit Vaccine Carriers

PubMed Central

Vartak, Abhishek; Sucheck, Steven J.

2016-01-01

The lower immunogenicity of synthetic subunit antigens, compared to live attenuated vaccines, is being addressed with improved vaccine carriers. Recent reports indicate that the physio-chemical properties of these carriers can be altered to achieve optimal antigen presentation, endosomal escape, particle bio-distribution, and cellular trafficking. The carriers can be modified with various antigens and ligands for dendritic cells targeting. They can also be modified with adjuvants, either covalently or entrapped in the matrix, to improve cellular and humoral immune responses against the antigen. As a result, these multi-functional carrier systems are being explored for use in active immunotherapy against cancer and infectious diseases. Advancing technology, improved analytical methods, and use of computational methodology have also contributed to the development of subunit vaccine carriers. This review details recent breakthroughs in the design of nano-particulate vaccine carriers, including liposomes, polymeric nanoparticles, and inorganic nanoparticles. PMID:27104575

Alleles versus mutations: Understanding the evolution of genetic architecture requires a molecular perspective on allelic origins.

PubMed

Remington, David L

2015-12-01

Perspectives on the role of large-effect quantitative trait loci (QTL) in the evolution of complex traits have shifted back and forth over the past few decades. Different sets of studies have produced contradictory insights on the evolution of genetic architecture. I argue that much of the confusion results from a failure to distinguish mutational and allelic effects, a limitation of using the Fisherian model of adaptive evolution as the lens through which the evolution of adaptive variation is examined. A molecular-based perspective reveals that allelic differences can involve the cumulative effects of many mutations plus intragenic recombination, a model that is supported by extensive empirical evidence. I discuss how different selection regimes could produce very different architectures of allelic effects under a molecular-based model, which may explain conflicting insights on genetic architecture from studies of variation within populations versus between divergently selected populations. I address shortcomings of genome-wide association study (GWAS) practices in light of more suitable models of allelic evolution, and suggest alternate GWAS strategies to generate more valid inferences about genetic architecture. Finally, I discuss how adopting more suitable models of allelic evolution could help redirect research on complex trait evolution toward addressing more meaningful questions in evolutionary biology. © 2015 The Author(s). Evolution © 2015 The Society for the Study of Evolution.

Association of APOA5 and APOC3 gene polymorphisms with plasma apolipoprotein A5 level in patients with metabolic syndrome.

PubMed

Niculescu, Loredan S; Vlădică, Maria; Sima, Anca V

2010-01-01

Apolipoprotein A5 gene (APOA5) variants are associated with increased plasma triglycerides, a risk factor for the metabolic syndrome (MS), but a correlation with apolipoprotein C3 (APOC3) genotypes is controversial. We investigated the correlation of APOA5 genotypes with plasma apoA5 levels and APOC3 genotypes in MS patients from a Romanian population. APOA5 (-1131T>C, c.56C>G) and APOC3 (-482C>T, -455T>C) genotypes and plasma apoA5 concentration were determined in MS patients and healthy subjects. Results showed higher apoA5 levels in plasma and high density lipoproteins (HDL) from MS patients, carriers of the APOA5 c.56G allele, as compared to MS carriers of APOA5 -1131C allele or the common genotype. ApoA5 levels in plasma and HDL fraction from MS carriers of -1131C and c.56G alleles correlated positively with plasma triglycerides levels and negatively with HDL-cholesterol in MS carriers of c.56G allele. Higher frequencies of APOC3 -482T and -455C alleles were detected in MS patients compared with healthy subjects. We demonstrated the association of APOC3 -482T and -455C with APOA5 -1131C allele, but not with c.56G allele in MS patients. We propose APOA5c.56C>G as a functional polymorphism, whereas APOA5 -1131T>C is not an independent risk factor, being effective only when associated with APOC3 -482T or -455C alleles. Copyright 2009 Elsevier Inc. All rights reserved.

The higher exercise intensity and the presence of allele I of ACE gene elicit a higher post-exercise blood pressure reduction and nitric oxide release in elderly women: an experimental study.

PubMed

Santana, Hugo A P; Moreira, Sérgio R; Neto, Willson B; Silva, Carla B; Sales, Marcelo M; Oliveira, Vanessa N; Asano, Ricardo Y; Espíndola, Foued S; Nóbrega, Otávio T; Campbell, Carmen S G; Simões, Herbert G

2011-12-02

The absence of the I allele of the angiotensin converting enzyme (ACE) gene has been associated with higher levels of circulating ACE, lower nitric oxide (NO) release and hypertension. The purposes of this study were to analyze the post-exercise salivary nitrite (NO2-) and blood pressure (BP) responses to different exercise intensities in elderly women divided according to their ACE genotype. Participants (n = 30; II/ID = 20 and DD = 10) underwent three experimental sessions: incremental test - IT (15 watts workload increase/3 min) until exhaustion; 20 min exercise 90% anaerobic threshold (90% AT); and 20 min control session without exercise. Volunteers had their BP and NO2- measured before and after experimental sessions. Despite both intensities showed protective effect on preventing the increase of BP during post-exercise recovery compared to control, post-exercise hypotension and increased NO2- release was observed only for carriers of the I allele (p < 0.05). Genotypes of the ACE gene may exert a role in post-exercise NO release and BP response.

Allelic analysis of low molecular weight glutenin subunits using 2-DGE in Korean wheat cultivars

USDA-ARS?s Scientific Manuscript database

Two-dimensional gel electrophoresis (2-DGE) was used to determine the allelic compositions of LMW-GS in 32 Korean wheat cultivars. Protein patterns generated by 2-DGE from each cultivar were compared to patterns from standard wheat cultivars for each allele. At the Glu-A3 locus, thirteen c, twelve ...

Analysis of FMR1 gene expression in female premutation carriers using robust segmented linear regression models

PubMed Central

García-Alegría, Eva; Ibáñez, Berta; Mínguez, Mónica; Poch, Marisa; Valiente, Alberto; Sanz-Parra, Arantza; Martinez-Bouzas, Cristina; Beristain, Elena; Tejada, Maria-Isabel

2007-01-01

Fragile X syndrome is caused by the absence or reduction of the fragile X mental retardation protein (FMRP) because FMR1 gene expression is reduced. Alleles with repeat sizes of 55–200 are classified as premutations, and it has been demonstrated that FMR1 expression is elevated in the premutation range. However, the majority of the studies reported were performed in males. We studied FMR1 expression in 100 female fragile X family members from the northern region of Spain using quantitative (fluorescence) real-time polymerase chain reaction. Of these 100 women, 19 had normal alleles, 19 were full mutation carriers, and 62 were premutation carriers. After confirming differences between the three groups of females, and increased levels of the FMR1 transcript among premutation carriers, we found that the relationship between mRNA levels and repeat size is nonlinear. These results were obtained using a novel methodology that, based on the size of the CGG repeats, allows us to find out the most probable threshold from which the relationship between CGG repeat number and mRNA levels changes. Using this approach, a significant positive correlation between CGG repeats and total mRNA levels has been found in the premutation range <100 CGG, but this correlation diminishes from 100 onward. However, when correcting by the X inactivation ratio, mRNA levels increase as the number of CGG repeats increases, and this increase is highly significant over 100 CGG. We suggest that due to skewed X inactivation, mRNA levels tend to normalize in females when the number of CGG repeats increases. PMID:17449730

Positive selection of deleterious alleles through interaction with a sex-ratio suppressor gene in African Buffalo: a plausible new mechanism for a high frequency anomaly.

PubMed

van Hooft, Pim; Greyling, Ben J; Getz, Wayne M; van Helden, Paul D; Zwaan, Bas J; Bastos, Armanda D S

2014-01-01

Although generally rare, deleterious alleles can become common through genetic drift, hitchhiking or reductions in selective constraints. Here we present a possible new mechanism that explains the attainment of high frequencies of deleterious alleles in the African buffalo (Syncerus caffer) population of Kruger National Park, through positive selection of these alleles that is ultimately driven by a sex-ratio suppressor. We have previously shown that one in four Kruger buffalo has a Y-chromosome profile that, despite being associated with low body condition, appears to impart a relative reproductive advantage, and which is stably maintained through a sex-ratio suppressor. Apparently, this sex-ratio suppressor prevents fertility reduction that generally accompanies sex-ratio distortion. We hypothesize that this body-condition-associated reproductive advantage increases the fitness of alleles that negatively affect male body condition, causing genome-wide positive selection of these alleles. To investigate this we genotyped 459 buffalo using 17 autosomal microsatellites. By correlating heterozygosity with body condition (heterozygosity-fitness correlations), we found that most microsatellites were associated with one of two gene types: one with elevated frequencies of deleterious alleles that have a negative effect on body condition, irrespective of sex; the other with elevated frequencies of sexually antagonistic alleles that are negative for male body condition but positive for female body condition. Positive selection and a direct association with a Y-chromosomal sex-ratio suppressor are indicated, respectively, by allele clines and by relatively high numbers of homozygous deleterious alleles among sex-ratio suppressor carriers. This study, which employs novel statistical techniques to analyse heterozygosity-fitness correlations, is the first to demonstrate the abundance of sexually-antagonistic genes in a natural mammal population. It also has important

HLA-DQA1/B1 alleles as putative susceptibility markers in congenital toxoplasmosis

PubMed Central

Shimokawa, Paulo Tadashi; Targa, Lília Spaleta; Yamamoto, Lidia; Rodrigues, Jonatas Cristian; Kanunfre, Kelly Aparecida; Okay, Thelma Suely

2016-01-01

ABSTRACT Host and parasite genotypes are among the factors associated with congenital toxoplasmosis pathogenesis. As HLA class II molecules play a key role in the immune system regulation, the aim of this study was to investigate whether HLA-DQA1/B1 alleles are associated with susceptibility or protection to congenital toxoplasmosis. One hundred and twenty-two fetuses with and 103 without toxoplasmosis were studied. The two study groups were comparable according to a number of socio-demographic and genetic variables. HLA alleles were typed by PCR-SSP. In the HLA-DQA1 region, the allele frequencies showed that *01:03 and *03:02 alleles could confer susceptibility (OR= 3.06, p = 0.0002 and OR= 9.60, p= 0.0001, respectively) as they were more frequent among infected fetuses. Regarding the HLA-DQB1 region, the *05:04 allele could confer susceptibility (OR = 6.95, p < 0.0001). Of the 122 infected fetuses, 10 presented susceptibility haplotypes contrasting with only one in the non-infected group. This difference was not statistically significant after correction for multiple comparison (OR = 9.37, p=0.011). In the casuistic, there were two severely damaged fetuses with high parasite loads determined in amniotic fluid samples and HLA-DQA1 susceptibility alleles. In the present study, a discriminatory potential of HLA-DQA1/B1 alleles to identify susceptibility to congenital toxoplasmosis and the most severe cases has been shown. PMID:26856406

MdPIN1b encodes a putative auxin efflux carrier and has different expression patterns in BC and M9 apple rootstocks.

PubMed

Gan, Zengyu; Wang, Yi; Wu, Ting; Xu, Xuefeng; Zhang, Xinzhong; Han, Zhenhai

2018-03-01

Lower promoter activity is closely associated with lower MdPIN1b expression in the M9 interstem, which might contribute to the dwarfing effect in apple trees. Apple trees grafted onto dwarfing rootstock Malling 9 (M9) produce dwarfing tree architecture with high yield and widely applying in production. Previously, we have reported that in Malus 'Red Fuji' (RF) trees growing on M9 interstem and Baleng Crab (BC) rootstock, IAA content was relatively higher in bark tissue of M9 interstem than that in scion or rootstock. As IAA polar transportation largely depends on the PIN-FORMED (PIN) auxin efflux carrier. Herein, we identify two putative auxin efflux carrier genes in Malus genus, MdPIN1a and MdPIN1b, which were closely related to the AtPIN1. We found that MdPIN1b was expressed preferentially in BC and M9, and the expression of MdPIN1b was significantly lower in the phloem of M9 interstem than that in the scion and rootstock. The distinct expression of MdPIN1b and IAA content were concentrated in the cambium and adjacent xylem or phloem, and MdPIN1b protein was localized on cell plasma membrane in onion epidermal cells transiently expressing 35S:MdPIN1b-GFP fusion protein. Interestingly, an MdPIN1b mutant allele in the promoter region upstream of M9 exhibited decreased MdPIN1b expression compared to BC. MdPIN1b over-expressing interstem in tobacco exhibited increased polar auxin transport. It is proposed that natural allelic differences decreased promoter activity is closely associated with lower MdPIN1b expression in the M9 interstem, which might limit the basipetal transport of auxin, and in turn might contribute to the dwarfing effect. Taken together, these results reveal allelic variation underlying an important apple rootstock trait, and specifically a novel molecular genetic mechanism underlying dwarfing mechanism.

Diversity of HLA-B61 alleles and haplotypes in East Asians and Spanish Gypsies.

PubMed

Ogawa, A; Tokunaga, K; Lin, L; Kashiwase, K; Tanaka, H; Herrero, M J; Vilches, C; Park, M H; Jia, G J; Chimge, N O; Sideltseva, E W; Ishikawa, Y; Akaza, T; Tadokoro, K; Juji, T

1998-04-01

The distribution of HLA-B61 alleles and their association with HLA-C and DRB1 alleles were investigated in six East Asian populations (South Korean, Chinese Korean, Man (Manchu), Northern Han, Mongolian and Buryat) and Spanish Gypsies and compared to our previous report on the Japanese population. The alleles were identified using a group-specific polymerase chain reaction (PCR) and genomic DNA followed by hybridization with sequence-specific oligonucleotide probes (SSOP). Both HLA-B*4002 and B*4006 were commonly detected in the South Korean, Chinese Korean, Man, Northern Han and Japanese populations, while HLA-B*4002 was predominant in the Mongolian and Buryat populations. Strong associations of B*4002 with Cw*0304 and of B*4006 with Cw*0801 were commonly observed in these East Asian populations. In contrast, in Spanish Gypsies, only HLA-B*4006 was found and the allele exhibited a strong association with Cw*1502. HLA-B*4003 was also identified in the South Korean, Chinese Korean, Northern Han, Mongolian and Japanese populations at relatively low frequencies, and exhibited an association with Cw*0304. Moreover, the association of these B61 alleles with the DRB1 alleles revealed considerable diversity among the different populations. HLA-B*4004 and B*4009 were not observed in these populations. Consequently, the frequencies of the B61 alleles varied among the different East Asian populations, but the individual B61 alleles were carried by specific haplotypes often regardless of the ethnic differences.

Molecular diversity of HLA-Cw alleles in the Maratha community of Mumbai, Maharashtra, western India.

PubMed

Shankarkumar, U; Ghosh, K; Mohanty, D

2005-08-01

Recent advances suggest a significant role for the HLA-C locus as a target of alloreactions after bone marrow transplantation. The biological importance of products of the HLA-C locus, both as transplant antigens and as ligands for natural killer (NK) cells, is well established. A total of 10 different serologically defined HLA-Cw antigen specificities (Cw1-Cw10) are encoded by the C locus; however, there are now 151 different alleles that can be identified by molecular methods. Serological definition of Cw alleles therefore includes 20-50% blanks, which cannot be detected by the available antisera. We used the molecular method of polymerase chain reaction (PCR)-based sequence-specific amplification and probe hybridization to define Cw alleles in 91 individuals from the Maratha community, and compared the data with data for 92 serologically typed Maratha individuals from India. We identified Cw*12, Cw*14, Cw*15, Cw*16 and Cw*18, along with the serologically identified Cw*01, Cw*02, Cw*03, Cw*04, Cw*06 and Cw*07 alleles. The HLA-Cw blank allele frequency in the Maratha was reduced from 0.5706 to 0.00. Furthermore, by using a molecular technique, it was possible to identify novel allele subtypes, such as Cw*0104, Cw*0203 and Cw*0707, and a high frequency of Cw* 1801 in the Maratha community compared with other Indian and world populations. Our results will have clinical implications in related and unrelated HLA-matched bone marrow transplantation in India.

Apolipoprotein E4 Allele and Gait Performance in Mild Cognitive Impairment: Results From the Gait and Brain Study.

PubMed

Sakurai, Ryota; Montero-Odasso, Manuel

2017-11-09

The apolipoprotein E polymorphism ε4 allele (ApoE4) and gait impairment are both known risk factors for developing cognitive decline and dementia. However, it is unclear the interrelationship between these factors, particularly among older adults with mild cognitive impairment (MCI) who are considered as prodromal for Alzheimer's disease. This study aimed to determine whether ApoE4 carrier individuals with MCI may experience greater impairment in gait performance. Fifty-six older adults with MCI from the "Gait and Brain Study" who were identified as either ApoE4 carriers (n = 20) or non-ApoE4 carriers (n = 36) with 1 year of follow-up were included. Gait variability, the main outcome variable, was assessed as stride time variability with an electronic walkway. Additional gait variables and cognitive performance (mini-mental state examination [MMSE] and Montreal Cognitive Assessment [MoCA]) were also recorded. Covariates included age, sex, education level, body mass index, and number of comorbidities. Baseline characteristics were similar for both groups. Repeated measures analysis of covariance showed that gait stride time and stride length variabilities significantly increased in ApoE4 carriers but was maintained in the non-ApoE4 carriers. Similarly, ApoE4 carriers showed greater decrease in MMSE score at follow-up. In this sample of older adults with MCI, the presence of at least one copy of ApoE4 was associated with the development of both increased gait variability and cognitive decline during 1 year of follow-up. ApoE4 genotype might be considered as a potential mediator of decline in mobility function in MCI; future studies with larger samples are needed to confirm our preliminary findings. © The Author 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

iASeq: integrative analysis of allele-specificity of protein-DNA interactions in multiple ChIP-seq datasets

PubMed Central

2012-01-01

Background ChIP-seq provides new opportunities to study allele-specific protein-DNA binding (ASB). However, detecting allelic imbalance from a single ChIP-seq dataset often has low statistical power since only sequence reads mapped to heterozygote SNPs are informative for discriminating two alleles. Results We develop a new method iASeq to address this issue by jointly analyzing multiple ChIP-seq datasets. iASeq uses a Bayesian hierarchical mixture model to learn correlation patterns of allele-specificity among multiple proteins. Using the discovered correlation patterns, the model allows one to borrow information across datasets to improve detection of allelic imbalance. Application of iASeq to 77 ChIP-seq samples from 40 ENCODE datasets and 1 genomic DNA sample in GM12878 cells reveals that allele-specificity of multiple proteins are highly correlated, and demonstrates the ability of iASeq to improve allelic inference compared to analyzing each individual dataset separately. Conclusions iASeq illustrates the value of integrating multiple datasets in the allele-specificity inference and offers a new tool to better analyze ASB. PMID:23194258

Serotonin transporter genotype modulates cognitive reappraisal of negative emotions: a functional magnetic resonance imaging study

PubMed Central

Siep, Nicolette; Markus, C. Rob

2013-01-01

A functional polymorphism within the serotonin transporter gene (5-HTTLPR) has been reported to modulate emotionality and risk for affective disorders. The short (S) allele has less functional efficacy than the long (L) allele and has been associated with enhanced emotional reactivity. One possible contributing factor to the high emotionality in S carriers may be inefficient use of cognitive strategies such as reappraisal to regulate emotional responses. The aim of the present study was to test whether the 5-HTTLPR genotype modulates the neural correlates of emotion regulation. To determine neural differences between S and L allele carriers during reappraisal of negative emotions, 15 homozygous S (S′/S′) and 15 homozygous L (L′/L′) carriers underwent functional magnetic resonance imaging (fMRI), while performing an instructed emotion regulation task including downregulation, upregulation and passive viewing of negative emotional pictures. Compared to L′/L′ allele carriers, subjects who carry the S′/S′ allele responded with lower posterior insula and prefrontal brain activation during passive perception of negative emotional information but showed greater prefrontal activation and anterior insula activation during down- and upregulation of negative emotional responses. The current results support and extend previous findings of enhanced emotionality in S carriers by providing additional evidence of 5-HTTLPR modulation of volitional emotion regulation. PMID:22345383

Allelic imbalance of multiple sclerosis susceptibility genes IKZF3 and IQGAP1 in human peripheral blood.

PubMed

Keshari, Pankaj K; Harbo, Hanne F; Myhr, Kjell-Morten; Aarseth, Jan H; Bos, Steffan D; Berge, Tone

2016-04-14

Multiple sclerosis is a chronic inflammatory, demyelinating disease of the central nervous system. Recent genome-wide studies have revealed more than 110 single nucleotide polymorphisms as associated with susceptibility to multiple sclerosis, but their functional contribution to disease development is mostly unknown. Consistent allelic imbalance was observed for rs907091 in IKZF3 and rs11609 in IQGAP1, which are in strong linkage disequilibrium with the multiple sclerosis associated single nucleotide polymorphisms rs12946510 and rs8042861, respectively. Using multiple sclerosis patients and healthy controls heterozygous for rs907091 and rs11609, we showed that the multiple sclerosis risk alleles at IKZF3 and IQGAP1 are expressed at higher levels as compared to the protective allele. Furthermore, individuals homozygous for the multiple sclerosis risk allele at IQGAP1 had a significantly higher total expression of IQGAP1 compared to individuals homozygous for the protective allele. Our data indicate a possible regulatory role for the multiple sclerosis-associated IKZF3 and IQGAP1 variants. We suggest that such cis-acting mechanisms may contribute to the multiple sclerosis association of single nucleotide polymorphisms at IKZF3 and IQGAP1.

Nucleation and Spread of an Invasive Allele

NASA Astrophysics Data System (ADS)

Korniss, Gyorgy; Caraco, Thomas

2005-03-01

We analyze a prototypical discrete spatial model for the spread of an invasive allele when individuals compete preemptively for common limiting resources. Initially, the population is genetically monomorphic with the resident allele at high density. The invasive allele is introduced through rare, but recurrent, mutation. The mutant allele is the better competitor (has an individual-level advantage) but its spread is limited by the local availability of resources. We find that each successful introduction of the mutant leads to strong spatial clustering. Spatial patterns in simulation resemble nucleation and subsequent growth, articulately described by Avrami's law in sufficiently large systemsootnotetextG. Korniss and T. Caraco, J. Theor. Biol. (in press, 2004); http://www.rpi.edu/ korniss/Research/JTB04.pdf.

Plasma Metabolomics Reveal Alterations of Sphingo- and Glycerophospholipid Levels in Non-Diabetic Carriers of the Transcription Factor 7-Like 2 Polymorphism rs7903146

PubMed Central

Kirchhofer, Anna; Grallert, Harald; Krug, Susanne; Kastenmüller, Gabi; Römisch-Margl, Werner; Claussnitzer, Melina; Illig, Thomas; Heier, Margit; Meisinger, Christa; Adamski, Jerzy; Thorand, Barbara; Huth, Cornelia; Peters, Annette; Prehn, Cornelia; Heukamp, Ina; Laumen, Helmut; Lechner, Andreas; Hauner, Hans; Seissler, Jochen

2013-01-01

Aims/Hypothesis Polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene have been shown to display a powerful association with type 2 diabetes. The aim of the present study was to evaluate metabolic alterations in carriers of a common TCF7L2 risk variant. Methods Seventeen non-diabetic subjects carrying the T risk allele at the rs7903146 TCF7L2 locus and 24 subjects carrying no risk allele were submitted to intravenous glucose tolerance test and euglycemic-hyperinsulinemic clamp. Plasma samples were analysed for concentrations of 163 metabolites through targeted mass spectrometry. Results TCF7L2 risk allele carriers had a reduced first-phase insulin response and normal insulin sensitivity. Under fasting conditions, carriers of TCF7L2 rs7903146 exhibited a non-significant increase of plasma sphingomyelins (SMs), phosphatidylcholines (PCs) and lysophosphatidylcholines (lysoPCs) species. A significant genotype effect was detected in response to challenge tests in 6 SMs (C16:0, C16:1, C18:0, C18:1, C24:0, C24:1), 5 hydroxy-SMs (C14:1, C16:1, C22:1, C22:2, C24:1), 4 lysoPCs (C14:0, C16:0, C16:1, C17:0), 3 diacyl-PCs (C28:1, C36:6, C40:4) and 4 long-chain acyl-alkyl-PCs (C40:2, C40:5, C44:5, C44:6). Discussion Plasma metabolomic profiling identified alterations of phospholipid metabolism in response to challenge tests in subjects with TCF7L2 rs7903146 genotype. This may reflect a genotype-mediated link to early metabolic abnormalities prior to the development of disturbed glucose tolerance. PMID:24205231

Impact of doping on the carrier dynamics in graphene

PubMed Central

Kadi, Faris; Winzer, Torben; Knorr, Andreas; Malic, Ermin

2015-01-01

We present a microscopic study on the impact of doping on the carrier dynamics in graphene, in particular focusing on its influence on the technologically relevant carrier multiplication in realistic, doped graphene samples. Treating the time- and momentum-resolved carrier-light, carrier-carrier, and carrier-phonon interactions on the same microscopic footing, the appearance of Auger-induced carrier multiplication up to a Fermi level of 300 meV is revealed. Furthermore, we show that doping favors the so-called hot carrier multiplication occurring within one band. Our results are directly compared to recent time-resolved ARPES measurements and exhibit an excellent agreement on the temporal evolution of the hot carrier multiplication for n- and p-doped graphene. The gained insights shed light on the ultrafast carrier dynamics in realistic, doped graphene samples. PMID:26577536

Use of allele scores as instrumental variables for Mendelian randomization

PubMed Central

Burgess, Stephen; Thompson, Simon G

2013-01-01

Background An allele score is a single variable summarizing multiple genetic variants associated with a risk factor. It is calculated as the total number of risk factor-increasing alleles for an individual (unweighted score), or the sum of weights for each allele corresponding to estimated genetic effect sizes (weighted score). An allele score can be used in a Mendelian randomization analysis to estimate the causal effect of the risk factor on an outcome. Methods Data were simulated to investigate the use of allele scores in Mendelian randomization where conventional instrumental variable techniques using multiple genetic variants demonstrate ‘weak instrument’ bias. The robustness of estimates using the allele score to misspecification (for example non-linearity, effect modification) and to violations of the instrumental variable assumptions was assessed. Results Causal estimates using a correctly specified allele score were unbiased with appropriate coverage levels. The estimates were generally robust to misspecification of the allele score, but not to instrumental variable violations, even if the majority of variants in the allele score were valid instruments. Using a weighted rather than an unweighted allele score increased power, but the increase was small when genetic variants had similar effect sizes. Naive use of the data under analysis to choose which variants to include in an allele score, or for deriving weights, resulted in substantial biases. Conclusions Allele scores enable valid causal estimates with large numbers of genetic variants. The stringency of criteria for genetic variants in Mendelian randomization should be maintained for all variants in an allele score. PMID:24062299

The PNPLA3 rs738409 G-allele associates with reduced fasting serum triglyceride and serum cholesterol in Danes with impaired glucose regulation.

PubMed

Krarup, Nikolaj Thure; Grarup, Niels; Banasik, Karina; Friedrichsen, Martin; Færch, Kristine; Sandholt, Camilla Helene; Jørgensen, Torben; Poulsen, Pernille; Witte, Daniel Rinse; Vaag, Allan; Sørensen, Thorkild; Pedersen, Oluf; Hansen, Torben

2012-01-01

Non-alcoholic fatty liver disease (NAFLD) is a common condition, associated with hepatic insulin resistance and the metabolic syndrome including hyperglycaemia and dyslipidemia. We aimed at studying the potential impact of the NAFLD-associated PNPLA3 rs738409 G-allele on NAFLD-related metabolic traits in hyperglycaemic individuals. The rs738409 variant was genotyped in the population-based Inter99 cohort examined by an oral glucose-tolerance test, and a combined study-sample consisting of 192 twins (96 twin pairs) and a sub-set of the Inter99 population (n = 63) examined by a hyperinsulinemic euglycemic clamp (n(total) = 255). In Inter99, we analyzed associations of rs738409 with components of the WHO-defined metabolic syndrome (n = 5,847) and traits related to metabolic disease (n = 5,663). In the combined study sample we elucidated whether the rs738409 G-allele altered hepatic or peripheral insulin sensitivity. Study populations were divided into individuals with normal glucose-tolerance (NGT) and with impaired glucose regulation (IGR). The case-control study showed no associations with components of the metabolic syndrome or the metabolic syndrome. Among 1,357 IGR individuals, the rs738409 G-allele associated with decreased fasting serum triglyceride levels (per allele effect(β) = -9.9% [-14.4%;-4.0% (95% CI)], p = 5.1×10(-5)) and fasting total cholesterol (β = -0.2 mmol/l [-0.3;-0.01 mmol/l(95% CI)], p = 1.5×10(-4)). Meta-analyses showed no impact on hepatic or peripheral insulin resistance in carriers of the rs738409 G-allele. Our findings suggest that the G-allele of PNPLA3 rs738409 associates with reduced fasting levels of cholesterol and triglyceride in individuals with IGR.

ALEA: a toolbox for allele-specific epigenomics analysis.

PubMed

Younesy, Hamid; Möller, Torsten; Heravi-Moussavi, Alireza; Cheng, Jeffrey B; Costello, Joseph F; Lorincz, Matthew C; Karimi, Mohammad M; Jones, Steven J M

2014-04-15

The assessment of expression and epigenomic status using sequencing based methods provides an unprecedented opportunity to identify and correlate allelic differences with epigenomic status. We present ALEA, a computational toolbox for allele-specific epigenomics analysis, which incorporates allelic variation data within existing resources, allowing for the identification of significant associations between epigenetic modifications and specific allelic variants in human and mouse cells. ALEA provides a customizable pipeline of command line tools for allele-specific analysis of next-generation sequencing data (ChIP-seq, RNA-seq, etc.) that takes the raw sequencing data and produces separate allelic tracks ready to be viewed on genome browsers. The pipeline has been validated using human and hybrid mouse ChIP-seq and RNA-seq data. The package, test data and usage instructions are available online at http://www.bcgsc.ca/platform/bioinfo/software/alea CONTACT: : mkarimi1@interchange.ubc.ca or sjones@bcgsc.ca Supplementary information: Supplementary data are available at Bioinformatics online. © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

A comparative study of quantitative immunohistochemistry and quantum dot immunohistochemistry for mutation carrier identification in Lynch syndrome.

PubMed

Barrow, Emma; Evans, D Gareth; McMahon, Ray; Hill, James; Byers, Richard

2011-03-01

Lynch Syndrome is caused by mutations in DNA mismatch repair (MMR) genes. Mutation carrier identification is facilitated by immunohistochemical detection of the MMR proteins MHL1 and MSH2 in tumour tissue and is desirable as colonoscopic screening reduces mortality. However, protein detection by conventional immunohistochemistry (IHC) is subjective, and quantitative techniques are required. Quantum dots (QDs) are novel fluorescent labels that enable quantitative multiplex staining. This study compared their use with quantitative 3,3'-diaminobenzidine (DAB) IHC for the diagnosis of Lynch Syndrome. Tumour sections from 36 mutation carriers and six controls were obtained. These were stained with DAB on an automated platform using antibodies against MLH1 and MSH2. Multiplex QD immunofluorescent staining of the sections was performed using antibodies against MLH1, MSH2 and smooth muscle actin (SMA). Multispectral analysis of the slides was performed. The staining intensity of DAB and QDs was measured in multiple colonic crypts, and the mean intensity scores calculated. Receiver operating characteristic (ROC) curves of staining performance for the identification of mutation carriers were evaluated. For quantitative DAB IHC, the area under the MLH1 ROC curve was 0.872 (95% CI 0.763 to 0.981), and the area under the MSH2 ROC curve was 0.832 (95% CI 0.704 to 0.960). For quantitative QD IHC, the area under the MLH1 ROC curve was 0.812 (95% CI 0.681 to 0.943), and the area under the MSH2 ROC curve was 0.598 (95% CI 0.418 to 0.777). Despite the advantage of QD staining to enable several markers to be measured simultaneously, it is of lower utility than DAB IHC for the identification of MMR mutation carriers. Automated DAB IHC staining and quantitative slide analysis may enable high-throughput IHC.

Alpha1-Antitrypsin Deficiency–Related Alleles Z and S and the Risk of Wegener’s Granulomatosis

PubMed Central

Mahr, Alfred D.; Edberg, Jeffrey C.; Stone, John H.; Hoffman, Gary S.; St. Clair, E. William; Specks, Ulrich; Dellaripa, Paul F.; Seo, Philip; Spiera, Robert F.; Rouhani, Farshid N.; Brantly, Mark L.; Merkel, Peter A.

2011-01-01

Objective Deficiency of α1-antitrypsin (α1AT) may be a determinant of susceptibility to Wegener’s granulomatosis (WG). Several previous, mainly small, case–control studies have shown that 5–27% of patients with WG carried the α1AT deficiency Z allele. It is not clear whether the S allele, the other major α1AT deficiency variant, is associated with WG. This study investigated the relationship of the α1AT deficiency Z and S alleles with the risk of developing WG in a large cohort. Methods We studied the distribution of the α1AT deficiency alleles Z and S in 433 unrelated Caucasian patients with WG and 421 ethnically matched controls. Genotyping was performed using an allele discrimination assay. Results were compared between cases and controls using exact statistical methods. Results Among the patients with WG, the allele carriage frequencies of Z and S were 7.4% and 11.5%, respectively. The frequencies of the 6 possible genotypes differed in a statistically significant manner between cases and controls (P = 0.01). The general genetic 2-parameter codominant model provided the best fit to the data. Compared with the normal MM genotype, the odds ratio (OR) for MZ or MS genotypes was 1.47 (95% confidence interval [95% CI] 0.98–2.22), and the OR for ZZ, SS, or SZ genotypes was 14.58 (95% CI 2.33–∞). ORs of similar direction and magnitude were observed within the restricted cohorts that excluded cases and controls carrying ≥1 Z or ≥1 S allele. Conclusion Both Z and S alleles display associations with risk of WG in a codominant genetic pattern. These findings strengthen the evidence of a causal link between α1AT deficiency and susceptibility to WG. PMID:20827781

Population based allele frequencies of disease associated polymorphisms in the Personalized Medicine Research Project.

