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1

Relationship of MTHFR gene polymorphisms with renal and cardiac disease  

PubMed Central

AIM: To investigate the effects of different methylenetetrahydrofolate reductase (MTHFR) 677C>T gene polymorphism and hyperhomocysteinemia for the development of renal failure and cardiovascular events, which are controversial. METHODS: We challenged the relationship, if any, of MTHFR 677C>T and MTHFR 1298A>C polymorphisms with renal and heart function. The present article is a reappraisal of these concepts, investigating within a larger population, and including a subgroup of dialysis patients, if the two most common MTHFR polymorphisms, C677T and A1298C, as homozygous, heterozygous or with a compound heterozygous state, show different association with chronic renal failure requiring hemodialysis. MTHFR polymorphism could be a favorable evolutionary factor, i.e., a protective factor for many ominous conditions, like cancer and renal failure. A similar finding was reported in fatty liver disease in which it is suggested that MTHFR polymorphisms could have maintained and maintain their persistence by an heterozygosis advantage mechanism. We studied a total of 630 Italian Caucasian subject aged 54.60 ± 16.35 years, addressing to the increased hazard of hemodialysis, if any, according to the studied MTHFR genetic polymorphisms. RESULTS: A favorable association with normal renal function of MTHFR polymorphisms, and notably of MTHFR C677T is present independently of the negative effects of left ventricular hypertrophy, increased Intra-Renal arterial Resistance and hyperparathyroidism. CONCLUSION: MTHFR gene polymorphisms could have a protective role on renal function as suggested by their lower frequency among our dialysis patients in end-stage renal failure; differently, the association with left ventricular hypertrophy and reduced left ventricular relaxation suggest some type of indirect, or concurrent mechanism. PMID:25664255

Trovato, Francesca M; Catalano, Daniela; Ragusa, Angela; Martines, G Fabio; Pirri, Clara; Buccheri, Maria Antonietta; Di Nora, Concetta; Trovato, Guglielmo M

2015-01-01

2

MTHFR Gene C677T Polymorphism in Autism Spectrum Disorders  

PubMed Central

Aim. Autism is a subgroup of autism spectrum disorders, classified as a heterogeneous neurodevelopmental disorder and symptoms occur in the first three years of life. The etiology of autism is largely unknown, but it has been accepted that genetic and environmental factors may both be responsible for the disease. Recent studies have revealed that the genes involved in the folate/homocysteine pathway may be risk factors for autistic children. In particular, C677T polymorphism in the MTHFR gene as a possible risk factor for autism is still controversial. We aimed to investigate the possible effect of C677T polymorphism in a Turkish cohort. Methods. Autism patients were diagnosed by child psychiatrists according to DSM-IV and DSM-V criteria. A total of 98 children diagnosed as autistic and 70 age and sex-matched children who are nonautistic were tested for C677T polymorphism. This polymorphism was studied by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Results. MTHFR 677T-allele frequency was found to be higher in autistic children compared with nonautistic children (29% versus 24%), but it was not found statistically significant. Conclusions. We conclude that other MTHFR polymorphisms such as A1298C or other folate/homocysteine pathway genes may be studied to show their possible role in autism. PMID:25431675

Oztop, Didem Behice; Ozkul, Yusuf

2014-01-01

3

Genomic scan for genes predisposing to schizophrenia  

SciTech Connect

We initiated a genome-wide search for genes predisposing to schizophrenia by ascertaining 9 families, each containing three to five cases of schizophrenia. The 9 pedigrees were initially genotyped with 329 polymorphic DNA loci distributed throughout the genome. Assuming either autosomal dominant or recessive inheritance, 254 DNA loci yielded lod scores less than -2.0 at {theta} = 0.0, 101 DNA markers gave lod scores less than -2.0 at {theta} = 0.05, while 5 DNA loci produced maximum lod scores greater than 1: D4S35, D14S17, D15S1, D22S84, and D22S55. Of the DNA markers yielding lod scores greater than 1, D4S35 and D22S55 also were suggestive of linkage when the Affected-Pedigree-Member method was used. The families were then genotyped with four highly polymorphic simple sequence repeat markers; possible linkage diminished with DNA markers mapping nearby D4S35, while suggestive evidence of linkage remained with loci in the region of D22S55. Although follow-up investigation of these chromosomal regions may be warranted, our linkage results should be viewed as preliminary observations, as 35 unaffected persons are not past the age of risk. 90 refs., 3 tabs.

Coon, H.; Jensen. S.; Holik, J. [Univ. of Utah Medical Center, Salt Lake City, UT (United States)] [and others

1994-03-15

4

MTHFR C677T Predisposes to POAG but Not to PACG in a North Indian Population: A Case Control Study  

PubMed Central

Hyperhomocysteinemia induced by the C677T genetic variant in MTHFR (methylenetetrahydrofolate reductase) has been implicated in neuronal cell death of retinal ganglion cells (RGC), which is a characteristic feature of glaucoma. However, association of MTHFR C677T with glaucoma has been controversial because of inconsistent results across association studies. Association between MTHFR C677T and glaucoma has not been reported in Indian population. Therefore, with a focus on neurodegenerative death of RGC in glaucoma, the current study aimed to investigate association of MTHFR C677T with Primary Open Angle Glaucoma (POAG) and Primary Angle Closure Glaucoma (PACG) in a North Indian population. A total of 404 participants (231 patients and 173 controls) were included in this study. Genotyping was performed by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism. A few random samples were also tested by direct sequencing. Genotypic and allelic distributions of the POAG and PACG cohorts were compared to that of controls by chi-square test and odds ratios were reported with 95% confidence intervals. Genotypic and allelic distributions between POAG cases and controls were significantly different (p?=?0.03 and p?=?0.01 respectively). Unlike POAG, we did not find significant difference in the genotypic and allelic distributions of C677T between PACG cases and controls (p>0.05). We also observed a higher proportion of TT associated POAG in females than that in males. However, this is a preliminary indication of gender specific risk of C677T that needs to be replicated in a larger cohort of males and females. The present investigation on MTHFR C677T and glaucoma reveals that the TT genotype and T allele of this polymorphism are significant risk factors for POAG but not for PACG in North Indian population. Ours is the first report demonstrating association of MTHFR C677T with POAG but not PACG in individuals from North India. PMID:25054348

Gupta, Shashank; Bhaskar, Pradeep Kumar; Bhardwaj, Ritu; Chandra, Abhishek; Chaudhry, Vidya Nair; Chaudhry, Prashaant; Ali, Akhtar; Mukherjee, Ashim; Mutsuddi, Mousumi

2014-01-01

5

Folate Metabolism Gene 5,10-Methylenetetrahydrofolate Reductase (MTHFR) Is Associated with ADHD in Myelomeningocele Patients  

PubMed Central

The objective of this study was to examine the relation between the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene and behaviors related to attention- deficit/hyperactivity disorder (ADHD) in individuals with myelomeningocele. The rationale for the study was twofold: folate metabolizing genes, (e.g. MTHFR), are important not only in the etiology of neural tube defects but are also critical to cognitive function; and individuals with myelomeningocele have an elevated incidence of ADHD. Here, we tested 478 individuals with myelomeningocele for attention-deficit hyperactivity disorder behavior using the Swanson Nolan Achenbach Pelham-IV ADHD rating scale. Myelomeningocele participants in this group for whom DNAs were available were genotyped for seven single nucleotide polymorphisms (SNPs) in the MTHFR gene. The SNPs were evaluated for an association with manifestation of the ADHD phenotype in children with myelomeningocele. The data show that 28.7% of myelomeningocele participants exhibit rating scale elevations consistent with ADHD; of these 70.1% had scores consistent with the predominantly inattentive subtype. In addition, we also show a positive association between the SNP rs4846049 in the 3?-untranslated region of the MTHFR gene and the attention-deficit hyperactivity disorder phenotype in myelomeningocele participants. These results lend further support to the finding that behavior related to ADHD is more prevalent in patients with myelomeningocele than in the general population. These data also indicate the potential importance of the MTHFR gene in the etiology of the ADHD phenotype. PMID:23227261

Spellicy, Catherine J.; Northrup, Hope; Fletcher, Jack M.; Cirino, Paul T.; Dennis, Maureen; Morrison, Alanna C.; Martinez, Carla A.; Au, Kit Sing

2012-01-01

6

Association between MTHFR gene polymorphism and NTDs in Chinese Han population  

PubMed Central

Objective: This study aims to investigate the single nucleotide polymorphisms (SNPs) of 5,10-methylenetetrahydrofolate reductase (MTHFR) gene and neural tube defects (NTDs) in Chinese population. Method: A total of 271 NTDs cases and 192 healthy controls were used in this study. Fifty-two selected single nucleotide polymorphism (SNP) sites in the MTHFR gene were analyzed with next-generation sequencing method. A series of statistical methods were carried out to investigate the correlation between the SNPs and the patient susceptibility to NTDs. Results: Statistical analysis showed a significant correlation between the SNP sites rs1801133 in MTHFR gene and NTDs. The GG genotype, G allele of rs1801133 in MTHFR significantly decreased the incidence of NTDs (OR = 0.449, 95% CI: 0.255-0.789 with genotype, and OR = 0.669, 95% CI: 0.508-0.881 with allele). Conclusions: The gene polymorphism loci rs1801133 in MTHFR gene maybe potential risk factors for NTD in Chinese population. PMID:25356156

Yu, Yang; Wang, Fang; Bao, Yihua; Lu, Xiaolin; Quan, Li; Lu, Ping

2014-01-01

7

Association of MTHFR gene C677T mutation with diabetic peripheral neuropathy and diabetic retinopathy  

PubMed Central

Purpose Diabetic peripheral neuropathy (DPN) is one of the most common diabetic chronic complications. Methylenetetrahydrofolate reductase (MTHFR) gene variants have been associated with vasculopathy that has been linked to diabetic neuropathy. The aim of the present study was to investigate the possible association between MTHFR gene C677T mutation and DPN and evaluate if there is an association with clinical features in a relatively large cohort of Turkish patients. Methods The study included 230 patients affected by DPN and 282 healthy controls. Genomic DNA was isolated and genotyped using the polymerase chain reaction–based restriction fragment length polymorphism assay for the MTHFR gene C677T mutation. Results The genotype and allele frequencies of the C677T mutation showed statistically significant differences between the patients with DPN and the controls (p=0.003 and p=0.002, respectively). After the patients with DPN were stratified according to clinical and demographic characteristics, a significant association was observed between the C677T mutation and history of retinopathy (p=0.039). Conclusions A high association between the MTHFR gene C677T mutation and DPN was observed in the present study. In addition, history of retinopathy was associated with the MTHFR C677T mutation in patients with DPN. PMID:23901246

Yigit, Serbulent; Inanir, Ahmet

2013-01-01

8

Association of C677T transition of the human methylenetetrahydrofolate reductase (MTHFR) gene with male infertility.  

PubMed

The human methylenetetrahydrofolate reductase (MTHFR) gene encodes one of the key enzymes in folate metabolism. This gene is located on chromosome 1 (1p36.3), which has 12 exons. The aim of the present study was to investigate the possible association of the two (C677T and A1298C) polymorphisms of this gene with male infertility. In a case-control study, 250 blood samples were collected from IVF centres in Sari and Babol (Iran): 118 samples were from oligospermic men and 132 were from controls. Two single nucleotide polymorphisms of the MTHFR genotype were detected using polymerase chain reaction-restriction fragment length polymorphism. There was no association found between the A1298C variant and male infertility. However, carriers of the 677T allele (CT and TT genotypes) were at a higher risk of infertility than individuals with other genotypes (odds ratio 1.84; 95% confidence interval 1.11-3.04; P=0.0174). Structural analysis of human MTHFR flavoprotein showed that C677T transition played an important role in the change in affinity of the MTHFR-Flavin adenine dinucleotide binding site. Based on our results, we suggest that C677T transition in MTHFR may increase the risk of male infertility, and detection of the C677T polymorphism biomarker may be helpful in the screening of idiopathic male infertility. PMID:25412139

Karimian, Mohammad; Colagar, Abasalt Hosseinzadeh

2014-11-21

9

Is methylenetetrahydrofolate reductase (MTHFR) gene A1298C polymorphism related with varicocele risk?  

PubMed

Varicocele is one of the main reasons for male infertility the exact aetiology of which remains unclear. Methylenetetrahydrofolate reductase (MTHFR) is important for DNA synthesis and methylation, which has a key role during spermatogenesis. Numerous literature suggests that the MTHFR polymorphism may be genetic risk factors for male infertility. In this study, we evaluated C677T and A1298C MTHFR gene polymorphism frequency in patients with varicocele and normal men. A total of 107 varicocele patients and 109 fertile healthy individuals were included. Genotyping of the MTHFR gene in C677T and A1298C base pairs carried out by using real-time PCR technique and afterwards, the statistical analysis accomplished. There is a statistical difference for the frequency of 1298AA genotype in patients with varicocele compared with normal controls (P = 0.0051, OR = 2.2750). Instead, subsequently, 1298/A allel frequency in patient group was significantly higher in comparison with control group (P = 0.0174). According to our results, 1298AA genotype in MTHFR gene raises the risk of varicocele approximately 2.3 times more compared with men carrying other genotypes. The results show that genetic factors have an important role in the molecular basis of varicocele. PMID:24456105

Ucar, V B; Nami, B; Acar, H; Kilinç, M

2015-02-01

10

Deep Sequencing Study of the MTHFR Gene to Identify Variants Associated with Myelomeningocele  

PubMed Central

INTRODUCTION Neural tube defects (NTDs) are congenital anomalies caused by a combination of genetic and environmental influences. A defect below the head region resulting in protuberance of meninges and nervous tissue is termed myelomeningocele (MM). MM, the most common NTD compatible with survival, occurs in approximately 1 in 1,000 births worldwide. Maternal pre- and periconceptional folate supplementation reduces the risk of NTDs by up to 70%. A key enzyme in folate metabolism is 5, 10-methylene-tetrahydrofolate reductase (MTHFR). OBJECTIVES Sequence the 12 exons of the MTHFR gene among 96 subjects with MM to identify variants potentially contributing to the disease trait. METHODS Exons were amplified by polymerase chain reaction and the products were sequenced by Sanger method to reveal sequence variants compared to MTHFR reference sequences. Association of variants was examined by Fisher’s test. RESULTS A novel variant c.171+3G>T was identified in intron 1 in one affected subject. The variant was not found in the subject’s unaffected mother’s DNA and the unaffected father’s DNA was unavailable. We found significant differences in allele frequencies for seven SNPs in MM subjects compared to ethnically matched reference populations reported in the single nucleotide polymorphism (SNP) database (dbSNP). CONCLUSION We identified a novel variant c.171+3G>T in the MTHFR gene that potentially affects splicing in an affected subject. Also, we observed five SNPs (rs13306561, rs2274976, rs2066462, rs12121543, and rs1476413) in the MTHFR gene not previously shown to associate with MM. The current study provides additional evidence that multiple variations in the MTHFR gene are associated with MM. PMID:22241680

Aneji, Chiamaka U; Northrup, Hope; Au, Kit Sing

2012-01-01

11

A COMMON POLYMORPHISM IN THE METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR) GENE IS ASSOCIATED WITH QUANTITATIVE ULTRASOUND IN THOSE WITH LOW PLASMA FOLATE  

Technology Transfer Automated Retrieval System (TEKTRAN)

A study of a polymorphism in the MTHFR gene, plasma folate, and bone phenotypes in 1632 individuals revealed that the genotype effect on BMD and quantitative ultrasound was dependent on the level of folate. Our findings support the hypothesis that the association between an MTHFR polymorphism and bo...