PubMed

Cross, Deanna S; Ivacic, Lynn C; Stefanski, Elisha L; McCarty, Catherine A

2010-06-17

There is a lack of knowledge regarding the frequency of disease associated polymorphisms in populations and population attributable risk for many populations remains unknown. Factors that could affect the association of the allele with disease, either positively or negatively, such as race, ethnicity, and gender, may not be possible to determine without population based allele frequencies.Here we used a panel of 51 polymorphisms previously associated with at least one disease and determined the allele frequencies within the entire Personalized Medicine Research Project population based cohort. We compared these allele frequencies to those in dbSNP and other data sources stratified by race. Differences in allele frequencies between self reported race, region of origin, and sex were determined. There were 19544 individuals who self reported a single racial category, 19027 or (97.4%) self reported white Caucasian, and 11205 (57.3%) individuals were female. Of the 11,208 (57%) individuals with an identifiable region of origin 8337 or (74.4%) were German.41 polymorphisms were significantly different between self reported race at the 0.05 level. Stratification of our Caucasian population by self reported region of origin revealed 19 polymorphisms that were significantly different (p = 0.05) between individuals of different origins. Further stratification of the population by gender revealed few significant differences in allele frequencies between the genders. This represents one of the largest population based allele frequency studies to date. Stratification by self reported race and region of origin revealed wide differences in allele frequencies not only by race but also by region of origin within a single racial group. We report allele frequencies for our Asian/Hmong and American Indian populations; these two minority groups are not typically selected for population allele frequency detection. Population wide allele frequencies are important for the design and

Association of MMP7 -181A→G Promoter Polymorphism with Gastric Cancer Risk: INFLUENCE OF NICOTINE IN DIFFERENTIAL ALLELE-SPECIFIC TRANSCRIPTION VIA INCREASED PHOSPHORYLATION OF cAMP-RESPONSE ELEMENT-BINDING PROTEIN (CREB).

PubMed

Kesh, Kousik; Subramanian, Lakshmi; Ghosh, Nillu; Gupta, Vinayak; Gupta, Arnab; Bhattacharya, Samir; Mahapatra, Nitish R; Swarnakar, Snehasikta

2015-06-05

Elevated expression of matrix metalloproteinase7 (MMP7) has been demonstrated to play a pivotal role in cancer invasion. The -181A→G (rs11568818) polymorphism in the MMP7 promoter modulates gene expression and possibly affects cancer progression. Here, we evaluated the impact of -181A→G polymorphism on MMP7 promoter activity and its association with gastric cancer risk in eastern Indian case-control cohorts (n = 520). The GG genotype as compared with the AA genotype was predisposed (p = 0.02; odds ratio = 1.9, 95% confidence interval = 1.1-3.3) to gastric cancer risk. Stratification analysis showed that tobacco addiction enhanced gastric cancer risk in GG subjects when compared with AA subjects (p = 0.03, odds ratio = 2.46, and 95% confidence interval = 1.07-5.68). Meta-analysis revealed that tobacco enhanced the risk for cancer more markedly in AG and GG carriers. Activity and expression of MMP7 were significantly higher in GG than in AA carriers. In support, MMP7 promoter-reporter assays showed greater transcriptional activity toward A to G transition under basal/nicotine-induced/cAMP-response element-binding protein (CREB) overexpressed conditions in gastric adenocarcinoma cells. Moreover, nicotine (a major component of tobacco) treatment significantly up-regulated MMP7 expression due to enhanced CREB phosphorylation followed by its nuclear translocation in gastric adenocarcinoma cells. Furthermore, chromatin immunoprecipitation experiments revealed higher binding of phosphorylated CREB with the -181G than the -181A allele. Altogether, specific binding of phosphorylated CREB to the G allele-carrying promoter enhances MMP7 gene expression that is further augmented by nicotine due to increased CREB phosphorylation and thereby increases the risk for gastric cancer. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Polymorphisms of the mu-opioid receptor and dopamine D4 receptor genes and subjective responses to alcohol in the natural environment.

PubMed

Ray, Lara A; Miranda, Robert; Tidey, Jennifer W; McGeary, John E; MacKillop, James; Gwaltney, Chad J; Rohsenow, Damaris J; Swift, Robert M; Monti, Peter M

2010-02-01

Polymorphisms of the mu-opioid receptor (OPRM1) and dopamine D4 receptor (DRD4) genes are associated with subjective responses to alcohol and urge to drink under laboratory conditions. This study examined these associations in the natural environment using ecological momentary assessment. Participants were non-treatment-seeking heavy drinkers (n = 112, 52% female, 61% alcohol dependent) who enrolled in a study of naltrexone effects on craving and drinking in the natural environment. Data were culled from 5 consecutive days of drinking reports prior to medication randomization. Analyses revealed that, after drinking, carriers of the Asp40 allele of the OPRM1 gene reported higher overall levels of vigor and lower levels negative mood, as compared to homozygotes for the Asn40 variant. Carriers of the long allele (i.e., >or=7 tandem repeats) of the DRD4 endorsed greater urge to drink than homozygotes for the short allele. Effects of OPRM1 and DRD4 variable-number-of-tandem-repeats genotypes appear to be alcohol dose-dependent. Specifically, carriers of the DRD4-L allele reported slight decreases in urge to drink at higher levels of estimated blood alcohol concentration (eBAC), and Asp40 carriers reported decreases in vigor and increases in negative mood as eBAC rose, as compared to carriers of the major allele for each gene. Self-reported vigor and urge to drink were positively associated with alcohol consumption within the same drinking episode. This study extends findings on subjective intoxication, urge to drink, and their genetic bases from controlled laboratory to naturalistic settings.

Altered Episodic Memory in Introverted Young Adults Carrying the BDNFMet Allele.

PubMed

Bombardier, Andreanne; Beauchemin, Maude; Gosselin, Nadia; Poirier, Judes; De Beaumont, Louis

2016-11-12

While most studies have been interested in the distinct, predisposing roles of the common BDNF Val66Met variant and extraversion personality traits on episodic memory, very few studies have looked at the synergistic effects of genetic and personality factors to account for cognitive variance. This is surprising considering recent reports challenging the long-held belief that the BDNF Met variant negatively impacts cognitive function. A total of 75 young healthy adults (26 of them carried at least one copy of the BDNF Met allele) took part in this study consisting of genetic profiling from saliva, personality assessment using the Revised NEO Personality Inventory (NEO PI-R) and a short battery of neuropsychological tests. An ANOVA revealed that BDNF Met carriers were significantly less extraverted than BDNF Val carriers ( F 1,73 = 9.54; p < 0.01; η p ² = 0.126). Moreover, extraversion was found to significantly moderate the relationship between the BDNF genotype and episodic memory performance ( p = 0.03). Subsequent correlational analyses yielded a strong and significant correlation ( r = 0.542; p < 0.005) between introversion and delayed episodic memory specific to BDNF Met individuals. The present study suggests that introversion and the BDNF Met variant synergistically interact to reduce episodic memory performance in healthy, young adults. These findings reaffirm that a more accurate explanation of cognitive variance can be achieved by looking at the synergistic effects of genotype and phenotype factors.

Prevalence of asthmatic symptoms in Lebanese patients with type 1 diabetes and their unaffected siblings compared to age-matched controls.

PubMed

Taleb, Nadine; Bou Khalil, Pierre; Zantout, Mira S; Zalloua, Pierre; Azar, Sami T

2010-12-01

Patients with type 1 diabetes (a TH1 disease) have been reported to be at a lower risk of developing asthma (a TH2 disease). Both diseases are affected by environmental and genetic factors. Our objective is to examine this relationship in Lebanon, a Middle-Eastern country, where no previous similar studies are available. This is a cross-sectional observational study conducted at the Chronic Care Center, a referral medical center for type 1 diabetics. Patients with type 1 diabetes aged 6-39 years old, their unaffected siblings and age-matched control completed the International Primary Care Airways Group asthma screening questionnaire. The prevalence of asthma symptoms was compared among the three groups and separately within a subgroup of diabetics in relation to their carrier state of previously collected genetic data. Among 305 diabetics, 776 siblings and 187 controls, diabetics were at lower risk of having any asthma symptoms than controls; OR 0.48 (95% CI 0.32-0.72, p < 0.001) and siblings were at lower risk than diabetics and controls; OR 0.64 (95% CI 0.45-0.91, p = 0.01) and 0.28 (95% CI 0.19-0.42, p < 0.001), respectively. Among 66 diabetics, carriers of the HLA-DQB1*0201 allele were at lower risk of having any asthma symptoms than non-carriers (25.5 vs. 53.3%, p = 0.04). Only a statistically non-significant trend of higher risk was observed in carriers of HLA-DQB1*0301 and G allele at the 49 (A/G) nucleotide of CTLA-4 gene. The TH1-TH2 paradigm might partially explain these findings, since siblings were the least to report asthma symptoms. Future research is needed with diagnostic tests for asthma and extensive genetic testing.

Association between HLA-B Alleles and Carbamazepine-Induced Maculopapular Exanthema and Severe Cutaneous Reactions in Thai Patients

PubMed Central

Chaichan, Chonlawat; Nakkrut, Thapanat; Satapornpong, Patompong; Jaruthamsophon, Kanoot; Jantararoungtong, Thawinee; Koomdee, Napatrupron; Sririttha, Suthida; Medhasi, Sadeep; Oo-Puthinan, Sarawut; Rerkpattanapipat, Ticha; Klaewsongkram, Jettanong; Rerknimitr, Pawinee; Tuchinda, Papapit; Chularojanamontri, Leena; Tovanabutra, Napatra; Puangpetch, Apichaya

2018-01-01

The HLA-B∗15:02 allele has been reported to have a strong association with carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in Thai patients. The HLA-B alleles associated with carbamazepine-induced maculopapular exanthema (MPE) and the drug reaction with eosinophilia and systemic symptoms (DRESS) among the Thai population have never been reported. The aim of the present study was to carry out an analysis of the involvement of HLA-B alleles in carbamazepine-induced cutaneous adverse drug reactions (cADRs) in the Thai population. A case-control study was performed by genotyping the HLA-B alleles of Thai carbamazepine-induced hypersensitivity reaction patients (17 MPE, 16 SJS/TEN, and 5 DRESS) and 271 carbamazepine-tolerant controls. We also recruited 470 healthy Thai candidate subjects who had not taken carbamazepine. HLA-B∗15:02 showed a significant association with carbamazepine-induced MPE (P = 0.0022, odds ratio (OR) (95% confidence interval [CI]) = 7.27 (2.04–25.97)) and carbamazepine-induced SJS/TEN (P = 4.46 × 10−13; OR (95% CI) = 70.91(19.67–255.65)) when compared with carbamazepine-tolerant controls. Carbamazepine-induced SJS/TEN also showed an association with HLA-B∗15:21 allele (P = 0.013; OR (95% CI) = 9.54 (1.61–56.57)) when compared with carbamazepine-tolerant controls. HLA-B∗58:01 allele was significantly related to carbamazepine-induced MPE (P = 0.007; OR (95% CI) = 4.73 (1.53–14.66)) and DRESS (P = 0.0315; OR (95% CI) = 7.55 (1.20–47.58)) when compared with carbamazepine-tolerant controls. These alleles may serve as markers to predict carbamazepine-induced cADRs in the Thai population. PMID:29546073

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.

Disrupted neural activity patterns to novelty and effort in young adult APOE-e4 carriers performing a subsequent memory task.

PubMed

Evans, Simon; Dowell, Nicholas G; Tabet, Naji; King, Sarah L; Hutton, Samuel B; Rusted, Jennifer M

2017-02-01

The APOE e4 allele has been linked to poorer cognitive aging and enhanced dementia risk. Previous imaging studies have used subsequent memory paradigms to probe hippocampal function in e4 carriers across the age range, and evidence suggests a pattern of hippocampal overactivation in young adult e4 carriers. In this study, we employed a word-based subsequent memory task under fMRI; pupillometry data were also acquired as an index of cognitive effort. Participants (26 non-e4 carriers and 28 e4 carriers) performed an incidental encoding task (presented as word categorization), followed by a surprise old/new recognition task after a 40 minute delay. In e4 carriers only, subsequently remembered words were linked to increased hippocampal activity. Across all participants, increased pupil diameter differentiated subsequently remembered from forgotten words, and neural activity covaried with pupil diameter in cuneus and precuneus. These effects were weaker in e4 carriers, and e4 carriers did not show greater pupil diameter to remembered words. In the recognition phase, genotype status also modulated hippocampal activity: here, however, e4 carriers failed to show the conventional pattern of greater hippocampal activity to novel words. Overall, neural activity changes were unstable in e4 carriers, failed to respond to novelty, and did not link strongly to cognitive effort, as indexed by pupil diameter. This provides further evidence of abnormal hippocampal recruitment in young adult e4 carriers, manifesting as both up and downregulation of neural activity, in the absence of behavioral performance differences.

Altered effective connectivity anchored in the posterior cingulate cortex and the medial prefrontal cortex in cognitively intact elderly APOE ε4 carriers: a preliminary study.

PubMed

Luo, Xiao; Li, Kaicheng; Jia, Y L; Zeng, Qingze; Jiaerken, Yeerfan; Qiu, Tiantian; Huang, Peiyu; Xu, Xiaojun; Shen, Zhujing; Guan, Xiaojun; Zhou, Jiong; Wang, Chao; Xu, J J; Zhang, Minming

2018-03-17

The APOE ε4 allele is associated with impaired intrinsic functional connectivity in neural networks, especially in the default mode network (DMN). However, effective connectivity (EC) reflects the direct causal effects of one brain region to another, which has rarely been investigated. Recently, Granger causality analysis (GCA) proved suitable for the study of directionality in neuronal interactions. Using GCA, we examined the differences in the EC between the anterior medial prefrontal cortex/posterior cingulate cortex (aMPFC/PCC) and the whole brain in 17 ε4 carrying and 32 non-carrying cognitively intact elderly individuals. Furthermore, correlation analyses were performed between the abnormal EC and cognition/neuropathological indices. Compared with the non-carriers, the results showed that the ε4 carriers exhibited decreased EC from the PCC to the whole brain in the middle temporal gyrus (MTG), the anterior cingulate cortex (ACC), and the precuneus (PCu). Meanwhile, the ε4 carriers demonstrated increased EC from the whole brain to the aMPFC in the inferior parietal lobe (IPL) and the postcentral gyrus (PCG). The correlation analyses suggested that the EC from the IPL/PCG to the aMPFC was related to episodic memory in non-carriers, while the decreased EC from the PCC to the ACC was associated with increased levels of t-tau in the ε4 carriers. In ε4 carriers, a negative influence can be traced from the PCC to both the anterior and posterior DMN subsystems; meanwhile, the anterior DMN subsystem receives compensatory effects from the parietal cortex. Early increases in AD-related pathologies in the PCC may act as first factors during this pathological process.

Allele frequencies of 15 STR loci in Bosnian and Herzegovinian population

PubMed Central

Pilav, Amela; Pojskić, Naris; Ahatović, Anesa; Džehverović, Mirela; Čakar, Jasmina; Marjanović, Damir

2017-01-01

Aim To determine newest the most accurate allele frequencies for 15 short tandem repeat (STR) loci in the Bosnian and Herzegovinian population, calculate statistical parameters, and compare them with the relevant data for seven neighboring populations. Methods Genomic DNA was obtained from buccal swabs of 1000 unrelated individuals from all regions of Bosnia and Herzegovina. Genotyping was performed using PowerPlex® 16 System to obtain allele frequencies for 15 polymorphic STR loci including D3S1358, TH01, D21S11, D18S51, Penta E, D5S818, D13S317, D7S820, D16S539, CSF1PO, Penta D, vWA, D8S1179, TPOX, and FGA. The calculated allele frequencies were also compared with the data from neighboring populations. Results The highest detected value of polymorphism information content (PIC) was detected at the PentaE locus, whereas the lowest value was detected at the TPOX locus. The power of discrimination (PD) values had similar distribution, with Penta E showing the highest PD of 0.9788. While D18S51 had the highest value of power of exclusion (PE), the lowest PE value was detected at the TPOX locus. Conclusion Upon comparison of Bosnian and Herzegovinian population data with those of seven neighboring populations, the highest allele frequency differentiation was noticed between Bosnian and Herzegovinian and Turkish population at 5 loci, the most informative of which was Penta E. The neighbor-joining dendrogram constructed on the basis of genetic distance showed grouping of Slovenian, Austrian, Hungarian, and Croatian populations. Bosnian and Herzegovinian population was between the mentioned cluster and Serbian population. To determine more accurate distribution of allelic frequencies and forensic parameters, our study included 1000 unrelated individuals from all regions of Bosnia and Herzegovina, and our findings demonstrated the applicability of these markers in both forensics and future population genetic studies. PMID:28613042

Allele frequencies of 15 STR loci in Bosnian and Herzegovinian population.

PubMed

Pilav, Amela; Pojskić, Naris; Ahatović, Anesa; Džehverović, Mirela; Čakar, Jasmina; Marjanović, Damir

2017-06-14

To determine newest the most accurate allele frequencies for 15 short tandem repeat (STR) loci in the Bosnian and Herzegovinian population, calculate statistical parameters, and compare them with the relevant data for seven neighboring populations. Genomic DNA was obtained from buccal swabs of 1000 unrelated individuals from all regions of Bosnia and Herzegovina. Genotyping was performed using PowerPlex® 16 System to obtain allele frequencies for 15 polymorphic STR loci including D3S1358, TH01, D21S11, D18S51, Penta E, D5S818, D13S317, D7S820, D16S539, CSF1PO, Penta D, vWA, D8S1179, TPOX, and FGA. The calculated allele frequencies were also compared with the data from neighboring populations. The highest detected value of polymorphism information content (PIC) was detected at the PentaE locus, whereas the lowest value was detected at the TPOX locus. The power of discrimination (PD) values had similar distribution, with Penta E showing the highest PD of 0.9788. While D18S51 had the highest value of power of exclusion (PE), the lowest PE value was detected at the TPOX locus. Upon comparison of Bosnian and Herzegovinian population data with those of seven neighboring populations, the highest allele frequency differentiation was noticed between Bosnian and Herzegovinian and Turkish population at 5 loci, the most informative of which was Penta E. The neighbor-joining dendrogram constructed on the basis of genetic distance showed grouping of Slovenian, Austrian, Hungarian, and Croatian populations. Bosnian and Herzegovinian population was between the mentioned cluster and Serbian population. To determine more accurate distribution of allelic frequencies and forensic parameters, our study included 1000 unrelated individuals from all regions of Bosnia and Herzegovina, and our findings demonstrated the applicability of these markers in both forensics and future population genetic studies.

Apolipoprotein E-epsilon 4 allele and familial risk in Alzheimer's disease.

PubMed

Li, G; Silverman, J M; Altstiel, L D; Haroutunian, V; Perl, D P; Purohit, D; Birstein, S; Lantz, M; Mohs, R C; Davis, K L

1996-01-01

Recent studies have found an association between presence of apolipoprotein E (APOE) epsilon 4 allele and Alzheimer's disease (AD). The present study compared the cumulative risk of primary progressive dementia (PPD) in relatives of AD probands carrying at least one copy of the epsilon 4 allele with the relatives of AD probands not carrying epsilon 4 and with relatives of non-demented controls. Our aim was to determine whether the familial aggregation of PPD in relatives of AD probands is primarily due to those carrying epsilon 4. Seventy-seven neuropathologically diagnosed AD patients were obtained as probands through our Alzheimer's Disease Research Center Brain Bank. AD probands were genotyped for APOE. As a comparison group, 198 non-demented probands were also included. Through family informants, demographic and diagnostic data were collected on 382 first-degree relatives (age > or = 45 years) of AD probands and 848 relatives of the controls. We found that the cumulative risk of PPD in both relatives of AD probands with and without the epsilon 4 allele was significantly higher than that in the relatives of non-demented controls. However, the increased risk in the relatives of AD probands with the epsilon 4 allele was marginally, but not significantly, lower than the risk in the relatives of probands without epsilon 4. A greater likelihood of death by heart diseases over developing PPD in relatives of AD probands with epsilon 4 (3.1-fold increase) was found compared to relatives of probands without epsilon 4 (1.7-fold increase), especially prior to age 70, although the difference was not statistically significant. The increased familial risk for PPD in the relatives of AD probands with the APOE-epsilon 4 allele relative to controls suggests that familial factors in addition to APOE-epsilon 4 are risk factors for AD. Differential censorship from increased mortality of heart diseases may have prevented a higher incidence of PPD among the relatives of probands with

XKR4 Gene Effects on Cerebellar Development Are Not Specific to ADHD

PubMed Central

Shook, Devon; Brouwer, Rachel; de Zeeuw, Patrick; Oranje, Bob; Durston, Sarah

2017-01-01

A single-nucleotide polymorphism (SNP) of the XKR4 gene has been linked to Attention-Deficit/Hyperactivity Disorder (ADHD). This gene is preferentially expressed in cerebellum, a brain structure implicated in this disorder. This study investigated the effects of this SNP on cerebellar development in children with and without ADHD. We collected 279 longitudinal T1-weighted structural images and DNA from 58 children with ADHD and 64 typically developing (TD) children matched for age, IQ, and gender. Groups were divided by the XKR4 rs2939678 SNP into A-allele carriers versus subjects homozygous for the G-allele. Cerebellar lobular volumes were segmented into 35 regions of interest using MAGeTBrain, an automated multi-atlas segmentation pipeline for anatomical MRI, and statistically analyzed using linear mixed models. We found decreased gray matter (GM) volumes in ADHD compared to TD children in bilateral lobules VIIIA, left VIIIB, right VIIB, and vermis VI. Furthermore, we found a linear age by gene interaction in left lobule VIIB where subjects homozygous for the G-allele showed a decrease in volume over time compared to A-allele carriers. We further found quadratic age × gene and age × diagnosis interactions in left lobule IV. Subjects homozygous for the G-allele (the genotype overtransmitted in ADHD) showed more suppressed, almost flat quadratic growth curves compared to A-allele carriers, similar to individuals with ADHD compared to controls. However, there was no interaction between genotype and diagnosis, suggesting that any effects of this SNP on cerebellar development are not specific to the disorder. PMID:29311829

XKR4 Gene Effects on Cerebellar Development Are Not Specific to ADHD.

PubMed

Shook, Devon; Brouwer, Rachel; de Zeeuw, Patrick; Oranje, Bob; Durston, Sarah

2017-01-01

A single-nucleotide polymorphism (SNP) of the XKR4 gene has been linked to Attention-Deficit/Hyperactivity Disorder (ADHD). This gene is preferentially expressed in cerebellum, a brain structure implicated in this disorder. This study investigated the effects of this SNP on cerebellar development in children with and without ADHD. We collected 279 longitudinal T1-weighted structural images and DNA from 58 children with ADHD and 64 typically developing (TD) children matched for age, IQ, and gender. Groups were divided by the XKR4 rs2939678 SNP into A-allele carriers versus subjects homozygous for the G-allele. Cerebellar lobular volumes were segmented into 35 regions of interest using MAGeTBrain, an automated multi-atlas segmentation pipeline for anatomical MRI, and statistically analyzed using linear mixed models. We found decreased gray matter (GM) volumes in ADHD compared to TD children in bilateral lobules VIIIA, left VIIIB, right VIIB, and vermis VI. Furthermore, we found a linear age by gene interaction in left lobule VIIB where subjects homozygous for the G-allele showed a decrease in volume over time compared to A-allele carriers. We further found quadratic age × gene and age × diagnosis interactions in left lobule IV. Subjects homozygous for the G-allele (the genotype overtransmitted in ADHD) showed more suppressed, almost flat quadratic growth curves compared to A-allele carriers, similar to individuals with ADHD compared to controls. However, there was no interaction between genotype and diagnosis, suggesting that any effects of this SNP on cerebellar development are not specific to the disorder.

Enhanced low-template DNA analysis conditions and investigation of allele dropout patterns.

PubMed

Hedell, Ronny; Dufva, Charlotte; Ansell, Ricky; Mostad, Petter; Hedman, Johannes

2015-01-01

Forensic DNA analysis applying PCR enables profiling of minute biological samples. Enhanced analysis conditions can be applied to further push the limit of detection, coming with the risk of visualising artefacts and allele imbalances. We have evaluated the consecutive increase of PCR cycles from 30 to 35 to investigate the limitations of low-template (LT) DNA analysis, applying the short tandem repeat (STR) analysis kit PowerPlex ESX 16. Mock crime scene DNA extracts of four different quantities (from around 8-84 pg) were tested. All PCR products were analysed using 5, 10 and 20 capillary electrophoresis (CE) injection seconds. Bayesian models describing allele dropout patterns, allele peak heights and heterozygote balance were developed to assess the overall improvements in EPG quality with altered PCR/CE settings. The models were also used to evaluate the impact of amplicon length, STR marker and fluorescent label on the risk for allele dropout. The allele dropout probability decreased for each PCR cycle increment from 30 to 33 PCR cycles. Irrespective of DNA amount, the dropout probability was not affected by further increasing the number of PCR cycles. For the 42 and 84 pg samples, mainly complete DNA profiles were generated applying 32 PCR cycles. For the 8 and 17 pg samples, the allele dropouts decreased from 100% using 30 cycles to about 75% and 20%, respectively. The results for 33, 34 and 35 PCR cycles indicated that heterozygote balance and stutter ratio were mainly affected by DNA amount, and not directly by PCR cycle number and CE injection settings. We found 32 and 33 PCR cycles with 10 CE injection seconds to be optimal, as 34 and 35 PCR cycles did not improve allele detection and also included CE saturation problems. We find allele dropout probability differences between several STR markers. Markers labelled with the fluorescent dyes CXR-ET (red in electropherogram) and TMR-ET (shown as black) generally have higher dropout risks compared with those

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

Uneven segregation of sporophytic self-incompatibility alleles in Arabidopsis lyrata.

PubMed

Bechsgaard, J; Bataillon, T; Schierup, M H

2004-05-01

Self-incompatibility in Arabidopsis lyrata is sporophytically controlled by the multi-allelic S-locus. Self-incompatibility alleles (S-alleles) are under strong negative frequency dependent selection because pollen carrying common S-alleles have fewer mating opportunities. Population genetics theory predicts that deleterious alleles can accumulate if linked to the S-locus. This was tested by studying segregation of S-alleles in 11 large full sib families in A. lyrata. Significant segregation distortion leading to an up to fourfold difference in transmission rates was found in six families. Differences in transmission rates were not significantly different in reciprocal crosses and the distortions observed were compatible with selection acting at the gametic stage alone. The S-allele with the largest segregation advantage is also the most recessive, and is very common in natural populations concordant with its apparent segregation advantage. These results imply that frequencies of S-alleles in populations of A. lyrata cannot be predicted based on simple models of frequency-dependent selection alone.

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.

Phenotypic effects of an allele causing obligate parthenogenesis in a rotifer.

PubMed

Scheuerl, Thomas; Riss, Simone; Stelzer, Claus-Peter

2011-01-01

Transitions to obligate asexuality have been documented in almost all metazoan taxa, yet the conditions favoring such transitions remained largely unexplored. We address this problem in the rotifer Brachionus calyciflorus. In this species, a polymorphism at a single locus, op, can result in transitions to obligate parthenogenesis. Homozygotes for the op allele reproduce strictly by asexual reproduction, whereas heterozygous clones (+/op) and wild-type clones (+/+) are cyclical parthenogens that undergo sexual reproduction at high population densities. Here, we examine dosage effects of the op allele by analyzing various life-history characteristics and population traits in 10 clones for each of the 3 possible genotypes (op/op, +/op, and +/+). For most traits, we found that op/op clones differed significantly (P < 0.05) from the 2 cyclical parthenogenetic genotypes (+/+ and +/op). By contrast, the 2 cyclical parthenogenetic genotypes were almost indistinguishable, except that heterozygote individuals were slightly but significantly smaller in body size compared with wild-type individuals. Overall, this indicates that the op allele is selectively neutral in the heterozygous state. Thus, selective sweeps of this allele in natural populations would first require conditions favoring the generation of homozygotes. This may be given by inbreeding in very small populations or by double mutants in very large populations.

Phenotypic Effects of an Allele Causing Obligate Parthenogenesis in a Rotifer

PubMed Central

Scheuerl, Thomas; Riss, Simone

2011-01-01

Transitions to obligate asexuality have been documented in almost all metazoan taxa, yet the conditions favoring such transitions remained largely unexplored. We address this problem in the rotifer Brachionus calyciflorus. In this species, a polymorphism at a single locus, op, can result in transitions to obligate parthenogenesis. Homozygotes for the op allele reproduce strictly by asexual reproduction, whereas heterozygous clones (+/op) and wild-type clones (+/+) are cyclical parthenogens that undergo sexual reproduction at high population densities. Here, we examine dosage effects of the op allele by analyzing various life-history characteristics and population traits in 10 clones for each of the 3 possible genotypes (op/op, +/op, and +/+). For most traits, we found that op/op clones differed significantly (P < 0.05) from the 2 cyclical parthenogenetic genotypes (+/+ and +/op). By contrast, the 2 cyclical parthenogenetic genotypes were almost indistinguishable, except that heterozygote individuals were slightly but significantly smaller in body size compared with wild-type individuals. Overall, this indicates that the op allele is selectively neutral in the heterozygous state. Thus, selective sweeps of this allele in natural populations would first require conditions favoring the generation of homozygotes. This may be given by inbreeding in very small populations or by double mutants in very large populations. PMID:21576287

Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers

PubMed Central

Antoniou, Antonis C; Kartsonaki, Christiana; Sinilnikova, Olga M.; Soucy, Penny; McGuffog, Lesley; Healey, Sue; Lee, Andrew; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Cattaneo, Elisa; Barile, Monica; Pensotti, Valeria; Pasini, Barbara; Dolcetti, Riccardo; Giannini, Giuseppe; Laura Putignano, Anna; Varesco, Liliana; Radice, Paolo; Mai, Phuong L.; Greene, Mark H.; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Thomassen, Mads; Gerdes, Anne-Marie; Kruse, Torben A.; Birk Jensen, Uffe; Crüger, Dorthe G.; Caligo, Maria A.; Laitman, Yael; Milgrom, Roni; Kaufman, Bella; Paluch-Shimon, Shani; Friedman, Eitan; Loman, Niklas; Harbst, Katja; Lindblom, Annika; Arver, Brita; Ehrencrona, Hans; Melin, Beatrice; Nathanson, Katherine L.; Domchek, Susan M.; Rebbeck, Timothy; Jakubowska, Ania; Lubinski, Jan; Gronwald, Jacek; Huzarski, Tomasz; Byrski, Tomasz; Cybulski, Cezary; Gorski, Bohdan; Osorio, Ana; Ramón y Cajal, Teresa; Fostira, Florentia; Andrés, Raquel; Benitez, Javier; Hamann, Ute; Hogervorst, Frans B.; Rookus, Matti A.; Hooning, Maartje J.; Nelen, Marcel R.; van der Luijt, Rob B.; van Os, Theo A.M.; van Asperen, Christi J.; Devilee, Peter; Meijers-Heijboer, Hanne E.J.; Gómez Garcia, Encarna B.; Peock, Susan; Cook, Margaret; Frost, Debra; Platte, Radka; Leyland, Jean; Gareth Evans, D.; Lalloo, Fiona; Eeles, Ros; Izatt, Louise; Adlard, Julian; Davidson, Rosemarie; Eccles, Diana; Ong, Kai-ren; Cook, Jackie; Douglas, Fiona; Paterson, Joan; John Kennedy, M.; Miedzybrodzka, Zosia; Godwin, Andrew; Stoppa-Lyonnet, Dominique; Buecher, Bruno; Belotti, Muriel; Tirapo, Carole; Mazoyer, Sylvie; Barjhoux, Laure; Lasset, Christine; Leroux, Dominique; Faivre, Laurence; Bronner, Myriam; Prieur, Fabienne; Nogues, Catherine; Rouleau, Etienne; Pujol, Pascal; Coupier, Isabelle; Frénay, Marc; Hopper, John L.; Daly, Mary B.; Terry, Mary B.; John, Esther M.; Buys, Saundra S.; Yassin, Yosuf; Miron, Alexander; Goldgar, David; Singer, Christian F.; Tea, Muy-Kheng; Pfeiler, Georg; Catharina Dressler, Anne; Hansen, Thomas v.O.; Jønson, Lars; Ejlertsen, Bent; Bjork Barkardottir, Rosa; Kirchhoff, Tomas; Offit, Kenneth; Piedmonte, Marion; Rodriguez, Gustavo; Small, Laurie; Boggess, John; Blank, Stephanie; Basil, Jack; Azodi, Masoud; Ewart Toland, Amanda; Montagna, Marco; Tognazzo, Silvia; Agata, Simona; Imyanitov, Evgeny; Janavicius, Ramunas; Lazaro, Conxi; Blanco, Ignacio; Pharoah, Paul D.P.; Sucheston, Lara; Karlan, Beth Y.; Walsh, Christine S.; Olah, Edith; Bozsik, Aniko; Teo, Soo-Hwang; Seldon, Joyce L.; Beattie, Mary S.; van Rensburg, Elizabeth J.; Sluiter, Michelle D.; Diez, Orland; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Ruehl, Ina; Varon-Mateeva, Raymonda; Kast, Karin; Deissler, Helmut; Niederacher, Dieter; Arnold, Norbert; Gadzicki, Dorothea; Schönbuchner, Ines; Caldes, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Aittomäki, Kristiina; Dumont, Martine; Chiquette, Jocelyne; Tischkowitz, Marc; Chen, Xiaoqing; Beesley, Jonathan; Spurdle, Amanda B.; Neuhausen, Susan L.; Chun Ding, Yuan; Fredericksen, Zachary; Wang, Xianshu; Pankratz, Vernon S.; Couch, Fergus; Simard, Jacques; Easton, Douglas F.; Chenevix-Trench, Georgia

2011-01-01

Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r2 = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11–1.23, P-trend = 4.5 × 10−9 for rs2046210; HR = 1.28, 95% CI: 1.18–1.40, P-trend = 1.3 × 10−8 for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01–1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02–1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92–1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women. PMID:21593217

Natural Allelic Variations in Highly Polyploidy Saccharum Complex

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

Song, Jian; Yang, Xiping; Resende, Jr., Marcio F. R.