12

Population- and Family-Based Studies Associate the "MTHFR" Gene with Idiopathic Autism in Simplex Families  

ERIC Educational Resources Information Center

Two methylenetetrahydrofolate reductase gene ("MTHFR") functional polymorphisms were studied in 205 North American simplex (SPX) and 307 multiplex (MPX) families having one or more children with an autism spectrum disorder. Case-control comparisons revealed a significantly higher frequency of the low-activity 677T allele, higher prevalence of the…

Liu, Xudong; Solehdin, Fatima; Cohen, Ira L.; Gonzalez, Maripaz G.; Jenkins, Edmund C.; Lewis, M. E. Suzanne; Holden, Jeanette J. A.

2011-01-01

13

Analysis of MTHFR and MTRR Gene Polymorphisms in Iranian Ventricular Septal Defect Subjects  

PubMed Central

Ventricular septal defect (VSD) is one of the most common types of congenital heart defects (CHD). There are vivid multifactorial causes for VSD in which both genetic and environmental risk factors are consequential in the development of CHD. Methionine synthase reductase (MTRR) and methylenetetrahydrofolate reductase (MTHFR) are two of the key regulatory enzymes involved in the metabolic pathway of homocysteine. Genes involved in homocysteine/folate metabolism may play an important role in CHDs. In this study; we determined the association of A66G and C524T polymorphisms of the MTRR gene and C677T polymorphism of the MTHFR gene in Iranian VSD subjects. A total of 123 children with VSDs and 125 healthy children were included in this study. Genomic DNA was extracted from the buccal cells of all the subjects. The restriction fragment length polymorphism polymerase chain reaction (PCR-RFLP) method was carried out to amplify the A66G and C524T polymorphism of MTRR and C677T polymorphism of MTHFR genes digested with Hinf1, Xho1 and Nde1 enzymes, respectively. The genotype frequencies of CC, CT and TT of MTRR gene among the studied cases were 43.1%, 40.7% and 16.3%, respectively, compared to 52.8%, 43.2% and 4.0%, respectively among the controls. For the MTRR A66G gene polymorphism, the genotypes frequencies of AA, AG and GG among the cases were 33.3%, 43.9% and 22.8%, respectively, while the frequencies were 49.6%, 42.4% and 8.0%, respectively, among control subjects. The frequencies for CC and CT genotypes of the MTHFR gene were 51.2% and 48.8%, respectively, in VSD patients compared to 56.8% and 43.2% respectively, in control subjects. Apart from MTHFR C677T polymorphism, significant differences were noticed (p < 0.05) in C524T and A66G polymorphisms of the MTRR gene between cases and control subjects. PMID:23358257

Pishva, Seyyed Reza; Vasudevan, Ramachandran; Etemad, Ali; Heidari, Farzad; Komara, Makanko; Ismail, Patimah; Othman, Fauziah; Karimi, Abdollah; Sabri, Mohammad Reza

2013-01-01

14

Coexistence of Neurofibromatosis Type-1 and MTHFR C677T Gene Mutation in a Young Stroke Patient: A Case Report  

PubMed Central

In neurofibromatosis type-1 (NF1), cerebrovascular disorders are rarely encountered although vasculopathy is a well-known complication. Several mutations seen in methylenetetrahydrofolate reductase (MTHFR) give rise to the formation of hyperhomocysteinemia and homocystinuria, a considerable risk factor for cardiovascular and cerebrovascular disorders, by leading to enzymatic inactivation. In the paper, a 31-year-old young stroke female patient with the coexistence of neurofibromatosis and MTHFR C677T gene mutation was presented. PMID:23533858

Yilmaz, Halim; Erkin, Gulten; Gumus, Haluk; Nalbant, Lutfiye

2013-01-01

15

The Association between MTHFR Gene Polymorphisms and Hepatocellular Carcinoma Risk: A Meta-Analysis  

PubMed Central

Background The association between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and hepatocellular carcinoma (HCC) risk was inconsistent and underpowered. To clarify the effects of MTHFR gene polymorphisms on the risk of HCC, a meta-analysis of all available studies relating C677T and/or A1298C polymorphisms of MTHFR gene to the risk of HCC was conducted. Methods The authors searched PubMed, EMBASE, Cochrane Library, Web of Science, and Chinese Biomedical Literature database (CBM) for the period up to July 2012. Data were extracted by two independent authors and pooled odds ratio (OR) with 95% confidence interval (CI) was calculated. Metaregression and subgroup analyses were performed to identify the source of heterogeneity. Results Finally, 12 studies with 2,351 cases and 4,091 controls were included for C677T polymorphism and 6 studies with 1,333 cases and 1,878 controls were included for A1298C polymorphism. With respect to A1298C polymorphism, significantly decreased HCC risk was found in the overall population (CC vs. AA: OR?=?0.660, 95%CI 0.460–0.946, P?=?0.024; recessive model: OR?=?0.667, 95%CI?=?0.470–0.948, P?=?0.024). In subgroup analyses, significantly decreased HCC risk was found in Asian population (CC vs. AA: OR?=?0.647, 95%CI?=?0.435–0.963; P?=?0.032) and population-based studies (CC vs. AA: OR?=?0.519, 95%CI?=?0.327–0.823; P?=?0.005). With respect to C677T polymorphism, no significant association with HCC risk was demonstrated in overall and stratified analyses. Conclusions We concluded that MTHFR A1298C polymorphism may play a protective role in the carcinogenesis of HCC. Further large and well-designed studies are needed to confirm this association. PMID:23457501

Deng, Yan; Huang, Shan; Xu, Juanjuan; Li, Haiwei; Li, Shan; Zhao, Jinmin

2013-01-01

16

Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and FOLFOX response in colorectal cancer patients  

PubMed Central

AIMS To test prospectively the predictive value of germinal gene polymorphisms related to fluorouracil (FU) and oxaliplatin (Oxa) pharmacodynamics on toxicity and responsiveness of colorectal cancer (CRC) patients receiving FOLFOX therapy. METHODS Advanced CRC patients (n= 117) receiving FOLFOX 7 therapy were enrolled. Gene polymorphisms relevant for FU [thymidylate synthase (TYMS, 28 bp repeats including the G?C mutation + 6 bp deletion in 3'UTR), methylenetetrahydrofolate reductase (MTHFR, 677C?T, 1298A?C), dihydropyrimidine deshydrogenase (IVS14+1G?A) and Oxa: glutathione S-transferase (GST) ? (105Ile?Val, 114Ala?Val), excision repair cross-complementing group 1 (ERCC1) (118AAT?AAC), ERCC2 (XPD, 751Lys?Gln) and XRCC1 (399Arg?Gln)] were determined (blood mononuclear cells). RESULTS None of the genotypes was predictive of toxicity. Response rate (54.7% complete response + partial response) was related to FU pharmacogenetics, with both 677C?T (P= 0.042) and 1298A?C (P= 0.004) MTHFR genotypes linked to clinical response. Importantly, the score of favourable MTHFR alleles (677T and 1298C) was positively linked to response, with response rates of 37.1, 53.3, 62.5 and 80.0% in patients bearing no, one, two or three favourable alleles, respectively (P= 0.040). Polymorphisms of genes related to Oxa pharmacodynamics showed an influence on progression-free survival, with a better outcome in patients bearing GST? 105 Val/Val genotype or XPD 751Lys-containing genotype (P= 0.054). CONCLUSIONS These results show that response to FOLFOX therapy in CRC patients may be driven by MTHFR germinal polymorphisms. PMID:20078613

Etienne-Grimaldi, Marie-Christine; Milano, Gérard; Maindrault-Gœbel, Frédérique; Chibaudel, Benoist; Formento, Jean-Louis; Francoual, Mireille; Lledo, Gérard; André, Thierry; Mabro, May; Mineur, Laurent; Flesch, Michel; Carola, Elisabeth; de Gramont, Aimery

2010-01-01

17

Screening of polymorphisms for MTHFR and DHFR genes in spina bifida children and their mothers  

NASA Astrophysics Data System (ADS)

Mechanism underlying the beneficial effect of folic acid supplementation in reducing the risk of neural tube defect is still not well understood. Current evidences show the involvement of folic acid metabolic gene's polymorphism as contributing factors that regulate this pathway. Therefore, the objective of this research was to determine the presence of C677T polymorphism for methylenetetrahydrofolate reductase (MTHFR) and dihydrofolate reductase (DHFR-19 bp deletion) genes between mother-children pairs of case and control. With the approval of UKMMC ethic committee, genomic DNA was extracted from one hundred and forty consented bloods. Polymerase chain reaction (PCR), PCR-RFLP (Restriction Fragment Length Polymorphism) and sequencing were employed to verify each nucleotide change. Our result shows that mutant MTHFR and DHFR alleles are present in all Malaysian sub-ethnic groups, case and control. Even though mutant MTHFR are found to be slightly higher in the case groups, 75% of the affected child is a non carrier for this allele and 62.5% of the mothers with an affected child are genotypically normal. For DHFR, almost all (87.5-100%) investigated samples are a carrier or having a double DHFR deletion be it a case or control pairs. However, strong maternal inheritance shown by the deleted allele might be due to a cascade effect of lacks of folate consumption or maternal uniparental disomy. In conclusion, the use of MTHFR and DHFR as markers in determining the risk of having spina bifida baby is uninformative and plays a small indirect role as the genetic causes of spina bifida. Therefore, spina bifida remains etiologically unknown polygenic and quantitative developmental trait whereby the searches for positive genetic marker need to be continued.

Husna, M. Z.; Endom, I.; Ibrahim, S.; Selvi, N. Amaramalar; Fakhrurazi, H.; Htwe, R. Ohnmar; Kanehaswari, Y.; Halim, A. R. Abdul; Wong, S. W.; Subashini, K.; Syahira, O. Nur; Aishah, S.

2013-11-01

18

Association of Polymorphisms in BDNF, MTHFR, and Genes Involved in the Dopaminergic Pathway with Memory in a Healthy Chinese Population  

ERIC Educational Resources Information Center

The contribution of genetic factors to the memory is widely acknowledged. Research suggests that these factors include genes involved in the dopaminergic pathway, as well as the genes for brain-derived neurotrophic factor (BDNF) and methylenetetrahydrofolate reductase (MTHFR). The activity of the products of these genes is affected by single…

Yeh, Ting-Kuang; Hu, Chung-Yi; Yeh, Ting-Chi; Lin, Pei-Jung; Wu, Chung-Hsin; Lee, Po-Lei; Chang, Chun-Yen

2012-01-01

19

Genetic Variability in the MTHFR gene and colorectal cancer risk using the Colorectal Cancer Family Registry  

PubMed Central

Background The MTHFR C677T TT genotype is associated with a 15%–18% reduction in colorectal cancer (CRC) risk but it is not clear if other variants of the gene are associated with CRC risk. Methods We used a tagSNP approach to comprehensively evaluate associations between variation in the MTHFR gene and CRC risk using a large family-based case control study of 1,750 population-based and 245 clinic-based families from the Colon Cancer Family Registry (CCFR).We assessed 22 TagSNPs, selected based on pairwise r2>95%, using Haploview Tagger and genotyped on the Illumina GoldenGate or Sequenom platforms. The association between SNPs and colorectal cancer was assessed using log additive, co-dominant, and recessive models. Results From studying the population-based families, the C677T (rs1801133) and A1298C (rs1801131) polymorphisms were associated with a decreased CRC risk overall (OR=0.81, 95% CI=0.63–1.04 and OR=0.82, 95% CI=0.64–1.07, respectively). The 677 TT genotype was associated with a decreased risk of microsatellite stable/microsatellite low tumors (OR=0.69, 95% CI=0.49–0.97) and an increased risk of microsatellite high tumors (OR= 2.22, 95% CI=0.91–5.43) (interaction p-value = 0.01), as well as an increased risk of proximal cancers and a decreased risk of distal and rectal cancers (interaction p-value = 0.02). No other SNP was associated with risk overall or within subgroups. Conclusion The 677 TT and 1298 CC genotypes may each be associated with a decrease in CRC risk. We observed little evidence of additional genetic variability in the MTHFR gene relevant to CRC risk. PMID:20056627

Levine, A. Joan; Figueiredo, Jane C.; Lee, Won; Poynter, Jenny N.; Conti, David; Duggan, David J; Campbell, Peter T.; Newcomb, Polly; Martinez, Maria Elena; Hopper, John L.; Le Marchand, Loic; Baron, John A.; Limburg, Paul J.; Ulrich, Cornelia M; Haile, Robert W

2009-01-01

20

Intermediate hyperhomocysteinaemia and compound heterozygosity for the common variant c.677C>T and a MTHFR gene mutation.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the regulation of plasma homocysteine levels. MTHFR deficiency, an autosomal recessive disorder, results in homocystinuria and hypomethioninaemia and presents with highly variable symptoms affecting many organs but predominantly the central nervous system. The common polymorphism of the MTHFR gene, c.677C>T, a known risk factor for elevated plasma homocysteine levels, occurs frequently in the caucasian population. In this study we investigated three subjects with moderate hyperhomocysteinaemia (total plasma homocysteine 72 micromol/L in case 1 and 90 micromol/L in case 3, total non-protein-bound homocysteine 144-186 micromol/L in case 2) but different clinical presentation with no symptoms in case 1, muscle weakness at 17 years of age in case 2, and syncopes and cerebral convulsions at 18 years of age in case 3. Each subject was compound heterozygous for the c.677C>T polymorphism and a novel mutation of the MTHFR gene (case 1: c.883G>A [p.D291N]; case 2: c.1552_c.1553delGA [p.E514fsX536]; case 3: c.616C>T [p.P202S]). Moderately decreased fibroblast MTHFR activity was associated with severely reduced affinity for NADPH and increased sensitivity to inhibition by S-adenosylmethionine (AdoMet) in case 2, and with mild FAD responsiveness in case 3. In case 1, fibroblast MTHFR activity was normal but the sensitivity to inhibition by AdoMet was slightly reduced. This study indicates that the sequence alteration c.677C>T combined with severe MTHFR mutations in compound heterozygous state may lead to moderate biochemical and clinical abnormalities exceeding those attributed to the c.677TT genotype and might require in addition to folate substitution further therapy to normalize homocysteine levels. PMID:17457696

Rummel, T; Suormala, T; Häberle, J; Koch, H G; Berning, C; Perrett, D; Fowler, B

2007-06-01

21

Haplotype analysis of the folate-related genes MTHFR, MTRR, and MTR and migraine with aura  

PubMed Central

Aims The C677T variant in the methylenetetrahydrofolate reductase (MTHFR; EC 1.5.1.20) enzyme, a key player in the folate metabolic pathway, has been associated with increased risk of migraine with aura. Other genes encoding molecular components of this pathway include Methionine synthase (MTR; EC 2.1.1.13), and Methionine synthase reductase (MTRR; EC 2.1.1.135) among others. We performed a haplotype analysis of migraine risk and MTHFR, MTR, and MTRR. Methods Study participants are from a random sub-sample participating in the population-based AGES-Reykjavik Study, including subjects with non-migraine headache (n=367), migraine without aura (n=85), migraine with aura (n=167), and no headache (n=1347). Haplotypes spanning each gene were constructed using Haploview. Association testing was performed on single SNPs and haplotypes using logistic regression, controlling for demographic and cardiovascular risk factors and correcting for multiple testing Results Haplotype analysis suggested an association between MTRR haplotypes and reduced risk of migraine with aura. All other associations were not significant after correcting for multiple testing. Conclusions These results suggest that MTRR variants may protect against migraine with aura in an older population. PMID:23430981

Roecklein, Kathryn A.; Scher, Ann I.; Smith, Albert; Harris, Tamara; Eiriksdottir, Gudny; Garcia, Melissa; Gudnason, Villi; Launer, Lenore J.

2014-01-01

22

5,10-Methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTRR), and methionine synthase reductase (MTR) gene polymorphisms and adult meningioma risk.  

PubMed

The causes of meningiomas are not well understood. Folate metabolism gene polymorphisms have been shown to be associated with various human cancers. It is still controversial and ambiguous between the functional polymorphisms of folate metabolism genes 5,10-methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTRR), and methionine synthase reductase (MTR) and risk of adult meningioma. A population-based case–control study involving 600 meningioma patients (World Health Organization [WHO] Grade I, 391 cases; WHO Grade II, 167 cases; WHO Grade III, 42 cases) and 600 controls was done for the MTHFR C677T and A1298C, MTRR A66G, and MTR A2756G variants in Chinese Han population. The folate metabolism gene polymorphisms were determined by using a polymerase chain reaction–restriction fragment length polymorphism assay. Meningioma cases had a significantly lower frequency of MTHFR 677 TT genotype [odds ratio (OR) = 0.49, 95 % confidence interval (CI) 0.33–0.74; P = 0.001] and T allele (OR = 0.80, 95 % CI 0.67–0.95; P = 0.01) than controls. A significant association between risk of meningioma and MTRR 66 GG (OR = 1.41, 95 % CI 1.02–1.96; P = 0.04) was also observed. When stratifying by the WHO grade of meningioma, no association was found. Our study suggested that MTHFR C677T and MTRR A66G variants may affect the risk of adult meningioma in Chinese Han population. PMID:23959833

Zhang, Jun; Zhou, Yan-Wen; Shi, Hua-Ping; Wang, Yan-Zhong; Li, Gui-Ling; Yu, Hai-Tao; Xie, Xin-You

2013-11-01

23

No association of the MTHFR gene A1298C polymorphism with the risk of prostate cancer: A meta-analysis  

PubMed Central

Various studies have demonstrated that the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism contributes to the risk of prostate cancer, while other studies have provided conflicting findings. In the present study, we carried out a comprehensive meta-analysis with the aim of determining whether there is a significant association of the MTHFR gene A1298C polymorphism with the susceptibility of prostate cancer. Studies on the MTHFR gene A1298C polymorphism and prostate cancer were retrieved using the electronic PubMed database without any restriction on language through Aug 21, 2011. Data were abstracted by a standardized protocol. Crude odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the strength of association. The analyses were conducted with Review Manager software version 4.2. Nine case-control studies were identified, including 2,723 prostate cancer patients and 3,442 controls. Overall, no significant associations were found between the MTHFR gene A1298C polymorphism and prostate cancer (codominant models: CC vs. AA, OR=1.03, 95% CI 0.79–1.34, P=0.84; AC vs. AA, OR=1.04, 95% CI 0.93–1.16, P=0.46; dominant model: AC + CC vs. AA, OR=1.04, 95% CI 0.94–1.15, P=0.48; recessive model: CC vs. AC + AA, OR=1.02, 95% CI 0.76–1.35, P=0.91; allele model: C vs. A, OR=1.04, 95% CI 0.90–1.19, P=0.61). Similarly, in the subgroup analyses by DNA source, ethnicity, control source, pathological stage and Hardy-Weinberg equilibrium, no significant associations were observed. Our meta-analysis suggests that the MTHFR gene A1298C polymorphism is not associated with the risk of prostate cancer. PMID:22969917

LI, DAWEI; TIAN, TIAN; GUO, CHUNHUI; REN, JUCHAO; YAN, LEI; LIU, HAINAN; XU, ZHONGHUA

2012-01-01

24

Role of 677C?T polymorphism a single substitution in methylenetetrahydrofolate reductase (MTHFR) gene in North Indian infertile men.  

PubMed

Failure or severe difficulty in conceiving a child is surprisingly common, worldwide problem. Half of these cases are due to male factors with defects in sperm (1 in 15 men) being the single most common cause. Also about 60-75 % of male infertility cases are idiopathic, since the molecular mechanisms underlying the defects remain unknown. DNA methylation is crucial for spermatogenesis and high methylenetetrahydrofolate reductase (MTHFR) activity in adult testis than other organs in mouse, signifies its critical role in spermatogenesis. According to recent findings there is a correlation of epigenetic regulation of several imprinted genes with disturbed spermatogenesis and fertility. Consequently any change in the MTHFR gene sequence can modify the spermatogenesis including transmission of infertility to the carriers. The aim of the study is to analyze the distribution of the single nucleotide polymorphism C677T in the MTHFR gene in 637 North Indian infertile patients and 364 fertile North Indian men as controls by using PCR-RFLP technique and Chi Square test for statistical analysis. The average MTHFR 677CC, 677CT, 677TT genotype frequencies of total infertile men were 70.17, 24.17, 5.65 % in infertile men and 75.27, 21.7, 2.74 % in controls, respectively. The average frequency of the MTHFR 677T allele was 17.73 % in infertile men as compared to 13.59 % in controls. The statistical difference was significant. Disease risk was found 2.27-folds increased in patients who were carrying T allele. We found an association of C677T polymorphism with male infertility and that it may be a genetic risk factor for male infertility in North Indian population. PMID:24366618

Naqvi, Hena; Hussain, Syed Rizwan; Ahmad, Mohammad Kaleem; Mahdi, Farzana; Jaiswar, Shyam Pyari; Shankhwar, Satya Narayain; Mahdi, Abbas Ali

2014-02-01

25

Variants in maternal COMT and MTHFR genes and risk of neural tube defects in offspring.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) C677T and catechol-O-Methyltransferase (COMT) G158A are associated with a risk of neural tube defects (NTDs) in offspring. This study examined the effect of a MTHFR × COMT interaction on the risk of NTDs in a Chinese population with a high prevalence of NTDs. A total of 576 fetuses or newborns with NTDs and 594 controls were genotyped for MTHFRrs1801133, MTHFRrs1801131, and COMTrs4680 and COMTrs737865. Information on maternal sociodemographic characteristics, reproductive history, and related behavior was collected through face-to-face interviews. Possible interactions between genetic variants of MTHFR and COMT were examined. MTHFR C677T homozygous TT was associated with an elevated risk of total NTDs (odds ratio [OR]?=?1.37, 95 % confidence interval [CI]?=?0.93-2.03) and of anencephaly (OR?=?1.67, 95 % CI?=?0.98-2.84) compared with the CC genotype. There was a COMT rs737865 CC × MTHFR rs1801133 TT interaction for total NTDs (OR?=?3.02, 95 % CI?=?1.00-9.14) and for anencephaly (OR?=?3.39, 95 % CI?=?0.94-12.18). No interaction was found between COMT rs4680 AA/AG and MTHFR CT/TT genotypes for total NTDs or any subtype of NTD. The interaction of COMT rs737865 and MTHFR C677T was associated with an increased risk of NTDs, especially anencephaly, in a Chinese population with a high prevalence of NTDs. PMID:24990354

Liu, Jufen; Zhang, Yali; Jin, Lei; Li, Guoxing; Wang, Linlin; Bao, Yanping; Fu, Yunting; Li, Zhiwen; Zhang, Le; Ye, Rongwei; Ren, Aiguo

2015-04-01

26

Association of the APOE, MTHFR and ACE Genes Polymorphisms and Stroke in Zambian Patients  

PubMed Central

The aim of the present study was to investigate the association of APOE, MTHFR and ACE polymorphisms with stroke in the Zambian population. We analyzed 41 stroke patients and 116 control subjects all of Zambian origin for associations between the genotype of the APOE, MTHFR and ACE polymorphisms and stroke. The APOE ?2?4 genotype showed increased risk for hemorrhagic stroke (P<0.05) and also a high risk for ischemic stroke (P=0.05). There was complete absence of the APOE ?2?2 and the MTHFR TT genotypes in the Zambian population. The difference between cases and controls was not significant for the other genetic variants when analyzed for relationship between stroke, stroke subtype and genotype. We show that genetic variation at the APOE locus affects susceptibility to stroke. No detectable association were observed for the MTHFR and ACE genotypes and stroke in the Zambian population. PMID:24416484

Atadzhanov, Masharip; Mwaba, Mwila H.; Mukomena, Patrice N.; Lakhi, Shabir; Rayaprolu, Sruti; Ross, Owen A.; Meschia, James F.

2013-01-01

27

A Common Variant in the FTO Gene Is Associated with Body Mass Index and Predisposes to Childhood and Adult Obesity  

Microsoft Academic Search

Obesity is a serious international health problem that increases the risk of several common diseases. The genetic factors predisposing to obesity are poorly understood. A genome-wide search for type 2 diabetes-susceptibility genes identified a common variant in the FTO (fat mass and obesity associated) gene that predisposes to diabetes through an effect on body mass index (BMI). An additive association

Timothy M. Frayling; Nicholas J. Timpson; Michael N. Weedon; Eleftheria Zeggini; Rachel M. Freathy; Cecilia M. Lindgren; John R. B. Perry; Katherine S. Elliott; Hana Lango; Nigel W. Rayner; Beverley Shields; Lorna W. Harries; Jeffrey C. Barrett; Sian Ellard; Christopher J. Groves; Bridget Knight; Ann-Marie Patch; Andrew R. Ness; Shah Ebrahim; Debbie A. Lawlor; Susan M. Ring; Yoav Ben-Shlomo; Marjo-Riitta Jarvelin; Ulla Sovio; Amanda J. Bennett; David Melzer; Luigi Ferrucci; Ruth J. F. Loos; Inês Barroso; Nicholas J. Wareham; Fredrik Karpe; Katharine R. Owen; Lon R. Cardon; Mark Walker; Graham A. Hitman; Colin N. A. Palmer; Alex S. F. Doney; Andrew D. Morris; George Davey Smith; Andrew T. Hattersley; Mark I. McCarthy

2007-01-01

28

MTHFR Gene Polymorphism and Age of Onset of Schizophrenia and Bipolar Disorder  

PubMed Central

Objective. Several studies with contradictory results from different cultures about association of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in schizophrenia and bipolar disorders. Little is known about this association in Arab culture and Egypt. So the present study aimed to assess the association of MTHFR C677T polymorphism in bipolar disorder (BD) and schizophrenia in comparison to control group. The association between MTHFR C677T polymorphism and the age at onset in schizophrenia or BD was also studied. Methods. Polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) were used to examine the genotype and allele frequencies of MTHFR C677T polymorphism in 149 healthy subjects and 134 bipolar and 103 schizophrenia patients. Results. In BD and schizophrenia, there was a higher prevalence of MTHFR C677T polymorphism than healthy subjects. Earlier age at onset was found in patients with BD, carrying one copy of the T allele or CT genotypes but not in patients with schizophrenia. Conclusion. The present findings suggest that the MTHFR C677T polymorphisms are likely to be associated with the risk of developing BD and schizophrenia and influence the age at onset of BD but not the age at onset of schizophrenia. PMID:25101272

El-Hadidy, Mohamed A.; Abdeen, Hanaa M.; Abd El-Aziz, Sherin M.

2014-01-01

29

Common folate gene variant, MTHFR C677T, is associated with brain structure in two independent cohorts of people with mild cognitive impairment?  

PubMed Central

A commonly carried C677T polymorphism in a folate-related gene, MTHFR, is associated with higher plasma homocysteine, a well-known mediator of neuronal damage and brain atrophy. As homocysteine promotes brain atrophy, we set out to discover whether people carrying the C677T MTHFR polymorphism which increases homocysteine, might also show systematic differences in brain structure. Using tensor-based morphometry, we tested this association in 359 elderly Caucasian subjects with mild cognitive impairment (MCI) (mean age: 75 ± 7.1 years) scanned with brain MRI and genotyped as part of Alzheimer's Disease Neuroimaging Initiative. We carried out a replication study in an independent, non-overlapping sample of 51 elderly Caucasian subjects with MCI (mean age: 76 ± 5.5 years), scanned with brain MRI and genotyped for MTHFR, as part of the Cardiovascular Health Study. At each voxel in the brain, we tested to see where regional volume differences were associated with carrying one or more MTHFR ‘T’ alleles. In ADNI subjects, carriers of the MTHFR risk allele had detectable brain volume deficits, in the white matter, of up to 2–8% per risk T allele locally at baseline and showed accelerated brain atrophy of 0.5–1.5% per T allele at 1 year follow-up, after adjusting for age and sex. We replicated these brain volume deficits of up to 5–12% per MTHFR T allele in the independent cohort of CHS subjects. As expected, the associations weakened after controlling for homocysteine levels, which the risk gene affects. The MTHFR risk variant may thus promote brain atrophy by elevating homocysteine levels. This study aims to investigate the spatially detailed effects of this MTHFR polymorphism on brain structure in 3D, pointing to a causal pathway that may promote homocysteine-mediated brain atrophy in elderly people with MCI. PMID:24179750

Rajagopalan, Priya; Jahanshad, Neda; Stein, Jason L.; Hua, Xue; Madsen, Sarah K.; Kohannim, Omid; Hibar, Derrek P.; Toga, Arthur W.; Jack, Clifford R.; Saykin, Andrew J.; Green, Robert C.; Weiner, Michael W.; Bis, Joshua C.; Kuller, Lewis H.; Riverol, Mario; Becker, James T.; Lopez, Oscar L.; Thompson, Paul M.

2012-01-01

30

Candidate colorectal cancer predisposing gene variants in Chinese early-onset and familial cases  

PubMed Central

AIM: To investigate whether whole-exome sequencing may serve as an efficient method to identify known or novel colorectal cancer (CRC) predisposing genes in early-onset or familial CRC cases. METHODS: We performed whole-exome sequencing in 23 Chinese patients from 21 families with non-polyposis CRC diagnosed at ? 40 years of age, or from multiple affected CRC families with at least 1 first-degree relative diagnosed with CRC at ? 55 years of age. Genomic DNA from blood was enriched for exome sequences using the SureSelect Human All Exon Kit, version 2 (Agilent Technologies) and sequencing was performed on an Illumina HiSeq 2000 platform. Data were processed through an analytical pipeline to search for rare germline variants in known or novel CRC predisposing genes. RESULTS: In total, 32 germline variants in 23 genes were identified and confirmed by Sanger sequencing. In 6 of the 21 families (29%), we identified 7 mutations in 3 known CRC predisposing genes including MLH1 (5 patients), MSH2 (1 patient), and MUTYH (biallelic, 1 patient), five of which were reported as pathogenic. In the remaining 15 families, we identified 20 rare and novel potentially deleterious variants in 19 genes, six of which were truncating mutations. One previously unreported variant identified in a conserved region of EIF2AK4 (p.Glu738_Asp739insArgArg) was found to represent a local Chinese variant, which was significantly enriched in our early-onset CRC patient cohort compared to a control cohort of 100 healthy Chinese individuals scored negative by colonoscopy (33.3% vs 7%, P < 0.001). CONCLUSION: Whole-exome sequencing of early-onset or familial CRC cases serves as an efficient method to identify known and potential pathogenic variants in established and novel candidate CRC predisposing genes.