Sugarcane ( Saccharum spp.) is an important sugar and biofuel crop with high polyploid and complex genomes. The Saccharum complex, comprised of Saccharum genus and a few related genera, are important genetic resources for sugarcane breeding. A large amount of natural variation exists within the Saccharum complex. Though understanding their allelic variation has been challenging, it is critical to dissect allelic structure and to identify the alleles controlling important traits in sugarcane. To characterize natural variations in Saccharum complex, a target enrichment sequencing approach was used to assay 12 representative germplasm accessions. In total, 55,946 highly efficient probes were designedmore » based on the sorghum genome and sugarcane unigene set targeting a total of 6 Mb of the sugarcane genome. A pipeline specifically tailored for polyploid sequence variants and genotype calling was established. BWAmem and sorghum genome approved to be an acceptable aligner and reference for sugarcane target enrichment sequence analysis, respectively. Genetic variations including 1,166,066 non-redundant SNPs, 150,421 InDels, 919 gene copy number variations, and 1,257 gene presence/absence variations were detected. SNPs from three different callers (Samtools, Freebayes, and GATK) were compared and the validation rates were nearly 90%. Based on the SNP loci of each accession and their ploidy levels, 999,258 single dosage SNPs were identified and most loci were estimated as largely homozygotes. An average of 34,397 haplotype blocks for each accession was inferred. The highest divergence time among the Saccharum spp. was estimated as 1.2 million years ago (MYA). Saccharum spp. diverged from Erianthus and Sorghum approximately 5 and 6 MYA, respectively. Furthermore, the target enrichment sequencing approach provided an effective way to discover and catalog natural allelic variation in highly polyploid or heterozygous genomes.« less

Natural Allelic Variations in Highly Polyploidy Saccharum Complex

DOE PAGES

Song, Jian; Yang, Xiping; Resende, Jr., Marcio F. R.; ...

2016-06-08

Sugarcane ( Saccharum spp.) is an important sugar and biofuel crop with high polyploid and complex genomes. The Saccharum complex, comprised of Saccharum genus and a few related genera, are important genetic resources for sugarcane breeding. A large amount of natural variation exists within the Saccharum complex. Though understanding their allelic variation has been challenging, it is critical to dissect allelic structure and to identify the alleles controlling important traits in sugarcane. To characterize natural variations in Saccharum complex, a target enrichment sequencing approach was used to assay 12 representative germplasm accessions. In total, 55,946 highly efficient probes were designedmore » based on the sorghum genome and sugarcane unigene set targeting a total of 6 Mb of the sugarcane genome. A pipeline specifically tailored for polyploid sequence variants and genotype calling was established. BWAmem and sorghum genome approved to be an acceptable aligner and reference for sugarcane target enrichment sequence analysis, respectively. Genetic variations including 1,166,066 non-redundant SNPs, 150,421 InDels, 919 gene copy number variations, and 1,257 gene presence/absence variations were detected. SNPs from three different callers (Samtools, Freebayes, and GATK) were compared and the validation rates were nearly 90%. Based on the SNP loci of each accession and their ploidy levels, 999,258 single dosage SNPs were identified and most loci were estimated as largely homozygotes. An average of 34,397 haplotype blocks for each accession was inferred. The highest divergence time among the Saccharum spp. was estimated as 1.2 million years ago (MYA). Saccharum spp. diverged from Erianthus and Sorghum approximately 5 and 6 MYA, respectively. Furthermore, the target enrichment sequencing approach provided an effective way to discover and catalog natural allelic variation in highly polyploid or heterozygous genomes.« less

Lower Frequency of HLA-DRB1 Type 1 Diabetes Risk Alleles in Pediatric Patients with MODY.

PubMed

Urrutia, Inés; Martínez, Rosa; López-Euba, Tamara; Velayos, Teresa; Martínez de LaPiscina, Idoia; Bilbao, José Ramón; Rica, Itxaso; Castaño, Luis

2017-01-01

The aim of this study was to determine the frequency of susceptible HLA-DRB1 alleles for type 1 diabetes in a cohort of pediatric patients with a confirmed genetic diagnosis of MODY. 160 families with a proband diagnosed with type 1 diabetes and 74 families with a molecular diagnosis of MODY (61 GCK-MODY and 13 HNF1A-MODY) were categorized at high definition for HLA-DRB1 locus. According to the presence or absence of the susceptible HLA-DRB1 alleles for type 1 diabetes, we considered three different HLA-DRB1 genotypes: 0 risk alleles (no DR3 no DR4); 1 risk allele (DR3 or DR4); 2 risk alleles (DR3 and/or DR4). Compared with type 1 diabetes, patients with MODY carried higher frequency of 0 risk alleles, OR 22.7 (95% CI: 10.7-48.6) and lower frequency of 1 or 2 risk alleles, OR 0.53 (95% CI: 0.29-0.96) and OR 0.06 (95% CI: 0.02-0.18), respectively. The frequency of HLA-DRB1 risk alleles for type 1 diabetes is significantly lower in patients with MODY. In children and adolescents with diabetes, the presence of 2 risk alleles (DR3 and/or DR4) reduces the probability of MODY diagnosis, whereas the lack of risk alleles increases it. Therefore, we might consider that HLA-DRB1 provides additional information for the selection of patients with high probability of monogenic diabetes.

Dynamin 2 gene is a novel susceptibility gene for late-onset Alzheimer disease in non-APOE-epsilon4 carriers.

PubMed

Aidaralieva, Nuripa Jenishbekovna; Kamino, Kouzin; Kimura, Ryo; Yamamoto, Mitsuko; Morihara, Takeshi; Kazui, Hiroaki; Hashimoto, Ryota; Tanaka, Toshihisa; Kudo, Takashi; Kida, Tomoyuki; Okuda, Jun-Ichiro; Uema, Takeshi; Yamagata, Hidehisa; Miki, Tetsuro; Akatsu, Hiroyasu; Kosaka, Kenji; Takeda, Masatoshi

2008-01-01

Alzheimer disease (AD) is characterized by progressive cognitive decline caused by synaptic dysfunction and neurodegeneration in the brain, and late-onset AD (LOAD), genetically classified as a polygenetic disease, is the major form of dementia in the elderly. It has been shown that beta amyloid, deposited in the AD brain, interacts with dynamin 1 and that the dynamin 2 (DNM2) gene homologous to the dynamin 1 gene is encoded at chromosome 19p13.2 where a susceptibility locus has been detected by linkage analysis. To test the genetic association of LOAD with the DNM2 gene, we performed a case-control study of 429 patients with LOAD and 438 sex- and age-matched control subjects in a Japanese population. We found a significant association of LOAD with single nucleotide polymorphism markers of the DNM2 gene, especially in non-carriers of the apolipoprotein E-epsilon4 allele. Even though subjects with the genotype homozygous for the risk allele at rs892086 showed no mutation in exons of the DNM2 gene, expression of DNM2 mRNA in the hippocampus was decreased in the patients compared to non-demented controls. We propose that the DNM2 gene is a novel susceptibility gene for LOAD.

Prevalence of -alpha(3.7) and alpha alpha alpha(anti3.7) alleles in sickle cell trait and beta-thalassemia patients in Mexico.

PubMed

Nava, María Paulina; Ibarra, Bertha; Magaña, María Teresa; de la Luz Chávez, María; Perea, F Javier

2006-01-01

The aim of this study was to determine the frequency of alpha-globin gene mutations in three groups of Mexican unrelated individuals. The first two groups were normal and sickle cell trait individuals from the Costa Chica region, a place with a 12.8% frequency of HbS carriers, and the third group comprised of Mexican mestizo patients with beta-thalassemia. We searched for -alpha(3.7) and -alpha(4.2) alpha(+)-thalassemia deletion alleles, as well as the alpha alpha alpha(anti3.7) triplication through long-gap PCR. The alleles -alpha(3.7) and alpha alpha alpha(anti3.7) were found in the heterozygote state only; 19% of the normal subjects had the -alpha(3.7) allele, and 2% showed the alpha alpha alpha(anti3.7) allele. In individuals with the sickle cell trait, 17% had the -alpha(3.7) deletion, and the alpha alpha alpha(anti3.7) triplication was observed in 3% of these individuals. We revealed that 16% of the subjects with beta-thalassemia showed the -alpha(3.7) deletion and 28% the alpha alpha alpha(anti3.7) triplication. The -alpha(4.2) deletion was not detected in any individual. The frequency of the -alpha(3.7) allele was roughly the same in the three groups studied; this can be explained by the fact that the three groups have common genes from Africa and the Mediterranean, where a high prevalence of alpha(+)-thalassemia has been observed. To our knowledge, the frequency of alpha alpha alpha(anti3.7) triplication observed in the Mexican beta-thalassemia patients is the highest reported. As the -alpha(3.7) and alpha alpha alpha(anti3.7) alleles are very common in our selected populations, we believe that there is a need to investigate systematically the alpha-globin gene mutations in all hemoglobinopathies in the Mexican population.

Association of HLA-B*5801 allele and allopurinol-induced stevens johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis

PubMed Central

2011-01-01

Background Despite some studies suggesting a possible association between human leukocyte antigen, HLA-B*5801 and allopurinol induced Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), the evidence of association and its magnitude remain inconclusive. This study aims to systematically review and meta-analyze the association between HLA-B*5801 allele and allopurinol-induced SJS/TEN. Methods A comprehensive search was performed in databases including MEDLINE, Pre-MEDLINE, Cochrane Library, EMBASE, International Pharmaceutical Abstracts (IPA), CINAHL, PsychInfo, the WHO International, Clinical Trial Registry, and ClinicalTrial.gov from their inceptions to June 2011. Only studies investigating association between HLA-B*5801 with allopurinol-induced SJS/TEN were included. All studies were extracted by two independent authors. The primary analysis was the carrier frequency of HLA-B*5801 comparison between allopurinol-induced SJS/TEN cases and each comparative group. The pooled odds ratios were calculated using a random effect model. Results A total of 4 studies with 55 SJS/TEN cases and 678 matched-controls (allopurinol-tolerant control) was identified, while 5 studies with 69 SJS/TEN cases and 3378 population-controls (general population) were found. SJS/TEN cases were found to be significantly associated with HLA-B*5801 allele in both groups of studies with matched-control (OR 96.60, 95%CI 24.49-381.00, p < 0.001) and population-control (OR 79.28, 95%CI 41.51-151.35, p < 0.001). Subgroup analysis for Asian and Non-Asian population yielded similar findings. Conclusion We found a strong and significant association between HLA-B*5801 and allopurinol-induced SJS/TEN. Therefore, HLA-B*5801 allele screening may be considered in patients who will be treated with allopurinol. PMID:21906289

India Allele Finder: a web-based annotation tool for identifying common alleles in next-generation sequencing data of Indian origin.

PubMed

Zhang, Jimmy F; James, Francis; Shukla, Anju; Girisha, Katta M; Paciorkowski, Alex R

2017-06-27

We built India Allele Finder, an online searchable database and command line tool, that gives researchers access to variant frequencies of Indian Telugu individuals, using publicly available fastq data from the 1000 Genomes Project. Access to appropriate population-based genomic variant annotation can accelerate the interpretation of genomic sequencing data. In particular, exome analysis of individuals of Indian descent will identify population variants not reflected in European exomes, complicating genomic analysis for such individuals. India Allele Finder offers improved ease-of-use to investigators seeking to identify and annotate sequencing data from Indian populations. We describe the use of India Allele Finder to identify common population variants in a disease quartet whole exome dataset, reducing the number of candidate single nucleotide variants from 84 to 7. India Allele Finder is freely available to investigators to annotate genomic sequencing data from Indian populations. Use of India Allele Finder allows efficient identification of population variants in genomic sequencing data, and is an example of a population-specific annotation tool that simplifies analysis and encourages international collaboration in genomics research.

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

14 CFR 380.11 - Payment to direct air carrier(s).

Code of Federal Regulations, 2010 CFR

2010-01-01

... carrier(s). Except for air taxi operators and commuter air carriers (which are governed by 14 CFR 298.38) and Canadian charter air taxi operators (which are governed by 14 CFR 294.32), the direct air carrier...

14 CFR 380.11 - Payment to direct air carrier(s).

Code of Federal Regulations, 2011 CFR

2011-01-01

... carrier(s). Except for air taxi operators and commuter air carriers (which are governed by 14 CFR 298.38) and Canadian charter air taxi operators (which are governed by 14 CFR 294.32), the direct air carrier...

Characterization of the treefrog null allele, 1991

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

Guttman, S.I.

1992-04-01

Spring peeper (Hyla crucifer) tadpoles collected from the waste storage area during the Biological and Ecological Site Characterization of the Feed Materials Production Center (FEMP) in 1986 and 1987 appeared to be unique. A null (inactive) allele was found at the glucose phosphate isomerase enzyme locus in significant frequencies (approximately 20%) each year; this allele did not appear to occur in the offsite sample collected approximately 15km from the FEMP. Null alleles at this locus have not been reported in other amphibian populations; when they have been found in other organisms they have invariably been lethal in the homozygous condition.

Apolipoprotein E alleles in Alzheimer`s and Parkinson`s patients

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

Poduslo, S.E.; Schwankhaus, J.D.

1994-09-01

A number of investigators have found an association between the apolipoprotein E4 allele and Alzheimer`s disease. The E4 allele appears at a higher frequency in late onset familial Alzheimer`s patients. In our studies we obtained blood samples from early and late onset familial and sporadic Alzheimer`s patients and spouses, as well as from Parkinson`s patients. The patients were diagnosed as probable Alzheimer`s patients after a neurological examination, extensive blood work, and a CAT scan. The diagnosis was made according to the NINCDS-ADRDA criteria. The apolipoprotein E4 polymorphism was detected after PCR amplification of genomic DNA, restriction enzyme digestion with Hhal,more » and polyacrylamide gel electrophoresis. Ethidium bromide-stained bands at 91 bp were designated as allele 3, at 83 bp as allele 2, and at 72 bp as allele 4. Of the 84 probable Alzheimer`s patients (all of whom were Caucasian), 47 were heterozygous and 13 were homozygous for the E4 allele. There were 26 early onset patients; 13 were heterozygous and 7 homozygous for the E4 allele. The frequencies for the E4 allele for late onset familial patients was 0.45 and for sporadic patients was 0.37. We analyzed 77 spouses with an average age of 71.9 {plus_minus} 7.4 years as controls, and 15 were heterozygous for the E4 allele for an E4 frequency of 0.097. Of the 53 Parkinson`s patients, 11 had the E4 allele for a frequency of 0.113. Thus our findings support the association of the ApoE4 allele with Alzheimer`s disease.« less

Hot carrier dynamics in plasmonic transition metal nitrides

NASA Astrophysics Data System (ADS)

Habib, Adela; Florio, Fred; Sundararaman, Ravishankar

2018-06-01

Extraction of non-equilibrium hot carriers generated by plasmon decay in metallic nano-structures is an increasingly exciting prospect for utilizing plasmonic losses, but the search for optimum plasmonic materials with long-lived carriers is ongoing. Transition metal nitrides are an exciting class of new plasmonic materials with superior thermal and mechanical properties compared to conventional noble metals, but their suitability for plasmonic hot carrier applications remains unknown. Here, we present fully first principles calculations of the plasmonic response, hot carrier generation and subsequent thermalization of all group IV, V and VI transition metal nitrides, fully accounting for direct and phonon-assisted transitions as well as electron–electron and electron–phonon scattering. We find the largest frequency ranges for plasmonic response in ZrN, HfN and WN, between those of gold and silver, while we predict strongest absorption in the visible spectrum for the VN, NbN and TaN. Hot carrier generation is dominated by direct transitions for most of the relevant energy range in all these nitrides, while phonon-assisted processes dominate only below 1 eV plasmon energies primarily for the group IV nitrides. Finally, we predict the maximum hot carrier lifetimes to be around 10 fs for group IV and VI nitrides, a factor of 3–4 smaller than noble metals, due to strong electron–phonon scattering. However, we find longer carrier lifetimes for group V nitrides, comparable to silver for NbN and TaN, while exceeding 100 fs (twice that of silver) for VN, making them promising candidates for efficient hot carrier extraction.

Rhinal hypometabolism on FDG PET in healthy APO-E4 carriers: impact on memory function and metabolic networks.

PubMed

Didic, Mira; Felician, Olivier; Gour, Natalina; Bernard, Rafaelle; Pécheux, Christophe; Mundler, Olivier; Ceccaldi, Mathieu; Guedj, Eric

2015-09-01

The ε4 allele of the apolipoprotein E (APO-E4) gene, a genetic risk factor for Alzheimer's disease (AD), also modulates brain metabolism and function in healthy subjects. The aim of the present study was to explore cerebral metabolism using FDG PET in healthy APO-E4 carriers by comparing cognitively normal APO-E4 carriers to noncarriers and to assess if patterns of metabolism are correlated with performance on cognitive tasks. Moreover, metabolic connectivity patterns were established in order to assess if the organization of neural networks is influenced by genetic factors. Whole-brain PET statistical analysis was performed at voxel-level using SPM8 with a threshold of p < 0.005, corrected for volume, with age, gender and level of education as nuisance variables. Significant hypometabolism between APO-E4 carriers (n = 11) and noncarriers (n = 30) was first determined. Mean metabolic values with clinical/neuropsychological data were extracted at the individual level, and correlations were searched using Spearman's rank test in the whole group. To evaluate metabolic connectivity from metabolic cluster(s) previously identified in the intergroup comparison, voxel-wise interregional correlation analysis (IRCA) was performed between groups of subjects. APO-E4 carriers had reduced metabolism within the left anterior medial temporal lobe (MTL), where neuropathological changes first appear in AD, including the entorhinal and perirhinal cortices. A correlation between metabolism in this area and performance on the DMS48 (delayed matching to sample-48 items) was found, in line with converging evidence involving the perirhinal cortex in object-based memory. Finally, a voxel-wise IRCA revealed stronger metabolic connectivity of the MTL cluster with neocortical frontoparietal regions in carriers than in noncarriers, suggesting compensatory metabolic networks. Exploring cerebral metabolism using FDG PET can contribute to a better understanding of the influence of

Multimer Formation Explains Allelic Suppression of PRDM9 Recombination Hotspots.

PubMed

Baker, Christopher L; Petkova, Pavlina; Walker, Michael; Flachs, Petr; Mihola, Ondrej; Trachtulec, Zdenek; Petkov, Petko M; Paigen, Kenneth

2015-09-01

Genetic recombination during meiosis functions to increase genetic diversity, promotes elimination of deleterious alleles, and helps assure proper segregation of chromatids. Mammalian recombination events are concentrated at specialized sites, termed hotspots, whose locations are determined by PRDM9, a zinc finger DNA-binding histone methyltransferase. Prdm9 is highly polymorphic with most alleles activating their own set of hotspots. In populations exhibiting high frequencies of heterozygosity, questions remain about the influences different alleles have in heterozygous individuals where the two variant forms of PRDM9 typically do not activate equivalent populations of hotspots. We now find that, in addition to activating its own hotspots, the presence of one Prdm9 allele can modify the activity of hotspots activated by the other allele. PRDM9 function is also dosage sensitive; Prdm9+/- heterozygous null mice have reduced numbers and less active hotspots and increased numbers of aberrant germ cells. In mice carrying two Prdm9 alleles, there is allelic competition; the stronger Prdm9 allele can partially or entirely suppress chromatin modification and recombination at hotspots of the weaker allele. In cell cultures, PRDM9 protein variants form functional heteromeric complexes which can bind hotspots sequences. When a heteromeric complex binds at a hotspot of one PRDM9 variant, the other PRDM9 variant, which would otherwise not bind, can still methylate hotspot nucleosomes. We propose that in heterozygous individuals the underlying molecular mechanism of allelic suppression results from formation of PRDM9 heteromers, where the DNA binding activity of one protein variant dominantly directs recombination initiation towards its own hotspots, effectively titrating down recombination by the other protein variant. In natural populations with many heterozygous individuals, allelic competition will influence the recombination landscape.

Multimer Formation Explains Allelic Suppression of PRDM9 Recombination Hotspots

PubMed Central

Baker, Christopher L.; Petkova, Pavlina; Walker, Michael; Flachs, Petr; Mihola, Ondrej; Trachtulec, Zdenek; Petkov, Petko M.; Paigen, Kenneth

2015-01-01

Genetic recombination during meiosis functions to increase genetic diversity, promotes elimination of deleterious alleles, and helps assure proper segregation of chromatids. Mammalian recombination events are concentrated at specialized sites, termed hotspots, whose locations are determined by PRDM9, a zinc finger DNA-binding histone methyltransferase. Prdm9 is highly polymorphic with most alleles activating their own set of hotspots. In populations exhibiting high frequencies of heterozygosity, questions remain about the influences different alleles have in heterozygous individuals where the two variant forms of PRDM9 typically do not activate equivalent populations of hotspots. We now find that, in addition to activating its own hotspots, the presence of one Prdm9 allele can modify the activity of hotspots activated by the other allele. PRDM9 function is also dosage sensitive; Prdm9 +/- heterozygous null mice have reduced numbers and less active hotspots and increased numbers of aberrant germ cells. In mice carrying two Prdm9 alleles, there is allelic competition; the stronger Prdm9 allele can partially or entirely suppress chromatin modification and recombination at hotspots of the weaker allele. In cell cultures, PRDM9 protein variants form functional heteromeric complexes which can bind hotspots sequences. When a heteromeric complex binds at a hotspot of one PRDM9 variant, the other PRDM9 variant, which would otherwise not bind, can still methylate hotspot nucleosomes. We propose that in heterozygous individuals the underlying molecular mechanism of allelic suppression results from formation of PRDM9 heteromers, where the DNA binding activity of one protein variant dominantly directs recombination initiation towards its own hotspots, effectively titrating down recombination by the other protein variant. In natural populations with many heterozygous individuals, allelic competition will influence the recombination landscape. PMID:26368021

Association of STin2 Variable Number of Tandem Repeat (VNTR) Polymorphism of Serotonin Transporter Gene with Lifelong Premature Ejaculation: A Case-Control Study in Han Chinese Subjects

PubMed Central

Huang, Yuanyuan; Zhang, Xiansheng; Gao, Jingjing; Tang, Dongdong; Gao, Pan; Peng, Dangwei; Liang, Chaozhao

2016-01-01

Background The STin2 VNTR polymorphism has a variable number of tandem repeats in intron 2 of the serotonin transporter gene. We aimed to explore the relationship between STin2 VNTR polymorphism and lifelong premature ejaculation (LPE). Material/Methods We recruited a total of 115 outpatients who complained of ejaculating prematurely and who were diagnosed as LPE, and 101 controls without PE complaint. Allelic variations of STin2 VNTR were genotyped using PCR-based technology. We evaluated the associations between STin2 VNTR allelic and genotypic frequencies and LPE, as well as the intravaginal ejaculation latency time (IELT) of different STin2 VNTR genotypes among LPE patients. Results The patients and controls did not differ significantly in terms of any characteristic except age. A significantly higher frequency of STin2.12/12 genotype was found among LPE patients versus controls (P=0.026). Frequency of patients carrying at least 1 copy of the 10-repeat allele was significantly lower compared to the control group (28.3% vs. 41.8%, OR=0.55; 95%CI=0.31–0.97, P=0.040). In the LPE group, the mean IELT showed significant difference in STin2.12/12 genotype when compared to those with STin2.12/10 and STin2.10/10 genotypes. The mean IELT in10-repeat allele carriers was 50% longer compared to homozygous carriers of the STin2.12 allele. Conclusions Our results indicate the presence of STin2.10 allele is a protective factor for LPE. Men carrying the higher expression genotype STin2. 12/12 have shorter IELT than 10-repeat allele carriers. PMID:27713390

APOE associated hemispheric asymmetry of entorhinal cortical thickness in aging and Alzheimer’s disease

PubMed Central

Donix, Markus; Burggren, Alison C.; Scharf, Maria; Marschner, Kira; Suthana, Nanthia A.; Siddarth, Prabha; Krupa, Allison K.; Jones, Michael; Martin-Harris, Laurel; Ercoli, Linda M.; Miller, Karen J.; Werner, Annett; von Kummer, Rüdiger; Sauer, Cathrin; Small, Gary W.; Holthoff, Vjera A.; Bookheimer, Susan Y.

2013-01-01

Across species structural and functional hemispheric asymmetry is a fundamental feature of the brain. Environmental and genetic factors determine this asymmetry during brain development and modulate its interaction with brain disorders. The e4 allele of the apolipoprotein E gene (APOE-4) is a risk factor for Alzheimer’s disease, associated with regionally specific effects on brain morphology and function during the life span. Furthermore, entorhinal and hippocampal hemispheric asymmetry could be modified by pathology during Alzheimer’s disease development. Using high-resolution magnetic resonance imaging and a cortical unfolding technique we investigated whether carrying the APOE-4 allele influences hemispheric asymmetry in the entorhinal cortex and the hippocampus among patients with Alzheimer’s disease as well as in middle-aged and older cognitively healthy individuals. APOE-4 carriers showed a thinner entorhinal cortex in the left hemisphere when compared with the right hemisphere across all participants. Non-carriers of the allele showed this asymmetry only in the patient group. Cortical thickness in the hippocampus did not vary between hemispheres among APOE-4 allele carriers and non-carriers. The APOE-4 allele modulates hemispheric asymmetry in entorhinal cortical thickness. Among Alzheimer’s disease patients, this asymmetry might be less dependent on the APOE genotype and a more general marker of incipient disease pathology. PMID:24080518

PNPLA3 148M Carriers with Inflammatory Bowel Diseases Have Higher Susceptibility to Hepatic Steatosis and Higher Liver Enzymes.

PubMed

Mancina, Rosellina Margherita; Spagnuolo, Rocco; Milano, Marta; Brogneri, Simona; Morrone, Attilio; Cosco, Cristina; Lazzaro, Veronica; Russo, Cristina; Ferro, Yvelise; Pingitore, Piero; Pujia, Arturo; Montalcini, Tiziana; Doldo, Patrizia; Garieri, Pietro; Piodi, Luca; Caprioli, Flavio; Valenti, Luca; Romeo, Stefano

2016-01-01

Inflammatory bowel diseases (IBD) are characterized by chronic relapsing inflammation of the gastrointestinal tract and encompass Crohn's disease and ulcerative colitis. IBD are often associated with extraintestinal manifestations affecting multiple organs including the liver. Increased levels of serum aminotransferases, possibly related to nonalcoholic fatty liver disease, constitute one of the most frequently described IBD-related liver diseases. The PNPLA3 I148M substitution is a major common genetic determinant of hepatic fat content and progression to chronic liver disease. The aim of this study was to investigate whether carriers of PNPLA3 148M allele with IBD have higher risk of liver steatosis and increase in transaminases levels. The PNPLA3 I148M (rs738409) genotype was performed by Taqman assays in 158 individuals from Southern Italy (namely, Catanzaro cohort) and in 207 individuals from Northern Italy (namely, Milan cohort) with a definite diagnosis of IBD. Demographic and clinical data and also alanine transaminase levels were collected for both cohorts. The Catanzaro cohort underwent liver evaluation by sonography and liver stiffness and controlled attenuation parameter measurements by transient elastography. Here, we show for the first time that carriers of the PNPLA3 148M allele with IBD have a greater risk of hepatic steatosis (odds ratio, 2.9, and confidence interval, 1.1-7.8), higher controlled attenuation parameter values (P = 0.029), and increased circulating alanine transaminase (P = 0.035) in the Catanzaro cohort. We further confirm the higher alanine transaminase levels in the Milan cohort (P < 0.001). Our results show that PNPLA3 148M carriers with IBD have higher susceptibility to hepatic steatosis and liver damage.

Triglyceride response to an intensive lifestyle intervention is enhanced in carriers of the GCKR Pro446Leu polymorphism.

PubMed

Pollin, Toni I; Jablonski, Kathleen A; McAteer, Jarred B; Saxena, Richa; Kathiresan, Sekar; Kahn, Steven E; Goldberg, Ronald B; Altshuler, David; Florez, Jose C

2011-07-01

Glucokinase regulatory protein (GCKR) regulates the trafficking and enzymatic activity of hepatic glucokinase, the rate-limiting enzyme in glycogen synthesis and glycolysis. The intronic single-nucleotide polymorphism (SNP) rs780094 (intron 16) and the missense SNP rs1260326 (P446L) in the GCKR gene are strongly associated with increased circulating triglyceride and C-reactive protein levels and, paradoxically, reductions in diabetes incidence, fasting glucose levels, and insulin resistance. OBJECTIVE, SETTING, AND PATIENTS: We sought to replicate these associations and evaluate interactions with lifestyle and metformin interventions in the multiethnic Diabetes Prevention Program (DPP). We genotyped the two GCKR SNP in 3346 DPP participants and evaluated association with progression to diabetes and both baseline levels and changes in triglycerides, homeostasis model assessment of insulin resistance (HOMA-IR), oral disposition index, and inflammatory markers along with their interactions with DPP interventions. GCKR variation did not predict development of type 2 diabetes. At baseline, the 446L allele was associated with higher triglyceride and C-reactive protein levels (both P < 0.0001) and lower fasting glucose (P = 0.001) and HOMA-IR (P = 0.06). The lifestyle intervention was associated with a decrease in magnitude of the effect of the 446L allele on triglyceride levels (interaction P = 0.04). Metformin was more effective in reducing HOMA-IR in carriers of the P446 allele (interaction P = 0.05). Intensive lifestyle intervention appears to partially mitigate the effect of the 446L allele on higher triglycerides, whereas the P446 allele appears to enhance responsiveness to the HOMA-IR-lowering effect of metformin.

SSR allelic variation in almond (Prunus dulcis Mill.).

PubMed

Xie, Hua; Sui, Yi; Chang, Feng-Qi; Xu, Yong; Ma, Rong-Cai

2006-01-01

Sixteen SSR markers including eight EST-SSR and eight genomic SSRs were used for genetic diversity analysis of 23 Chinese and 15 international almond cultivars. EST- and genomic SSR markers previously reported in species of Prunus, mainly peach, proved to be useful for almond genetic analysis. DNA sequences of 117 alleles of six of the 16 SSR loci were analysed to reveal sequence variation among the 38 almond accessions. For the four SSR loci with AG/CT repeats, no insertions or deletions were observed in the flanking regions of the 98 alleles sequenced. Allelic size variation of these loci resulted exclusively from differences in the structures of repeat motifs, which involved interruptions or occurrences of new motif repeats in addition to varying number of AG/CT repeats. Some alleles had a high number of uninterrupted repeat motifs, indicating that SSR mutational patterns differ among alleles at a given SSR locus within the almond species. Allelic homoplasy was observed in the SSR loci because of base substitutions, interruptions or compound repeat motifs. Substitutions in the repeat regions were found at two SSR loci, suggesting that point mutations operate on SSRs and hinder the further SSR expansion by introducing repeat interruptions to stabilize SSR loci. Furthermore, it was shown that some potential point mutations in the flanking regions are linked with new SSR repeat motif variation in almond and peach.

Mutant maize variety containing the glt1-1 allele

DOEpatents

Nelson, O.E.; Pan, D.

1994-07-19

A maize plant has in its genome a non-mutable form of a mutant allele designated vitX-8132. The allele is located at a locus designated as glt which conditions kernels having an altered starch characteristic. Maize plants including such a mutant allele produce a starch that does not increase in viscosity on cooling, after heating. 2 figs.

Mutant maize variety containing the glt1-1 allele

DOEpatents

Nelson, Oliver E.; Pan, David

1994-01-01

A maize plant has in its genome a non-mutable form of a mutant allele designated vitX-8132. The allele is located at a locus designated as glt which conditions kernels having an altered starch characteristic. Maize plants including such a mutant allele produce a starch that does not increase in viscosity on cooling, after heating.

The Equilibrium Allele Frequency Distribution for a Population with Reproductive Skew

PubMed Central

Der, Ricky; Plotkin, Joshua B.

2014-01-01

We study the population genetics of two neutral alleles under reversible mutation in a model that features a skewed offspring distribution, called the Λ-Fleming–Viot process. We describe the shape of the equilibrium allele frequency distribution as a function of the model parameters. We show that the mutation rates can be uniquely identified from this equilibrium distribution, but the form of the offspring distribution cannot itself always be so identified. We introduce an estimator for the mutation rate that is consistent, independent of the form of reproductive skew. We also introduce a two-allele infinite-sites version of the Λ-Fleming–Viot process, and we use it to study how reproductive skew influences standing genetic diversity in a population. We derive asymptotic formulas for the expected number of segregating sites as a function of sample size and offspring distribution. We find that the Wright–Fisher model minimizes the equilibrium genetic diversity, for a given mutation rate and variance effective population size, compared to all other Λ-processes. PMID:24473932

Reduced Height (Rht) Alleles Affect Wheat Grain Quality.