Zhang, Jun-Xiao; Fu, Lei; de Voer, Richarda M; Hahn, Marc-Manuel; Jin, Peng; Lv, Chen-Xi; Verwiel, Eugène TP; Ligtenberg, Marjolijn JL; Hoogerbrugge, Nicoline; Kuiper, Roland P; Sheng, Jian-Qiu; Geurts van Kessel, Ad

2015-01-01

31

Association of Tagging SNPs in the MTHFR Gene with Risk of Type 2 Diabetes Mellitus and Serum Homocysteine Levels in a Chinese Population  

PubMed Central

Diabetes is a global public health crisis, and the prevalence is increasing rapidly. Folate supplementation is proved to be effective in reducing the risk of diabetes or improving its symptoms. Methylenetetrahydrofolate reductase is an important enzyme involved in folate metabolism. The aim of this study is to examine whether polymorphisms in the MTHFR gene are associated with risk of type 2 diabetes mellitus (T2DM) and fasting total serum homocysteine (tHcy) levels. We genotyped nine tagging SNPs in the MTHFR gene in a case-control study, including 595 T2DM cases and 681 healthy controls in China. We found that C allele of rs9651118 had significant decreased risk of T2DM (adjusted odds ratio (OR) = 0.69, 95% confidence interval (CI): 0.55–0.87, P = 0.002) compared with T allele. Haplotype analysis also showed that MTHFR CTCCGA haplotype (rs12121543-rs13306553-rs9651118-rs1801133-rs2274976-rs1801131) had significant reduced risk of T2DM (adjusted OR = 0.71, 95% CI: 0.58–0.87, P = 0.001) compared with CTTTGA haplotype. Besides, the MTHFR rs1801133 was significantly associated with serum levels of tHcy in healthy controls (P = 0.0002). These associations were still significant after Bonferroni corrections (P < 0.0056). These findings suggest that variants in the MTHFR gene may influence the risk of T2DM and tHcy levels. PMID:25165408

Wang, Han; Wan, Bin

2014-01-01

32

Meta-analysis supports association of a functional SNP (rs1801133) in the MTHFR gene with Parkinson's disease.  

PubMed

The MTHFR is a candidate risk gene for Parkinson's disease (PD), and a functional SNP (rs1801133) in the coding region of this gene has been investigated for the associations with the illness extensively among worldwide populations, but overall the results were inconsistent. Here, to assess the relationship between rs1801133 and risk of PD in general populations, we conducted a systematic meta-analysis by combining all available case-control samples in European and Asian populations, with a total of 1820 PD cases and 7530 healthy controls, and the pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) for rs1801133 and PD were calculated using the Mantel-Haenszel method with a fixed-effect model. Overall, rs1801133 was significantly associated with the risk of PD (allelic model, pooled OR=1.212 for T allele, 95% CI=1.097-1.340, p-value=0.0002). When stratifying for ethnicity, significant association was also observed in European (allelic model, pooled OR=1.187 for T allele, 95% CI=1.058-1.332, p-value=0.004) and Asian samples (allelic model, pooled OR=1.293 for T allele, 95% CI=1.058-1.580, p-value=0.012) respectively. In addition, rs1801133 was also significantly associated with MTHFR mRNA expression in both CEU (European, p-value=0.0149) and CHB (Chinese, p-value=0.0178) HapMap populations. Collectively, our meta-analysis suggests that rs1801133 is significantly associated with susceptibility to PD in European and Asian populations, and MTHFR is likely an authentic risk gene for PD. PMID:23916622

Zhu, Zhi-Gang; Ai, Qing-Long; Wang, Wen-Min; Xiao, Zhi-Cheng

2013-11-15

33

Genetic variants in metabolizing genes NQO1, NQO2, MTHFR and risk of prostate cancer: a study from North India.  

PubMed

Quinone oxidoreductases (NAD(P)H): quinone oxidoreductase 1 (NQO1) and NRH: quinone oxidoreductase 2 (NQO2) are an antioxidant enzyme, important in the detoxification of environmental carcinogens. Methylene-tetra-hydrofolate reductase (MTHFR), plays a role in folate metabolism and may have oncogenic role through disruption of normal DNA methylation pattern, synthesis, and impaired DNA repair. In a case-control study, genotyping was done in 195 PCa and 250 age matched unrelated healthy controls of similar ethnicity to determine variants in NQO1 exon 4 (C > T, rs4986998), exon 6 (C > T, rs1800566), NQO2 -3423 (G > A, rs2070999) and MTHFR exon 4 (C > T, rs1801133) by PCR-RFLP methods. Heterozygous genotype CT and variant allele career genotype (CT + TT) of NQO1 exon 4 showed increased risk of PCa (OR = 2.06, p = 0.033; OR = 2.02, p = 0.027). Variant allele T also revealed increased risk (OR = 1.87, p = 0.029). Similarly variant genotype TT (OR = 2.71, p = 0.009), combined genotype (CT + TT) (OR = 1.59, p = 0.019) and T allele (OR = 1.63, p = 0.002) of NQO1 exon 6 demonstrated significant risk for PCa. Diplotypes of NQO1 (exon 4 and 6), C-T (OR = 1.56, Pc = 0.007) and T-T (OR = 0.011, Pc = 3.86) was associated with an increased risk for PCa. NQO2 and MTHFR did not show any risk with PCa. Our results strongly support that common sequence variants and diplotypes of NQO1 exon 4 and 6 genes may have role in PCa risk in the North Indian population, indicating the importance of genes involved in metabolism with respect to PCa risk. Additional studies on larger populations are needed to clarify the role of variation in these genes in PCa carcinogenesis. PMID:23054000

Mandal, Raju K; Nissar, Kamran; Mittal, Rama D

2012-12-01

34

Significance of the use of the ViennaLab “Cardiovascular Disease panel” (CVD) Assay as a reflex test for the “Factor V/II/MTHFR Assay”?  

PubMed Central

Introduction Trends toward identifying risk factors of thrombotic complications had become essential as an attempt to prevent and decrease the incidence of the complications. Thrombosis has been associated with predisposing factors like mutations in FV, PTH, MTHFR and other genes. Aim Evaluate whether the CVD StripAssay has an added value in the screening for more thrombophilia risk factors, which may predispose for the development of cardiovascular diseases and other thrombotic clinical conditions. Methods We compared the results for 94 patients who were previously tested for Factor V, Factor II and MTHFR gene mutations using the ViennaLab FV-PTH-MTHFR StripAssay, and for whom additional testing for the Cardiovascular Disease panel (CVD StripAssay, ViennaLab) was requested. Results Using the CVD StripAssay, 66% of patients who had no mutations when tested using the FV-PTH-MTHFR StripAssay or carried a mutation for MTHFR, were found to have additional genes' SNPs or mutations that are highly associated with a risk of thrombosis as per the available international literature. Conclusion This observation is of extreme importance in clinical practice for the introduction of the extended CVD panel into routine molecular diagnostic test menus and highlights the importance of genetic analysis of the implicated genes in the management of patients with a thrombotic episode presentation. PMID:25606377

Hoteit, Rouba; Abbas, Fatmeh; Antar, Ahmad; Abdel Khalek, Rabab; Shammaa, Dina; Mahfouz, Rami

2013-01-01

35

MTHFR C677T polymorphisms are associated with aberrant methylation of the IGF-2 gene in transitional cell carcinoma of the bladder  

PubMed Central

The purpose of this study was to determine the relationship between methylation status of the insulin-like growth factor 2 (IGF-2) gene and methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphisms in bladder transitional cell carcinoma tissues in a Chinese population. The polymorphisms of the folate metabolism enzyme gene MTHFR were studied by restrictive fragment length polymorphism (RFLP). PCR-based methods of DNA methylation analysis were used to detect the CpG island methylation status of the IGF-2 gene. The association between the methylation status of the IGF-2 gene and clinical characteristics, as well as MTHFR C677T polymorphisms, was analyzed. Aberrant hypomethylation of the IGF-2 gene was found in 68.3% bladder cancer tissues and 12.4% normal bladder tissues, respectively, while hypomethylation was not detected in almost all normal bladder tissues. The hypomethylation rate of the IGF-2 gene in cancer tissues was significantly higher in patients with lymph node metastasis than in those without lymph node metastasis (46.3% vs 17.2%, P = 0.018). No association was found between aberrant DNA methylation and selected factors including sex, age, tobacco smoking, alcohol consumption and green tea consumption. After adjusting for potential confounding variables the variant allele of MTHFR C677T was found to be associated with hypomethylation of the IGF-2 gene. Compared with wildtype CC, the odds ratio was 4.33 (95% CI=1.06-10.59) for CT and 4.95 (95% CI=1.18-12.74) for TT. MTHFR 677 CC and CT genotypes might be one of the reasons that cause abnormal hypomethylation of the IGF-2 gene, and the aberrant CpG island hypomethylation of the IGF-2 gene may contribute to the genesis and progression of bladder transitional cell carcinoma. PMID:23554734

Cheng, Huan; Deng, Zhonglei; Wang, Zengjun; Zhang, Wei; Su, Jiantang

2012-01-01

36

The Genetic Diversity and Structure of Linkage Disequilibrium of the MTHFR Gene in Populations of Northern Eurasia  

PubMed Central

The structure of the haplotypes and linkage disequilibrium (LD) of the methylenetetrahydrofolate reductase gene (MTHFR) in 9 population groups from Northern Eurasia and populations of the international HapMap project was investigated in the present study. The data suggest that the architecture of LD in the human genome is largely determined by the evolutionary history of populations; however, the results of phylogenetic and haplotype analyses seems to suggest that in fact there may be a common “old” mechanism for the formation of certain patterns of LD. Variability in the structure of LD and the level of diversity of MTHFRhaplotypes cause a certain set of tagSNPs with an established prognostic significance for each population. In our opinion, the results obtained in the present study are of considerable interest for understanding multiple genetic phenomena: namely, the association of interpopulation differences in the patterns of LD with structures possessing a genetic susceptibility to complex diseases, and the functional significance of the pleiotropicMTHFR gene effect. Summarizing the results of this study, a conclusion can be made that the genetic variability analysis with emphasis on the structure of LD in human populations is a powerful tool that can make a significant contribution to such areas of biomedical science as human evolutionary biology, functional genomics, genetics of complex diseases, and pharmacogenomics. PMID:22708063

Trifonova, E.A.; Eremina, E.R.; Urnov, F.D.; Stepanov, V.A.

2012-01-01

37

Genotypes of the C677T and A1298C polymorphisms of the MTHFR gene as a cause of human spontaneous embryo loss  

Microsoft Academic Search

BACKGROUND: Polymorphisms C677T and A1298C of the MTHFR gene have been implicated in fetal viability. In this study, we determined the allele and genotype frequencies of these polymorphisms in different populations, includ- ing spontaneous abortion (SA) fetal tissues, with the objective of evaluating their impact on fetal viability. METHODS: 342 samples of fetal tissues, selected from SA occurring during the

G. Callejon; A. Mayor-Olea; A. J. Jimenez; M. J. Gaitan; A. R. Palomares; F. Martinez; M. Ruiz; Armando Reyes-Engel

2007-01-01

38

MTHFR, MTR, and MTHFD1 gene polymorphisms compared to homocysteine and asymmetric dimethylarginine concentrations and their metabolites in epileptic patients treated with antiepileptic drugs  

Microsoft Academic Search

PurposeThe purpose of the study was to determine the frequency of occurrence of polymorphisms of genes MTHFR (C677T), MTR (A2756G), and MTHFD1 (G1958A), as well as to analyze the concentration of homocysteine (Hcy), methionine (Met), asymmetric dimethylarginine (ADMA), and arginine (Arg) in epileptics treatment with antiepileptic drugs (AEDs), and controls.

Aleksandra Sniezawska; Jolanta Dorszewska; Agata Rozycka; Elzbieta Przedpelska-Ober; Margarita Lianeri; Pawel P. Jagodzinski; Wojciech Kozubski

2011-01-01

39

Variation in Telangiectasia Predisposing Genes Is Associated With Overall Radiation Toxicity  

SciTech Connect

Purpose: In patients receiving radiotherapy for breast cancer where the heart is within the radiation field, cutaneous telangiectasiae could be a marker of potential radiation-induced heart disease. We hypothesized that single nucleotide polymorphisms (SNPs) in genes known to cause heritable telangiectasia-associated disorders could predispose to such late, normal tissue vascular damage. Methods and Materials: The relationship between cutaneous telangiectasia as a late normal tissue radiation injury phenotype in 633 breast cancer patients treated with radiotherapy was examined. Patients were clinically assessed for the presence of cutaneous telangiectasia and genotyped at nine SNPs in three candidate genes. Candidate SNPs were within the endoglin (ENG) and activin A receptor, type II-like 1 (ACVRL1) genes, mutations in which cause hereditary hemorrhagic telangiectasia and the ataxia-telangiectasia mutated (ATM) gene associated with ataxia-telangiectasia. Results: A total of 121 (19.1%) patients exhibited a degree of cutaneous telangiectasiae on clinical examination. Regression was used to examine the associations between the presence of telangiectasiae in patients who underwent breast-conserving surgery, controlling for the effects of boost and known brassiere size (n=388), and individual geno- or haplotypes. Inheritance of ACVRL1 SNPs marginally contributed to the risk of cutaneous telangiectasiae. Haplotypic analysis revealed a stronger association between inheritance of a ATM haplotype and the presence of cutaneous telangiectasiae, fibrosis and overall toxicity. No significant association was observed between telangiectasiae and the coinheritance of the candidate ENG SNPs. Conclusions: Genetic variation in the ATM gene influences reaction to radiotherapy through both vascular damage and increased fibrosis. The predisposing variation in the ATM gene will need to be better defined to optimize it as a predictive marker for assessing radiotherapy late effects.