PubMed

Casebow, Richard; Hadley, Caroline; Uppal, Rajneet; Addisu, Molla; Loddo, Stefano; Kowalski, Ania; Griffiths, Simon; Gooding, Mike

2016-01-01

The effects of dwarfing alleles (reduced height, Rht) in near isogenic lines on wheat grain quality are characterised in field experiments and related to effects on crop height, grain yield and GA-sensitivity. Alleles included those that conferred GA-insensitivity (Rht-B1b, Rht-B1c, Rht-D1b, Rht-D1c) as well as those that retained GA-sensitivity (rht(tall), Rht8, Rht8 + Ppd-D1a, Rht12). Full characterisation was facilitated by including factors with which the effects of Rht alleles are known to interact for grain yield (i.e. system, [conventional or organic]; tillage intensity [plough-based, minimum or zero]; nitrogen fertilizer level [0-450 kg N/ha]; and genetic backgrounds varying in height [cvs Maris Huntsman, Maris Widgeon, and Mercia]. Allele effects on mean grain weight and grain specific weight were positively associated with final crop height: dwarfing reduced these quality criteria irrespective of crop management or GA-sensitivity. In all but two experiments the effects of dwarfing alleles on grain nitrogen and sulphur concentrations were closely and negatively related to effects on grain yield, e.g. a quadratic relationship between grain yield and crop height manipulated by the GA-insensitive alleles was mirrored by quadratic relationships for nitrogen and sulphur concentrations: the highest yields and most dilute concentrations occurred around 80cm. In one of the two exceptional experiments the GA-insensitive Rht-B1b and Rht-B1c significantly (P<0.05) reduced grain nitrogen concentration in the absence of an effect on yield, and in the remaining experiment the GA-sensitive Rht8 significantly reduced both grain yield and grain nitrogen concentration simultaneously. When Rht alleles diluted grain nitrogen concentration, N:S ratios and SDS-sedimentation volumes were often improved. Hagberg falling number (HFN) was negatively related to crop height but benefits from dwarfing were only seen for GA-insensitive alleles. For HFN, therefore, there was the

Beta2-adrenergic receptor allele frequencies in the Quechua, a high altitude native population.

PubMed

Rupert, J L; Monsalve, M V; Devine, D V; Hochachka, P W

2000-03-01

The beta2-adrenergic receptor is involved in the control of numerous physiological processes and, as the primary catecholamine receptor in the lungs, is of particular importance in the regulation of pulmonary function. There are several polymorphic loci in the beta2-adrenergic receptor gene that have alleles that alter receptor function, including two (A/G46, G/C79) that increase agonist sensitivity. As such a phenotype may increase vaso and bronchial dilation, thereby facilitating air and blood flow through the lungs, we hypothesized that selection may have favoured these alleles in high altitude populations as part of an adaptive strategy to deal with the hypoxic conditions characteristic of such environments. We tested this hypothesis by determining the allele frequencies for these two polymorphisms, as well one additional missense mutation (C/T491) and two silent mutations (G/A252 and C/A523) in 63 Quechua speaking natives from communities located between 3200 and 4200 m on the Peruvian altiplano. These frequencies were compared with those of two lowland populations, one native American (Na-Dene from the west coast of Canada) and one Caucasian of Western European descent. The Quechua manifest many of the pulmonary characteristics of high altitude populations and differences in allele frequencies between the Quechua and lowlanders could be indicative of a selective advantage conferred by certain genotypes in high altitude environments. Allele frequencies varied between populations at some loci and patterns of linkage disequilibrium differed between the old-world and new-world samples; however, as these populations are not closely related, significant variation would be expected due to stochastic effects alone. Neither of the alleles associated with increased receptor sensitivity (A46, G79) was significantly over-represented in the Quechua compared with either lowland group. The Quechua were monomorphic for the C allele at base 79. This variant has been

[Comparison between porous polymer carrier and activated carbon carrier used for treating organic wastewater in anaerobic fluidized-bed reactor].

PubMed

Yang, P; Fang, Z; Shi, Y

2001-01-01

A comparative performance between porous polymer carriers (HP) and granular activated carbon carriers (GAC) in anaerobic fluidied-bed reactors was undertaken to evaluate their characters. The results showed that the COD removal and the biogas volume yield rate were 84% and 16.5 m3/(m3.d) respectively when HP was used as carrier to treat synthetic wastewater, at the top COD organic load rate of 65.5 kg/(m3.d), however those were 74.2% and 14.5% respectively for GAC carrier at the top load rate of 63.25 kg/(m3.d). The COD removal and biogas volume yield rate were 64.7%-54.5% and 1.89-2.7 m3/(m3.d) respectively when HP was used as carriers to treat straw pulping wastewater, at the load rate of 14.5-36.15 kg/(m3.d), and those were 61.0%-52.1% and 0.73-2.0 m3/(m3.d) respectively for GAC carriers at the load rate 9.16-19.06 kg/(m3.d). The study revealed that the HP carriers reactor is more efficient than the GAC carriers reactor in microbial immobilization and the wastewater treatment.

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.

Maize ARGOS1 (ZAR1) transgenic alleles increase hybrid maize yield.

PubMed

Guo, Mei; Rupe, Mary A; Wei, Jun; Winkler, Chris; Goncalves-Butruille, Marymar; Weers, Ben P; Cerwick, Sharon F; Dieter, Jo Ann; Duncan, Keith E; Howard, Richard J; Hou, Zhenglin; Löffler, Carlos M; Cooper, Mark; Simmons, Carl R

2014-01-01

Crop improvement for yield and drought tolerance is challenging due to the complex genetic nature of these traits and environmental dependencies. This study reports that transgenic over-expression of Zea mays AR GOS1 (ZAR1) enhanced maize organ growth, grain yield, and drought-stress tolerance. The ZAR1 transgene exhibited environmental interactions, with yield increase under Temperate Dry and yield reduction under Temperate Humid or High Latitude environments. Native ZAR1 allele variation associated with drought-stress tolerance. Two founder alleles identified in the mid-maturity germplasm of North America now predominate in Pioneer's modern breeding programme, and have distinct proteins, promoters and expression patterns. These two major alleles show heterotic group partitioning, with one predominant in Pioneer's female and the other in the male heterotic groups, respectively. These two alleles also associate with favourable crop performance when heterozygous. Allele-specific transgene testing showed that, of the two alleles discussed here, each allele differed in their impact on yield and environmental interactions. Moreover, when transgenically stacked together the allelic pair showed yield and environmental performance advantages over either single allele, resembling heterosis effects. This work demonstrates differences in transgenic efficacy of native alleles and the differences reflect their association with hybrid breeding performance.

Maize ARGOS1 (ZAR1) transgenic alleles increase hybrid maize yield

PubMed Central

Guo, Mei

2014-01-01

Crop improvement for yield and drought tolerance is challenging due to the complex genetic nature of these traits and environmental dependencies. This study reports that transgenic over-expression of Zea mays ARGOS1 (ZAR1) enhanced maize organ growth, grain yield, and drought-stress tolerance. The ZAR1 transgene exhibited environmental interactions, with yield increase under Temperate Dry and yield reduction under Temperate Humid or High Latitude environments. Native ZAR1 allele variation associated with drought-stress tolerance. Two founder alleles identified in the mid-maturity germplasm of North America now predominate in Pioneer’s modern breeding programme, and have distinct proteins, promoters and expression patterns. These two major alleles show heterotic group partitioning, with one predominant in Pioneer’s female and the other in the male heterotic groups, respectively. These two alleles also associate with favourable crop performance when heterozygous. Allele-specific transgene testing showed that, of the two alleles discussed here, each allele differed in their impact on yield and environmental interactions. Moreover, when transgenically stacked together the allelic pair showed yield and environmental performance advantages over either single allele, resembling heterosis effects. This work demonstrates differences in transgenic efficacy of native alleles and the differences reflect their association with hybrid breeding performance. PMID:24218327

Association of the HLA-B*52 allele with non-progression to AIDS in Brazilian HIV-1-infected individuals.

PubMed

Teixeira, S L M; de Sá, N B R; Campos, D P; Coelho, A B; Guimarães, M L; Leite, T C N F; Veloso, V G; Morgado, M G

2014-04-01

Several human leukocyte antigen (HLA) class I alleles are associated with the susceptibility to human immunodeficiency virus-1 (HIV-1) infection and/or AIDS progression. Of these, the HLA-B alleles are considered the strongest genetic determinant of disease outcome. We evaluated the influence of the HLA-B alleles on AIDS progression among HIV-1-positive individuals from Rio de Janeiro, Brazil, who were categorized as rapid progressors (RPs), typical progressors (TPs) or long-term non-progressors (LTNPs). In this study, significant differences in HLA-B allele frequencies were observed among the three progression groups for the B*48, B*49 and B*52 alleles. After controlling for other factors associated with AIDS progression, the presence of the B*52 allele was shown to be a significant protective factor (hazard ratio (HR) 0.49 (95% confidence interval (CI) 0.27-0.90) P<0.03). Although no direct association was observed between the presence of the B*27 or B*57 allele and the LTNP profile compared with the TP or RP groups, the adjusted model confirmed that these alleles are protective factors against AIDS progression (HR 0.62 (95% CI 0.38-0.99) P<0.05), as previously described. These data corroborate the existence of significant differences in HLA-B allele frequencies among the distinct AIDS progression profiles and further elucidate the role of HLA alleles in the outcome of HIV infections in diverse populations.

The Landscape of Somatic Genetic Alterations in Breast Cancers From ATM Germline Mutation Carriers.

PubMed

Weigelt, Britta; Bi, Rui; Kumar, Rahul; Blecua, Pedro; Mandelker, Diana L; Geyer, Felipe C; Pareja, Fresia; James, Paul A; Couch, Fergus J; Eccles, Diana M; Blows, Fiona; Pharoah, Paul; Li, Anqi; Selenica, Pier; Lim, Raymond S; Jayakumaran, Gowtham; Waddell, Nic; Shen, Ronglai; Norton, Larry; Wen, Hannah Y; Powell, Simon N; Riaz, Nadeem; Robson, Mark E; Reis-Filho, Jorge S; Chenevix-Trench, Georgia

2018-02-28

Pathogenic germline variants in ataxia-telangiectasia mutated (ATM), a gene that plays a role in DNA damage response and cell cycle checkpoints, confer an increased breast cancer (BC) risk. Here, we investigated the phenotypic characteristics and landscape of somatic genetic alterations in 24 BCs from ATM germline mutation carriers by whole-exome and targeted sequencing. ATM-associated BCs were consistently hormone receptor positive and largely displayed minimal immune infiltrate. Although 79.2% of these tumors exhibited loss of heterozygosity of the ATM wild-type allele, none displayed high activity of mutational signature 3 associated with defective homologous recombination DNA (HRD) repair. No TP53 mutations were found in the ATM-associated BCs. Analysis of an independent data set confirmed that germline ATM variants and TP53 somatic mutations are mutually exclusive. Our findings indicate that ATM-associated BCs often harbor bi-allelic inactivation of ATM, are phenotypically distinct from BRCA1/2-associated BCs, lack HRD-related mutational signatures, and that TP53 and ATM genetic alterations are likely epistatic.

Direct Fluorescence Detection of Allele-Specific PCR Products Using Novel Energy-Transfer Labeled Primers.

PubMed

Winn-Deen

1998-12-01

Background: Currently analysis of point mutations can be done by allele-specific polymerase chain reaction (PCR) followed by gel analysis or by gene-specific PCR followed by hybridization with an allele-specific probe. Both of these mutation detection methods require post-PCR laboratory time and run the risk of contaminating subsequent experiments with the PCR product liberated during the detection step. The author has combined the PCR amplification and detection steps into a single procedure suitable for closed-tube analysis. Methods and Results: Allele-specific PCR primers were designed as Sunrise energy-transfer primers and contained a 3' terminal mismatch to distinguish between normal and mutant DNA. Cloned normal (W64) and mutant (R64) templates of the beta3-adrenergic receptor gene were tested to verify amplification specificity and yield. A no-target negative control was also run with each reaction. After PCR, each reaction was tested for fluorescence yield by measuring fluorescence on a spectrofluorimeter or fluorescent microtitreplate reader. The cloned controls and 24 patient samples were tested for the W64R mutation by two methods. The direct fluorescence results with the Sunrise allele-specific PCR method gave comparable genotypes to those obtained with the PCR/ restriction digest/gel electrophoresis control method. No PCR artifacts were observed in the negative controls or in the PCR reactions run with the mismatched target. Conclusions: The results of this pilot study indicate good PCR product and fluorescence yield from allele-specific energy-transfer labeled primers, and the capability of distinguishing between normal and mutant alleles based on fluorescence alone, without the need for restriction digestion, gel electrophoresis, or hybridization with an allele-specific probe.

Offering fragile X syndrome carrier screening: a prospective mixed-methods observational study comparing carrier screening of pregnant and non-pregnant women in the general population

PubMed Central

Martyn, M; Anderson, V; Archibald, A; Carter, R; Cohen, J; Delatycki, M; Donath, S; Emery, J; Halliday, J; Hill, M; Sheffield, L; Slater, H; Tassone, F; Younie, S; Metcalfe, S

2013-01-01

Introduction Fragile X syndrome (FXS) is the leading cause of inherited intellectual and developmental disability. Policy development relating to carrier screening programmes for FXS requires input from large studies examining not only test uptake but also psychosocial aspects. This study will compare carrier screening in pregnant and non-pregnant populations, examining informed decision-making, psychosocial issues and health economics. Methods and Analysis Pregnant and non-pregnant women are being recruited from general practices and obstetric services. Women receive study information either in person or through clinic mail outs. Women are provided pretest counselling by a genetic counsellor and make a decision about testing in their own time. Data are being collected from two questionnaires: one completed at the time of making the decision about testing and the second 1 month later. Additional data are gathered through qualitative interviews conducted at several time points with a subset of participating women, including all women with a positive test result, and with staff from recruiting clinics. A minimum sample size of 500 women/group has been calculated to give us 88% power to detect a 10% difference in test uptake and 87% power to detect a 10% difference in informed choice between the pregnant and non-pregnant groups. Questionnaire data will be analysed using descriptive statistics and multivariate logistic regression models. Interview data will be thematically analysed. Willingness-to-pay and cost effectiveness analyses will also be performed. Recruitment started in July 2009 and data collection will be completed by December 2013. Ethics and Dissemination Ethics approval has been granted by the Universities of Melbourne and Western Australia and by recruiting clinics, where required. Results will be reported in peer-reviewed publications, conference presentations and through a website http://www.fragilexscreening.net.au. The results of this study will

Genetic predictor of working memory and prefrontal function in women with HIV.

PubMed

Sundermann, Erin E; Bishop, Jeffrey R; Rubin, Leah H; Little, Deborah M; Meyer, Vanessa J; Martin, Eileen; Weber, Kathleen; Cohen, Mardge; Maki, Pauline M

2015-02-01

The Val158Met (rs4680) single-nucleotide polymorphism (SNP) of the catechol-O-methyltransferase gene (COMT) influences executive function and prefrontal function through its effect on dopamine (DA) metabolism. Both HIV and the Val allele of the Val158Met SNP are associated with compromised executive function and inefficient prefrontal function. The present study used behavioral and neuroimaging techniques to determine independent and interactive associations between HIV serostatus and COMT genotype on working memory and prefrontal function in women. For the behavioral study, 54 HIV-infected and 33 HIV-uninfected women completed the 0-, 1-, and 2-back conditions of the verbal N-back, a working memory test. For the imaging study, 36 women (23 HIV-infected, 13 HIV-uninfected) underwent functional magnetic resonance imaging (fMRI) assessments while completing the N-back task. HIV-infected women demonstrated significantly worse N-back performance compared with HIV-uninfected women (p < 0.05). A significant serostatus by genotype interaction (p < 0.01) revealed that, among Val/Val, but not Met allele carriers, HIV-infected women performed significantly worse than HIV-uninfected controls across N-back conditions (p < 0.01). Analogous to behavioral findings, a serostatus by genotype interaction revealed that HIV-infected Val/Val carriers showed significantly greater prefrontal activation compared with HIV-uninfected Val/Val carriers (p < 0.01). Conversely, HIV-uninfected Met allele carriers demonstrated significantly greater prefrontal activation compared with HIV-infected Met allele carriers. Findings suggest that the combination of HIV infection and the Val/Val COMT genotype leads to working memory deficits and altered prefrontal function in HIV-infected individuals.

Radio Science Measurements with Suppressed Carrier

NASA Technical Reports Server (NTRS)

Asmar, Sami; Divsalar, Dariush; Oudrhiri, Kamal

2013-01-01

Radio Science started when it became apparent with early Solar missions that occultations by planetary atmospheres would affect the quality of radio communications. Since then the atmospheric properties and other aspects of planetary science, solar science, and fundamental physics were studied by scientists. Radio Science data was always extracted from a received pure residual carrier (without data modulation). For some missions, it is very desirable to obtain Radio Science data from a suppressed carrier modulation. In this paper we propose a method to extract Radio Science data when a coded suppressed carrier modulation is used in deep space communications. Type of modulation can be BPSK, QPSK, OQPSK, MPSK or even GMSK. However we concentrate mostly on BPSK modulation. The proposed method for suppressed carrier simply tries to wipe out data that acts as an interference for Radio Science measurements. In order to measure the estimation errors in amplitude and phase of the Radio Science data we use Cramer-Rao bound (CRB). The CRB for the suppressed carrier modulation with non-ideal data wiping is then compared with residual carrier modulation under the same noise condition. The method of derivation of CRB for non-ideal data wiping is an innovative method that presented here. Some numerical results are provided for coded system.

Carrier-mediated transport of riboflavin in the rat colon.

PubMed

Yuasa, H; Hirobe, M; Tomei, S; Watanabe, J

2000-03-01

Carriers involved in riboflavin transport have generally been presumed to be localized in the upper small intestine. However, using a closed loop technique, we found that in the rat colon the absorption of riboflavin could be significantly reduced by raising the concentration from 0.1 to 200 microM and by adding lumiflavin, an analogue of riboflavin. These results suggest that saturable transport by the carrier that is specific for riboflavin and analogues may also be involved in riboflavin absorption in the colon. At the lower concentration of 0.1 microM, carrier-mediated transport was suggested to prevail, compared with passive transport, both in the colon and the small intestine. Furthermore, carrier-mediated transport in the colon was comparable with that in the small intestine. This study is the first to suggest carrier-mediated riboflavin transport in the colon. Although the riboflavin transport system in the colon needs to be subjected to more detailed investigation of its transport functions and role in riboflavin absorption after oral administration, it would be of interest to explore potential use of this carrier as a system for drug delivery.

A rare FANCA gene variation as a breast cancer susceptibility allele in an Iranian population

PubMed Central

Abbasi, Sakineh; Rasouli, Mina

2017-01-01

Fanconi Anemia (FA) is an autosomal recessive syndrome characterized by congenital abnormalities, progressive bone marrow failure and Fanconi anemia complementation group A (FANCA) is also a potential breast and ovarian cancer susceptibility gene. A novel allele with tandem duplication of 13 base pair sequence in promoter region was identified. To investigate whether the 13 base pair sequence of tandem duplication in promoter region of the FANCA gene is of high penetrance in patients with breast cancer and to determine if the presence of the duplicated allele was associated with an altered risk of breast cancer, the present study screened DNA in blood samples from 304 breast cancer patients and 295 normal individuals as controls. The duplication allele had a frequency of 35.4 and 21.2% in patients with breast cancer and normal controls, respectively. There was a significant increase in the frequency of the duplication allele in patients with familial breast cancer compared with controls (45.1%, P=0.001). Furthermore, the estimated risk of breast cancer in individuals with a homozygote [odds ratio (OR), 4.093; 95% confidence intervals (CI), 1.957–8.561] or heterozygote duplicated genotype (OR, 3.315; 95% CI, 1.996–5.506) was higher compared with the corresponding normal homozygote genotype. In conclusion, the present study indicated that the higher the frequency of the duplicated allele, the higher the risk of breast cancer. To the best of our knowledge, the present study is the first to report FANCA gene duplication in patients with breast cancer. PMID:28440412

A rare FANCA gene variation as a breast cancer susceptibility allele in an Iranian population.

PubMed

Abbasi, Sakineh; Rasouli, Mina

2017-06-01

Fanconi Anemia (FA) is an autosomal recessive syndrome characterized by congenital abnormalities, progressive bone marrow failure and Fanconi anemia complementation group A (FANCA) is also a potential breast and ovarian cancer susceptibility gene. A novel allele with tandem duplication of 13 base pair sequence in promoter region was identified. To investigate whether the 13 base pair sequence of tandem duplication in promoter region of the FANCA gene is of high penetrance in patients with breast cancer and to determine if the presence of the duplicated allele was associated with an altered risk of breast cancer, the present study screened DNA in blood samples from 304 breast cancer patients and 295 normal individuals as controls. The duplication allele had a frequency of 35.4 and 21.2% in patients with breast cancer and normal controls, respectively. There was a significant increase in the frequency of the duplication allele in patients with familial breast cancer compared with controls (45.1%, P=0.001). Furthermore, the estimated risk of breast cancer in individuals with a homozygote [odds ratio (OR), 4.093; 95% confidence intervals (CI), 1.957‑8.561] or heterozygote duplicated genotype (OR, 3.315; 95% CI, 1.996‑5.506) was higher compared with the corresponding normal homozygote genotype. In conclusion, the present study indicated that the higher the frequency of the duplicated allele, the higher the risk of breast cancer. To the best of our knowledge, the present study is the first to report FANCA gene duplication in patients with breast cancer.

Molecular analyses of the agouti allele in the Japanese house mouse identify a novel variant of the agouti gene.

PubMed

Iwasa, Masahiro A; Kawamura, Sayaka; Myoshu, Hikari; Suzuki, Taichi A

2018-03-01

It has been thought that the Japanese house mouse carries the A w allele at the agouti locus causing light-colored bellies, but they do not always show this coloration. Thus, the presence of the A w allele seems to be doubtful in them. To ascertain whether the A w allele is present, a two-pronged approach was used. First, we compared lengths of DNA fragments obtained from three PCRs conducted on them to the known fragment sizes generated from mouse strains exhibiting homozygosities of either a/a, A/A, or A w /A w . PCR I, PCR II, and PCR III amplify only in the A and A w alleles, the a and A w alleles, and the a allele, respectively, and we detected amplifications in strains with A/A and A w /A w by PCR I, in those with a/a and the Japanese house mouse by PCR II, and in those with a/a by PCR III. Second, we sequenced the exon 1A region of the agouti gene and obtained sequences corresponding to the above strains and the Japanese house mouse, but their sequences were similar to those of the a allele. We concluded that their agouti allele is not identical to the A w allele and seems to be a novel type similar to the a allele.

Molecular analysis of the L1CAM gene in patients with X-linked hydrocephalus demonstrates eight novel mutations and suggests non-allelic heterogeneity of the trait.

PubMed

Gu, S M; Orth, U; Zankl, M; Schröder, J; Gal, A

1997-08-22

Eight novel mutations were identified in the gene encoding L1CAM, a neural cell adhesion protein, in patients/families with X-linked hydrocephalus (XHC) providing additional evidence for extreme allelic heterogeneity of the trait. The two nonsense mutations (Gln440Ter and Gln1042Ter) result most likely in functional null-alleles and complete absence of L1CAM at the cell surface. The four missense mutations (Leu482Pro, Ser542Pro, Met741Thr, and Val752Met) as well as delSer526 may considerably alter the structure of L1CAM. Interestingly, a missense mutation in an XHC family predicting the Val768Ile change in the second fibronectin type III domain of L1CAM was found not only in the two affected cousins and their obligate carrier mothers but also in two unaffected male relatives of the patients. Several possible explanations of this finding are discussed; the most likely being that Val768Ile is a rare non-pathogenic variant. If this were indeed the case, our data suggest that the XHC in this family is not due to a mutation of the L1CAM gene, i.e., that, in addition to the extreme allelic heterogeneity of XHC, a non-allelic form of genetic heterogeneity may also exist in this trait.

Characterization of a Weak Allele of Zebrafish cloche Mutant

PubMed Central

Ma, Ning; Huang, Zhibin; Chen, Xiaohui; He, Fei; Wang, Kun; Liu, Wei; Zhao, Linfeng; Xu, Xiangmin; Liao, Wangjun; Ruan, Hua; Luo, Shenqiu; Zhang, Wenqing

2011-01-01

Hematopoiesis is a complicated and dynamic process about which the molecular mechanisms remain poorly understood. Danio rerio (zebrafish) is an excellent vertebrate system for studying hematopoiesis and developmental mechanisms. In the previous study, we isolated and identified a cloche 172 (clo 172) mutant, a novel allele compared to the original cloche (clo) mutant, through using complementation test and initial mapping. Here, according to whole mount in-situ hybridization, we report that the endothelial cells in clo 172 mutant embryos, although initially developed, failed to form the functional vascular system eventually. In addition, further characterization indicates that the clo 172 mutant exhibited weaker defects instead of completely lost in primitive erythroid cells and definitive hematopoietic cells compared with the clo s5 mutant. In contrast, primitive myeloid cells were totally lost in clo 172 mutant. Furthermore, these reappeared definitive myeloid cells were demonstrated to initiate from the remaining hematopoietic stem cells (HSCs) in clo 172 mutant, confirmed by the dramatic decrease of lyc in clo 172 runx1w84x double mutant. Collectively, the clo 172 mutant is a weak allele compared to the clo s5 mutant, therefore providing a model for studying the early development of hematopoietic and vascular system, as well as an opportunity to further understand the function of the cloche gene. PMID:22132109

Allelic Variation of Cytochrome P450s Drives Resistance to Bednet Insecticides in a Major Malaria Vector.

PubMed

Ibrahim, Sulaiman S; Riveron, Jacob M; Bibby, Jaclyn; Irving, Helen; Yunta, Cristina; Paine, Mark J I; Wondji, Charles S

2015-10-01

Scale up of Long Lasting Insecticide Nets (LLINs) has massively contributed to reduce malaria mortality across Africa. However, resistance to pyrethroid insecticides in malaria vectors threatens its continued effectiveness. Deciphering the detailed molecular basis of such resistance and designing diagnostic tools is critical to implement suitable resistance management strategies. Here, we demonstrated that allelic variation in two cytochrome P450 genes is the most important driver of pyrethroid resistance in the major African malaria vector Anopheles funestus and detected key mutations controlling this resistance. An Africa-wide polymorphism analysis of the duplicated genes CYP6P9a and CYP6P9b revealed that both genes are directionally selected with alleles segregating according to resistance phenotypes. Modelling and docking simulations predicted that resistant alleles were better metabolizers of pyrethroids than susceptible alleles. Metabolism assays performed with recombinant enzymes of various alleles confirmed that alleles from resistant mosquitoes had significantly higher activities toward pyrethroids. Additionally, transgenic expression in Drosophila showed that flies expressing resistant alleles of both genes were significantly more resistant to pyrethroids compared with those expressing the susceptible alleles, indicating that allelic variation is the key resistance mechanism. Furthermore, site-directed mutagenesis and functional analyses demonstrated that three amino acid changes (Val109Ile, Asp335Glu and Asn384Ser) from the resistant allele of CYP6P9b were key pyrethroid resistance mutations inducing high metabolic efficiency. The detection of these first DNA markers of metabolic resistance to pyrethroids allows the design of DNA-based diagnostic tools to detect and track resistance associated with bednets scale up, which will improve the design of evidence-based resistance management strategies.

Allelic Variation of Cytochrome P450s Drives Resistance to Bednet Insecticides in a Major Malaria Vector

PubMed Central

Ibrahim, Sulaiman S.; Riveron, Jacob M.; Bibby, Jaclyn; Irving, Helen; Yunta, Cristina; Paine, Mark J. I.; Wondji, Charles S.

2015-01-01

Scale up of Long Lasting Insecticide Nets (LLINs) has massively contributed to reduce malaria mortality across Africa. However, resistance to pyrethroid insecticides in malaria vectors threatens its continued effectiveness. Deciphering the detailed molecular basis of such resistance and designing diagnostic tools is critical to implement suitable resistance management strategies. Here, we demonstrated that allelic variation in two cytochrome P450 genes is the most important driver of pyrethroid resistance in the major African malaria vector Anopheles funestus and detected key mutations controlling this resistance. An Africa-wide polymorphism analysis of the duplicated genes CYP6P9a and CYP6P9b revealed that both genes are directionally selected with alleles segregating according to resistance phenotypes. Modelling and docking simulations predicted that resistant alleles were better metabolizers of pyrethroids than susceptible alleles. Metabolism assays performed with recombinant enzymes of various alleles confirmed that alleles from resistant mosquitoes had significantly higher activities toward pyrethroids. Additionally, transgenic expression in Drosophila showed that flies expressing resistant alleles of both genes were significantly more resistant to pyrethroids compared with those expressing the susceptible alleles, indicating that allelic variation is the key resistance mechanism. Furthermore, site-directed mutagenesis and functional analyses demonstrated that three amino acid changes (Val109Ile, Asp335Glu and Asn384Ser) from the resistant allele of CYP6P9b were key pyrethroid resistance mutations inducing high metabolic efficiency. The detection of these first DNA markers of metabolic resistance to pyrethroids allows the design of DNA-based diagnostic tools to detect and track resistance associated with bednets scale up, which will improve the design of evidence-based resistance management strategies. PMID:26517127

The carrier rate and mutation spectrum of genes associated with hearing loss in South China hearing female population of childbearing age

PubMed Central

2013-01-01

Background Given that hearing loss occurs in 1 to 3 of 1,000 live births and approximately 90 to 95 percent of them are born into hearing families, it is of importance and necessity to get better understanding about the carrier rate and mutation spectrum of genes associated with hearing impairment in the general population. Methods 7,263 unrelated women of childbearing age with normal hearing and without family history of hearing loss were tested with allele-specific PCR-based universal array. Further genetic testing were provided to the spouses of the screened carriers. For those couples at risk, multiple choices were provided, including prenatal diagnosis. Results Among the 7,263 normal hearing participants, 303 subjects carried pathogenic mutations included in the screening chip, which made the carrier rate 4.17%. Of the 303 screened carriers, 282 harbored heterozygous mutated genes associated with autosomal recessive hearing loss, and 95 spouses took further genetic tests. 8 out of the 9 couples harbored deafness-causing mutations in the same gene received prenatal diagnosis. Conclusions Given that nearly 90 to 95 percent of deaf and hard-of-hearing babies are born into hearing families, better understanding about the carrier rate and mutation spectrum of genes associated with hearing impairment in the female population of childbearing age may be of importance in carrier screening and genetic counseling. PMID:23718755

The carrier rate and mutation spectrum of genes associated with hearing loss in South China hearing female population of childbearing age.

PubMed

Yin, Aihua; Liu, Chang; Zhang, Yan; Wu, Jing; Mai, Mingqin; Ding, Hongke; Yang, Jiexia; Zhang, Xiaozhuang

2013-05-29

Given that hearing loss occurs in 1 to 3 of 1,000 live births and approximately 90 to 95 percent of them are born into hearing families, it is of importance and necessity to get better understanding about the carrier rate and mutation spectrum of genes associated with hearing impairment in the general population. 7,263 unrelated women of childbearing age with normal hearing and without family history of hearing loss were tested with allele-specific PCR-based universal array. Further genetic testing were provided to the spouses of the screened carriers. For those couples at risk, multiple choices were provided, including prenatal diagnosis. Among the 7,263 normal hearing participants, 303 subjects carried pathogenic mutations included in the screening chip, which made the carrier rate 4.17%. Of the 303 screened carriers, 282 harbored heterozygous mutated genes associated with autosomal recessive hearing loss, and 95 spouses took further genetic tests. 8 out of the 9 couples harbored deafness-causing mutations in the same gene received prenatal diagnosis. Given that nearly 90 to 95 percent of deaf and hard-of-hearing babies are born into hearing families, better understanding about the carrier rate and mutation spectrum of genes associated with hearing impairment in the female population of childbearing age may be of importance in carrier screening and genetic counseling.

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

An evolutionary approach to major histocompatibility diversity based on allele supertypes.

PubMed

Naugler, Christopher; Liwski, Robert

2008-01-01

Human leukocyte antigens are traditionally classified by serologic or molecular techniques into a bewildering variety of alleles. It is generally believed that this allelic diversity is maintained by selection pressures for inbreeding avoidance and/or maximal immune system diversity. While the usual antigen-based classification of individual alleles may be most appropriate in the artificial situation of tissue transplantation, we hypothesize that a functional classification based on allele supertypes may represent a more biologically relevant way to view MHC diversity in the contexts of mate choice and disease pathogenesis. Furthermore, immune system diversity could be quantitatively estimated by calculating a Supertype Diversity Index (SDI) which is the number of different MHC supertypes possessed by an individual. This hypothesis generates a number of testable predictions. First, it predicts that a reduced inherited diversity of MHC allele supertypes may predispose to the development of malignancies because of a decreased native ability to present different tumor-associated antigens. Furthermore, specific autoimmune diseases may be associated with the presence or absence of a particular MHC supertype rather than a particular MHC haplotype. In transplant medicine, it is possible that unmatched alleles may trigger a weaker foreign antigen response if they are matched by allele supertype. Finally, there have been several studies documenting dissortative mating in humans for dissimilar MHC alleles. We predict that natural selection should favor maximization of the heterozygosity of allele supertypes instead of the heterozygosity of individual alleles and that the previously observed dissortative mating may actually be an adaptive strategy to maximize allele supertype diversity.