Tanteles, George A. [Department of Genetics, University of Leicester, Leicester (United Kingdom) [Department of Genetics, University of Leicester, Leicester (United Kingdom); Department of Cancer Studies and Molecular Medicine, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester (United Kingdom); Murray, Robert J.S. [Department of Genetics, University of Leicester, Leicester (United Kingdom)] [Department of Genetics, University of Leicester, Leicester (United Kingdom); Mills, Jamie [Department of Cancer Studies and Molecular Medicine, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester (United Kingdom)] [Department of Cancer Studies and Molecular Medicine, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester (United Kingdom); Barwell, Julian [Department of Genetics, University of Leicester, Leicester (United Kingdom) [Department of Genetics, University of Leicester, Leicester (United Kingdom); Department of Cancer Studies and Molecular Medicine, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester (United Kingdom); Chakraborti, Prabir [Department of Clinical Oncology, Derby Hospitals NHS Foundation Trust, Derby (United Kingdom)] [Department of Clinical Oncology, Derby Hospitals NHS Foundation Trust, Derby (United Kingdom); Chan, Steve [Department of Clinical Oncology, Nottingham University Hospitals NHS Trust, Nottingham (United Kingdom)] [Department of Clinical Oncology, Nottingham University Hospitals NHS Trust, Nottingham (United Kingdom); Cheung, Kwok-Leung [Division of Breast Surgery, University of Nottingham, Nottingham (United Kingdom)] [Division of Breast Surgery, University of Nottingham, Nottingham (United Kingdom); Ennis, Dawn [Department of Clinical Oncology, Derby Hospitals NHS Foundation Trust, Derby (United Kingdom)] [Department of Clinical Oncology, Derby Hospitals NHS Foundation Trust, Derby (United Kingdom); Khurshid, Nazish [Department of Genetics, University of Leicester, Leicester (United Kingdom)] [Department of Genetics, University of Leicester, Leicester (United Kingdom); Lambert, Kelly [Department of Breast Surgery, University Hospitals of Leicester, Glenfield Hospital, Leicester (United Kingdom)] [Department of Breast Surgery, University Hospitals of Leicester, Glenfield Hospital, Leicester (United Kingdom); Machhar, Rohan; Meisuria, Mitul [Department of Genetics, University of Leicester, Leicester (United Kingdom)] [Department of Genetics, University of Leicester, Leicester (United Kingdom); Osman, Ahmed; Peat, Irene [Department of Cancer Studies and Molecular Medicine, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester (United Kingdom)] [Department of Cancer Studies and Molecular Medicine, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester (United Kingdom); Sahota, Harjinder [Department of Genetics, University of Leicester, Leicester (United Kingdom)] [Department of Genetics, University of Leicester, Leicester (United Kingdom); Woodings, Pamela [Department of Clinical Oncology, Derby Hospitals NHS Foundation Trust, Derby (United Kingdom)] [Department of Clinical Oncology, Derby Hospitals NHS Foundation Trust, Derby (United Kingdom); Talbot, Christopher J., E-mail: cjt14@le.ac.uk [Department of Genetics, University of Leicester, Leicester (United Kingdom); and others

2012-11-15

40

MTHFR Gene variants C677T, A1298C and association with Down syndrome: A Case-control study from South India  

PubMed Central

BACKGROUND: The 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms and low folate levels are associated with inhibition of DNA methyltransferase and consequently DNA hypomethylation. The expanding spectrum of common conditions linked with MTHFR polymorphisms includes certain adverse birth outcome, pregnancy complications, cancers, adult cardiovascular diseases and psychiatric disorders, with several of these associations remaining still controversial. Trisomy 21 or Down syndrome (DS) is the most common genetic cause of mental retardation. It stems predominantly from the failure of chromosome 21 to segregate normally during meiosis. Despite substantial research, the molecular mechanisms underlying non-disjunction leading to trisomy 21 are poorly understood. MATERIALS AND METHODS: Two common variants C677T and A1298C of the MTHFR gene were screened in 36 parents with DS children and 60 healthy couples from Tamil Nadu and Karnataka. The MTHFR genotypes were studied by RFLP analysis of PCR-amplified products and confirmed by sequencing. RESULTS: The CT genotype was seen in three each (8.3%) of case mothers and fathers. One case father showed TT genotype. All the control individuals exhibited the wild type CC genotype. A similar frequency for the uncommon allele C of the second polymorphism was recorded in case mothers (0.35) and fathers (0.37) in comparison with the control mothers (0.39) and fathers (0.37). CONCLUSION: This first report on MTHFR C677T and A1298C polymorphisms in trisomy 21 parents from south Indian population revealed that MTHFR 677CT polymorphism was associated with a risk for Down syndrome. PMID:20680153

Cyril, Cyrus; Rai, Padmalatha; Chandra, N.; Gopinath, P. M.; Satyamoorthy, K.

2009-01-01

41

Is there any genetic predisposition of MMP-9 gene C1562T and MTHFR gene C677T polymorphisms with essential hypertension?  

PubMed

The current study was conducted to determine whether there is a relation between hypertension and two different polymorphisms, including C1562T of the Matrix metalloproteinase-9 (MMP-9) gene and C677T of the methylenetetrahydrofolate reductase (MTHFR) gene. Genomic DNA obtained from 224 persons (125 patients with hypertension and 99 healthy controls) were used in the study. Polymorphisms were determined by using polymerase chain reaction-restriction fragment length polymorphism and electrophoresis. The results were statistically analyzed and were found to be statistically significant. The frequencies of the C1562T genotypes were found to be, in controls CC 75.8 % and CT 24.2 % and in patients CC 71.2 %, and CT 28.8 %. The frequencies of C677T genotype were found to be, in controls CC 56.6 %, CT 38.4 and TT 5.1 % in controls and in patients CC 52 %, CT 30.4 % and TT 17.6 %. In conclusion, we may suggest that there is no relation between the essential hypertension and C1562T polymorphism of MMP-9 gene; on the other hand C677T polymorphism (genotype TT) of MTHFR gene can be regarded as a genetic indicator for the development of essential hypertension. PMID:24254300

Bayramoglu, Aysegul; Urhan Kucuk, Meral; Guler, Hal?l Ibrahim; Abaci, Okay; Kucukkaya, Yunus; Colak, Ertugrul

2015-01-01

42

MTHFR 677TT genotype and disease risk: is there a modulating role for B-vitamins?  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) is a critical folate-metabolising enzyme which requires riboflavin as its co-factor. A common polymorphism (677C?T) in the MTHFR gene results in reduced MTHFR activity in vivo which in turn leads to impaired folate metabolism and elevated homocysteine concentrations. Homozygosity for this polymorphism (TT genotype) is associated with an increased risk of a number of conditions including heart disease and stroke, but there is considerable variability in the extent of excess risk in various reports. The present review will explore the evidence which supports a role for this polymorphism as a risk factor for a number of adverse health outcomes, and the potential modulating roles for B-vitamins in alleviating disease risk. The evidence is convincing in the case which links this polymorphism with hypertension and hypertensive disorders of pregnancy, particularly preeclampsia. Furthermore, elevated blood pressure was found to be highly responsive to riboflavin intervention specifically in individuals with the MTHFR 677TT genotype. Future intervention studies targeted at these genetically predisposed individuals are required to further investigate this novel gene-nutrient interaction. This polymorphism has also been associated with an increased risk of neural tube defects (NTD) and other adverse pregnancy outcomes; however, the evidence in this area has been inconsistent. Preliminary evidence has suggested that there may be a much greater need for women with the MTHFR 677TT genotype to adhere to the specific recommendation of commencing folic acid prior to conception for the prevention of NTD, but this requires further investigation. PMID:24131523

Reilly, R; McNulty, H; Pentieva, K; Strain, J J; Ward, M

2014-02-01

43

Folate intake, alcohol consumption, and the methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism: influence on prostate cancer risk and interactions  

PubMed Central

Purpose: Folate is essential to DNA methylation and synthesis and may have a complex dualistic role in prostate cancer. Alcohol use may increase risk and epigenetic factors may interact with lifestyle exposures. We aimed to characterize the independent and joint effects of folate intake, alcohol consumption, and the MTHFR C677T gene polymorphism on prostate cancer risk, while accounting for intakes of vitamins B2, B6, B12, methionine, total energy, and confounders. Methods: A case-control study was conducted at Kingston General Hospital of 80 incident primary prostate cancer cases and 334 urology clinic controls, all with normal age-specific PSA levels (to exclude latent prostate cancers). Participants completed a questionnaire on folate and alcohol intakes and potential confounders prior to knowledge of diagnosis, eliminating recall bias, and blood was drawn for MTHFR genotyping. Joint effects of exposures were assessed using unconditional logistic regression and significance of multiplicative and additive interactions using general linear models. Results: Folate, vitamins B2, B6, B12, methionine, and the CT and TT genotypes were not associated with prostate cancer risk. The highest tertile of lifetime alcohol consumption was associated with increased risk (OR = 2.08; 95% CI: 1.12–3.86). Consumption of >5 alcoholic drinks per week was associated with increased prostate cancer risk among men with low folate intake (OR = 2.38; 95% CI: 1.01–5.57), and higher risk among those with the CC MTHFR genotype (OR = 4.43; 95% CI: 1.15–17.05). Increased risk was also apparent for average weekly alcohol consumption when accounting for the multiplicative interaction between folate intake and MTHFR C677T genotype (OR = 3.22; 95% CI: 1.36–7.59). Conclusion: Alcohol consumption is associated with increased prostate cancer risk, and this association is stronger among men with low folate intake, with the CC MTHFR genotype, and when accounting for the joint effect of folate intake and MTHFR C677T genotype. PMID:22912935

Kobayashi, Lindsay C.; Limburg, Heather; Miao, Qun; Woolcott, Christy; Bedard, Leanne L.; Massey, Thomas E.; Aronson, Kristan J.

2012-01-01

44

Mutation in Phex gene predisposes BALB/c-Phex(Hyp-Duk)/Y mice to otitis media.  

PubMed

Genetic susceptibility underlying otitis media (OM) remains to be understood. We show in this study that mutation in Phex gene predisposes the BALB/c-Phex(Hyp-Duk)/Y (abbreviated Hyp-Duk/Y) mice to OM, which occurs at post-natal day 21 (P21) with an average penetrance of 73%. The OM was identified by effusion in the middle ear cavity and/or thickening of middle ear mucosae, and was characterised by increase in goblet cells, deformity of epithelial cilia and higher expression of proliferating cell nuclear antigen (PCNA) in cells of the middle ear mucosae. Moreover, the transcription levels of Tlr2, Tlr4, Nfkb1, Ccl4, Il1b and Tnf? in the ears of the Hyp-Duk/Y mice at P35 were significantly upregulated, compared to those of the controls. Higher expression levels of TLR2, TLR4, NF-?B and TNF-? in the middle ears were demonstrated by immunohistochemistry (IHC). However, the OM in the mice was not prevented by azithromycin administration from gestational day 18 to P35. Further study showed that, in contrast to the low mRNA levels of Phex gene in the ears of the Hyp-Duk/Y mice, the mRNA level of Fgf23 was significantly elevated at P9, P14, P21 and P35. Meanwhile, mRNA levels of EP2 (PGE2 receptor), which expressed in the middle ear epithelia as demonstrated by IHC, were already increased at P14 even before the occurrence of OM, indicating that PGE2, an inflammatory mediator, is involved in the OM development in the mutants. Taking together, Phex mutation primarily up-regulates gene expression levels in FGF23 mediated pathways in the middle ears, resulting in cell proliferation and defence impairment at the mucosae and subsequently bacterial infection. The Hyp-Duk/Y mouse is a new genetic mouse model of OM. PMID:23028440

Han, Fengchan; Yu, Heping; Li, Ping; Zhang, Jiangping; Tian, Cong; Li, Hongbo; Zheng, Qing Yin

2012-01-01

45

Mutation in Phex Gene Predisposes BALB/c-PhexHyp-Duk/Y Mice to Otitis Media  

PubMed Central

Genetic susceptibility underlying otitis media (OM) remains to be understood. We show in this study that mutation in Phex gene predisposes the BALB/c-PhexHyp-Duk/Y (abbreviated Hyp-Duk/Y) mice to OM, which occurs at post-natal day 21 (P21) with an average penetrance of 73%. The OM was identified by effusion in the middle ear cavity and/or thickening of middle ear mucosae, and was characterised by increase in goblet cells, deformity of epithelial cilia and higher expression of proliferating cell nuclear antigen (PCNA) in cells of the middle ear mucosae. Moreover, the transcription levels of Tlr2, Tlr4, Nfkb1, Ccl4, Il1b and Tnf? in the ears of the Hyp-Duk/Y mice at P35 were significantly upregulated, compared to those of the controls. Higher expression levels of TLR2, TLR4, NF-?B and TNF-? in the middle ears were demonstrated by immunohistochemistry (IHC). However, the OM in the mice was not prevented by azithromycin administration from gestational day 18 to P35. Further study showed that, in contrast to the low mRNA levels of Phex gene in the ears of the Hyp-Duk/Y mice, the mRNA level of Fgf23 was significantly elevated at P9, P14, P21 and P35. Meanwhile, mRNA levels of EP2 (PGE2 receptor), which expressed in the middle ear epithelia as demonstrated by IHC, were already increased at P14 even before the occurrence of OM, indicating that PGE2, an inflammatory mediator, is involved in the OM development in the mutants. Taking together, Phex mutation primarily up-regulates gene expression levels in FGF23 mediated pathways in the middle ears, resulting in cell proliferation and defence impairment at the mucosae and subsequently bacterial infection. The Hyp-Duk/Y mouse is a new genetic mouse model of OM. PMID:23028440

Han, Fengchan; Yu, Heping; Li, Ping; Zhang, Jiangping; Tian, Cong; Li, Hongbo; Zheng, Qing Yin

2012-01-01

46

Phosphoinositide 3-kinase ? gene mutation predisposes to respiratory infection and airway damage.  

PubMed

Genetic mutations cause primary immunodeficiencies (PIDs) that predispose to infections. Here, we describe activated PI3K-? syndrome (APDS), a PID associated with a dominant gain-of-function mutation in which lysine replaced glutamic acid at residue 1021 (E1021K) in the p110? protein, the catalytic subunit of phosphoinositide 3-kinase ? (PI3K?), encoded by the PIK3CD gene. We found E1021K in 17 patients from seven unrelated families, but not among 3346 healthy subjects. APDS was characterized by recurrent respiratory infections, progressive airway damage, lymphopenia, increased circulating transitional B cells, increased immunoglobulin M, and reduced immunoglobulin G2 levels in serum and impaired vaccine responses. The E1021K mutation enhanced membrane association and kinase activity of p110?. Patient-derived lymphocytes had increased levels of phosphatidylinositol 3,4,5-trisphosphate and phosphorylated AKT protein and were prone to activation-induced cell death. Selective p110? inhibitors IC87114 and GS-1101 reduced the activity of the mutant enzyme in vitro, which suggested a therapeutic approach for patients with APDS. PMID:24136356

Angulo, Ivan; Vadas, Oscar; Garçon, Fabien; Banham-Hall, Edward; Plagnol, Vincent; Leahy, Timothy R; Baxendale, Helen; Coulter, Tanya; Curtis, James; Wu, Changxin; Blake-Palmer, Katherine; Perisic, Olga; Smyth, Deborah; Maes, Mailis; Fiddler, Christine; Juss, Jatinder; Cilliers, Deirdre; Markelj, Gašper; Chandra, Anita; Farmer, George; Kielkowska, Anna; Clark, Jonathan; Kracker, Sven; Debré, Marianne; Picard, Capucine; Pellier, Isabelle; Jabado, Nada; Morris, James A; Barcenas-Morales, Gabriela; Fischer, Alain; Stephens, Len; Hawkins, Phillip; Barrett, Jeffrey C; Abinun, Mario; Clatworthy, Menna; Durandy, Anne; Doffinger, Rainer; Chilvers, Edwin R; Cant, Andrew J; Kumararatne, Dinakantha; Okkenhaug, Klaus; Williams, Roger L; Condliffe, Alison; Nejentsev, Sergey

2013-11-15

47

Phosphoinositide 3-kinase ? gene mutation predisposes to respiratory infection and airway damage  

PubMed Central

Genetic mutations cause primary immunodeficiencies (PIDs), which predispose to infections. Here we describe Activated PI3K-? Syndrome (APDS), a PID associated with a dominant gain-of-function mutation E1021K in the p110? protein, the catalytic subunit of phosphoinositide 3-kinase ? (PI3K?), encoded by the PIK3CD gene. We found E1021K in 17 patients from seven unrelated families, but not among 3,346 healthy subjects. APDS was characterized by recurrent respiratory infections, progressive airway damage, lymphopenia, increased circulating transitional B cells, increased IgM and reduced IgG2 levels in serum and impaired vaccine responses. The E1021K mutation enhanced membrane association and kinase activity of p110?. Patient-derived lymphocytes had increased levels of phosphatidylinositol 3,4,5-trisphosphate and phosphorylated AKT protein and were prone to activation-induced cell death. Selective p110? inhibitors IC87114 and GS-1101 reduced the activity of the mutant enzyme in vitro, suggesting a therapeutic approach for patients with APDS. PMID:24136356

Angulo, Ivan; Vadas, Oscar; Garçon, Fabien; Banham-Hall, Edward; Plagnol, Vincent; Leahy, Timothy R.; Baxendale, Helen; Coulter, Tanya; Curtis, James; Wu, Changxin; Blake-Palmer, Katherine; Perisic, Olga; Smyth, Deborah; Maes, Mailis; Fiddler, Christine; Juss, Jatinder; Cilliers, Deirdre; Markelj, Gašper; Chandra, Anita; Farmer, George; Kielkowska, Anna; Clark, Jonathan; Kracker, Sven; Debré, Marianne; Picard, Capucine; Pellier, Isabelle; Jabado, Nada; Morris, James A.; Barcenas-Morales, Gabriela; Fischer, Alain; Stephens, Len; Hawkins, Phillip; Barrett, Jeffrey C.; Abinun, Mario; Clatworthy, Menna; Durandy, Anne; Doffinger, Rainer; Chilvers, Edwin; Cant, Andrew J.; Kumararatne, Dinakantha; Okkenhaug, Klaus; Williams, Roger L.; Condliffe, Alison; Nejentsev, Sergey

2014-01-01

48

Tmem79/Matt is the matted mouse gene and is a predisposing gene for atopic dermatitis in human subjects  

PubMed Central

Background Atopic dermatitis (AD) is a major inflammatory condition of the skin caused by inherited skin barrier deficiency, with mutations in the filaggrin gene predisposing to development of AD. Support for barrier deficiency initiating AD came from flaky tail mice, which have a frameshift mutation in Flg and also carry an unknown gene, matted, causing a matted hair phenotype. Objective We sought to identify the matted mutant gene in mice and further define whether mutations in the human gene were associated with AD. Methods A mouse genetics approach was used to separate the matted and Flg mutations to produce congenic single-mutant strains for genetic and immunologic analysis. Next-generation sequencing was used to identify the matted gene. Five independently recruited AD case collections were analyzed to define associations between single nucleotide polymorphisms (SNPs) in the human gene and AD. Results The matted phenotype in flaky tail mice is due to a mutation in the Tmem79/Matt gene, with no expression of the encoded protein mattrin in the skin of mutant mice. Mattft mice spontaneously have dermatitis and atopy caused by a defective skin barrier, with mutant mice having systemic sensitization after cutaneous challenge with house dust mite allergens. Meta-analysis of 4,245 AD cases and 10,558 population-matched control subjects showed that a missense SNP, rs6694514, in the human MATT gene has a small but significant association with AD. Conclusion In mice mutations in Matt cause a defective skin barrier and spontaneous dermatitis and atopy. A common SNP in MATT has an association with AD in human subjects. PMID:24084074

Saunders, Sean P.; Goh, Christabelle S.M.; Brown, Sara J.; Palmer, Colin N.A.; Porter, Rebecca M.; Cole, Christian; Campbell, Linda E.; Gierlinski, Marek; Barton, Geoffrey J.; Schneider, Georg; Balmain, Allan; Prescott, Alan R.; Weidinger, Stephan; Baurecht, Hansjörg; Kabesch, Michael; Gieger, Christian; Lee, Young-Ae; Tavendale, Roger; Mukhopadhyay, Somnath; Turner, Stephen W.; Madhok, Vishnu B.; Sullivan, Frank M.; Relton, Caroline; Burn, John; Meggitt, Simon; Smith, Catherine H.; Allen, Michael A.; Barker, Jonathan N.W. N.; Reynolds, Nick J.; Cordell, Heather J.; Irvine, Alan D.; McLean, W.H. Irwin; Sandilands, Aileen; Fallon, Padraic G.

2013-01-01

49

Evidence of Paternal N5, N10 - Methylenetetrahydrofolate Reductase (MTHFR) C677T Gene Polymorphism in Couples with Recurrent Spontaneous Abortions (RSAs) in Kolar District- A South West of India  

PubMed Central

Introduction: Recurrent spontaneous abortion (RSA) is a multifactorial clinical obstetrics complication commonly occurring in pregnancy. Many research studies have noted the mutations such as C677T in N5, N10 - Methylenetetrahydrofolate reductase (MTHFR)gene which is regarded as RSA risk factor. This study was carried out to determine the occurrence of frequency of C677T of the MTHFR gene mutations with RSA. Aim: The purpose of present study is to determine the frequency of MTHFR C677T polymorphisms in couples with recurrent pregnancy loss and the impact of paternal polymorphisms of MTHFR C677T in recurrent pregnancy loss in population of couples living in Kolar district of Karnataka with RSA. Design: A total of 15 couples with a history of two or more unexplained RSA were enrolled as subjects in the study and a total of 15 couples with normal reproductive history, having two or more children and no history of miscarriages were enrolled as controls. Materials and Methods: DNA extraction from samples case and control group couples and its quantification by Agarose gel electrophoresis, assessment of DNA purity, MTHFR C 677T gene mutation detection by PCR-RFLP method. Statistical analysis: Carried out by web based online SPSS tool. Results: The frequency of C677T genotype showed homozygous wild type CC (80%), heterozygous CT type (13.3%) and homozygous mutation TT type (6.67%) observed in males. Similarly from female’s homozygous wild type CC (86.6%), heterozygous type (13.3%), and homozygous type mutations TT (0%) was recorded. In couple control groups, we observed homozygous wild type CC (86.6%), heterozygous CT type (13.3%) and homozygous type mutations TT type (0%). Conclusion: We noticed a high frequency of MTHFR specifically T allele associated with paternal side.Therefore, the present study indicated the impact of paternal gene polymorphism of MTHFR C677T on screening in couples with recurrent pregnancy loss.

Vanilla, Shiny; Kotur, Pushpa F; Kutty, Moideen A; Vegi, Pradeep Kumar

2015-01-01

50

MTHFR C677T Gene Polymorphism and Head and Neck Cancer Risk: A Meta-Analysis Based on 23 Publications  

PubMed Central

Objective. Conflicting results on the association between MTHFR polymorphism and head and neck cancer (HNC) risk were reported. We therefore performed a meta-analysis to derive a more precise relationship between MTHFR C677T polymorphism and HNC risk. Methods. Three online databases of PubMed, Embase, and CNKI were researched on the associations between MTHFR C677T polymorphism and HNC risk. Twenty-three published case-control studies involving 4,955 cases and 8,805 controls were collected. Odds ratios (ORs) with 95% confidence interval (CI) were used to evaluate the relationship between MTHFR C677T polymorphism and HNC risk. Sensitivity analysis, cumulative analyses, and publication bias were conducted to validate the strength of the results. Results. Overall, no significant association between MTHFR C677T polymorphism and HNC risk was found in this meta-analysis (T versus C: OR = 1.04, 95% CI = 0.92–1.18; TT versus CC: OR = 1.15, 95% CI = 0.90–1.46; CT versus CC: OR = 1.00, 95% CI = 0.85–1.17; CT + TT versus CC: OR = 1.01, 95% CI = 0.87–1.18; TT versus CC + CT: OR = 1.11, 95% CI = 0.98–1.26). In the subgroup analysis by HWE, ethnicity, study design, cancer location, and negative significant associations were detected in almost all genetic models, except for few significant risks that were found in thyroid cancer. Conclusion. This meta-analysis demonstrates that MTHFR C677T polymorphism may not be a risk factor for the developing of HNC.

Niu, Yu-Ming; Deng, Mo-Hong; Chen, Wen; Zeng, Xian-Tao; Luo, Jie

2015-01-01

51

Hyperhomocysteinemia, intima-media thickness and C677T MTHFR gene polymorphism: A correlation study in patients with cognitive impairment  

Microsoft Academic Search

ObjectiveIntima-media thickness (IMT) seems associated with risk of Alzheimer disease (AD). Homocysteine (hcy) is a risk factor for vascular diseases and dementia. This study aimed at investigating the possible relationship among IMT, plasma hcy and C677T methylentetrahydrofolate reductase (MTHFR) polymorphism in relation to cognitive status.

Gaetano Gorgone; Francesca Ursini; Claudia Altamura; Federica Bressi; Mario Tombini; Giuseppe Curcio; Paola Chiovenda; Rosanna Squitti; Mauro Silvestrini; Riccardo Ientile; Francesco Pisani; Paolo Maria Rossini; Fabrizio Vernieri

2009-01-01

52

MTHFR (C677T) polymorphism and PR (PROGINS) mutation as genetic factors for preterm delivery, fetal death and low birth weight: A Northeast Indian population based study  

PubMed Central

Preterm delivery (PTD) is one of the most significant contributors to neonatal mortality, morbidity, and long-term adverse consequences for health; with highest prevalence reported from India. The incidence of PTD is alarmingly very high in Northeast India. The objective of the present study is to evaluate the associative role of MTHFR gene polymorphism and progesterone receptor (PR) gene mutation (PROGINS) in susceptibility to PTD, negative pregnancy outcome and low birth weights (LBW) in Northeast Indian population. Methods A total of 209 PTD cases {extreme preterm (< 28 weeks of gestation, n = 22), very preterm (28–32 weeks of gestation, n = 43) and moderate preterm (32–37 weeks of gestation, n = 144) and 194 term delivery cases were studied for MTHFR C677T polymorphism and PR (PROGINS) gene mutation. Statistical analysis was performed using SPSS software. Results Distribution of MTHFR and PR mutation was higher in PTD cases. Presence of MTHFR C677T polymorphism was significantly associated and resulted in the increased risk of PTD (p < 0.001), negative pregnancy outcome (p < 0.001) and LBW (p = 0.001); more significantly in extreme and very preterm cases. Presence of PR mutation (PROGINS) also resulted in increased risk of PTD and negative pregnancy outcome; but importantly was found to increase the risk of LBW significantly in case of very preterm (p < 0.001) and moderately preterm (p < 0.001) delivery cases. Conclusions Both MTHFR C677T polymorphism and PR (PROGINS) mutation are evident genetic risk factors associated with the susceptibility of PTD, negative pregnancy outcome and LBW. MTHFR C677T may be used as a prognostic marker to stratify subpopulation of pregnancy cases predisposed to PTD; thereby controlling the risks associated with PTD. PMID:25709895

Tiwari, Diptika; Bose, Purabi Deka; Das, Somdatta; Das, Chandana Ray; Datta, Ratul; Bose, Sujoy

2015-01-01

53

MTHFR and ACE Gene Polymorphisms and Risk of Vascular and Degenerative Dementias in the Elderly  

ERIC Educational Resources Information Center

Focal lacunar infarctions due to cerebral small vessel atherosclerosis or single/multiple large cortical infarcts lead to vascular dementia, and different genes and environmental factors have been implicated in causation or aggravation of the disease. Previous reports suggest that some of the risk factors may be common to both vascular as well as…

Pandey, Pratima; Pradhan, Sunil; Modi, Dinesh Raj; Mittal, Balraj

2009-01-01

54

The 677C>T (rs1801133) Polymorphism in the MTHFR Gene Contributes to Colorectal Cancer Risk: A Meta-Analysis Based on 71 Research Studies  

PubMed Central

Background The 677C>T polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene is considered to have a significant effect on colorectal cancer susceptibility, but the results are inconsistent. In order to investigate the association between the MTHFR 677C>T polymorphism and the risk of colorectal cancer, a meta-analysis was held based on 71 published studies. Methods Eligible studies were identified through searching the MEDLINE, EMBASE, PubMed, Web of Science, Chinese Biomedical Literature database (CBM) and CNKI database. Odds ratios (OR) and 95% confidence intervals (CIs) were used to assess the association. The statistical heterogeneity across studies was examined with x2-based Q-test. Begg's and Egger's test were also carried out to evaluate publication bias. Sensitive and subgroup analysis were also held in this meta-analysis. Results Overall, 71 publications including 31,572 cases and 44,066 controls were identified. The MTHFR 677 C>T variant genotypes are significantly associated with increased risk of colorectal cancer. In the stratified analysis by ethnicity, significantly increased risks were also found among Caucasians for CC vs TT (OR?=?1.076; 95%CI?=? 1.008–1.150; I2?=?52.3%), CT vs TT (OR?=?1.102; 95%CI?=?1.032–1.177; I2?=?51.4%) and dominant model (OR?=?1.086; 95%CI?=?1.021–1.156; I2?=?53.6%). Asians for CC vs TT (OR ?=?1.226; 95%CI ?=?1.116–1.346; I2 ?=?55.3%), CT vs TT (OR ?=?1.180; 95%CI ?=?1.079–1.291; I2 ?=?36.2%), recessive (OR ?=?1.069; 95%CI ?=?1.003-1.140; I2 ?=?30.9%) and dominant model (OR ?=?1.198; 95%CI ?=?1.101-1.303; I2 ?=?52.4%), and Mixed populations for CT vs TT (OR ?=?1.142; 95%CI ?=?1.005-1.296; I2 ?=?0.0%). However, no associations were found in Africans for all genetic models. Conclusion This meta-analysis suggests that the MTHFR 677C>T polymorphism increases the risk for developing colorectal cancer, while there is no association among Africans found in subgroup analysis by ethnicity. PMID:23437053

Teng, Zan; Wang, Lei; Cai, Shuang; Yu, Ping; Wang, Jin; Gong, Jing; Liu, Yunpeng

2013-01-01

55

MTHFR A1298C and C677T gene polymorphisms and susceptibility to chronic myeloid leukemia in Egypt  

PubMed Central

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating the intracellular folate metabolism which plays an important role in carcinogenesis through DNA methylation. We aimed to evaluate the association between MTHFR A1298C and C677T polymorphisms and the risks of chronic myeloid leukemia (CML). Eighty-five patients with CML and a control group containing 100 healthy, age and sex matched individuals were examined for MTHFR C677T and A1298C polymorphisms using polymerase chain reaction-restriction fragment-length (PCR-RFLP) method. The frequency of 677TT genotype in patients with CML was significantly higher compared to controls (OR = 2.513, 95% CI: 0.722-4.086, P = 0.025). No such association was shown for heterozygous 677CT (OR = 1.010, 95% CI: 0.460-2.218, P = 0.981). Moreover, for A1298C genotype, a statistically significant higher frequency of 1298CC was also detected in CML patients compared to control group (OR = 1.1816, 95% CI: 0.952-3.573, P = 0.036), 0.036). No such statistical significance was demonstrable for heterozygote 1298AC (OR = 1.046, 95% CI: 0.740-1.759, P = 0.092). In addition, patients with joint 677CT/1298AC or 677TT/1298CC genotypes showed an association with increased risk of CML (OR = 1.849, 95% CI: 0.935-2.540, P = 0.024; OR = 1.915, 95% CI: 1.202-3.845, P = 0.020 respectively). .A statistically significant increased risk of resistant to therapy was observed with 677CT and 1298AC genotypes (P = 0.001, P = 0.002 respectively). We conclude that both MTHFR 677TT and 1298CC polymorphisms have been associated with risk of CML and both 677CT and 1298AC genotypes are associated with higher risk of resistant to therapy. PMID:24966971