Drug carrier in cancer therapy: A simulation study based on magnetic carrier substances

NASA Astrophysics Data System (ADS)

Adam, Tijjani; Dhahi, Th S.; Mohammed, Mohammed; Hashim, U.; Noriman, N. Z.; Dahham, Omar S.

2017-09-01

The principle of magnetic carrier is a medium for transferring information by sending the drug to the specific part to kill tumor cells. Generally, there are seven stages of cancer. Most of the patient with cancer can only be detected when reaches stage four. At that stage, the cancer is difficult to destroy or to cure. Comparing to the nearly stage, there are probability to destroy tumor cell completely by sending the drug through magnetic carrier directly to nerve. Another way to destroyed tumor completely is by using Deoxyribonucleic acid (DNA). This project is about the simulation study based on magnetic carrier substances. The COMSOL multiphysic software is used in this project. The simulation model represents a permanent magnet, blood vessel, surrounding tissues and air in 2D. Based on result obtained, the graph shown during sending the magnetic flux is high. However, as its carry information the magnetic flux reducess from the above, the move from 0m until 0.009 m it become the lowers and start increase the flux from this until maximum at 0.018m. This is due the fact that carrier start to increase after because the low information is gradually reduce until 0.018m.

Brief communication: Molecular characterization of O alleles at the ABO locus in Chilean Aymara and Huilliche Indians.

PubMed

Llop, Elena; Henríquez, Hugo; Moraga, Mauricio; Castro, Mario; Rothhammer, Francisco

2006-12-01

A molecular characterization of alleles O1, O1variant (O1v), and the mutation G542A of the ABO blood group was performed in two Amerindian populations of Chile, the Aymara (n = 84) and the Huilliche (n = 75). In addition, a sample of 82 individuals of Santiago belonging to the mixed Chilean population was typed for comparative purposes. The polymorphisms which allow for molecular differentiation of different alleles of the O blood group were studied in genomic DNA. The mutations G188, G261-, G542A, T646A, and C771T, described for alleles O1, O1v, and G542A, were determined using the PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) technique. All individuals studied were group O homozygotes for the deletion G261-, which defines the O1 alleles. Results obtained indicate that allele O1v exhibits frequencies of 0.65, 0.81, and 0.60 in Aymara, Huilliche, and Santiago populations, respectively. The frequencies of allele O1(G542A) were 0.119, 0.113, and 0.079 in the same populations. Frequencies for alleles O1 and O1v obtained in the Chilean populations studied concur with the results obtained by other authors, respecting the greater frequency of allele O1v as well as with its heterogeneous distribution in aboriginal South American populations. In Chilean populations, Allele G542A exhibits lower frequencies than those described for indigenous populations from Brazil and may be used as an Amerind admixture marker. 2006 Wiley-Liss, Inc.

How allele frequency and study design affect association test statistics with misrepresentation errors.

PubMed

Escott-Price, Valentina; Ghodsi, Mansoureh; Schmidt, Karl Michael

2014-04-01

We evaluate the effect of genotyping errors on the type-I error of a general association test based on genotypes, showing that, in the presence of errors in the case and control samples, the test statistic asymptotically follows a scaled non-central $\\chi ^2$ distribution. We give explicit formulae for the scaling factor and non-centrality parameter for the symmetric allele-based genotyping error model and for additive and recessive disease models. They show how genotyping errors can lead to a significantly higher false-positive rate, growing with sample size, compared with the nominal significance levels. The strength of this effect depends very strongly on the population distribution of the genotype, with a pronounced effect in the case of rare alleles, and a great robustness against error in the case of large minor allele frequency. We also show how these results can be used to correct $p$-values.

No association of TGFB1 L10P genotypes and breast cancer risk in BRCA1 and BRCA2 mutation carriers: a multi-center cohort study

PubMed Central

Antoniou, Antonis C.; Llopis, Trinidad Caldes; Nevanlinna, Heli; Aittomäki, Kristiina; Simard, Jacques; Spurdle, Amanda B.; Couch, Fergus J.; Pereira, Lutecia H. Mateus; Greene, Mark H.; Andrulis, Irene L.; Pasche, Boris; Kaklamani, Virginia; Hamann, Ute; Szabo, Csilla; Peock, Susan; Cook, Margaret; Harrington, Patricia A.; Donaldson, Alan; Male, Allison M.; Gardiner, Carol Anne; Gregory, Helen; Side, Lucy E.; Robinson, Anne C.; Emmerson, Louise; Ellis, Ian; Peyrat, Jean-Philippe; Fournier, Joëlle; Vennin, Philippe; Adenis, Claude; Muller, Danièle; Fricker, Jean-Pierre; Longy, Michel; Sinilnikova, Olga M.; Stoppa-Lyonnet, Dominique; Schmutzler, Rita K.; Versmold, Beatrix; Engel, Christoph; Meindl, Alfons; Kast, Karin; Schaefer, Dieter; Froster, Ursula G.; Chenevix-Trench, Georgia; Easton, Douglas F.

2008-01-01

Background The transforming growth factor β-1 gene (TGFB1) is a plausible candidate for breast cancer susceptibility. The L10P variant of TGFB1 is associated with higher circulating levels and secretion of TGF-β, and recent large-scale studies suggest strongly that this variant is associated with breast cancer risk in the general population. Methods To evaluate whether TGFB1 L10P also modifies the risk of breast cancer in BRCA1 or BRCA2 mutation carriers, we undertook a multi-center study of 3,442 BRCA1 and 2,095 BRCA2 mutation carriers. Results We found no evidence of association between TGFB1 L10P and breast cancer risk in either BRCA1 or BRCA2 mutation carriers. The per-allele HR for the L10P variant was 1.01 (95%CI: 0.92–1.11) in BRCA1 carriers and 0.92 (95%CI: 0.81–1.04) in BRCA2 mutation carriers. Conclusions These results do not support the hypothesis that TGFB1 L10P genotypes modify the risk of breast cancer in BRCA1 or BRCA2 mutation carriers. PMID:18523885

The normal huntington disease (HD) allele, or a closely linked gene, influences age at onset of HD

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

Farrer, L.A.; Cupples, L.A.; Conneally, P.M.

1993-07-01

The authors evaluated the hypothesis that Huntington disease (HD) is influenced by the normal HD allele by comparing transmission patterns of genetically linked markers at the D4S10 locus in the normal parent against age at onset in the affected offspring. Analysis of information from 21 sibships in 14 kindreds showed a significant tendency for sibs who have similar onset ages to share the same D4S10 allele from the normal parent. Affected sibs who inherited different D4S10 alleles from the normal parent tended to have more variable ages at onset. These findings suggest that the expression of HD is modulated bymore » the normal HD allele or by a closely linked locus. 38 refs., 2 figs., 1 tab.« less

Reduced Height (Rht) Alleles Affect Wheat Grain Quality

PubMed Central

Casebow, Richard; Hadley, Caroline; Uppal, Rajneet; Addisu, Molla; Loddo, Stefano; Kowalski, Ania; Griffiths, Simon; Gooding, Mike

2016-01-01

The effects of dwarfing alleles (reduced height, Rht) in near isogenic lines on wheat grain quality are characterised in field experiments and related to effects on crop height, grain yield and GA-sensitivity. Alleles included those that conferred GA-insensitivity (Rht-B1b, Rht-B1c, Rht-D1b, Rht-D1c) as well as those that retained GA-sensitivity (rht(tall), Rht8, Rht8 + Ppd-D1a, Rht12). Full characterisation was facilitated by including factors with which the effects of Rht alleles are known to interact for grain yield (i.e. system, [conventional or organic]; tillage intensity [plough-based, minimum or zero]; nitrogen fertilizer level [0–450 kg N/ha]; and genetic backgrounds varying in height [cvs Maris Huntsman, Maris Widgeon, and Mercia]. Allele effects on mean grain weight and grain specific weight were positively associated with final crop height: dwarfing reduced these quality criteria irrespective of crop management or GA-sensitivity. In all but two experiments the effects of dwarfing alleles on grain nitrogen and sulphur concentrations were closely and negatively related to effects on grain yield, e.g. a quadratic relationship between grain yield and crop height manipulated by the GA-insensitive alleles was mirrored by quadratic relationships for nitrogen and sulphur concentrations: the highest yields and most dilute concentrations occurred around 80cm. In one of the two exceptional experiments the GA-insensitive Rht-B1b and Rht-B1c significantly (P<0.05) reduced grain nitrogen concentration in the absence of an effect on yield, and in the remaining experiment the GA-sensitive Rht8 significantly reduced both grain yield and grain nitrogen concentration simultaneously. When Rht alleles diluted grain nitrogen concentration, N:S ratios and SDS-sedimentation volumes were often improved. Hagberg falling number (HFN) was negatively related to crop height but benefits from dwarfing were only seen for GA-insensitive alleles. For HFN, therefore, there was the

Breast cancer sensitivity to neoadjuvant therapy in BRCA1 and CHEK2 mutation carriers and non-carriers.

PubMed

Pfeifer, Werner; Sokolenko, Anna P; Potapova, Olga N; Bessonov, Alexandr A; Ivantsov, Alexandr O; Laptiev, Sergey A; Zaitseva, Olga A; Yatsuk, Olga S; Matsko, Dmitry E; Semiglazova, Tatiana Yu; Togo, Alexandr V; Imyanitov, Evgeny N

2014-12-01

Breast carcinomas caused by inheritance of cancer-predisposing germ-line mutations have specific bioclinical features. This study aimed to analyze the efficacy of conventional cytotoxic treatment in BRCA1 and CHEK2 mutation carriers and non-carriers. The study included 415 Russian breast cancer patients aged 50 years or younger, who were subjected to various standard schemes of neoadjuvant therapy. The choice of therapy was done without the knowledge of the mutations status, because DNA testing was performed retrospectively using the archival tissue samples. 19 BRCA1 (4.6%) and 8 CHEK2 (1.9%) heterozygous genotypes were identified. BRCA1 mutation carriers achieved pathological complete response more frequently than non-carriers [6/19 (31.6%) vs. 46/388 (11.9%), p = 0.024]; this effect was limited to women treated by anthracycline-based therapy without taxanes [5/9 (55.6%) vs. 28/247 (11.3%), p = 0.002] and was not observed in any of 7 BRCA1 carriers receiving taxane-containing regimens. CHEK2 heterozygotes did not experience pathological complete response and showed lower frequency of objective clinical responses as compared to mutation non-carriers [4/8 (50%) vs. 333/388 (85.5%), p = 0.020]; the efficacy of neoadjuvant therapy was particularly poor in CHEK2 carriers receiving anthracyclines without taxanes. This study provides evidence for distinct sensitivity of BRCA1 and CHEK2 mutation-driven breast carcinomas to standard chemotherapeutic schemes.

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

GABRA2 Alcohol Dependence Risk Allele is Associated with Reduced Expression of Chromosome 4p12 GABAA Subunit Genes in Human Neural Cultures.

PubMed

Lieberman, Richard; Kranzler, Henry R; Joshi, Pujan; Shin, Dong-Guk; Covault, Jonathan

2015-09-01

Genetic variation in a region of chromosome 4p12 that includes the GABAA subunit gene GABRA2 has been reproducibly associated with alcohol dependence (AD). However, the molecular mechanisms underlying the association are unknown. This study examined correlates of in vitro gene expression of the AD-associated GABRA2 rs279858*C-allele in human neural cells using an induced pluripotent stem cell (iPSC) model system. We examined mRNA expression of chromosome 4p12 GABAA subunit genes (GABRG1, GABRA2, GABRA4, and GABRB1) in 36 human neural cell lines differentiated from iPSCs using quantitative polymerase chain reaction and next-generation RNA sequencing. mRNA expression in adult human brain was examined using the BrainCloud and BRAINEAC data sets. We found significantly lower levels of GABRA2 mRNA in neural cell cultures derived from rs279858*C-allele carriers. Levels of GABRA2 RNA were correlated with those of the other 3 chromosome 4p12 GABAA genes, but not other neural genes. Cluster analysis based on the relative RNA levels of the 4 chromosome 4p12 GABAA genes identified 2 distinct clusters of cell lines, a low-expression cluster associated with rs279858*C-allele carriers and a high-expression cluster enriched for the rs279858*T/T genotype. In contrast, there was no association of genotype with chromosome 4p12 GABAA gene expression in postmortem adult cortex in either the BrainCloud or BRAINEAC data sets. AD-associated variation in GABRA2 is associated with differential expression of the entire cluster of GABAA subunit genes on chromosome 4p12 in human iPSC-derived neural cell cultures. The absence of a parallel effect in postmortem human adult brain samples suggests that AD-associated genotype effects on GABAA expression, although not present in mature cortex, could have effects on regulation of the chromosome 4p12 GABAA cluster during neural development. Copyright © 2015 by the Research Society on Alcoholism.

Enhanced cytotoxicity of anticancer drug delivered by novel nanoscale polymeric carrier

NASA Astrophysics Data System (ADS)

Stoika, R.; Boiko, N.; Senkiv, Y.; Shlyakhtina, Y.; Panchuk, R.; Finiuk, N.; Filyak, Y.; Bilyy, R.; Kit, Y.; Skorohyd, N.; Klyuchivska, O.; Zaichenko, A.; Mitina, N.; Ryabceva, A.

2013-04-01

We compared in vitro action of highly toxic anticancer drug doxorubicin under its delivery to the mammalian tumor cells in free form and after encapsulation in novel bio-functionalized nanoscale polymeric carrier. Such encapsulation was found to enhance significantly drug uptake by the targeted cells, as well as its cytotoxic action. 10 times higher cytotoxicity of the carrier-immobilized doxorubicin comparing to its free form was demonstrated by direct cell counting, and 5 times higher cytotoxicity of encapsulated doxorubicin was shown by FACS analysis. The polymeric carrier itself did not possess significant toxicity in vitro or in vivo (laboratory mice). The carrier protected against negative side effects of doxorubicin in mice with experimental NK/Ly lymphoma. The life duration of tumor-bearing animals treated with doxorubicin-carrier complex was significantly longer than life duration in animals treated with free doxorubicin. Besides, the effective treatment dose of the carrier-delivered doxorubicin in tumor-bearing mice was 10 times lower than such dose of free doxorubicin. Thus, novel nanoscale polymers possess high potential as drug carrier.

Feelings Associated with Being a Carrier and Characteristics of Reproductive Decision Making in Women Known to Be Carriers of X-linked Conditions.

PubMed

Kay, Elizabeth; Kingston, Helen

2002-03-01

Qualitative data were collected from 14 women known to be carriers of an X-linked condition associated with 'serious' disability on feelings about being a carrier and impact on reproductive decisions. Guilt and responsibility were commonly expressed by carriers about issues surrounding pregnancy. Personal experience of the condition influenced their approach to reproductive decisions. Those who had lived with an affected brother were more concrete in their decisions to avoid having an affected child compared to those with less personal experience of the condition. It is concluded that feelings of guilt associated with difficult reproductive decisions are reflected in the strong sense of responsibility attached to being a carrier. Personal experience of the condition has a clear influence on reproductive decisions of X-linked carriers.

Allelic Associations between 100 DNA Markers and High versus Low IQ.

ERIC Educational Resources Information Center

Plomin, Robert; And Others

1995-01-01

For DNA markers in or near genes of neurological relevance, allelic frequencies were compared for groups of high- and low-IQ children (total sample of 86). This study adds 40 markers to the 60 already studied. Only one showed a significant association with IQ in original and replication samples. (SLD)

Apolipoprotein E polymorphism in Southern Iran: E4 allele in the lowest reported amounts.

PubMed

Bazrgar, Masood; Karimi, Mehran; Fathzadeh, Mohsen; Senemar, Sara; Peiravian, Farah; Shojaee, Ashraf; Saadat, Mostafa

2008-12-01

Apolipoprotein E (apoE) with three major alleles E2, E3 and E4 is one of the critical genes in lipid metabolism. Common apoE alleles are in association with an increase in risk for central nervous and cardiovascular diseases such as Alzheimer's disease, dementia, multiple sclerosis, atherosclerosis, coronary heart disease, hyperlipoproteinemia and stroke. ApoE3 is known as the most frequent allele in all populations, while association of apoE gene polymorphism with reported diseases have mostly been related to other two major alleles especially apoE4. To determine of apoE alleles frequencies in Southern Iran and comparison of those frequencies with other populations. DNA was extracted from the whole blood of 198 healthy unrelated candidates from population of Fars Province, Southern Iran, for apoE genotyping who were checked up by a physician. The frequencies of apoE alleles were compared with other populations by chi(2) test. The frequencies of E2, E3 and E4 were 0.063, 0.886 and 0.051 respectively. These values were similar to those reported from populations of Kuwait, Oman, Lebanon, India, Turkey, Greece, Spain, Sardinia Islands of Italy and two Iranian populations but were different from South of Italy and Caucasians in other Europe regions, American, American-Indian, African, East Asian and Saudi populations (P < 0.05). The frequency of E4 allele as a genetic risk factor for some multifactorial diseases in the population of Southern Iran is in the lowest reported amounts in the world. Iranian population has Caucasoid origin but differs from some Caucasian populations in Europe and America. The results of present study are in agreement with the historical evidences which show admixture of Iranian population with other populations and some studies based on genetic polymorphisms in the population of Southern Iran.

14 CFR 221.204 - Adoption of provisions of one carrier by another carrier.

Code of Federal Regulations, 2010 CFR

2010-01-01

... Adoption of provisions of one carrier by another carrier. When one carrier adopts the tariffs of another carrier, the effective and prospective fares of the adopted carrier shall be changed to reflect the name of the adopting carrier and the effective date of the adoption. Further, each adopted fare shall bear...

Brittle cornea syndrome ZNF469 mutation carrier phenotype and segregation analysis of rare ZNF469 variants in familial keratoconus.

PubMed

Davidson, Alice E; Borasio, Edmondo; Liskova, Petra; Khan, Arif O; Hassan, Hala; Cheetham, Michael E; Plagnol, Vincent; Alkuraya, Fowzan S; Tuft, Stephen J; Hardcastle, Alison J

2015-01-06

Brittle cornea syndrome 1 (BCS1) is a rare recessive condition characterized by extreme thinning of the cornea and sclera, caused by mutations in ZNF469. Keratoconus is a relatively common disease characterized by progressive thinning and ectasia of the cornea. The etiology of keratoconus is complex and not yet understood, but rare ZNF469 variants have recently been associated with disease. We investigated the phenotype of BCS1 carriers with known pathogenic ZNF469 mutations, and recruited families in which aggregation of keratoconus was observed to establish if rare variants in ZNF469 segregated with disease. Patients and family members were recruited and underwent comprehensive anterior segment examination, including corneal topography. Blood samples were donated and genomic DNA was extracted. The coding sequence and splice sites of ZNF469 were PCR amplified and Sanger sequenced. Four carriers of three BCS1-associated ZNF469 loss-of-function mutations (p.[Glu1392Ter], p.[Gln1930Argfs*6], p.[Gln1930fs*133]) were examined and none had keratoconus. One carrier had partially penetrant features of BCS1, including joint hypermobility. ZNF469 sequencing in 11 keratoconus families identified 9 rare (minor allele frequency [MAF] ≤ 0.025) variants predicted to be potentially damaging. However, in each instance the rare variant(s) identified, including two previously reported as potentially keratoconus-associated, did not segregate with the disease. The presence of heterozygous loss-of-function alleles in the ZNF469 gene did not cause keratoconus in the individuals examined. None of the rare nonsynonymous ZNF469 variants identified in the familial cohort conferred a high risk of keratoconus; therefore, genetic variants contributing to disease pathogenesis in these 11 families remain to be identified. Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.

Loss of RNA expression and allele-specific expression associated with congenital heart disease

PubMed Central

McKean, David M.; Homsy, Jason; Wakimoto, Hiroko; Patel, Neil; Gorham, Joshua; DePalma, Steven R.; Ware, James S.; Zaidi, Samir; Ma, Wenji; Patel, Nihir; Lifton, Richard P.; Chung, Wendy K.; Kim, Richard; Shen, Yufeng; Brueckner, Martina; Goldmuntz, Elizabeth; Sharp, Andrew J.; Seidman, Christine E.; Gelb, Bruce D.; Seidman, J. G.

2016-01-01

Congenital heart disease (CHD), a prevalent birth defect occurring in 1% of newborns, likely results from aberrant expression of cardiac developmental genes. Mutations in a variety of cardiac transcription factors, developmental signalling molecules and molecules that modify chromatin cause at least 20% of disease, but most CHD remains unexplained. We employ RNAseq analyses to assess allele-specific expression (ASE) and biallelic loss-of-expression (LOE) in 172 tissue samples from 144 surgically repaired CHD subjects. Here we show that only 5% of known imprinted genes with paternal allele silencing are monoallelic versus 56% with paternal allele expression—this cardiac-specific phenomenon seems unrelated to CHD. Further, compared with control subjects, CHD subjects have a significant burden of both LOE genes and ASE events associated with altered gene expression. These studies identify FGFBP2, LBH, RBFOX2, SGSM1 and ZBTB16 as candidate CHD genes because of significantly altered transcriptional expression. PMID:27670201

Genetic exchange of fimbrial alleles exemplifies the adaptive virulence strategy of Porphyromonas gingivalis.

PubMed

Kerr, Jennifer E; Abramian, Jared R; Dao, Doan-Hieu V; Rigney, Todd W; Fritz, Jamie; Pham, Tan; Gay, Isabel; Parthasarathy, Kavitha; Wang, Bing-yan; Zhang, Wenjian; Tribble, Gena D

2014-01-01

Porphyromonas gingivalis is a gram-negative anaerobic bacterium, a member of the human oral microbiome, and a proposed "keystone" pathogen in the development of chronic periodontitis, an inflammatory disease of the gingiva. P. gingivalis is a genetically diverse species, and is able to exchange chromosomal DNA between strains by natural competence and conjugation. In this study, we investigate the role of horizontal DNA transfer as an adaptive process to modify behavior, using the major fimbriae as our model system, due to their critical role in mediating interactions with the host environment. We show that P. gingivalis is able to exchange fimbrial allele types I and IV into four distinct strain backgrounds via natural competence. In all recombinants, we detected a complete exchange of the entire fimA allele, and the rate of exchange varies between the different strain backgrounds. In addition, gene exchange within other regions of the fimbrial genetic locus was identified. To measure the biological implications of these allele swaps we compared three genotypes of fimA in an isogenic background, strain ATCC 33277. We demonstrate that exchange of fimbrial allele type results in profound phenotypic changes, including the quantity of fimbriae elaborated, membrane blebbing, auto-aggregation and other virulence-associated phenotypes. Replacement of the type I allele with either the type III or IV allele resulted in increased invasion of gingival fibroblast cells relative to the isogenic parent strain. While genetic variability is known to impact host-microbiome interactions, this is the first study to quantitatively assess the adaptive effect of exchanging genes within the pan genome cloud. This is significant as it presents a potential mechanism by which opportunistic pathogens may acquire the traits necessary to modify host-microbial interactions.

AURKA F31I Polymorphism and Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers: A CIMBA study

PubMed Central

Couch, Fergus J.; Sinilnikova, Olga; Vierkant, Robert A; Pankratz, V. Shane; Fredericksen, Zachary S.; Stoppa-Lyonnet, Dominique; Coupier, Isabelle; Hughes, David; Hardouin, Agnès; Berthet, Pascaline; Peock, Susan; Cook, Margaret; Baynes, Caroline; Hodgson, Shirley; Morrison, Patrick J.; Porteous, Mary E.; Jakubowska, Anna; Lubinski, Jan; Gronwald, Jacek; Spurdle, Amanda B.; Schmutzler, Rita; Versmold, Beatrix; Engel, Christoph; Meindl, Alfons; Sutter, Christian; Horst, Jurgen; Schaefer, Dieter; Offit, Kenneth; Kirchhoff, Tomas; Andrulis, Irene L.; Ilyushik, Eduard; Glendon, Gordon; Devilee, Peter; Vreeswijk, Maaike P.G.; Vasen, Hans F.A.; Borg, Ake; Backenhorn, Katja; Struewing, Jeffery P.; Greene, Mark H.; Neuhausen, Susan L.; Rebbeck, Timothy R.; Nathanson, Katherine; Domchek, Susan; Wagner, Theresa; Garber, Judy E.; Szabo, Csilla; Zikan, Michal; Foretova, Lenka; Olson, Janet E.; Sellers, Thomas A.; Lindor, Noralane; Nevanlinna, Heli; Tommiska, Johanna; Aittomaki, Kristiina; Hamann, Ute; Rashid, Muhammad U.; Torres, Diana; Simard, Jacques; Durocher, Francine; Guenard, Frederic; Lynch, Henry T.; Isaacs, Claudine; Weitzel, Jeffrey; Olopade, Olufunmilayo I.; Narod, Steven; Daly, Mary B.; Godwin, Andrew K.; Tomlinson, Gail; Easton, Douglas F.; Chenevix-Trench, Georgia; Antoniouon, Antonis C.

2009-01-01

The AURKA oncogene is associated with abnormal chromosome segregation and aneuploidy and predisposition to cancer. Amplification of AURKA has been detected at higher frequency in tumors from BRCA1 and BRCA2 mutation carriers than in sporadic breast tumors, suggesting that overexpression of AURKA and inactivation of BRCA1 and BRCA2 co-operate during tumor development and progression. The F31I polymorphism in AURKA has been associated with breast cancer risk in the homozygous state in prior studies. We evaluated whether the AURKA F31I polymorphism modifies breast cancer risk in BRCA1 and BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). CIMBA was established to provide sufficient statistical power through increased numbers of mutation carriers to identify polymorphisms that act as modifiers of cancer risk and can refine breast cancer risk estimates in BRCA1 and BRCA2 mutation carriers. A total of 4935 BRCA1 and 2241 BRCA2 mutation carriers and 11 individuals carrying both BRCA1 and BRCA2 mutations were genotyped for F31I. Overall, homozygosity for the 31I allele was not significantly associated with breast cancer risk in BRCA1 and BRCA2 carriers combined (HR = 0.91; 95% CI 0.77-1.06). Similarly, no significant association was seen in BRCA1 (HR = 0.90; 95% CI 0.75-1.08) or BRCA2 carriers (HR = 0.93; 95% CI 0.67-1.29) or when assessing the modifying effects of either bilateral prophylactic oophorectomy or menopausal status of BRCA1 and BRCA2 carriers. In summary, the F31I polymorphism in AURKA is not associated with a modified risk of breast cancer in BRCA1 and BRCA2 carriers. PMID:17627006

Lack of association of the caspase-12 long allele with community-acquired pneumonia in people of African descent.

PubMed

Chen, Jiwang; Wilson, Esther S; Dahmer, Mary K; Quasney, Michael W; Waterer, Grant W; Feldman, Charles; Wunderink, Richard G

2014-01-01

Community-acquired pneumonia (CAP) is a common cause of sepsis. Active full-length caspase-12 (CASP12L), confined to the people of African descent, has been associated with increased susceptibility to and mortality from severe sepsis. The objective of this study was to determine whether CASP12L was a marker for susceptibility and/or severity of CAP. We examined three CAP cohorts and two control populations: 241 adult Memphis African American CAP patients, 443 pediatric African American CAP patients, 90 adult South African CAP patients, 120 Memphis healthy adult African American controls and 405 adult Chicago African American controls. Clinical outcomes including mortality, acute respiratory distress syndrome (ARDS), septic shock or severe sepsis, need for mechanical ventilation, and S. pneumoniae bacteremia. Neither in the three individual CAP cohorts nor in the combined CAP cohorts, was mortality in CASP12L carriers significantly different from that in non-CASP12L carriers. No statistically significant association between genotype and any measures of CAP severity was found in any cohort. We conclude that the functional CASP12L allele is not a marker for susceptibility and/or severity of CAP.

KIR2DL2/2DL3-E35 alleles are functionally stronger than -Q35 alleles

NASA Astrophysics Data System (ADS)

Bari, Rafijul; Thapa, Rajoo; Bao, Ju; Li, Ying; Zheng, Jie; Leung, Wing

2016-03-01

KIR2DL2 and KIR2DL3 segregate as alleles of a single locus in the centromeric motif of the killer cell immunoglobulin-like receptor (KIR) gene family. Although KIR2DL2/L3 polymorphism is known to be associated with many human diseases and is an important factor for donor selection in allogeneic hematopoietic stem cell transplantation, the molecular determinant of functional diversity among various alleles is unclear. In this study we found that KIR2DL2/L3 with glutamic acid at position 35 (E35) are functionally stronger than those with glutamine at the same position (Q35). Cytotoxicity assay showed that NK cells from HLA-C1 positive donors with KIR2DL2/L3-E35 could kill more target cells lacking their ligands than NK cells with the weaker -Q35 alleles, indicating better licensing of KIR2DL2/L3+ NK cells with the stronger alleles. Molecular modeling analysis reveals that the glutamic acid, which is negatively charged, interacts with positively charged histidine located at position 55, thereby stabilizing KIR2DL2/L3 dimer and reducing entropy loss when KIR2DL2/3 binds to HLA-C ligand. The results of this study will be important for future studies of KIR2DL2/L3-associated diseases as well as for donor selection in allogeneic stem cell transplantation.

Cystic fibrosis carrier screening in a North American population.

PubMed

Zvereff, Val V; Faruki, Hawazin; Edwards, Marcia; Friedman, Kenneth J

2014-07-01

The aim of this study was to compare the mutation frequency distribution for a 32-mutation panel and a 69-mutation panel used for cystic fibrosis carrier screening. Further aims of the study were to examine the race-specific detection rates provided by both panels and to assess the performance of extended panels in large-scale, population-based cystic fibrosis carrier screening. Although genetic screening for the most common CFTR mutations allows detection of nearly 90% of cystic fibrosis carriers, the large number of other mutations, and their distribution within different ethnic groups, limits the utility of general population screening. Patients referred for cystic fibrosis screening from January 2005 through December 2010 were tested using either a 32-mutation panel (n = 1,601,308 individuals) or a 69-mutation panel (n = 109,830). The carrier frequencies observed for the 69-mutation panel study population (1/36) and Caucasian (1/27) and African-American individuals (1/79) agree well with published cystic fibrosis carrier frequencies; however, a higher carrier frequency was observed for Hispanic-American individuals (1/48) using the 69-mutation panel as compared with the 32-mutation panel (1/69). The 69-mutation panel detected ~20% more mutations than the 32-mutation panel for both African-American and Hispanic-American individuals. Expanded panels using race-specific variants can improve cystic fibrosis carrier detection rates within specific populations. However, it is important that the pathogenicity and the relative frequency of these variants are confirmed.

The effect of APOE ε4 allele on cholinesterase inhibitors in patients with Alzheimer disease: evaluation of the feasibility of resting state functional connectivity magnetic resonance imaging.

PubMed

Wang, Liang; Day, Jonathan; Roe, Catherine M; Brier, Matthew R; Thomas, Jewell B; Benzinger, Tammie L; Morris, John C; Ances, Beau M

2014-01-01

This work is to determine whether apolipoprotein E (APOE) genotype modulates the effect of cholinesterase inhibitor (ChEI) treatment on resting state functional connectivity magnetic resonance imaging (rs-fcMRI) in patients with Alzheimer disease (AD). We retrospectively studied very mild and mild AD participants who were treated (N=25) or untreated (N=19) with ChEIs with respect to rs-fcMRI measure of 5 resting state networks (RSNs): default mode, dorsal attention (DAN), control (CON), salience (SAL), and sensory motor. For each network, a composite score was computed as the mean of Pearson correlations between pairwise time courses extracted from areas comprising this network. The composite scores were analyzed as a function of ChEI treatment and APOE ε4 allele. Across all participants, significant interactions between ChEI treatment and APOE ε4 allele were observed for all 5 RSNs. Within APOE ε4 carriers, significantly greater composite scores were observed in the DAN, CON, and SAL for treated compared with untreated participants. Within APOE ε4 noncarriers, treated and untreated participants did not have significantly different composite scores for all RSNs. These data suggest that APOE genotype affects the response to ChEI using rs-fcMRI. Rs-fcMRI may be useful for assessing the therapeutic effect of medications in AD clinical trials.

Allelic distribution of human leucocyte antigen in historical and recently diagnosed tuberculosis patients in Southern Italy.

PubMed

Ruggiero, Giuseppina; Cosentini, Elena; Zanzi, Delia; Sanna, Veronica; Terrazzano, Giuseppe; Matarese, Giuseppe; Sanduzzi, Alessandro; Perna, Francesco; Zappacosta, Serafino

2004-03-01

This study addresses the analysis of the human leucocyte antigen (HLA) allele distribution in 54 historical and in 68 recently diagnosed tuberculosis (TB) patients. The historical cohort was characterized by the presence of large fibrocavernous lesions effectively treated with therapeutic pneumothorax during the period 1950-55. Patients and healthy controls enrolled in the study were from the Campania region of southern Italy. No significant association between HLA alleles and TB in the population of recently diagnosed TB patients was observed. On the contrary, among the historical TB patients there was a strong association with an increased frequency of the HLA-DR4 allele alone and/or in the presence of the HLA-B14 allele (P = 0.000004; Pc = 0.0008), as well as with a decreased frequency of the HLA-A2+,-B14-,DR4- allele association (P = 0.00005; Pc = 0.01). In order to exclude any interference from age-related factors, these results were confirmed by comparing the historical cohort of TB patients with an age-matched healthy control population of the same ethnic origin (P = 0.00004; Pc = 0.008; and P = 0.0001; and Pc = 0.02, respectively).