Aly, Rabab M; Taalab, Mona M; Ghazy, Hayam F

2014-01-01

56

Association of polymorphisms in DNMT1, DNMT3A, DNMT3B, MTHFR and MTRR genes with global DNA methylation levels and prognosis of autoimmune thyroid disease  

PubMed Central

To clarify the association between factors regulating DNA methylation and the prognosis of autoimmune thyroid diseases (AITDs), we genotyped single nucleotide polymorphisms in genes encoding DNA methyltransferase 1 (DNMT1), DNMT3A, DNMT3B, methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR), which are enzymes essential for DNA methylation. Subjects for this study included 125 patients with Hashimoto's disease (HD), including 48 patients with severe HD and 49 patients with mild HD; 176 patients with Graves’ disease (GD), including 79 patients with intractable GD and 47 patients with GD in remission; and 83 healthy volunteers (control subjects). The DNMT1+32204GG genotype was more frequent in patients with intractable GD than in patients with GD in remission. Genomic DNA showed significantly lower levels of global methylation in individuals with the DNMT1+32204GG genotype than in those with the AA genotype. The MTRR+66AA genotype was observed to be more frequent in patients with severe HD than in those with mild HD. The DNMT1+14395A/G, DNMT3B?579G/T, MTHFR+677C/T and +1298A/C polymorphisms were not correlated with the development or prognosis of AITD. Our study indicates that the DNMT1+32204GG genotype correlates with DNA hypomethylation and with the intractability of GD, and that the MTRR+66AA genotype may correlate with the severity of HD. PMID:23039890

Arakawa, Y; Watanabe, M; Inoue, N; Sarumaru, M; Hidaka, Y; Iwatani, Y

2012-01-01

57

The Two Main Forms of Histiocytic Sarcoma in the Predisposed Flatcoated Retriever Dog Display Variation in Gene Expression  

PubMed Central

Examination of gene functions in specific tumor types improves insight in tumorigenesis and helps design better treatments. Due to the rarity of histiocytic/dendritic cell sarcoma in humans, it is difficult to accrue such knowledge. Therefore, comparative research of these cancers in predisposed dog breeds, such as the Flatcoated retriever, can be of value. Histiocytic sarcoma in the dog can be grouped into a soft tissue- and visceral form. The soft tissue form at first is localized, while the visceral form progresses more quickly to a terminal state, which might be related to variations in gene expression. Microarray analyses were performed on fresh-frozen tissue from Flatcoated retrievers with either soft tissue- or visceral histiocytic sarcoma. Expression differences of ten most significantly differentially expressed genes were validated with quantitative real-time PCR (q PCR) analyses. Q PCR analyses confirmed the significantly aberrant expression of three of the selected genes: C6 was up-regulated; CLEC12A and CCL5 were down-regulated in the visceral histiocytic sarcoma compared to the soft tissue form. The findings of our study indicate that these two forms of histiocytic sarcoma in the dog display a variation in gene expression and warrant analysis of functional changes in the expression of those genes in these rare sarcomas in man. PMID:24886914

Boerkamp, Kim M.; van Steenbeek, Frank G.; Penning, Louis C.; Groot Koerkamp, Marian J. A.; van Leenen, Dik; Vos-Loohuis, Manon; Grinwis, Guy C. M.; Rutteman, Gerard R.

2014-01-01

58

Germline variants in the SEMA4A gene predispose to familial colorectal cancer type X  

PubMed Central

Familial colorectal cancer type X (FCCTX) is characterized by clinical features of hereditary non-polyposis colorectal cancer with a yet undefined genetic background. Here we identify the SEMA4A p.Val78Met germline mutation in an Austrian kindred with FCCTX, using an integrative genomics strategy. Compared with wild-type protein, SEMA4AV78M demonstrates significantly increased MAPK/Erk and PI3K/Akt signalling as well as cell cycle progression of SEMA4A-deficient HCT-116 colorectal cancer cells. In a cohort of 53 patients with FCCTX, we depict two further SEMA4A mutations, p.Gly484Ala and p.Ser326Phe and the single-nucleotide polymorphism (SNP) p.Pro682Ser. This SNP is highly associated with the FCCTX phenotype exhibiting increased risk for colorectal cancer (OR 6.79, 95% CI 2.63 to 17.52). Our study shows previously unidentified germline variants in SEMA4A predisposing to FCCTX, which has implications for surveillance strategies of patients and their families. PMID:25307848

Schulz, Eduard; Klampfl, Petra; Holzapfel, Stefanie; Janecke, Andreas R.; Ulz, Peter; Renner, Wilfried; Kashofer, Karl; Nojima, Satoshi; Leitner, Anita; Zebisch, Armin; Wölfler, Albert; Hofer, Sybille; Gerger, Armin; Lax, Sigurd; Beham-Schmid, Christine; Steinke, Verena; Heitzer, Ellen; Geigl, Jochen B.; Windpassinger, Christian; Hoefler, Gerald; Speicher, Michael R.; Richard Boland, C.; Kumanogoh, Atsushi; Sill, Heinz

2014-01-01

59

Germline variants in the SEMA4A gene predispose to familial colorectal cancer type X.  

PubMed

Familial colorectal cancer type X (FCCTX) is characterized by clinical features of hereditary non-polyposis colorectal cancer with a yet undefined genetic background. Here we identify the SEMA4A p.Val78Met germline mutation in an Austrian kindred with FCCTX, using an integrative genomics strategy. Compared with wild-type protein, SEMA4A(V78M) demonstrates significantly increased MAPK/Erk and PI3K/Akt signalling as well as cell cycle progression of SEMA4A-deficient HCT-116 colorectal cancer cells. In a cohort of 53 patients with FCCTX, we depict two further SEMA4A mutations, p.Gly484Ala and p.Ser326Phe and the single-nucleotide polymorphism (SNP) p.Pro682Ser. This SNP is highly associated with the FCCTX phenotype exhibiting increased risk for colorectal cancer (OR 6.79, 95% CI 2.63 to 17.52). Our study shows previously unidentified germline variants in SEMA4A predisposing to FCCTX, which has implications for surveillance strategies of patients and their families. PMID:25307848

Schulz, Eduard; Klampfl, Petra; Holzapfel, Stefanie; Janecke, Andreas R; Ulz, Peter; Renner, Wilfried; Kashofer, Karl; Nojima, Satoshi; Leitner, Anita; Zebisch, Armin; Wölfler, Albert; Hofer, Sybille; Gerger, Armin; Lax, Sigurd; Beham-Schmid, Christine; Steinke, Verena; Heitzer, Ellen; Geigl, Jochen B; Windpassinger, Christian; Hoefler, Gerald; Speicher, Michael R; Richard Boland, C; Kumanogoh, Atsushi; Sill, Heinz

2014-01-01

60

Nature and Nurture Predispose to Violent Behavior: Serotonergic Genes and Adverse Childhood Environment  

Microsoft Academic Search

Aggressive behavior is influenced by variation in genes of the serotonergic circuitry and early-life experience alike. The present study aimed at investigating the contribution of polymorphisms shown to moderate transcription of two genes involved in serotonergic neurotransmission (serotonin transporter, 5HTT, and monoamine oxidase A, MAOA) to the development of violence and to test for gene–environment interactions relating to adverse childhood

Andreas Reif; Michael Rösler; Christine M Freitag; Marc Schneider; Andrea Eujen; Christian Kissling; Denise Wenzler; Christian P Jacob; Petra Retz-Junginger; Johannes Thome; Klaus-Peter Lesch; Wolfgang Retz

2007-01-01

61

Homocysteine, MTHFR C677T gene polymorphism, folic acid and vitamin B 12 in patients with retinal vein occlusion  

PubMed Central

Background Many available data have suggested that hyperhomocysteinaemia, an established independent risk factor for thrombosis (arterial and venous), may be associated with an increased risk of retinal vein occlusion (RVO). Aim of the study To evaluate homocysteine metabolism in consecutive caucasian patients affected by RVO from Northern Italy. Patients and Methods 69 consecutive patients from Northern Italy (mean age 64.1 ± 14.6 yy) with recent RVO, were tested for plasma levels of homocysteine (tHcy: fasting and after loading with methionine), cyanocobalamine and folic acid levels (CMIA-Abbot) and looking for MTHFR C677T mutation (Light Cycler-Roche) and compared to 50 volunteers, enrolled as a control group. Results Fasting levels of tHcy were significantly higher in patients than in controls: mean value 14.7 ± 7.7 vs 10.2 ± 8 nmol/ml. Post load levels were also significantly higher: mean value 42.7 ± 23.7 vs 30.4 ± 13.3 nmol/ml; Total homocysteine increase was also evaluated (i.e. ?-tHcy) after methionine load and was also significantly higher in patients compared to control subjects: mean ?-tHcy 27.8 ± 21.5 vs 21.0 ± 16 nmol/ml (normal value < 25 nmol/ml). Furthermore, patients affected by RVO show low folic acid and/or vitamin B12 levels, although differences with control group did not reach statistical significance. Heterozygous and homozygous MTHFR mutation were respectively in study group 46% and 29% vs control group 56% and 4%. Conclusion our data confirm that hyperhomocysteinaemia is a risk factor for RVO, and also that TT genotype of MTHFR C677T is more frequently associated with RVO: if the mutation per se is a risk factor for RVO remains an open question to be confirmed because another study from US did not reveal this aspect. Hyperomocysteinemia is modifiable risk factor for thrombotic diseases. Therefore, a screening for tHcy plasma levels in patients with recent retinal vein occlusion could allow to identify patients who might benefit from supplementation with vitamins and normalization of homocysteine levels, in fasting and after methionine load. PMID:16144556

Ferrazzi, Paola; Di Micco, Pierpaolo; Quaglia, Ilaria; Rossi, Lisa Simona; Bellatorre, Alessandro Giacco; Gaspari, Giorgio; Rota, Lidia Luciana; Lodigiani, Corrado

2005-01-01

62

Pharmacogenetic variants in the DPYD, TYMS, CDA and MTHFR genes are clinically significant predictors of fluoropyrimidine toxicity  

PubMed Central

Background: Fluoropyrimidine drugs are extensively used for the treatment of solid cancers. However, adverse drug reactions are a major clinical problem, often necessitating treatment discontinuation. The aim of this study was to identify pharmacogenetic markers predicting fluoropyrimidine toxicity. Methods: Toxicity in the first four cycles of 5-fluorouracil or capecitabine-based chemotherapy were recorded for a series of 430 patients. The association between demographic variables, DPYD, DPYS, TYMS, MTHFR, CDA genotypes, and toxicity were analysed using logistic regression models. Results: Four DPYD sequence variants (c.1905+1G>A, c.2846A>T, c.1601G>A and c.1679T>G) were found in 6% of the cohort and were significantly associated with grade 3–4 toxicity (P<0.0001). The TYMS 3?-untranslated region del/del genotype substantially increased the risk of severe toxicity (P=0.0123, odds ratio (OR)=3.08, 95% confidence interval (CI): 1.38–6.87). For patients treated with capecitabine, a MTHFR c.1298CC homozygous variant genotype predicted hand–foot syndrome (P=4.1 × 10?6, OR=9.99, 95% CI: 3.84–27.8). The linked CDA c.?92A>G and CDA c.?451C>T variants predicted grade 2–4 diarrhoea (P=0.0055, OR=2.3, 95% CI: 1.3–4.2 and P=0.0082, OR=2.3, 95% CI: 1.3–4.2, respectively). Conclusion: We have identified a panel of clinically useful pharmacogenetic markers predicting toxicity to fluoropyrimidine therapy. Dose reduction should be considered in patients carrying these sequence variants. PMID:23736036

Loganayagam, A; Arenas Hernandez, M; Corrigan, A; Fairbanks, L; Lewis, C M; Harper, P; Maisey, N; Ross, P; Sanderson, J D; Marinaki, A M

2013-01-01

63

First-stage autosomal genome screen in extended pedigrees suggests genes predisposing to low bone mineral density on chromosomes 1p, 2p and 4q  

Microsoft Academic Search

Osteoporosis is characterized by low bone density, and osteopenia is responsible for 1.5 million fractures in the United States annually.1 In order to identify regions of the genome which are likely to contain genes predisposing to osteopenia, we genotyped 149 members of seven large pedigrees having recurrence of low bone mineral density (BMD) with 330 DNA markers spread throughout the

M Devoto; K Shimoya; J Caminis; J Ott; A Tenenhouse; MP Whyte; L Sereda; S Hall; E Considine; CJ Williams; G Tromp; H Kuivaniemi; L Ala-Kokko; DJ Prockop; LD Spotila

1998-01-01

64

Gene Expression Profiling of Histiocytic Sarcomas in a Canine Model: The Predisposed Flatcoated Retriever Dog  

PubMed Central

Background The determination of altered expression of genes in specific tumor types and their effect upon cellular processes may create insight in tumorigenesis and help to design better treatments. The Flatcoated retriever is a dog breed with an exceptionally high incidence of histiocytic sarcomas. The breed develops two distinct entities of histiocytic neoplasia, a soft tissue form and a visceral form. Gene expression studies of these tumors have value for comparable human diseases such as histiocytic/dendritic cell sarcoma for which knowledge is difficult to accrue due to their rare occurrence. In addition, such studies may help in the search for genetic aberrations underlying the genetic predisposition in this dog breed. Methods Microarray analysis and pathway analyses were performed on fresh-frozen tissues obtained from Flatcoated retrievers with localized, soft tissue histiocytic sarcomas (STHS) and disseminated, visceral histiocytic sarcomas (VHS) and on normal canine spleens from various breeds. Expression differences of nine genes were validated with quantitative real-time PCR (qPCR) analyses. Results QPCR analyses identified the significantly altered expression of nine genes; PPBP, SpiC, VCAM1, ENPEP, ITGAD (down-regulated), and GTSF1, Col3a1, CD90 and LUM (up-regulated) in the comparison of both the soft tissue and the visceral form with healthy spleen. DAVID pathway analyses revealed 24 pathways that were significantly involved in the development of HS in general, most of which were involved in the DNA repair and replication process. Conclusions This study identified altered expression of nine genes not yet implicated in histiocytic sarcoma manifestations in the dog nor in comparable human histiocytic/dendritic sarcomas. Exploration of the downside effect of canine inbreeding strategies for the study of similar sarcomas in humans might also lead to the identification of genes related to these rare malignancies in the human. PMID:23936488

Boerkamp, Kim M.; van Wolferen, Monique E.; Groot Koerkamp, Marian J. A.; van Leenen, Dik; Grinwis, Guy C. M.; Penning, Louis C.; Wiemer, Erik A. C.; Rutteman, Gerard R.