Association of the apolipoprotein E {epsilon}4 allele with clinical subtypes of autopsy-confirmed Alzheimer`s Disease

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

Zubenko, G.S.; Stiffler, S.; Kopp, U.

1994-09-15

Consistent with previous reports, we observed a significant association of the APOE {epsilon}4 allele with Alzheimer`s Disease (AD) in a series of 91 autopsy-confirmed cases. The {epsilon}4 allele frequency was higher in cases with a family history of AD-like dementia (0.54 {+-} 0.07), although the {epsilon}4 allele frequency in the AD cases with a negative family history (0.38 {+-} 0.05) remained significantly greater than that for the non-AD control group (0.13 {+-} 0.03). A similar increase in {epsilon}4 allele frequency (0.54 {+-} 0.07) was observed in the AD cases with amyloid angiopathy, compared to those who did not have amyloidmore » angiopathy (0.35 {+-} 0.04). Contrary to previous reports, no effect of the dosage of the {epsilon}4 allele was found on the age of onset of dementia among the AD cases and, contrary to reports suggesting an association of {epsilon}4 and atherosclerosis, the {epsilon}4 allele frequency was similar in cases with or without concurrent brain infarcts. Modest but consistent correlations were observed between the dosage of {epsilon}4 alleles and the cortical density of senile plaques, but not neurofibrillary tangles. The last finding suggests that the pathogenic events mediated by the {epsilon}4 allele may be more directly involved in the formation of senile plaques, the identifying lesions in AD, than neurofibrillary tangles. A robust association of both the presence of an {epsilon}4 allele and a family history of AD-like dementia with concurrent amyloid angiopathy occurred within our sample of AD cases. This association arose from an interaction of the {epsilon}4 allele with a separate familial factor for which a family history of dementia served as a surrogate. These results suggest that amyloid angiopathy may be a common or central feature of a form of familial AD that is associated with the transmission of the APOE {epsilon}4 allele. 22 refs., 2 figs., 5 tabs.« less

Germline variation in the MTHFR and MTRR genes determines the nadir of bone density in pediatric acute lymphoblastic leukemia: a prospective study.

PubMed

te Winkel, M L; de Muinck Keizer-Schrama, S M P F; de Jonge, R; van Beek, R D; van der Sluis, I M; Hop, W C J; Pieters, R; van den Heuvel-Eibrink, M M

2011-03-01

This study aims to identify folate-metabolism-related genetic risk factors for low bone mineral density (BMD) during/after pediatric acute lymphoblastic leukemia (ALL) treatment. We investigated the influence of methylenetetrahydrofolate reductase (MTHFR 677C > T and 1298A > C) and methionine synthase reductase (MTRR 66A > G) single nucleotide polymorphisms (SNPs) on total body BMD (BMD(TB)) and lumbar spine BMD (BMD(LS)) in 83 patients. Homocysteine, folate and vitamin B12 were determined. BMD was measured repeatedly using dual-energy X-ray absorptiometry in patients ≥ 4 years (n = 68). Carriers of the MTHFR 677 T-allele showed a lower baseline BMD(TB) than non-carriers (-0.38 SDS vs. +0.55 SDS, p = 0.01) and BMD(TB) remained lower during/after treatment. MTHFR 677C>T did not influence treatment-related loss of BMD(TB) (p = 0.39). The MTRR 66 G-allele carriers showed a trend towards a lower BMD(TB) compared with non-carriers. Combining these two SNPs, patients carrying ≥ 2 risk alleles had a significantly lower BMD(TB) (-1.40 SDS) than patients with one (-0.80 SDS) or no risk alleles (-0.31 SDS). Although carriers of the MTHFR 1298A > C had higher homocysteine levels, this SNP was not related to BMD(TB). BMD(LS) of carriers was similar to non-carriers of the investigated SNPs. The MTHFR 677C>T SNP and the MTRR 66A >G SNP were identified as determinants of impaired BMD(TB) in childhood ALL patients. Crown Copyright © 2010. Published by Elsevier Inc. All rights reserved.

Performance indicators for carrier-based DPIs: Carrier surface properties for capsule filling and API properties for in vitro aerosolisation.

PubMed

Faulhammer, E; Zellnitz, S; Wutscher, T; Stranzinger, S; Zimmer, A; Paudel, A

2018-01-30

This study investigates engineered carrier, as well as engineered API particles, and shows that there are distinct performance indicators of particle engineering for carrier-based dry powder inhalers (DPIs). Spray dried (SDSS) and jet-milled (JMSS) salbutamol sulphate (SS) was blended with untreated α-lactose monohydrate (LAC_R) and α-lactose monohydrate engineered (LAC_E). Subsequent capsule filling was performed with different process settings on a dosator nozzle capsule filling machine in order to reach a target fill weight of 20-25 mg. To evaluate the performance of the different mixtures, in vitro lung deposition experiments were carried out with a next generation impactor, the emitted dose (ED) and fine particle fraction (FPF) were calculated based on the specification of the European pharmacopoeia. The FPF of micronised powder blends is significantly higher (20%) compared to the FPF of spray dried blends (5%). Compared to API engineering, carrier engineering had a positive effect on the capsule filling performance (weight variability and mean fill weight) at lower compression ratios (setting 1). Results further showed that higher compression ratios appear to be beneficial in terms of capsule filling performance (higher fill weight and less fill weight variation). Concluding, it can be stated that the carrier engineering, or generally carrier properties, govern downstream processing, whereas the API engineering and API properties govern the aerosolisation performance and thereby significantly affect the dose delivery to the lungs. Copyright © 2017 Elsevier B.V. All rights reserved.

Tay-Sachs disease preconception screening in Australia: self-knowledge of being an Ashkenazi Jew predicts carrier state better than does ancestral origin, although there is an increased risk for c.1421 + 1G > C mutation in individuals with South African heritage.

PubMed

Lew, Raelia; Burnett, Leslie; Proos, Anné

2011-12-01

The Australasian Community Genetics Program provided a preconception screening for Tay-Sachs disease (TSD) to 4,105 Jewish high school students in Sydney and Melbourne over the 12-year period 1995-2007. By correlating the frequencies of mutant HEXA, MIM *606869 (gene map locus 15q23-q24) alleles with subjects' nominated ethnicity (Ashkenazi/Sephardi/Mixed) and grandparental birthplaces, we established that Ashkenazi ethnicity is a better predictor of TSD carrier status than grandparental ancestral origins. Screening self-identified Ashkenazi subjects detected 95% of TSD carriers (carrier frequency 1:25). Having mixed Ashkenazi and non-Ashkenazi heritage reduced the carrier frequency (1:97). South African heritage conveyed a fourfold risk of c.1421 + 1G > C mutation compared with other AJ subjects (odds ratio (OR), 4.19; 95% confidence interval (CI), 1.83-9.62, p = 0.001), but this was the only specific case of ancestral origin improving diagnostic sensitivity over that based on determining Ashkenazi ethnicity. Carriers of c.1278insTATC mutations were more likely to have heritage from Western Europe (OR, 1.65 (95% CI, 1.04-2.60), p = 0.032) and South Eastern Europe (OR, 1.77 (95% CI, 1.14-2.73), p = 0.010). However, heritage from specific European countries investigated did not significantly alter the overall odds of TSD carrier status.

Stepwise positive association between APOA5 minor allele frequencies and increasing plasma triglyceride quartiles in random patients with hypertriglyceridemia of unclarified origin.

PubMed

Hadarits, Ferenc; Kisfali, Péter; Mohás, Márton; Maász, Anita; Sümegi, Katalin; Szabó, Melinda; Hetyésy, Katalin; Valasek, Andrea; Janicsek, Ingrid; Wittmann, István; Melegh, Béla

2011-03-01

Apolipoprotein A5 (ApoA5) gene and its protein product play a central role in the complex regulation of circulating triglyceride levels in humans. Naturally occurring variants of the apolipoprotein A5 gene have been associated with increased triglyceride levels and have been found to confer risk for cardiovascular diseases. In our study, four polymorphisms, the T-1131C, IVS3+G476A, T1259C, and C56G alleles of APOA5 were analyzed in a total of 436 patients by polymerase chain reaction-restriction fragment length polymorphism methods. The randomly selected patients were classified into four quartile (q) groups based on triglyceride levels (q1: TG<1.31 mmol/l; q2: 1.31-2.90 mmol/l; q3: 2.91-4.85 mmol/l; q4: TG>4.85 mmol/l). We observed significant stepwise increasing association between the four APOA5 minor allele carrier frequencies and plasma triglyceride quartiles: -1131C (q1: 4.44%; q2: 8.95%; q3: 12.9%; q4: 20.6%), IVS3 + 476A (q1: 4.44%; q2: 5.79%; q3: 11.1%; q4: 19.7%), 1259C (q1: 4.44%; q2: 6.84%; q3: 11.1%; q4: 20.6%) and 56G (q1: 5.64%; q2: 6.31%; q3: 11.16%; q4: 11.9%). The serum total cholesterol and high density lipoprotein-cholesterol levels also showed allele-dependent differences in the quartiles. The findings presented here revealed a special arrangement of APOA5 minor alleles in patients with different serum triglyceride ranges in Hungarians.

MAOA genotype influences neural response during an inhibitory task in adolescents with conduct disorder.

PubMed

Sun, Xiaoqiang; Ma, Ren; Jiang, Yali; Gao, Yidian; Ming, Qingsen; Wu, Qiong; Dong, Daifeng; Wang, Xiang; Yao, Shuqiao

2018-05-31

Conduct disorder (CD), a common psychiatric disorder in children and adolescents, is characterized by encroaching upon other rights and violations of age-appropriate social expectations repeatedly and persistently. Individuals with CD often have high aggressiveness and low inhibitory capacity. The monoamine oxidase A (MAOA) gene has long been associated with aggression. Effects of MAOA genotype on inhibitory control have been examined in general population. Several studies had revealed reduced activation in prefrontal areas, especially the anterior cingulate cortex (ACC), in low-expression MAOA (MAOA-L) allele carriers compared to high-expression MAOA (MAOA-H) allele carriers. However, little is known about its genetic risk influences on inhibitory processes in clinical samples. In this study, functional magnetic resonance imaging (fMRI) was administered to a sample of adolescent boys with CD during the performance of a GoStop task, 29 of whom carrying MAOA-L allele and 24 carrying MAOA-H allele. Relative to MAOA-H carriers, MAOA-L carriers in CD showed more pronounced deactivation in the precuneus, supplementary motor area (SMA) and dorsal anterior cingulate cortex (dACC). Deactivation within the default mode network (DMN) and inhibitory-related areas in MAOA-L carriers may be related to compensation for low sensitivity to inhibition and/or an atypical allocation of cognitive resources. The results suggested a possible neural mechanism through which MAOA affects inhibitory processes in a clinical sample.

Cattle with the BoLA class II DRB3*0902 allele have significantly lower bovine leukemia proviral loads.

PubMed

Hayashi, Takumi; Mekata, Hirohisa; Sekiguchi, Satoshi; Kirino, Yumi; Mitoma, Shuya; Honkawa, Kazuyuki; Horii, Yoichiro; Norimine, Junzo

2017-09-12

The bovine MHC (BoLA) class II DRB3 alleles are associated with polyclonal expansion of lymphocytes caused by bovine leukemia virus (BLV) infection in cattle. To examine whether the DRB3*0902 allele, one of the resistance-associated alleles, is associated with the proviral load, we measured BLV proviral load of BLV-infected cattle and clarified their DRB3 alleles. Fifty-seven animals with DRB3*0902 were identified out of 835 BLV-infected cattle and had significantly lower proviral load (P<0.000001) compared with the rest of the infected animals, in both Japanese Black and Holstein cattle. This result strongly indicates that the BoLA class II DRA/DRB3*0902 molecule plays an important immunological role in suppressing viral replication, resulting in resistance to the disease progression.

HLA-A*02 allele frequencies and haplotypic associations in Koreans.

PubMed

Park, M H; Whang, D H; Kang, S J; Han, K S

2000-03-01

We have investigated the frequencies of HLA-A*02 alleles and their haplotypic associations with HLA-B and -DRB1 loci in 439 healthy unrelated Koreans, including 214 parents from 107 families. All of the 227 samples (51.7%) typed as A2 by serology were analyzed for A*02 alleles using polymerase chain reaction (PCR)-low ionic strength-single-strand conformation polymorphism (LIS-SSCP) method. A total of six different A*02 alleles were detected (A*02 allele frequency 29.6%): A*0201/9 (16.6%), *0203 (0.5%), *0206 (9.3%), *0207 (3.0%), and one each case of *0210 and *02 undetermined type. Two characteristic haplotypes showing the strongest linkage disequilibrium were A*0203-B38-DRB]*1502 and A*0207-B46-DRB1*0803. Besides these strong associations, significant two-locus associations (P<0.001) were observed for A*0201 with B61, DRB1*0901 and DRB1*1401, and for A*0206 with B48 and B61. HLA haplotypes carrying HLA-A2 showed a variable distribution of A*02 alleles, and all of the eight most common A2-B-DR haplotypes occurring at frequencies of > or =1% were variably associated with two different A*02 alleles. These results demonstrate that substantial heterogeneity is present in the distribution of HLA-A*02 alleles and related haplotypes in Koreans.

Angiotensin Converting Enzyme Inhibitors and the Reduced Risk of Alzheimer’s Disease in the Absence of Apolipoprotein E4 Allele

PubMed Central

Qiu, Wei Qiao; Mwamburi, Mkaya; Besser, Lilah M.; Zhu, Haihao; Li, Huajie; Wallack, Max; Phillips, Leslie; Qiao, Liyan; Budson, Andrew E.; Stern, Robert; Kowall, Neil

2014-01-01

Our cross-sectional study showed that the interaction between apolipoprotein E4 (ApoE4) and angiotensin converting enzyme (ACE) inhibitors was associated with Alzheimer’s disease (AD). The aim of this longitudinal study was to differentiate whether ACE inhibitors accelerate or reduce the risk of AD in the context of ApoE alleles. Using the longitudinal data from the National Alzheimer’s Coordinating Center (NACC) with ApoE genotyping and documentation of ACE inhibitors use, we found that in the absence of ApoE4, subjects who had been taking central ACE inhibitor use (χ2 test: 21% versus 27%, p = 0.0002) or peripheral ACE inhibitor use (χ2 test: 13% versus 27%, p < 0.0001) had lower incidence of AD compared with those who had not been taking an ACE inhibitor. In contrast, in the presence of ApoE4, there was no such association between ACE inhibitor use and the risk of AD. After adjusting for the confounders, central ACE inhibitor use (OR = 0.68, 95% CI = 0.55, 0.83, p = 0.0002) or peripheral ACE inhibitor use (OR = 0.33, 95% CI = 0.33, 0.68, p < 0.0001) still remained inversely associated with a risk of developing AD in ApoE4 non-carriers. In conclusion, ACE inhibitors, especially peripherally acting ones, were associated with a reduced risk of AD in the absence of ApoE4, but had no such effect in those carrying the ApoE4 allele. A double-blind clinical trial should be considered to determine the effect of ACE inhibitors on prevention of AD in the context of ApoE genotype. PMID:23948883

Detection of Ancestry Informative HLA Alleles Confirms the Admixed Origins of Japanese Population

PubMed Central

Nakaoka, Hirofumi; Mitsunaga, Shigeki; Hosomichi, Kazuyoshi; Shyh-Yuh, Liou; Sawamoto, Taiji; Fujiwara, Tsutomu; Tsutsui, Naohisa; Suematsu, Koji; Shinagawa, Akira; Inoko, Hidetoshi; Inoue, Ituro

2013-01-01

The polymorphisms in the human leukocyte antigen (HLA) region are powerful tool for studying human evolutionary processes. We investigated genetic structure of Japanese by using five-locus HLA genotypes (HLA-A, -B, -C, -DRB1, and -DPB1) of 2,005 individuals from 10 regions of Japan. We found a significant level of population substructure in Japanese; particularly the differentiation between Okinawa Island and mainland Japanese. By using a plot of the principal component scores, we identified ancestry informative alleles associated with the underlying population substructure. We examined extent of linkage disequilibrium (LD) between pairs of HLA alleles on the haplotypes that were differentiated among regions. The LDs were strong and weak for pairs of HLA alleles characterized by low and high frequencies in Okinawa Island, respectively. The five-locus haplotypes whose alleles exhibit strong LD were unique to Japanese and South Korean, suggesting that these haplotypes had been recently derived from the Korean Peninsula. The alleles characterized by high frequency in Japanese compared to South Korean formed segmented three-locus haplotype that was commonly found in Aleuts, Eskimos, and North- and Meso-Americans but not observed in Korean and Chinese. The serologically equivalent haplotype was found in Orchid Island in Taiwan, Mongol, Siberia, and Arctic regions. It suggests that early Japanese who existed prior to the migration wave from the Korean Peninsula shared ancestry with northern Asian who moved to the New World via the Bering Strait land bridge. These results may support the admixture model for peopling of Japanese Archipelago. PMID:23577161

Detection of ancestry informative HLA alleles confirms the admixed origins of Japanese population.

PubMed

Nakaoka, Hirofumi; Mitsunaga, Shigeki; Hosomichi, Kazuyoshi; Shyh-Yuh, Liou; Sawamoto, Taiji; Fujiwara, Tsutomu; Tsutsui, Naohisa; Suematsu, Koji; Shinagawa, Akira; Inoko, Hidetoshi; Inoue, Ituro

2013-01-01

The polymorphisms in the human leukocyte antigen (HLA) region are powerful tool for studying human evolutionary processes. We investigated genetic structure of Japanese by using five-locus HLA genotypes (HLA-A, -B, -C, -DRB1, and -DPB1) of 2,005 individuals from 10 regions of Japan. We found a significant level of population substructure in Japanese; particularly the differentiation between Okinawa Island and mainland Japanese. By using a plot of the principal component scores, we identified ancestry informative alleles associated with the underlying population substructure. We examined extent of linkage disequilibrium (LD) between pairs of HLA alleles on the haplotypes that were differentiated among regions. The LDs were strong and weak for pairs of HLA alleles characterized by low and high frequencies in Okinawa Island, respectively. The five-locus haplotypes whose alleles exhibit strong LD were unique to Japanese and South Korean, suggesting that these haplotypes had been recently derived from the Korean Peninsula. The alleles characterized by high frequency in Japanese compared to South Korean formed segmented three-locus haplotype that was commonly found in Aleuts, Eskimos, and North- and Meso-Americans but not observed in Korean and Chinese. The serologically equivalent haplotype was found in Orchid Island in Taiwan, Mongol, Siberia, and Arctic regions. It suggests that early Japanese who existed prior to the migration wave from the Korean Peninsula shared ancestry with northern Asian who moved to the New World via the Bering Strait land bridge. These results may support the admixture model for peopling of Japanese Archipelago.

Prolonged P300 latency in children with the D[sub 2] dopamine receptor A1 allele

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

Noble, E.P.; Berman, S.M.; Ozkaragoz, T.Z.

1994-04-01

Previous studies have indicated the presence of a hereditary component in the generation of the P300, or P3, a late positive component of the event-related potential. Moreover, the dopaminergic system has been implicated in the P3. In the present study, 98 healthy Caucasian boys, mean age of 12.5 years and of above-average intelligence, were studied. The sample was composed of 32 sons of active alcoholic (SAA) fathers, 36 sons of recovering alcoholic (SRA) fathers, and 30 sons of social drinker (SSD) fathers, with none of them having yet begun to consume alcohol or other drugs. TaqI A D[sub 2] dopaminemore » receptor alleles (A1 and A2) were determined. A significant difference in the frequency of the A1 allele was found among these three groups of boys, with the SAA group having the highest A1 allele frequency (.313), followed by the SRA (.139) and the SSD (.133) groups. The relationship of the A1 and A2 alleles to P3 amplitude and latency was also determined. The results showed no significant difference in P3 amplitude between boys with the A1 and A2 allele. However, P3 latency was significantly longer in the total sample of boys with the A1 allele compared with those carrying the A2 allele. These findings suggest that polymorphism of the D[sub 2] dopamine receptor gene is an important determinant of P3 latency. 84 refs., 2 figs., 3 tabs.« less

D2-Thr92Ala, thyroid hormone levels and biochemical hypothyroidism in preeclampsia.

PubMed

Procopciuc, Lucia Maria; Caracostea, Gabriela; Hazi, Georgeta; Nemeti, Georgiana; Stamatian, Florin

2017-02-01

To identify if there is a relationship between the deiodinase D2-Thr92Ala genetic variant, thyroid hormone levels and biochemical hypothyroidism in preeclampsia. We genotyped 125 women with preeclampsia and 131 normal pregnant women using PCR-RFLP. Serum thyroid hormone levels were determined using ELISA. Our study showed higher TSH and FT4 levels and lower FT3 levels in women with preeclampsia compared to normal pregnant women, with statistical significance for women with mild and severe preeclampsia. The risk to develop pregnancy-induced hypertension (PIH), mild or severe preeclampsia was increased in carriers of at least one D2-Ala92 allele. TSH and FT4 levels were significantly higher and FT3 levels were significantly lower in preeclamptic women with severe preeclampsia if they carried the D2-Ala92 allele compared to non-carriers. Pregnant women with PIH and mild preeclampsia, carriers of at least one D2-Ala92 allele, delivered at lower gestational age neonates with a lower birth weight compared to non-carriers, but the results were statistically significant only in severe preeclampsia. The D2-Thr92Ala genetic variant is associated with the severity and the obstetric outcome of preeclampsia, and it also influences thyroid hormone levels. The study demonstrates non-thyroidal biochemical hypothyroidism - as a result of deiodination effects due to D2 genotypes.

A Novel Bio-carrier Fabricated Using 3D Printing Technique for Wastewater Treatment

PubMed Central

Dong, Yang; Fan, Shu-Qian; Shen, Yu; Yang, Ji-Xiang; Yan, Peng; Chen, You-Peng; Li, Jing; Guo, Jin-Song; Duan, Xuan-Ming; Fang, Fang; Liu, Shao-Yang

2015-01-01

The structure of bio-carriers is one of the key operational characteristics of a biofilm reactor. The goal of this study is to develop a series of novel fullerene-type bio-carriers using the three-dimensional printing (3DP) technique. 3DP can fabricate bio-carriers with more specialized structures compared with traditional fabrication processes. In this research, three types of fullerene-type bio-carriers were fabricated using the 3DP technique and then compared with bio-carrier K3 (from AnoxKaldnes) in the areas of physicochemical properties and biofilm growth. Images acquired by 3D profiling and SEM indicated that the surface roughness of the 3DP bio-carrier was greater than that of K3. Furthermore, contact angle data indicated that the 3DP bio-carriers were more hydrophilic than K3. The biofilm on the 3DP bio-carriers exhibited higher microbial activity and stronger adhesion ability. These findings were attributed to excellent mass transfer of the substrate (and oxygen) between the vapour-liquid-solid tri-phase system and to the surface characteristics. It is concluded that the novel 3DP fullerene-type bio-carriers are ideal carriers for biofilm adherence and growth. PMID:26202477

A Novel Bio-carrier Fabricated Using 3D Printing Technique for Wastewater Treatment.

PubMed

Dong, Yang; Fan, Shu-Qian; Shen, Yu; Yang, Ji-Xiang; Yan, Peng; Chen, You-Peng; Li, Jing; Guo, Jin-Song; Duan, Xuan-Ming; Fang, Fang; Liu, Shao-Yang

2015-07-23

The structure of bio-carriers is one of the key operational characteristics of a biofilm reactor. The goal of this study is to develop a series of novel fullerene-type bio-carriers using the three-dimensional printing (3DP) technique. 3DP can fabricate bio-carriers with more specialized structures compared with traditional fabrication processes. In this research, three types of fullerene-type bio-carriers were fabricated using the 3DP technique and then compared with bio-carrier K3 (from AnoxKaldnes) in the areas of physicochemical properties and biofilm growth. Images acquired by 3D profiling and SEM indicated that the surface roughness of the 3DP bio-carrier was greater than that of K3. Furthermore, contact angle data indicated that the 3DP bio-carriers were more hydrophilic than K3. The biofilm on the 3DP bio-carriers exhibited higher microbial activity and stronger adhesion ability. These findings were attributed to excellent mass transfer of the substrate (and oxygen) between the vapour-liquid-solid tri-phase system and to the surface characteristics. It is concluded that the novel 3DP fullerene-type bio-carriers are ideal carriers for biofilm adherence and growth.

HLA-DR2-associated DRB1 and DRB5 alleles and haplotypes in Koreans.

PubMed

Song, E Y; Kang, S J; Lee, Y J; Park, M H

2000-09-01

There are considerable racial differences in the distribution of HLA-DR2-associated DRB1 and DRB5 alleles and the characteristics of linkage disequilibrium between these alleles. In this study, the frequencies of DR2-associated DRB1 and DRB5 alleles and related haplotypes were analyzed in 186 DR2-positive individuals out of 800 normal Koreans registered for unrelated bone marrow donors. HLA class I antigen typing was performed by the serological method and DRB1 and DRB5 genotyping by the PCR-single strand conformational polymorphism method. Only 3 alleles were detected for DR2-associated DRB1 and DRB5 genes, respectively: DRB1(*)1501 (gene frequency 8.0%), (*)1502 (3.2%), (*)1602 (0.9%); DRB5(*)0101 (8.0%), (*)0102 (3.2%), and (*)0202 (0.9%). DRB1-DRB5 haplotype analysis showed an exclusive association between these alleles: DRB1*1501-DRB5*0101 (haplotype frequency 8.0%), DRB1(*)1502-DRB5(*)0102 (3.2%), and DRB1(*)1602-DRB5(*)0202 (0.9%). The 5 most common DR2-associated A-B-DRB1 haplotypes occurring at frequencies of > or = 0.5% were A24-B52-DRB1(*)1502 (1.8%), A2-B62-DRB1(*)1501, A2-B54-DRB1(*)1501, A26-B61-DRB1(*)1501, and A24-B51-DRB1(*)1501. The remarkable homogeneity in the haplotypic associations between DR2-associated DRB1 and DRB5 alleles in Koreans would be advantageous for organ transplantation compared with other ethnic groups showing considerable heterogeneity in the distribution of DRB1-DRB5 haplotypes.

Silvicultural management and the manipulation of rare alleles

Treesearch

Paul G. Schaberg; Gary J. Hawley; Donald H. DeHayes; Samuel E. Nijensohn

2004-01-01

Because rare alleles provide a means for adaptation to environmental change they are often considered important to long-term forest health. Through the selective removal of trees (and genes), silvicultural management may alter the genetic structure of forests, with rare alleles perhaps being uniquely vulnerable to manipulation due to their low frequencies or...

A high-carbohydrate diet enhances the adverse effect of the S2 allele of APOC3 SstI polymorphism on the TG/HDL-C ratio only in young Chinese females.

PubMed

Song, Yong Yan; Gong, Ren Rong; Zhang, Zhen; Li, Yuan Hao; Xiao, Li Ying; Zhou, Xue Dong; Fang, Ding Zhi

2011-06-01

Both genetic background and diet have profound effects on plasma lipid profiles. We hypothesized that a high-carbohydrate (high-CHO) diet may affect the ratios of serum lipids and apolipoproteins (apo) differently in subjects with different genotypes of the SstI polymorphism in the apoCIII gene (APOC3). Fifty-six healthy university students (27 males and 29 females, 22.89 ± 1.80 years) were given a washout diet of 54% carbohydrate for 7 days, followed by a high-CHO diet of 70% carbohydrate for 6 days without total energy restriction. Serum triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apoB100, apoAI, and the APOC3 SstI polymorphism were analyzed. The ratios of serum lipids and apoB100/apoAI were calculated. At baseline, the TG/HDL-C ratio was significantly higher in females, but not in males, with the S2 allele. The differences in the TG/HDL-C ratio between genotypes remained the same after the washout and the high-CHO diet in females. When compared with those before the high-CHO diet, the TC/HDL-C (male S2 carriers: 3.13 ± 1.00 vs 2.36 ± 0.65, P = 0.000; male subjects with the S1S1 genotype: 2.97 ± 0.74 vs 2.09 ± 0.55, P = 0.000; female S2 carriers: 2.68 ± 0.36 vs 2.24 ± 0.37, P = 0.004; female subjects with the S1S1 genotype: 2.69 ± 0.41 vs 2.09 ± 0.31, P = 0.000) and LDL-C/HDL-C (male S2 carriers: 1.44 ± 0.71 vs 1.06 ± 0.26, P = 0.012; male subjects with the S1S1 genotype: 1.35 ± 0.61 vs 1.01 ± 0.29, P = 0.005; female S2 carriers: 1.18 ± 0.33 vs 1.00 ± 0.18, P = 0.049; female subjects with the S1S1 genotype: 1.18 ± 0.35 vs 1.04 ± 0.19, P = 0.026) ratios were significantly decreased after the high-CHO diet regardless of gender and of genotype of the APOC3 SstI polymorphism. However, in female S2 carriers, the TG/HDL-C (1.38 ± 0.46 vs 1.63 ± 0.70, P = 0.039) ratio was significantly increased after the high-CHO diet. In conclusion, the high-CHO diet has

Agricultural Commodity and Utility Carriers Hours of Service Exemption Analysis.

DOT National Transportation Integrated Search

2010-05-01

The study was conducted in two phases. Phase 1 compares the safety performance of agricultural and non-agricultural carriers for the period 2005 through 2008, and also examines two additional industries: livestock and utility carriers, whose operatio...

14 CFR 399.82 - Passing off of carrier identity by affiliation between carriers.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false Passing off of carrier identity by... Relating to Enforcement § 399.82 Passing off of carrier identity by affiliation between carriers. (a... points served by both carriers should preserve the identity of the individual carriers; (5) Where joint...

14 CFR 399.82 - Passing off of carrier identity by affiliation between carriers.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 4 2011-01-01 2011-01-01 false Passing off of carrier identity by... Relating to Enforcement § 399.82 Passing off of carrier identity by affiliation between carriers. (a... points served by both carriers should preserve the identity of the individual carriers; (5) Where joint...

14 CFR 399.82 - Passing off of carrier identity by affiliation between carriers.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 4 2014-01-01 2014-01-01 false Passing off of carrier identity by... Relating to Enforcement § 399.82 Passing off of carrier identity by affiliation between carriers. (a... points served by both carriers should preserve the identity of the individual carriers; (5) Where joint...

14 CFR 399.82 - Passing off of carrier identity by affiliation between carriers.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 4 2012-01-01 2012-01-01 false Passing off of carrier identity by... Relating to Enforcement § 399.82 Passing off of carrier identity by affiliation between carriers. (a... points served by both carriers should preserve the identity of the individual carriers; (5) Where joint...

14 CFR 399.82 - Passing off of carrier identity by affiliation between carriers.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 4 2013-01-01 2013-01-01 false Passing off of carrier identity by... Relating to Enforcement § 399.82 Passing off of carrier identity by affiliation between carriers. (a... points served by both carriers should preserve the identity of the individual carriers; (5) Where joint...

Evaluation of Lumicyano™ cyanoacrylate fuming process for the development of latent fingermarks on plastic carrier bags by means of a pseudo operational comparative trial.

PubMed

Farrugia, Kevin J; Deacon, Paul; Fraser, Joanna

2014-03-01

There are a number of studies discussing recent developments of a one-step fluorescent cyanoacrylate process. This study is a pseudo operational trial to compare an example of a one-step fluorescent cyanoacrylate product, Lumicyano™, with the two recommended techniques for plastic carrier bags; cyanoacrylate fuming followed by basic yellow 40 (BY40) dyeing and powder suspensions. 100 plastic carrier bags were collected from the place of work and the items were treated as found without any additional fingermark deposition. The bags were split into three and after treatment with the three techniques a comparable number of fingermarks were detected by each technique (average of 300 fingermarks). The items treated with Lumicyano™ were sequentially processed with BY40 and an additional 43 new fingermarks were detected. Lumicyano™ appears to be a suitable technique for the development of fingermarks on plastic carrier bags and it can help save lab space and time as it does not require dyeing or drying procedures. Furthermore, contrary to other one-step cyanoacrylate products, existing cyanoacrylate cabinets do not require any modification for the treatment of articles with Lumicyano™. To date, there is little peer reviewed articles in the literature on trials related to Lumicyano™ and this study aims to contribute to fill this gap. © 2013.

Precise frequency calibration using television video carriers

NASA Technical Reports Server (NTRS)

Burkhardt, Edward E.

1990-01-01

The availability of inexpensive and quick precise frequency calibration methods is limited. VLF and GPS do offer precise calibration. However, antenna placement, cost of equipment, and calibration time place many restrictions on the user. The USNO maintained line-10 television Time of Coincidence (TOC) of station WTTG, channel 5, Washington, DC requires a frequency stable video carrier. This video carrier, 77.24 MHz is controlled by the same cesium beam standard controlling the TOC of line-10. Excellent frequency comparisons against this video carrier have been accomplished at 95 miles (153 km). With stable propagation and a three foot wire antenna, a part in 10(exp 9) can be determined in a few minutes. Inexpensive field equipment with a synthesized 1 kHz offset from the video carrier offers parts in 10(exp 11) calibrations in a few minutes using an oscilloscope as a phase comparator.

Precise frequency calibration using television video carriers

NASA Astrophysics Data System (ADS)

Burkhardt, Edward E.

1990-05-01

The availability of inexpensive and quick precise frequency calibration methods is limited. VLF and GPS do offer precise calibration. However, antenna placement, cost of equipment, and calibration time place many restrictions on the user. The USNO maintained line-10 television Time of Coincidence (TOC) of station WTTG, channel 5, Washington, DC requires a frequency stable video carrier. This video carrier, 77.24 MHz is controlled by the same cesium beam standard controlling the TOC of line-10. Excellent frequency comparisons against this video carrier have been accomplished at 95 miles (153 km). With stable propagation and a three foot wire antenna, a part in 10(exp 9) can be determined in a few minutes. Inexpensive field equipment with a synthesized 1 kHz offset from the video carrier offers parts in 10(exp 11) calibrations in a few minutes using an oscilloscope as a phase comparator.

Allelic Prevalence of ABO Blood Group Genes in Iranian Azari Population.

PubMed

Nojavan, Mohammad; Shamsasenjan, Karrim; Movassaghpour, Ali Akbar; Akbarzadehlaleh, Parvin; Torabi, Seyd Esmail; Ghojazadeh, Morteza

2012-01-01

ABO blood group system is the most important blood group in transfusion and has been widely used in population studies. Several molecular techniques for ABO allele's detection are widely used for distinguishing various alleles of glycosyl transferase locus on chromosome 9. 744 randomly selected samples from Azari donors of East Azerbaijan province (Iran) were examined using well-adjusted multiplex allele- specific PCR ABO genotyping technique. The results were consistent for all individuals. The ABO blood group genotype of 744 healthy Azari blood donors was: 25.8% AA/AO (2), 7.6% AO (1), 1.6% BB, 11.3% B0 (1), 10% AB, 9.3% 0(1)0(1) and 15.3%0(1)0(2). The highest genotype frequency belonged to O01/O02 genotype (15.3%) and the lowest frequency belonged to A101/A102 genotype (0.4%). The frequencies of ABO alleles didn't show significant differences between East Azerbaijan province population and that of other areas of the country. Meanwhile, statistical analysis of frequencies of A and B alleles between East Azerbaijan province population and neighbor countries showed significant differences whereas the frequency of allele O between them did not show significant difference (P>0.05). The frequencies of ABO alleles didn't show significant differences between East Azerbaijan province population and that of other areas of the country. Meanwhile, statistical analysis of frequencies of A and B alleles between East Azerbaijan province population and neighbor countries showed significant differences whereas the frequency of allele O between them did not show significant difference (P>0.05).

Forensic applicability of multi-allelic InDels with mononucleotide homopolymer structures.

PubMed

Zhang, Shu; Zhu, Qiang; Chen, Xiaogang; Zhao, Yuancun; Zhao, Xiaohong; Yang, Yiwen; Gao, Zehua; Fang, Ting; Wang, Yufang; Zhang, Ji

2018-04-27

Insertion/deletion polymorphisms (InDels), which possess the characteristics of low mutation rates and a short amplicon size, have been regarded as promising markers for forensic DNA analysis. InDels can be classified as bi-allelic or multi-allelic, depending on the number of alleles. Many studies have explored the use of bi-allelic InDels in forensic applications, such as individual identification and ancestry inference. However, multi-allelic InDels have received relatively little attention. In this study, InDels with 2-6 alleles and a minor allele frequency ≥0.01, in Chinese Southern Han (CHS), were retrieved from the 1000 Genomes Project Phase III. Based on the structural analysis of all retrieved InDels, 17 multi-allelic markers with mononucleotide homopolymer structures were selected and combined in one multiplex PCR reaction system. Sensitivity, species specificity and applicability in forensic case work of the multiplex were analyzed. A total of 218 unrelated individuals from a Chinese Han population were genotyped. The combined discriminatory power (CDP), the combined match probability (CMP) and the cumulative probability of exclusion (CPE) were 0.9999999999609, 3.91E-13 and 0.9956, respectively. The results demonstrated that this InDel multiplex panel was highly informative in the investigated population and most of the 26 populations of the 1000 Genomes Project. The data also suggested that multi-allelic InDel markers with monomeric base pair expansions are useful for forensic applications. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Frequency of null allele of Human Leukocyte Antigen-G (HLA-G) locus in subjects to recurrent miscarriage.

PubMed

Alizadeh, Nazila; Mosaferi, Elnaz; Farzadi, Laya; Majidi, Jafar; Monfaredan, Amir; Yousefi, Bahman; Baradaran, Behzad

2016-07-01

Human leukocyte antigen-G (HLA-G) is a non-classical class I molecule highly expressed by extravillous cytotrophoblast cells. Due to a single base pair deletion, its function can be compensated by other isoforms. Investigating the frequency of null allele in Recurrent Miscarriage (RM) subjects could be useful in understanding the relationship between frequency of this allele and RM in a given population. This study aimed to determine the frequency of HLA-G*0105N null allele and its potential association with down-regulation of HLA-G in subjects with RM. Western blotting was used to assess the level of HLA-G protein expression. For investigating the frequency of HLA-G*0105N null allele in RM subjects, PCR-RFLP method was used. Exon 3 of HLA-G gene was amplified by polymerase chain reaction (PCR). Subsequently, PpuM-1 enzyme was employed to digest the PCR products and fragments were analyzed using gel electrophoresis. Digestion using restriction enzyme showed the presence of heterozygous HLA-G*0105N null allele in 10% of the test population. Western blotting results confirmed the decrease in expression of HLA-G in the placental tissue of subjects with RM compared to subjects who could give normal birth. The frequency of heterozygous HLA-G*0105N null allele was high to some extent in subjects with RM. The mutation rate in subjects suggested that there is a significant association between RM and frequency of mutations in this allele.

Influence of cytochrome 2C19 allelic variants on on-treatment platelet reactivity evaluated by five different platelet function tests.

PubMed

Gremmel, Thomas; Kopp, Christoph W; Moertl, Deddo; Seidinger, Daniela; Koppensteiner, Renate; Panzer, Simon; Mannhalter, Christine; Steiner, Sabine

2012-05-01

The antiplatelet effect of clopidogrel has been linked to cytochrome P450 2C19 (CYP2C19) carrier status. The presence of loss of function and gain of function variants were found to have a gene-dose effect on clopidogrel metabolism. However, genotyping is only one aspect of predicting response to clopidogrel and several platelet function tests are available to measure platelet response. Patients and methods We studied the influence of CYP2C19 allelic variants on on-treatment platelet reactivity as assessed by light transmission aggregometry (LTA), the VerifyNow P2Y12 assay, the VASP assay, multiple electrode aggregometry (MEA), and the Impact-R in 288 patients after stenting for cardiovascular disease. Allelic variants of CYP2C19 were determined with the Infiniti® CYP450 2C19+ assay and categorized into four metabolizer states (ultrarapid, extensive, intermediate, poor). Platelet reactivity increased linearly from ultrarapid to poor metabolizers using the VerifyNow P2Y12 assay (P = 0.04), the VASP assay (P = 0.02) and the Impact-R (P = 0.04). The proportion of patients with high on-treatment residual platelet reactivity (HRPR) identified by LTA, the VerifyNow P2Y12 assay and the VASP assay increased when the metabolizer status decreased, while no such relationship could be identified for results of MEA and Impact-R. The presence of loss of function variants (*2/*2, *2-8*/wt, *2/*17) was an independent predictor of HRPR in LTA and the VASP assay while it did not reach statistical significance in the VerifyNow P2Y12 assay, MEA, and the Impact-R. Depending on the type of platelet function test differences in the association of on-treatment platelet reactivity with CYP2C19 carrier status are observed. Copyright © 2011 Elsevier Ltd. All rights reserved.

Readressing the role of Toll-like receptor-4 alleles in inflammatory bowel disease: colitis, smoking, and seroreactivity.

PubMed

Manolakis, Anastassios C; Kapsoritakis, Andreas N; Kapsoritaki, Anastasia; Tiaka, Elisavet K; Oikonomou, Konstantinos A; Lotis, Vassilis; Vamvakopoulou, Dimitra; Davidi, Ioanna; Vamvakopoulos, Nikolaos; Potamianos, Spyros P

2013-02-01

Toll-like receptor (TLR) polymorphisms, and especially TLR-4 Asp299Gly and TLR-4 Thr399Ile, have been linked with Crohn's disease (CD) and to a lesser extent with ulcerative colitis (UC), CD behavior, and compromised seroreactivity to microbial antigens. Available data, however, are conflicting. To address these issues, the distribution of TLR-4 polymorphic alleles was assessed in patients with UC, CD, and healthy controls (HC), considering patient and disease characteristics as well as related serological markers. TLR-4 Asp299Gly and TLR-4 Thr399Ile polymorphisms were determined in 187 UC and 163 CD patients and 274 randomly selected HC. C reactive protein, anti-Saccharomyces cerevisiae mannan antibodies, anti-mannobioside carbohydrate antibodies, anti-laminariobioside carbohydrate antibodies IgG, and anti-chitobioside carbohydrate antibodies (ACCA) IgA levels were also assessed. UC and especially pancolitis patients carried the mutant alleles more frequently compared to CD patients and HC or UC patients with different disease extents (P = 0.002 and P < 0.0001, respectively). Involvement of the colon was more frequent in CD patients with mutant TLR-4 compared to those with wild-type alleles (P = 0.004). Levels and positivity rates of ACCA IgA were lower in inflammatory bowel disease (IBD) patients carrying the mutant compared to those with wild-type alleles (0.075 < P < 0.05). Despite the mutant TLR-4 predisposition for UC pancolitis, smoking was associated with more limited disease (P < 0.001). The presence of TLR-4 Asp299Gly and TLR-4 Thr399Ile polymorphisms is related to UC pancolitis, involvement of the colon in CD, and lower ACCA IgA levels. Smoking reduces the extent of UC, even in the presence of mutant alleles.

Haemophilia A carriers experience reduced health-related quality of life.

PubMed

Gilbert, L; Paroskie, A; Gailani, D; Debaun, M R; Sidonio, R F

2015-11-01

Haemophilia A is an X-linked recessive bleeding disorder that primarily affects males. Emerging data support evidence for increased bleeding in female haemophilia A carriers despite factor VIII activity within the normal range. Data regarding the effect of increased bleeding on health-related quality of life (HR-QOL) in haemophilia A carriers is sparse. We tested the hypothesis that haemophilia A carriers have reduced HR-QOL related to bleeding symptoms. We conducted a cross-sectional study at Vanderbilt University. Case subjects were obligate or genetically verified haemophilia A carriers age 18-60 years. Control subjects were mothers of children with cancer who receive care at the Vanderbilt paediatric haematology-oncology clinic. Trained interviewers administered the Rand 36-Item Health Survey 1.0, a validated questionnaire evaluating eight health concepts that may affect HR-QOL, to each study participant. Mann-Whitney U-tests were used to compare median scores for the eight health domains between the case and control groups. Forty-two haemophilia A carriers and 36 control subjects were included in analyses. Haemophilia A carriers had significantly lower median scores for the domains of 'Pain' (73.75 vs. 90; P = 0.02) and 'General health' (75 vs. 85; P = 0.01) compared to control subjects. Haemophilia A carriers in our study demonstrated significantly lower median scores on the Rand 36-item Health Survey 1.0 in the domains of 'Pain' and 'General Health' compared to women in the control group. Our findings highlight the need for further investigation of the effect of bleeding on HR-QOL in this population. © 2015 John Wiley & Sons Ltd.

Allelic-based gene-gene interaction associated with quantitative traits.

PubMed

Jung, Jeesun; Sun, Bin; Kwon, Deukwoo; Koller, Daniel L; Foroud, Tatiana M

2009-05-01

Recent studies have shown that quantitative phenotypes may be influenced not only by multiple single nucleotide polymorphisms (SNPs) within a gene but also by the interaction between SNPs at unlinked genes. We propose a new statistical approach that can detect gene-gene interactions at the allelic level which contribute to the phenotypic variation in a quantitative trait. By testing for the association of allelic combinations at multiple unlinked loci with a quantitative trait, we can detect the SNP allelic interaction whether or not it can be detected as a main effect. Our proposed method assigns a score to unrelated subjects according to their allelic combination inferred from observed genotypes at two or more unlinked SNPs, and then tests for the association of the allelic score with a quantitative trait. To investigate the statistical properties of the proposed method, we performed a simulation study to estimate type I error rates and power and demonstrated that this allelic approach achieves greater power than the more commonly used genotypic approach to test for gene-gene interaction. As an example, the proposed method was applied to data obtained as part of a candidate gene study of sodium retention by the kidney. We found that this method detects an interaction between the calcium-sensing receptor gene (CaSR), the chloride channel gene (CLCNKB) and the Na, K, 2Cl cotransporter gene (CLC12A1) that contributes to variation in diastolic blood pressure.

Frequency analysis of the delta32ccr5 HIV resistance allele in a medieval plague mass grave.

PubMed

Kremeyer, Barbara; Hummel, Susanne; Herrmann, Bernd

2005-03-01

The 32 basepair deletion in the gene for the human chemokine receptor CCR5 (delta32ccr5) conferring resistance against HIV-1 infection is present in Caucasian populations. The mutant allele is believed to have originated by a single mutational event in historic times and to have reached its present population frequency of an average 10 % in Europe through selective pressure by a pathogenic agent. Because of their great impact on European populations, the medieval Plague epidemics have been considered as a possible candidate. To test this hypothesis, we studied the delta32ccr5-frequency in 35 individuals from a mass grave containing victims of the 14th century Plague pandemic in Lübeck, Northern Germany, and compared them to the frequency in a control group from the same burial site, dating from the time before the first Plague pandemic. If the delta32ccr5 allele conferred an at least partial resistance against the medieval Plague, its frequency would be expected to be lower in those that died in the pandemic, than it was in the local population before the arrival of the Plague. The CCR5 locus could be typed successfully for 14 Plague victims and for 20 individuals from the medieval control group. We found a delta32ccr5 allelic frequency of 14.2% and 12.5%, respectively. The difference between these figures is not statistically significant. Furthermore, they are comparable to the delta32ccr5 frequency for nowadays Northern Europe. We therefore conclude that the medieval Plague pandemic has not contributed to an increase in the allelic frequency of the mutant delta32ccr5 allele and that, if there has been a positive selection of this allele, it is likely to have occurred before the 14th century and thus before the arrival of the Plague in Europe.

The Maintenance of Single-Locus Polymorphism. IV. Models with Mutation from Existing Alleles

PubMed Central

Spencer, H. G.; Marks, R. W.

1992-01-01

The ability of viability selection to maintain allelic polymorphism is investigated using a constructionist approach. In extensions to the models we have previously proposed, a population is bombarded with a series of mutations whose fitnesses in conjunction with other alleles are functions of the corresponding fitnesses with a particular allele, the parent allele, already in the population. Allele frequencies are iterated simultaneously, thus allowing alleles to be driven to extinction by selection. Such models allow very high levels of polymorphism to evolve: up to 38 alleles in one case. Alleles that are lethal as homozygotes can evolve to surprisingly high frequencies. The joint evolution of allele frequencies and viabilities highlights the necessity to consider more than the current morphology of a population. Comparisons are made with the neutral theory of evolution and it is suggested that failure to reject neutrality using the Ewens-Watterson test cannot be regarded as evidence for the neutral theory. PMID:1732162

The maintenance of single-locus polymorphism. IV. Models with mutation from existing alleles.

PubMed

Spencer, H G; Marks, R W

1992-01-01

The ability of viability selection to maintain allelic polymorphism is investigated using a constructionist approach. In extensions to the models we have previously proposed, a population is bombarded with a series of mutations whose fitnesses in conjunction with other alleles are functions of the corresponding fitnesses with a particular allele, the parent allele, already in the population. Allele frequencies are iterated simultaneously, thus allowing alleles to be driven to extinction by selection. Such models allow very high levels of polymorphism to evolve: up to 38 alleles in one case. Alleles that are lethal as homozygotes can evolve to surprisingly high frequencies. The joint evolution of allele frequencies and viabilities highlights the necessity to consider more than the current morphology of a population. Comparisons are made with the neutral theory of evolution and it is suggested that failure to reject neutrality using the Ewens-Watterson test cannot be regarded as evidence for the neutral theory.

Distribution of HLA-DRB1 and HLA-DQB1 alleles in Lak population of Iran.

PubMed

Varzi, Ali Mohammad; Shahsavar, Farhad; Tarrahi, Mohammad Javad

2016-07-01

Human leukocyte antigen (HLA) genes are the most polymorphic loci in the human genome and encode the highly polymorphic molecules critically involved in immune responses. Anthropological studies based on highly polymorphic HLA genes provide useful information for bone marrow donor registry, forensic medicine, disease association studies, as well as designing peptide vaccines against tumors, and infectious or autoimmune diseases. The aim of this study was to determine the HLA-DRB1 and HLA-DQB1 allele frequencies in 100 unrelated Lak individuals from Lorestan province of Iran. Finally, we compared the results with those previously described in four other Iranian populations. Commercial HLA-Type kits were used for determination of the HLA-DRB1 and HLA-DQB1 allele frequencies. Differences between populations in the distribution of HLA-DRB1 and HLA-DQB1 alleles were estimated by χ2 test with Yate's correction and Fisher's exact test. The most frequent HLA-DRB1 alleles were (*)1103=4 (23%), (*)1502 (9.5%), (*)0701 (9%), (*)0301 (8.5%), (*)1101 (7.5%) and (*)1501 (6%) while HLA-DQB1(*)0301 (40%), (*)0201 (15%), (*)0502 (10.5%), (*)0303 (10%), (*)0602=3 (9.5%), and (*)0501 (7.5%) were the most frequent alleles in Lak population. HLA-DRB1(*)0409, (*)0804, (*)1102, (*)1112, (*)1405, and HLA-DQB1(*)0503, (*)0604 were the least observed frequencies in Lak population. Our results based on HLA-DRB1 and HLA-DQB1 allele frequencies showed that the Lak population possesses the previously reported general features of the Lur and Kurd populations but still with unique, decreased or increased frequencies of several alleles. In other words, the Lak population is close to Lurs Khorramabadi and Kurd but far from Lurs Kohkiloyeh/Boyerahmad and Bakhtiari. Copyright © 2016 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

Independent regulation of the two Pax5 alleles during B-cell development.

PubMed

Nutt, S L; Vambrie, S; Steinlein, P; Kozmik, Z; Rolink, A; Weith, A; Busslinger, M

1999-04-01

The developmental control genes of the Pax family are frequently associated with mouse mutants and human disease syndromes. The function of these transcription factors is sensitive to gene dosage, as mutation of one allele or a modest increase in gene number results in phenotypic abnormalities. Pax5 has an important role in B-cell and midbrain development. By following the expression of individual Pax5 alleles at the single-cell level, we demonstrate here that Pax5 is subject to allele-specific regulation during B-lymphopoiesis. Pax5 is predominantly transcribed from only one allele in early progenitors and mature B cells, whereas it switches to a biallelic transcription mode in immature B cells. The allele-specific regulation of Pax5 is stochastic, reversible, independent of parental origin and correlates with synchronous replication, in contrast with imprinted and other monoallelically expressed genes. As a consequence, B-lymphoid tissues are mosaics with respect to the transcribed Pax5 allele, and thus mutation of one allele in heterozygous mice results in deletion of the cell population expressing the mutant allele due to loss of Pax5 function at the single-cell level. Similar allele-specific regulation may be a common mechanism causing the haploinsufficiency and frequent association of other Pax genes with human disease.

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.

Association of low-risk MSH3 and MSH2 variant alleles with Lynch syndrome: probability of synergistic effects.

PubMed

Duraturo, Francesca; Liccardo, Raffaella; Cavallo, Angela; De Rosa, Marina; Grosso, Michela; Izzo, Paola

2011-10-01

Mutations in the MLH1 and MSH2 genes account for a majority of cases of families with Lynch Syndrome. Germ-line mutations in MSH6, PMS2 and MLH3 are responsible for disease in a minority of cases, usually associated with milder and variable phenotypes. No germ-line mutations in MSH3 have so far been associated with Lynch Syndrome, although it is known that impaired MSH3 activity leads to a partial defect in mismatch repair (MMR), with low levels of microsatellite instability at the loci with dinucleotide repeats in colorectal cancer (CRC), thus suggesting a role for MSH3 in carcinogenesis. To determine a possible role of MSH3 as predisposing to CRC in Lynch syndrome, we screened MSH3 for germ-line mutations in 79 unrelated Lynch patients who were negative for pathogenetic mutations in MLH1, MSH2 and MSH6. We found 13 mutant alleles, including silent, missense and intronic variants. These variants were identified through denaturing high performance liquid chromatography and subsequent DNA sequencing. In one Lynch family, the index case with early-onset colon cancer was a carrier of a polymorphism in the MSH2 gene and two variants in the MSH3 gene. These variants were associated with the disease in the family, thus suggesting the involvement of MSH3 in colon tumour progression. We hypothesise a model in which variants of the MSH3 gene behave as low-risk alleles that contribute to the risk of colon cancer in Lynch families, mostly with other low-risk alleles of MMR genes. Copyright © 2010 UICC.

Carrier Injection and Scattering in Atomically Thin Chalcogenides

NASA Astrophysics Data System (ADS)

Li, Song-Lin; Tsukagoshi, Kazuhito

2015-12-01

Atomically thin two-dimensional chalcogenides such as MoS2 monolayers are structurally ideal channel materials for the ultimate atomic electronics. However, a heavy thickness dependence of electrical performance is shown in these ultrathin materials, and the device performance normally degrades while exhibiting a low carrier mobility as compared with corresponding bulks, constituting a main hurdle for application in electronics. In this brief review, we summarize our recent work on electrode/channel contacts and carrier scattering mechanisms to address the origins of this adverse thickness dependence. Extrinsically, the Schottky barrier height increases at the electrode/channel contact area in thin channels owing to bandgap expansion caused by quantum confinement, which hinders carrier injection and degrades device performance. Intrinsically, thin channels tend to suffer from intensified Coulomb impurity scattering, resulting from the reduced interaction distance between interfacial impurities and channel carriers. Both factors are responsible for the adverse dependence of carrier mobility on channel thickness in two-dimensional semiconductors.

A rural mail-carrier index of North Dakota red foxes

USGS Publications Warehouse

Allen, S.H.; Sargeant, A.B.

1975-01-01

Rural mail-carrier sightings of red foxes (Vulpes vulpes) during mid-April, -July, and -September of 1969-73 were compared to spring fox family estimates derived by aerial searches of six townships. The mid-April mail-carrier index reflected annual fox density changes on the six townships (correlation coefficient = 0.958) . Random exclusions of individual mail-carrier reports indicated participation could decline 40 percent without affecting index accuracy.

Long-term episodic memory decline is associated with olfactory deficits only in carriers of ApoE-є4.

PubMed

Olofsson, Jonas K; Josefsson, Maria; Ekström, Ingrid; Wilson, Donald; Nyberg, Lars; Nordin, Steven; Nordin Adolfsson, Annelie; Adolfsson, Rolf; Nilsson, Lars-Göran; Larsson, Maria

2016-05-01

The ɛ4 allele of the Apolipoprotein E gene is a genetic risk factor for late-onset dementia of the Alzheimers' type (DAT), which is characterized by loss of both episodic memory and olfactory functions. Little is known about the possible role of ɛ4 in the association between ongoing episodic memory decline and olfactory deficits in the general population, but such information is relevant in determining the relevance of olfaction as a marker of DAT risk. The present study was based on a large, population-based sample (n=1087, aged 45-90 years, of which 324 were ɛ4-carriers). Episodic memory change rates were established using data collected every 5 years for a 10-20 year interval leading up to an olfactory assessment using the Scandinavian Odor Identification Test at the last wave of data collection. Participants were classified according to whether or not their episodic memory ability declined more rapidly than the age-typical norm (by >1SD). Our main result is that only in ɛ4-carriers was episodic memory decline associated with odor identification impairment. In individuals without ɛ4, odor identification was unrelated to episodic memory decline status. Follow-up analyses indicated that this moderation by ɛ4 was due to the olfactory nature of the identification test, and that the effect was not caused by 63 individuals with dementia. Our results suggest that the ɛ4 determines the functional association between ongoing episodic memory decline and olfaction. These findings are consistent with the notion that ɛ4-carriers with DAT, compared to non-carriers, display a cortical atrophy pattern that is more focused on mediotemporal lobe regions supporting olfactory and episodic memory functions. Olfactory and memory assessments might provide complementary information on mediotemporal atrophy prior to clinical dementia onset, but the ɛ4 should be considered when using olfactory assessment as an early-stage indicator. Copyright © 2016. Published by Elsevier Ltd.

Genome-wide analysis of allele frequency change in sunflower crop-wild hybrid populations evolving under natural conditions.

PubMed

Corbi, Jonathan; Baack, Eric J; Dechaine, Jennifer M; Seiler, Gerald; Burke, John M

2018-01-01

Crop-wild hybridization occurs in numerous plant species and could alter the genetic structure and evolutionary dynamics of wild populations. Studying crop-derived alleles in wild populations is also relevant to assessing/mitigating the risks associated with transgene escape. To date, crop-wild hybridization has generally been examined via short-term studies, typically within a single generation, focusing on few traits or genetic markers. Little is known about patterns of selection on crop-derived alleles over multiple generations, particularly at a genome-wide scale. Here, we documented patterns of natural selection in an experimental crop × wild sunflower population that was allowed to evolve under natural conditions for two generations at two locations. Allele frequencies at a genome-wide collection of SNPs were tracked across generations, and a common garden experiment was conducted to compare trait means between generations. These data allowed us to identify instances of selection on crop-derived alleles/traits and, in concert with QTL mapping results, test for congruence between our genotypic and phenotypic results. We found that natural selection overwhelmingly favours wild alleles and phenotypes. However, crop alleles in certain genomic regions can be favoured, and these changes often occurred in parallel across locations. We did not, however, consistently observe close agreement between our genotypic and phenotypic results. For example, when a trait evolved towards the wild phenotype, wild QTL alleles associated with that trait did not consistently increase in frequency. We discuss these results in the context of crop allele introgression into wild populations and implications for the management of GM crops. © 2017 John Wiley & Sons Ltd.

Polymorphism of neuropeptide Y gene rs16147 modifies the response to a hypocaloric diet on cardiovascular risk biomarkers and adipokines.

PubMed

de Luis, D A; Izaola, O; de la Fuente, B; Primo, D; Aller, R

2017-04-01

The main genetic variant described in NPY gene is rs16147 (G-399A) and it is located within the promoter region upstream of the gene for neropeptide Y (NPY). We evaluate the effects of the rs16147 NPY gene polymorphism on metabolic changes secondary to weight loss after 3 months of a hypocaloric diet in adult obese patients. A population of 82 obese patients was analysed in an interventional design of one arm. Before and after 3 months on a hypocaloric diet, an anthropometric evaluation, an assessment of nutritional intake and a biochemical analysis were performed. The statistical analysis was performed for combined GA and AA as a group (minor allele group) and GG as second group (major allele group) (dominant model). In A allele carriers, the mean (SD) decrease in weight was -2.8 (2.2) kg [decrease in non A allele carriers -2.6 (1.1) kg, P > 0.05), body mass index was -1.2 (0.6) kg m -2 [decrease in non A allele carriers -1.1 (0.8) kg m -2 , P > 0.05], fat mass was -1.7 (1.4) kg [decrease in non A allele carriers -1.9 (1.3) kg, P > 0.05], waist circumference was -5.5 (3.4) cm [decrease in non A allele carriers -3.7 (4.1) cm, P = 0.006], C-reactive protein (CRP) was -0.7 (0.6) mg dL -1 [decrease in non A allele carriers -0.1 (0.3) mg dL -1 , P = 0.02], insulin was -1.5 (0.4) mUI L -1 [decrease in non A allele carriers -0.8 (2.0) mUI L -1 , P = 0.001] and homeostasis model assessment-insulin resistance (HOMA-IR) was -0.4 (0.5) [decrease in non A allele carriers -0.2 (0.1), P = 0.005]. interleukin (IL)-6 changes were significant in A allele carriers [-0.7 (0.2) pg mL -1 ] versus non A allele carriers [-0.1 (0.3) pg mL -1 ] (P = 0.01). We found that the rs164147 genotype affected the reduction of waist circumference, HOMA-IR, insulin, CRP and IL-6 levels in response to weight loss diet in obese subjects. © 2016 The British Dietetic Association Ltd.

An historical perspective on "The world-wide distribution of allele frequencies at the human dopamine D4 receptor locus".

PubMed

Kidd, Kenneth K; Pakstis, Andrew J; Yun, Libing

2014-04-01

Human population genetics is a completely different science today compared to two decades ago, at least at the empiric level. Our paper [Chang (Hum Genet 98:91-101, 1996a)] demonstrated that three different alleles were common when one considered many populations although other low frequency alleles occurred. Because previous work had been largely done on European subjects, our findings involved 36 distinct populations and showed that East Asian populations had nearly lost the 7-repeat allele, and that Native American populations had the highest frequencies of that allele globally, was a significant early empiric demonstration of the potential magnitude of population variation at important genes. There are thousands of loci tested on many of the same populations and the gene frequency pattern seen for the DRD4 7-repeat allele is seen at other loci, arguing that this pattern commonly reflects the pattern of divergence of populations and accumulated random genetic drift.

Implementation and validation of an improved allele specific stutter filtering method for electropherogram interpretation.

PubMed

Kalafut, Tim; Schuerman, Curt; Sutton, Joel; Faris, Tom; Armogida, Luigi; Bright, Jo-Anne; Buckleton, John; Taylor, Duncan

2018-03-31

Modern probabilistic genotyping (PG) software is capable of modeling stutter as part of the profile weighting statistic. This allows for peaks in stutter positions to be considered as allelic or stutter or both. However, prior to running any sample through a PG calculator, the examiner must first interpret the sample, considering such things as artifacts and number of contributors (NOC or N). Stutter can play a major role both during the assignment of the number of contributors, and the assessment of inclusion and exclusion. If stutter peaks are not filtered when they should be, it can lead to the assignment of an additional contributor, causing N contributors to be assigned as N + 1. If peaks in the stutter position of a major contributor are filtered using a threshold that is too high, true alleles of minor contributors can be lost. Until now, the software used to view the electropherogram stutter filters are based on a locus specific model. Combined stutter peaks occur when a peak could be the result of both back stutter (stutter one repeat shorter than the allele) and forward stutter (stutter one repeat unit larger than the allele). This can challenge existing filters. We present here a novel stutter filter model in the ArmedXpert™ software package that uses a linear model based on allele for back stutter and applies an additive filter for combined stutter. We term this the allele specific stutter model (AM). We compared AM with a traditional model based on locus specific stutter filters (termed LM). This improved stutter model has the benefit of: Instances of over filtering were reduced 78% from 101 for a traditional model (LM) to 22 for the allele specific model (AM) when scored against each other. Instances of under filtering were reduced 80% from 85 (LM) to 17 (AM) when scored against ground truth mixtures. Published by Elsevier B.V.

The 148 M allele of the PNPLA3 is associated with plasma irisin levels in a population sample of Caucasian children: The PANIC Study.

PubMed

Viitasalo, Anna; Atalay, Mustafa; Pihlajamäki, Jussi; Jääskeläinen, Jarmo; Korkmaz, Ayhan; Kaminska, Dorota; Lindi, Virpi; Lakka, Timo A

2015-07-01

There are no previous data on the association of PNPLA3 I148M polymorphism (rs738409) with circulating adipokines and myokines in children. Subjects were a population sample of 481 Caucasian children aged 6-8 years. We assessed circulating levels of irisin together with IL-6, TNF-α, leptin, high molecular weight (HMW)-adiponectin, alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) while the subjects were stratified according to PNPLA3 I148M variants. The PNPLA3 rs738409 polymorphism had a linear relationship with plasma levels of irisin after adjustment for age, sex and body height (p=0.007) but it was not associated with circulating levels of interleukin- 6 (IL-6), tumor-necrosis factor α (TNF-α), leptin or HMW-adiponectin. PNPLA3 148M allele carriers had higher plasma levels of irisin than the non-carriers. This might be due to compensatory mechanism to limit early steatotic and inflammatory changes in the liver. Copyright © 2015 Elsevier Inc. All rights reserved.

ASSORTATIVE MATING CAN IMPEDE OR FACILITATE FIXATION OF UNDERDOMINANT ALLELES

PubMed Central

NEWBERRY, MITCHELL G; MCCANDLISH, DAVID M; PLOTKIN, JOSHUA B

2017-01-01

Underdominant mutations have fixed between divergent species, yet classical models suggest that rare underdominant alleles are purged quickly except in small or subdivided populations. We predict that underdominant alleles that also influence mate choice, such as those affecting coloration patterns visible to mates and predators alike, can fix more readily. We analyze a mechanistic model of positive assortative mating in which individuals have n chances to sample compatible mates. This one-parameter model naturally spans random mating (n =1) and complete assortment (n → ∞), yet it produces sexual selection whose strength depends non-monotonically on n. This sexual selection interacts with viability selection to either inhibit or facilitate fixation. As mating opportunities increase, underdominant alleles fix as frequently as neutral mutations, even though sexual selection and underdominance independently each suppress rare alleles. This mechanism allows underdominant alleles to fix in large populations and illustrates how life history can affect evolutionary change. PMID:27497738

Assortative mating can impede or facilitate fixation of underdominant alleles.

PubMed

Newberry, Mitchell G; McCandlish, David M; Plotkin, Joshua B

2016-12-01

Underdominant mutations have fixed between divergent species, yet classical models suggest that rare underdominant alleles are purged quickly except in small or subdivided populations. We predict that underdominant alleles that also influence mate choice, such as those affecting coloration patterns visible to mates and predators alike, can fix more readily. We analyze a mechanistic model of positive assortative mating in which individuals have n chances to sample compatible mates. This one-parameter model naturally spans random mating (n=1) and complete assortment (n→∞), yet it produces sexual selection whose strength depends non-monotonically on n. This sexual selection interacts with viability selection to either inhibit or facilitate fixation. As mating opportunities increase, underdominant alleles fix as frequently as neutral mutations, even though sexual selection and underdominance independently each suppress rare alleles. This mechanism allows underdominant alleles to fix in large populations and illustrates how life history can affect evolutionary change. Copyright © 2016 Elsevier Inc. All rights reserved.

DRD4 dopamine receptor allelic diversity in various primate species

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

Adamson, M.; Higley, D.; O`Brien, S.

The DRD4 dopamine receptor is uniquely characterized by a 48 bp repeating segment within the coding region, located in exon III. Different DRD4 alleles are produced by the presence of additional 48 bp repeats, each of which adds 16 amino acids to the length of the 3rd intracytoplasmic loop of the receptor. The DRD4 receptor is therefore an intriguing candidate gene for behaviors which are influenced by dopamine function. In several human populations, DRD4 alleles with 2-8 and 10 repeats have previously been identified, and the 4 and 7 repeat alleles are the most abundant. We have determined DRD4 genotypesmore » in the following nonhuman primate species: chimpanzee N=2, pygmy chimpanzee N=2, gorilla N=4, siamang N=2, Gelada baboon N=1, gibbon N=1, orangutan (Bornean and Sumatran) N=62, spider monkey N=4, owl monkey N=1, Colobus monkey N=1, Patas monkey N=1, ruffed lemur N=1, rhesus macaque N=8, and vervet monkey N=28. The degree of DRD4 polymorphism and which DRD4 alleles were present both showed considerable variation across primate species. In contrast to the human, rhesus macaque monkeys were monomorphic. The 4 and 7 repeat allels, highly abundant in the human, may not be present in certain other primates. For example, the four spider monkeys we studied showed the 7, 8 and 9 repeat length alleles and the only gibbon we analyzed was homozygous for the 9 repeat allele (thus far not observed in the human). Genotyping of other primate species and sequencing of the individual DRD4 repeat alleles in different species may help us determine the ancestral DRD4 repeat length and identify connections between DRD4 genotype and phenotype.« less

Association between diabetes type 1 and DQB1 alleles in a case-control study conducted in Montevideo, Uruguay.

PubMed

Mimbacas, Adriana; Pérez-Bravo, Francisco; Hidalgo, Pedro C; Javiel, Gerardo; Pisciottano, Carmen; Grignola, Rosario; Jorge, Ana María; Gallino, Juan Pablo; Gasagoite, Jackeline; Cardoso, Horacio

2003-03-31

We studied HLA DQB1 allele frequencies and the relative risk (RR) of various genotypes in 72 type 1 diabetic patients and 40 control individuals in Uruguay. This is a tri-racial (Caucasian, Black and Indo-American) mixed population. The products of the polymerase chain reaction amplifications were hybridized with oligonucleotides by allele-specific oligonucleotide reverse or dot blot methods. Significant differences between these two groups were observed only for allele DQB1*0302 (35%, RR = 7.34, P<0.001). The frequency of the alleles carrying a non-aspartic acid residue at position 57 was significantly higher in the diabetic patients (85 vs 53%, P<0.001). In contrast, the frequency of Asp alleles was negatively associated with type 1 diabetes (RR = 0.20, P<0.001). The genotype DQB1*0302/DQB1*0201 (33%, RR = 5.41, P<0.05) was positively associated with this disease. The genotype frequencies associated with type 1 diabetes in our population were significantly different from what is known for Caucasian and Black populations as well as compared with another admixed population, from Chile.

Phenotypic analysis of separation-of-function alleles of MEI-41, Drosophila ATM/ATR.

PubMed Central

Laurençon, Anne; Purdy, Amanda; Sekelsky, Jeff; Hawley, R Scott; Su, Tin Tin

2003-01-01

ATM/ATR kinases act as signal transducers in eukaryotic DNA damage and replication checkpoints. Mutations in ATM/ATR homologs have pleiotropic effects that range from sterility to increased killing by genotoxins in humans, mice, and Drosophila. Here we report the generation of a null allele of mei-41, Drosophila ATM/ATR homolog, and the use of it to document a semidominant effect on a larval mitotic checkpoint and methyl methanesulfonate (MMS) sensitivity. We also tested the role of mei-41 in a recently characterized checkpoint that delays metaphase/anaphase transition after DNA damage in cellular embryos. We then compare five existing mei-41 alleles to the null with respect to known phenotypes (female sterility, cell cycle checkpoints, and MMS resistance). We find that not all phenotypes are affected equally by each allele, i.e., the functions of MEI-41 in ensuring fertility, cell cycle regulation, and resistance to genotoxins are genetically separable. We propose that MEI-41 acts not in a single rigid signal transduction pathway, but in multiple molecular contexts to carry out its many functions. Sequence analysis identified mutations, which, for most alleles, fall in the poorly characterized region outside the kinase domain; this allowed us to tentatively identify additional functional domains of MEI-41 that could be subjected to future structure-function studies of this key molecule. PMID:12807779

Identification of novel alleles of the rice blast resistance gene Pi54

NASA Astrophysics Data System (ADS)

Vasudevan, Kumar; Gruissem, Wilhelm; Bhullar, Navreet K.

2015-10-01

Rice blast is one of the most devastating rice diseases and continuous resistance breeding is required to control the disease. The rice blast resistance gene Pi54 initially identified in an Indian cultivar confers broad-spectrum resistance in India. We explored the allelic diversity of the Pi54 gene among 885 Indian rice genotypes that were found resistant in our screening against field mixture of naturally existing M. oryzae strains as well as against five unique strains. These genotypes are also annotated as rice blast resistant in the International Rice Genebank database. Sequence-based allele mining was used to amplify and clone the Pi54 allelic variants. Nine new alleles of Pi54 were identified based on the nucleotide sequence comparison to the Pi54 reference sequence as well as to already known Pi54 alleles. DNA sequence analysis of the newly identified Pi54 alleles revealed several single polymorphic sites, three double deletions and an eight base pair deletion. A SNP-rich region was found between a tyrosine kinase phosphorylation site and the nucleotide binding site (NBS) domain. Together, the newly identified Pi54 alleles expand the allelic series and are candidates for rice blast resistance breeding programs.

HLA class II and TNF genes in African Americans from the Southeastern United States: regional differences in allele frequencies.

PubMed

Kuffner, Tamara; Whitworth, William; Jairam, Maya; McNicholl, Janet

2003-06-01

Knowledge of population major histocompatibility complex gene frequencies is important for construction of organ donor pools and for studies of disease association. Human leukocyte antigen DRB1 (HLA-DRB1), HLA-DQB1, and TNFalpha -308 (G-A) promoter genetic typing was performed in 112 healthy, unrelated African Americans (AAs) from the southeastern United States. Allele frequencies were compared with published frequency data from other AA populations. Our AA population had the highest frequency of HLA- DRB1*09 (6.7%) reported in any AA population. The frequency of the TNF alpha -308A polymorphism was also high (14.4%), when compared with published frequencies in AAs. Significant regional differences in the distribution of most HLA-DRB1 and HLA-DQB1 alleles were observed in all AA populations examined. The AA HLA-DRB1 and -DQB1 frequencies also differed from published Caucasian frequencies. This is the first report describing the distribution of TNF alpha promoter alleles in the Southeastern United States. The high DRB1*09 and TNF alpha -308A allele frequencies of our population most resemble the frequencies of these alleles in certain West African populations. These varying major histocompatibility complex gene frequencies may reflect different regional population structures among AAs in the United States, which may be due to differences in ancestral origins, migration, and racial admixture.

Carrier-interleaved orthogonal multi-electrode multi-carrier resistivity-measurement tool

NASA Astrophysics Data System (ADS)

Cai, Yu; Sha, Shuang

2016-09-01

This paper proposes a new carrier-interleaved orthogonal multi-electrode multi-carrier resistivity-measurement tool used in a cylindrical borehole environment during oil-based mud drilling processes. The new tool is an orthogonal frequency division multiplexing access-based contactless multi-measurand detection tool. The tool can measure formation resistivity in different azimuthal angles and elevational depths. It can measure many more measurands simultaneously in a specified bandwidth than the legacy frequency division multiplexing multi-measurand tool without a channel-select filter while avoiding inter-carrier interference. The paper also shows that formation resistivity is not sensitive to frequency in certain frequency bands. The average resistivity collected from N subcarriers can increase the measurement of the signal-to-noise ratio (SNR) by N times given no amplitude clipping in the current-injection electrode. If the clipping limit is taken into account, with the phase rotation of each single carrier, the amplitude peak-to-average ratio can be reduced by 3 times, and the SNR can achieve a 9/N times gain over the single-carrier system. The carrier-interleaving technique is also introduced to counter the carrier frequency offset (CFO) effect, where the CFO will cause inter-pad interference. A qualitative analysis and simulations demonstrate that block-interleaving performs better than tone-interleaving when coping with a large CFO. The theoretical analysis also suggests that increasing the subcarrier number can increase the measurement speed or enhance elevational resolution without sacrificing receiver performance. The complex orthogonal multi-pad multi-carrier resistivity logging tool, in which all subcarriers are complex signals, can provide a larger available subcarrier pool than other types of transceivers.

Molecular genetic mechanisms of allelic specific regulation of murine Comt expression

PubMed Central

Segall, Samantha K.; Shabalina, Svetlana A.; Meloto, Carolina B.; Wen, Xia; Cunningham, Danielle; Tarantino, Lisa M.; Wiltshire, Tim; Gauthier, Josée; Tohyama, Sarasa; Martin, Loren J.; Mogil, Jeffrey S.; Diatchenko, Luda

2015-01-01

Abstract A functional allele of the mouse catechol-O-methyltransferase (Comt) gene is defined by the insertion of a B2 short interspersed repeat element in its 3′-untranslated region (UTR). This allele has been associated with a number of phenotypes, such as pain and anxiety. In comparison with mice carrying the ancestral allele (Comt+), ComtB2i mice show higher Comt mRNA and enzymatic activity levels. Here, we investigated the molecular genetic mechanisms underlying this allelic specific regulation of Comt expression. Insertion of the B2 element introduces an early polyadenylation signal generating a shorter Comt transcript, in addition to the longer ancestral mRNA. Comparative analysis and in silico prediction of Comt mRNA potential targets within the transcript 3′ to the B2 element was performed and allowed choosing microRNA (miRNA) candidates for experimental screening: mmu-miR-3470a, mmu-miR-3470b, and mmu-miR-667. Cell transfection with each miRNA downregulated the expression of the ancestral transcript and COMT enzymatic activity. Our in vivo experiments showed that mmu-miR-667-3p is strongly correlated with decreasing amounts of Comt mRNA in the brain, and lentiviral injections of mmu-miR-3470a, mmu-miR-3470b, and mmu-miR-667 increase hypersensitivity in the mouse formalin model, consistent with reduced COMT activity. In summary, our data demonstrate that the Comt+ transcript contains regulatory miRNA signals in its 3′-untranslated region leading to mRNA degradation; these signals, however, are absent in the shorter transcript, resulting in higher mRNA expression and activity levels. PMID:26067582

Variant in OXTR gene and functional connectivity of the hypothalamus in normal subjects.

PubMed

Wang, Junping; Qin, Wen; Liu, Bing; Wang, Dawei; Zhang, Yunting; Jiang, Tianzi; Yu, Chunshui

2013-11-01

The oxytocin receptor gene (OXTR) rs53576A has been associated with autism spectrum disorders (ASDs). A smaller hypothalamic volume has been reported in healthy male A-allele carriers than in male GG homozygotes and in patients with ASDs than in healthy controls. These findings prompt the hypothesis that male AA homozygotes may have weaker hypothalamic functional connectivity when compared to male G-allele carriers. We calculated local functional connectivity density (FCD) using a voxel-wise data-driven approach based on resting-state functional MRI data in 270 young healthy subjects. Both the main effect of genotype and the gender-by-genotype interaction were considered. Of the whole brain, only the local FCD of the hypothalamus exhibited the main effect of genotype. Post-hoc testing revealed significantly lower local FCD in male AA homozygotes compared to male G-allele carriers although there was only a trend of significance in the gender-by-genotype interaction. We further analyzed the resting-state functional connectivity (rsFC) of the hypothalamic region that demonstrating significant genotype differences in local FCD. We found a significant gender-by-genotype interaction in rsFC between the hypothalamic region and the left dorsolateral prefrontal cortex, but no significant main effect of genotype was found. Post-hoc testing revealed that this rsFC was significantly weaker in male AA homozygotes compared to male G-allele carriers. Our findings identify gender-dependent mechanisms of OXTR rs53576 gene variation impacting the functional connectivity of the hypothalamus in healthy individuals and suggest that these mechanisms are important for understanding ASDs. Copyright © 2013 Elsevier Inc. All rights reserved.

Direct testing for allele-specific expression differences between conditions

USDA-ARS?s Scientific Manuscript database

Genetic differences in cis regulatory regions contribute to the phenotypic variation observed in natural and human populations, including beneficial, potentially adaptive, traits as well as disease states. The two alleles in a diploid cell can differ in their allele-specific expression leading to al...

Peripheral retinopathy in offspring of carriers of Norrie disease gene mutations. Possible transplacental effect of abnormal Norrin.

PubMed

Mintz-Hittner, H A; Ferrell, R E; Sims, K B; Fernandez, K M; Gemmell, B S; Satriano, D R; Caster, J; Kretzer, F L

1996-12-01

The Norrie disease (ND) gene (Xp11.3) (McKusick 310600) consists of one untranslated exon and two exons partially translated as the Norrie disease protein (Norrin). Norrin has sequence homology and computer-predicted tertiary structure of a growth factor containing a cystine knot motif, which affects endothelial cell migration and proliferation. Norrie disease (congenital retinal detachment), X-linked primary retinal dysplasia (congenital retinal fold), and X-linked exudative vitreoretinopathy (congenital macular ectopia) are allelic disorders. Blood was drawn for genetic studies from members of two families to test for ND gene mutations. Sixteen unaffected family members were examined ophthalmologically. If any retinal abnormality were identified, fundus photography and fluorescein angiography was performed. Family A had ND (R109stp), and family B had X-linked exudative vitreoretinopathy (R121L). The retinas of 11 offspring of carrier females were examined: three of seven carrier females, three of three otherwise healthy females, and one of one otherwise healthy male had peripheral inner retinal vascular abnormalities. The retinas of five offspring of affected males were examined: none of three carrier females and none of two otherwise healthy males had this peripheral retinal finding. Peripheral inner retinal vascular abnormalities similar to regressed retinopathy of prematurity were identified in seven offspring of carriers of ND gene mutations in two families. These ophthalmologic findings, especially in four genetically healthy offspring, strongly support the hypothesis that abnormal Norrin may have an adverse transplacental (environmental) effect on normal inner retinal vasculogenesis.

Association of HLA-A and HLA-B Alleles with Lamotrigine-Induced Cutaneous Adverse Drug Reactions in the Thai Population

PubMed Central

Koomdee, Napatrupron; Pratoomwun, Jirawat; Jantararoungtong, Thawinee; Theeramoke, Voralaksana; Tassaneeyakul, Wichittra; Klaewsongkram, Jettanong; Rerkpattanapipat, Ticha; Santon, Siwalee; Puangpetch, Apichaya; Intusoma, Utcharee; Tempark, Therdpong; Deesudchit, Tayard; Satapornpong, Patompong; Visudtibhan, Anannit; Sukasem, Chonlaphat

2017-01-01

Background: Lamotrigine (LTG) is commonly used for treatment of epilepsy and bipolar disorder. It is one of the common cause of cutaneous adverse drug reactions (CADR). Clinical symptoms of LTG-induced CADR range from maculopapular exanthema (MPE) to severe cutaneous adverse reactions (SCAR). This study aimed to determine the association of the LTG-induced CADR with human leukocyte antigen (HLA) alleles in Thai patients. Methods: Fifteen patients with LTG-induced CADR [10 MPE; 4 Stevens–Johnson syndrome; and 1 drug reaction with eosinophilia and systemic symptoms] and 50 LTG-tolerant controls were included in the study. HLA-A and HLA-B genotyping was performed using polymerase chain reaction-sequence-specific oligonucleotides probes. Results: The proportion of HLA-A∗02:07 and HLA-B∗15:02 allele carriers were significantly higher in the LTG-induced CADR group than in the tolerant controls [odds ratio (OR): 7.83; 95% confidence interval (CI): 1.60–38.25; P = 0.013, and OR: 4.89; 95% CI: 1.28–18.67; P = 0.014]. In addition, subjects with HLA-A∗33:03, HLA-B∗15:02, and HLA-B∗44:03 were significantly higher in the LTG-induced MPE group than in the tolerant controls (OR: 8.27; 95% CI: 1.83–37.41; P = 0.005, OR: 7.33; 95% CI: 1.63–33.02; P = 0.005; and OR: 10.29; 95% CI: 1.45–72.81; P = 0.029). In contrast to the LTG-induced MPE group, there were no significant differences between HLA alleles and LTG-induced SCAR group. Conclusion: HLA-A∗02:07 and HLA-B∗15:02 were associated with LTG-induced CADR in Thai patients. We also identified an association between HLA-A∗33:03, HLA-B∗15:02, and HLA-B∗44:03 and LTG-induced MPE in this population. These results suggest that these alleles could be useful screening markers for preventing CADR before LTG treatment in Thai patients, but further replication studies with larger sample sizes are needed. PMID:29238301

Frequency of null allele of Human Leukocyte Antigen-G (HLA-G) locus in subjects to recurrent miscarriage

PubMed Central

Alizadeh, Nazila; Mosaferi, Elnaz; Farzadi, Laya; Majidi, Jafar; Monfaredan, Amir; Yousefi, Bahman; Baradaran, Behzad

2016-01-01

Background: Human leukocyte antigen-G (HLA-G) is a non-classical class I molecule highly expressed by extravillous cytotrophoblast cells. Due to a single base pair deletion, its function can be compensated by other isoforms. Investigating the frequency of null allele in Recurrent Miscarriage (RM) subjects could be useful in understanding the relationship between frequency of this allele and RM in a given population. Objective: This study aimed to determine the frequency of HLA-G*0105N null allele and its potential association with down-regulation of HLA-G in subjects with RM. Materials and Methods: Western blotting was used to assess the level of HLA-G protein expression. For investigating the frequency of HLA-G*0105N null allele in RM subjects, PCR-RFLP method was used. Exon 3 of HLA-G gene was amplified by polymerase chain reaction (PCR). Subsequently, PpuM-1 enzyme was employed to digest the PCR products and fragments were analyzed using gel electrophoresis. Results: Digestion using restriction enzyme showed the presence of heterozygous HLA-G*0105N null allele in 10% of the test population. Western blotting results confirmed the decrease in expression of HLA-G in the placental tissue of subjects with RM compared to subjects who could give normal birth. Conclusion: The frequency of heterozygous HLA-G*0105N null allele was high to some extent in subjects with RM. The mutation rate in subjects suggested that there is a significant association between RM and frequency of mutations in this allele. PMID:27525330

Heterozygous carriers of classical homocystinuria tend to have higher fasting serum homocysteine concentrations than non-carriers in the presence of folate deficiency.

PubMed

Lu, Yung-Hsiu; Cheng, Li-Mei; Huang, Yu-Hsiu; Lo, Ming-Yu; Wu, Tina Jui-Ting; Lin, Hsiang-Yu; Hsu, Ting-Rong; Niu, Dau-Ming

2015-12-01

Many studies have reported that serum total homocysteine (tHcy) levels in cystathionine-beta-synthase (CBS) carriers are usually normal and only elevated after a methionine load. However, the amount of methionine required for a loading test is non-physiological and is never reached with regular feeding. Therefore, CBS carriers do not seem to be at an increased risk of cardiovascular diseases. However, the risk of cardiovascular diseases of CBS carriers with folate deficiency has not been studied. We recently found an extraordinarily high carrier rate (1/7.78) of a novel CBS mutation (p.D47E, c.T141A) in an Austronesian Taiwanese Tao tribe who live in a geographic area with folate deficiency. We evaluated if the CBS carriers tend to have higher fasting serum tHcy concentrations than non-carriers in presence of folate deficiency. The serum tHcy and folate levels before and after folate replacement were measured in 48 adult Tao carriers, 40 age-matched Tao non-carriers and 40 age-matched Han Taiwanese controls. The serum tHcy level of the Tao CBS carriers (17.9 ± 3.8 μmol/l) was significantly higher than in Tao non-carriers (15.7 ± 3.5 μmol/l; p < 0.008) and Taiwanese controls (11.8 ± 2.9 μmol/l; p < 0.001). Furthermore, a high prevalence of folate deficiency in the Tao compared with the Taiwanese controls (4.9 ± 1.8 ng/ml vs. 10.6 ± 5.5 ng/ml; p < 0.001) was also noted. Of note, the difference in tHcy levels between the carriers and non-carriers was eliminated by folate supplementation. (carriers:13.65 ± 2.13 μmol/l; non-carriers:12.39 ± 3.25 μmol/l, p = 0.321). CBS carriers tend to have a higher tHcy level in the presence of folate deficiency than non-carriers. Although many reports have indicated that CBS carriers are not associated with cardiovascular disease, the risk for CBS carriers with folate deficiency has not been well studied. Owing to a significantly elevated level of fasting tHcy without methionine loading, it is important to evaluate the

S-genotype identification based on allele-specific PCR in Japanese pear

PubMed Central

Nashima, Kenji; Terakami, Shingo; Nishio, Sogo; Kunihisa, Miyuki; Nishitani, Chikako; Saito, Toshihiro; Yamamoto, Toshiya

2015-01-01

Gametophytic self-incompatibility in Japanese pear (Pyrus pyrifolia Nakai) is controlled by the single, multi-allelic S-locus. Information about the S-genotypes is important for breeding and the selection of pollen donors for fruit production. Rapid and reliable S-genotype identification system is necessary for efficient breeding of new cultivars in Japanese pear. We designed S allele-specific PCR primer pairs for ten previously reported S-RNase alleles (S1–S9 and Sk) as simple and reliable method. Specific nucleotide sequences were chosen to design the primers to amplify fragments of only the corresponding S alleles. The developed primer pairs were evaluated by using homozygous S-genotypes (S1/S1–S9/S9 and S4sm/S4sm) and 14 major Japanese pear cultivars, and found that S allele-specific primer pairs can identify S-genotypes effectively. The S allele-specific primer pairs developed in this study will be useful for efficient S-genotyping and for marker-assisted selection in Japanese pear breeding programs. PMID:26175617

A comparative study of carrier lifetimes in ESWIR and MWIR materials: HgCdTe, InGaAs, InAsSb, and GeSn (Conference Presentation)

NASA Astrophysics Data System (ADS)

Bellotti, Enrico; Wen, Hanqing; Dominici, Stefano; Glasmann, Andreu L.

2017-02-01

HgCdTe has been the material of choice for MWIR, and LWIR infrared sensing due to its highly tunable band gap and favorable material properties. However, HgCdTe growth and processing for the ESWIR spectral region is less developed, so alternative materials are actively researched. It is important to compare the fundamental limitations of each material to determine which offers optimal device performance. In this article, we investigate the intrinsic recombination mechanisms of ESWIR materials—InGaAs, GeSn, and HgCdTe—with cutoff wavelength near 2.5μm, and MWIR with cutoff of 5μm. First, using an empirical pseudo-potential model, we calculate the full band structure of each alloy using the virtual crystal approximation, modified to include disorder effects and spin-orbit coupling. We then evaluate the Auger and radiative recombination rates using a Green's function based model, applied to the full material band structure, yielding intrinsic carrier lifetimes for each given temperature, carrier injection, doping density, and cutoff wavelength. For example, we show that ESWIR HgCdTe has longer carrier lifetimes than InGaAs when strained or relaxed near room temperature, which is advantageous for high operating temperature photodetectors. We perform similar analyses for varying composition GeSn by comparing the calculated lifetimes with InGaAs and HgCdTe. Finally, we compare HgCdTe, InAsSb and GeSn with a cutoff in the MWIR spectral band.

Do methicillin resistant staphylococcus (MRSA) carrier patients influence MRSA infection more than MRSA-carrier medical officers and MRSA-carrier family?

PubMed

Dilogo, Ismail H; Arya, Abikara; Phedy; Loho, Tony

2013-07-01

to determine the rate of MRSA-carrier among patients, family members and health care providers, and the association between MRSA-carrier family members and health care providers on MRSA infection patient after orthopaedic surgery. this is a cross-sectional analytical study. Samples were taken consecutively during December 2010 to December 2011, consisting of postoperative patients infected with MRSA, attending family members, and the medical officers with history of contact with the patient. Swab culture were taken from nasal and axilla of all subjects. The incidence of MRSA infection, and MRSA-carrier on the patient, family members and medical officers were presented descriptively, while their association with MRSA infection was statistically tested using Fischer exact test. during the study period, there were 759 surgeries, with 4 (0.5%) patients were identified to have MRSA infection. Of these four cases, 48 subjects were enrolled. The rate of MRSA-carrier among patients, family and health care providers were 50%, 25% and 0% respectively. There were no significant association between MRSA and the rates of MRSA-carrier on the family member or health care providers. the incidence of MRSA infection, MRSA-carrier patient, MRSA-carrier health care providers, and family member carrier were 0.5%, 50%, 0%, and 25% respectively. No significant association found between MRSA-carrier on the family member or health care providers and MRSA infection patient. There were no MRSA infection found on the health care provider.

Lunch eating predicts weight-loss effectiveness in carriers of the common allele at PERILIPIN1: the ONTIME (Obesity, Nutrigenetics, Timing, Mediterranean) study

USDA-ARS?s Scientific Manuscript database

Background: We propose that eating lunch late impairs the mobilization of fat from adipose tissue, particularly in carriers of PERILIPIN1 (PLIN1) variants. Objective: The aim was to test the hypothesis that PLIN1, a circadian lipid-stabilizing protein in the adipocyte, interacts with the timing of ...

Distinguishing functional polymorphism from random variation in the sequences of >10,000 HLA-A, -B and -C alleles.

PubMed

Robinson, James; Guethlein, Lisbeth A; Cereb, Nezih; Yang, Soo Young; Norman, Paul J; Marsh, Steven G E; Parham, Peter

2017-06-01

HLA class I glycoproteins contain the functional sites that bind peptide antigens and engage lymphocyte receptors. Recently, clinical application of sequence-based HLA typing has uncovered an unprecedented number of novel HLA class I alleles. Here we define the nature and extent of the variation in 3,489 HLA-A, 4,356 HLA-B and 3,111 HLA-C alleles. This analysis required development of suites of methods, having general applicability, for comparing and analyzing large numbers of homologous sequences. At least three amino-acid substitutions are present at every position in the polymorphic α1 and α2 domains of HLA-A, -B and -C. A minority of positions have an incidence >1% for the 'second' most frequent nucleotide, comprising 70 positions in HLA-A, 85 in HLA-B and 54 in HLA-C. The majority of these positions have three or four alternative nucleotides. These positions were subject to positive selection and correspond to binding sites for peptides and receptors. Most alleles of HLA class I (>80%) are very rare, often identified in one person or family, and they differ by point mutation from older, more common alleles. These alleles with single nucleotide polymorphisms reflect the germ-line mutation rate. Their frequency predicts the human population harbors 8-9 million HLA class I variants. The common alleles of human populations comprise 42 core alleles, which represent all selected polymorphism, and recombinants that have assorted this polymorphism.

Distinguishing functional polymorphism from random variation in the sequences of >10,000 HLA-A, -B and -C alleles

PubMed Central

Cereb, Nezih; Yang, Soo Young; Marsh, Steven G. E.; Parham, Peter

2017-01-01

HLA class I glycoproteins contain the functional sites that bind peptide antigens and engage lymphocyte receptors. Recently, clinical application of sequence-based HLA typing has uncovered an unprecedented number of novel HLA class I alleles. Here we define the nature and extent of the variation in 3,489 HLA-A, 4,356 HLA-B and 3,111 HLA-C alleles. This analysis required development of suites of methods, having general applicability, for comparing and analyzing large numbers of homologous sequences. At least three amino-acid substitutions are present at every position in the polymorphic α1 and α2 domains of HLA-A, -B and -C. A minority of positions have an incidence >1% for the ‘second’ most frequent nucleotide, comprising 70 positions in HLA-A, 85 in HLA-B and 54 in HLA-C. The majority of these positions have three or four alternative nucleotides. These positions were subject to positive selection and correspond to binding sites for peptides and receptors. Most alleles of HLA class I (>80%) are very rare, often identified in one person or family, and they differ by point mutation from older, more common alleles. These alleles with single nucleotide polymorphisms reflect the germ-line mutation rate. Their frequency predicts the human population harbors 8–9 million HLA class I variants. The common alleles of human populations comprise 42 core alleles, which represent all selected polymorphism, and recombinants that have assorted this polymorphism. PMID:28650991

Structural and resting-state MRI detects regional brain differences in young and mid-age healthy APOE-e4 carriers compared with non-APOE-e4 carriers.

PubMed

Dowell, Nicholas G; Evans, Simon L; Tofts, Paul S; King, Sarah L; Tabet, Naji; Rusted, Jennifer M

2016-05-01

The presence of the e4 allele of the apolipoprotein E (APOE) gene is the best-known genetic risk factor for Alzheimer's disease. In this study, we investigated the link between functional and behavioural differences and regional brain volume and cortical thickness differences in those who carry the e4 allele (e4+) and those who only carry the e3 allele (e3/e3). We studied these genotype populations in two age groups: a young group (average age, 21 years) and a mid-age group (average age, 50 years). High-resolution T1 -weighted MRI scans were analysed with Freesurfer to measure regional white matter brain volume and cortical thickness differences between genotype groups at each age. These data were correlated with behavioural findings in the same cohort. Resting-state MRI was also conducted to identify differences in underlying brain functional connectivity. We found that there was a positive correlation between the thickness of the parahippocampal cortex in young e4+ individuals and performance on an episodic memory task. Young e4+ individuals also showed a positive correlation between white matter volume in the left anterior cingulate and performance on a covert attention task. At mid-age, e4+ individuals had structural differences relative to e3/e3 individuals in these areas: the parahippocampal cortex was thicker and white matter volume in the left anterior cingulate was greater than in e3/e3 individuals. We discuss the possibility that an over-engagement with these regions by e4+ individuals in youth may have a neurogenic effect that is observable later in life. The cuneus appears to be an important region for APOE-driven differences in the brain, with greater functional connectivity among young e3/e3 individuals and greater white matter volume in young e4+ individuals. Copyright © 2016 John Wiley & Sons, Ltd.

Numerical modeling of carrier gas flow in atomic layer deposition vacuum reactor: A comparative study of lattice Boltzmann models

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

Pan, Dongqing; Chien Jen, Tien; Li, Tao

2014-01-15

This paper characterizes the carrier gas flow in the atomic layer deposition (ALD) vacuum reactor by introducing Lattice Boltzmann Method (LBM) to the ALD simulation through a comparative study of two LBM models. Numerical models of gas flow are constructed and implemented in two-dimensional geometry based on lattice Bhatnagar–Gross–Krook (LBGK)-D2Q9 model and two-relaxation-time (TRT) model. Both incompressible and compressible scenarios are simulated and the two models are compared in the aspects of flow features, stability, and efficiency. Our simulation outcome reveals that, for our specific ALD vacuum reactor, TRT model generates better steady laminar flow features all over the domainmore » with better stability and reliability than LBGK-D2Q9 model especially when considering the compressible effects of the gas flow. The LBM-TRT is verified indirectly by comparing the numerical result with conventional continuum-based computational fluid dynamics solvers, and it shows very good agreement with these conventional methods. The velocity field of carrier gas flow through ALD vacuum reactor was characterized by LBM-TRT model finally. The flow in ALD is in a laminar steady state with velocity concentrated at the corners and around the wafer. The effects of flow fields on precursor distributions, surface absorptions, and surface reactions are discussed in detail. Steady and evenly distributed velocity field contribute to higher precursor concentration near the wafer and relatively lower particle velocities help to achieve better surface adsorption and deposition. The ALD reactor geometry needs to be considered carefully if a steady and laminar flow field around the wafer and better surface deposition are desired.« less

Apolipoprotein E type epsilon4 allele, heritability and age at onset in twins with Alzheimer disease and vascular dementia.

PubMed

Bergem, A L; Lannfelt, L

1997-11-01

The apolipoprotein E (APOE) epsilon4 allele is a risk factor in Alzheimer disease (AD), but not in vascular dementia (VaD). We have investigated whether the epsilon4 allele is more common in twin pairs concordant for AD, compared with those discordant for AD, and whether the epsilon4 allele is more common in AD twins than in VaD twins. In addition, we have investigated the relationship of the epsilon4 allele and the age at onset in AD and VaD. APOE genotype was analysed in 29 senile demented twin pairs. The epsilon4 allele was associated with AD and not with VaD. However, there was no difference in the frequency of the APOE epsilon4 allele in concordant (33.3%) and discordant (31.3%) AD dizygotic twin pairs. Age at onset in AD was significantly lower in epsilon4 homozygotes than in individuals with one or no copies of epsilon4 (62.4 vs. 73.5, p<0.01). In concordant AD twin pairs, the epsilon4 allele frequency was somewhat higher in the twins with earlier onset (41.7% vs. 25%), but the difference was not statistically significant. In the VaD group the age at onset was not significantly different between individuals with or without epsilon4 in their genotypes.

Over-representation of the APOE*4 allele in autopsy confirmed early- and late-onset sporadic Alzheimer`s disease