2013-01-01

65

Knockout of the TauT Gene Predisposes C57BL/6 Mice to Streptozotocin-Induced Diabetic Nephropathy  

PubMed Central

Diabetic nephropathy is the leading cause of end stage renal disease in the world. Although tremendous efforts have been made, scientists have yet to identify an ideal animal model that can reproduce the characteristics of human diabetic nephropathy. In this study, we hypothesize that taurine insufficiency is a critical risk factor for development of diabetic nephropathy associated with diabetes mellitus. This hypothesis was tested in vivo in TauT heterozygous (TauT+/-) and homozygous (TauT-/-) knockout in C57BL/6 background mice. We have shown that alteration of the TauT gene (also known as SLC6A6) has a substantial effect on the susceptibility to development of extensive diabetic kidney disease in both TauT+/- and TauT-/-mouse models of diabetes. These animals developed histological changes characteristic of human diabetic nephropathy that included glomerulosclerosis, nodular lesions, arteriosclerosis, arteriolar dilation, and tubulointerstitial fibrosis. Immunohistochemical staining of molecular markers of smooth muscle actin, CD34, Ki67 and collagen IV further confirmed these observations. Our results demonstrated that both homozygous and heterozygous TauT gene deletion predispose C57BL/6 mice to develop end-stage diabetic kidney disease, which closely replicates the pathological features of diabetic nephropathy in human diabetic patients. PMID:25629817

Han, Xiaobin; Patters, Andrea B.; Ito, Takashi; Schaffer, Stephen W.; Chesney, Russell W.

2015-01-01

66

Associations of MTHFR C677T and MTRR A66G Gene Polymorphisms with Metabolic Syndrome: A Case-Control Study in Northern China  

PubMed Central

Prior evidence indicates that homocysteine plays a role in the development of metabolic syndrome (MetS). Methylenetetrahydrofolate reductase (MTHFR) C677T and methionine synthase reductase (MTRR) A66G polymorphisms are common genetic determinants of homocysteine levels. To investigate the associations of the MTHFR C677T and MTRR A66G polymorphisms with MetS, 692 Chinese Han subjects with MetS and 878 controls were recruited. The component traits of MetS and the MTHFR C677T and MTRR A66G genotypes were determined. A significant association was observed between the MTHFR 677T allele and increased risk of MetS, high fasting blood glucose, high waist circumference, and increasing number of MetS components. The MTRR A66G polymorphism was associated with an increased risk of MetS when combined with the MTHFR 677TT genotype, although there was no association found between MetS and MTRR A66G alone. Furthermore, the MTRR 66GG genotype was associated with high fasting blood glucose and triglycerides. Our data suggest that the MTHFR 677T allele may contribute to an increased risk of MetS in the northern Chinese Han population. The MTRR A66G polymorphism is not associated with MetS. However, it may exacerbate the effect of the MTHFR C677T variant alone. Further large prospective population-based studies are required to confirm our findings. PMID:25429430

Yang, Boyi; Fan, Shujun; Zhi, Xueyuan; Wang, Da; Li, Yongfang; Wang, Yinuo; Wang, Yanxun; Wei, Jian; Zheng, Quanmei; Sun, Guifan

2014-01-01

67

Germline mutations in the PAF1 complex gene CTR9 predispose to Wilms tumour  

PubMed Central

Wilms tumour is a childhood kidney cancer. Here we identify inactivating CTR9 mutations in 3 of 35 Wilms tumour families, through exome and Sanger sequencing. By contrast, no similar mutations are present in 1,000 population controls (P<0.0001). Each mutation segregates with Wilms tumour in the family and a second mutational event is present in available tumours. CTR9 is a key component of the polymerase-associated factor 1 complex which has multiple roles in RNA polymerase II regulation and is implicated in embryonic organogenesis and maintenance of embryonic stem cell pluripotency. These data establish CTR9 as a Wilms tumour predisposition gene and suggest it acts as a tumour suppressor gene. PMID:25099282

Hanks, Sandra; Perdeaux, Elizabeth R.; Seal, Sheila; Ruark, Elise; Mahamdallie, Shazia S.; Murray, Anne; Ramsay, Emma; Del Vecchio Duarte, Silvana; Zachariou, Anna; de Souza, Bianca; Warren-Perry, Margaret; Elliott, Anna; Davidson, Alan; Price, Helen; Stiller, Charles; Pritchard-Jones, Kathy; Rahman, Nazneen

2014-01-01

68

Association of 677 C>T (rs1801133) and 1298 A>C (rs1801131) Polymorphisms in the MTHFR Gene and Breast Cancer Susceptibility: A Meta-Analysis Based on 57 Individual Studies  

PubMed Central

Objective The 677 C>T and 1298 A>C polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene have been widely reported and considered to have a significant effect on breast cancer risk, but the results are inconsistent. A meta-analysis based on 57 eligible studies was carried out to clarify the role of MTHFR gene polymorphisms in breast cancer. Methods and Results Eligible articles were identified by searching databases including PubMed, Web of Science, EMBASE, CNKI and CBM for the period up to August 2012. Finally, a total of 57 studies were included in this meta-analysis. Crude ORs with 95% CIs were used to assess the association between the MTHFR polymorphisms and breast cancer risk. The pooled ORs were performed with additive model, dominant model and recessive model, respectively. Subgroup analysis was also performed by ethnicity. The statistical heterogeneity across studies was examined with ?2-based Q-test. A meta-analysis was performed using the Stata 12.0 software. Overall, the 677 C allele was significantly associated with breast cancer risk (OR?=?0.942, 95%CI?=?0.898 to 0.988) when compared with the 677 T allele in the additive model, and the same results were also revealed under other genetic models. Simultaneously, the 1298 A allele was not associated with the breast cancer susceptibility when compared with the 1298 C allele (OR?=?0.993, 95%CI?=?0.978 to 1.009). Furthermore, analyses under the dominant, recessive and the allele contrast model yielded similar results. Conclusions The results of this meta-analysis suggest that 677 C>T polymorphism in the MTHFR gene may contribute to breast cancer development. However, the 1298 A>C polymorphism is not significantly associated with increased risks of breast cancer. PMID:24945727

Li, Kai; Li, Wusheng; Dong, Xi

2014-01-01

69

Low-copy repeats at the human VIPR2 gene predispose to recurrent and nonrecurrent rearrangements  

PubMed Central

Submicroscopic structural variations, including deletions, duplications, inversions and more complex rearrangements, are widespread in normal human genomes. Inverted segmental duplications or highly identical low-copy repeat (LCR) sequences can mediate the formation of inversions and more complex structural rearrangements through non-allelic homologous recombination. In a patient with 7q36 inverted duplication/terminal deletion, we demonstrated the central role of a pair of short inverted LCRs in the vasoactive intestinal peptide receptor gene (VIPR2)-LCRs in generating the rearrangement. We also revealed a relatively common VIPR2-LCR-associated inversion polymorphism disrupting the gene in almost 1% of healthy subjects, and a small number of complex duplications/triplications. In genome-wide studies of several thousand patients, a significant association of rare microduplications with variable size, all involving VIPR2, with schizophrenia was recently described, suggesting that altered vasoactive intestinal peptide signaling is likely implicated in the pathogenesis of schizophrenia. Genetic testing for VIPR2-LCR-associated inversions should be performed on available cohorts of psychiatric patients to evaluate their potential pathogenic role. PMID:23073313

Beri, Silvana; Bonaglia, Maria Clara; Giorda, Roberto

2013-01-01

70

Polymorphism in the Serotonin Receptor 2a (HTR2A) Gene as Possible Predisposal Factor for Aggressive Traits  

PubMed Central

Aggressive manifestations and their consequences are a major issue of mankind, highlighting the need for understanding the contributory factors. Still, aggression-related genetic analyses have so far mainly been conducted on small population subsets such as individuals suffering from a certain psychiatric disorder or a narrow-range age cohort, but no data on the general population is yet available. In the present study, our aim was to identify polymorphisms in genes affecting neurobiological processes that might explain some of the inter-individual variation between aggression levels in the non-clinical Caucasian adult population. 55 single nucleotide polymorphisms (SNP) were simultaneously determined in 887 subjects who also filled out the self-report Buss-Perry Aggression Questionnaire (BPAQ). Single marker association analyses between genotypes and aggression scores indicated a significant role of rs7322347 located in the HTR2A gene encoding serotonin receptor 2a following Bonferroni correction for multiple testing (p = 0.0007) both for males and females. Taking the four BPAQ subscales individually, scores for Hostility, Anger and Physical Aggression showed significant association with rs7322347 T allele in themselves, while no association was found with Verbal Aggression. Of the subscales, relationship with rs7322347 was strongest in the case of Hostility, where statistical significance virtually equaled that observed with the whole BPAQ. In conclusion, this is the first study to our knowledge analyzing SNPs in a wide variety of genes in terms of aggression in a large sample-size non-clinical adult population, also describing a novel candidate polymorphism as predisposal to aggressive traits. PMID:25658328

Banlaki, Zsofia; Elek, Zsuzsanna; Nanasi, Tibor; Szekely, Anna; Nemoda, Zsofia; Sasvari-Szekely, Maria; Ronai, Zsolt

2015-01-01

71

Common Mutations of the Methylenetetrahydrofolate Reductase (MTHFR) Gene in Non-Syndromic Cleft Lips and Palates Children in North-West of Iran  

PubMed Central

Introduction: Cleft lips and cleft palates are common congenital abnormalities in children. Various chromosomal loci have been suggested to be responsible the development of these abnormalities. The present study was carried out to investigate the association between the suspected genes (methylenetetrahydrofolate reductase [MTHFR] A1298C and C677T) that might contribute into the etiology of these disorders through application of molecular methods. Materials and Methods: This cross-sectional and explanatory study was carried out on a study population of 65 affected children, 130 respective parents and 50 healthy individuals between 2009 and 2012 at Tabriz University of Medical Sciences, IR Iran. After DNA extraction, amplification refractory mutation system–polymerase chain reaction (ARMS-PCR) and restriction fragment length polymorphism (RFLP)-PCR were used respectively to investigate the C677T and A1298C mutations for the MTHFR gene. Results: There was a significant difference in the rates of the C677T mutation when affected patients and their fathers were compared with the control group (odds ratio [OR]=0.44) (OR=0.64). However, there was no significant difference observed in the rate of this mutation between the patients’ mothers and the control group (OR=1.35). In addition, the abnormality rate was higher in patients with the A1298C mutation and their parents, when compared with the control group. This abnormality rate was higher for the affected children and their fathers in comparison with their mothers (Fathers, OR=0.26; Mothers, OR=0.65; Children, OR=0.55). No significant difference was seen in the rate of the polymorphism C677T in its CC, when the affected children and their parents were compared with the control group. However, there was a significant difference in the A1298C mutation. Conclusion: An association was seen between the A1298C mutation and cleft lip and cleft palate abnormalities in Iran. However, there seems to be a stronger relationship between the C67TT mutation and these abnormalities in other countries, which could be explained by racial differences. Moreover, this association was more notable between the affected children and their fathers than their mothers. The findings in this study may be helpful in future studies and screening programs.

Abdollahi-Fakhim, Shahin; Asghari Estiar, Mehrdad; Varghaei, Parizad; Alizadeh Sharafi, Mahdi; Sakhinia, Masoud; Sakhinia, Ebrahim

2015-01-01

72

A genome-wide search for genes predisposing to manic-depression, assuming autosomal dominant inheritance  

SciTech Connect

Manic-depressive illness (MDI), also known as [open quotes]bipolar affective disorder[close quotes], is a common and devastating neuropsychiatric illness. Although pivotal biochemical alterations underlying the disease are unknown, results of family, twin, and adoption studies consistently implicate genetic transmission in the pathogenesis of MDI. In order to carry out linkage analysis, the authors ascertained eight moderately sized pedigrees containing multiple cases of the disease. For a four-allele marker mapping at 5 cM from the disease gene, the pedigree sample has >97% power to detect a dominant allele under genetic homogeneity and has >73% power under 20% heterogeneity. To date, the eight pedigrees have been genotyped with 328 polymorphic DNA loci throughout the genome. When autosomal dominant inheritance was assumed, 273 DNA markers gave lod scores <[minus]2.0 at [theta] = .05, and 4 DNA marker loci yielded lod scores >1 (chromosome 5 -- D5S39, D5S43, and D5S62; chromosome 11 -- D11S85). Of the markers giving lod scores >1, only D5S62 continued to show evidence for linkage when the affected-pedigree-member method was used. The D5S62 locus maps to distal 5q, a region containing neurotransmitter-receptor genes for dopamine, norepinephrine, glutamate, and gamma-aminobutyric acid. Although additional work in this region may be warranted, the linkage results should be interpreted as preliminary data, as 68 unaffected individuals are not past the age of risk. 72 refs., 2 tabs.

Coon, H.; Jensen, S.; Hoff, M.; Holik, J.; Plaetke, R.; Reimherr, F.; Wender, P.; Leppert, M.; Byerley, W. (Univ. of Utah, Salt Lake City (United States))

1993-06-01

73

Anterior ischemic optic neuropathy in a patient with Crohn's disease and aberrant MTHFR and GPIIIa gene variants.  

PubMed

Large spectrums of ophthalmic manifestations from the anterior to the posterior segment have been so far reported in patients with inflammatory bowel disease. Anterior ischemic optic neuropathy is caused by acute ischemic infarction of the optic nerve head and is distinguished in two different types, non-arteritic anterior ischemic optic neuroparhy (NAION) which is the most frequent type and arteritic anterior ischemic optic neuropathy. Non-arteritic anterior ischemic optic neuroparhy may result in severe visual field loss. We present the case of a 69 year-old man with known history of Crohn's disease that was referred to the Department of Ophthalmology after noticing sudden blurred vision of his left eye. Ophthalmologic examination revealed a corrected visual acuity of 8/10 OS and 10/10 OD. Pupil examination showed a relative afferent pupillary defect of the left pupil and fluoroangiography revealed hyperfluorescence of the left optic disc, indicating edema and NAION attack on his left eye. Genetic analysis showed that the patient was homozygous for MTHFR C677T genetic polymorphism and A1/A2 heterozygous for GPIIIa polymorphism. PMID:21122545

Felekis, T; Katsanos, K H; Zois, C D; Vartholomatos, G; Kolaitis, N; Asproudis, I; Tsianos, E V

2010-10-01

74

Homocysteine Level and Mechanisms of Injury in Parkinson's Disease as Related to MTHFR, MTR, and MTHFD1 Genes Polymorphisms and L-Dopa Treatment.  

PubMed

An elevated concentration of total homocysteine (tHcy) in plasma and cerebrospinal fluid is considered to be a risk factor for Alzheimer's disease (AD) and Parkinson's disease (PD). Homocysteine (Hcy) levels are influenced by folate concentrations and numerous genetic factors through the folate cycle, however, their role in the pathogenesis of PD remains controversial. Hcy exerts a neurotoxic action and may participate in the mechanisms of neurodegeneration, such as excitotoxicity, oxidative stress, calcium accumulation, and apoptosis. Elevated Hcy levels can lead to prooxidative activity, most probably through direct interaction with N-methyl-D-aspartate (NMDA) receptors and sensitization of dopaminergic neurons to age-related dysfunction and death. Several studies have shown that higher concentration of Hcy in PD is related to long-term administration of levodopa (L-dopa). An elevation of plasma tHcy levels can also reflect deficiencies of cofactors in remethylation of Hcy to methionine (Met) (folates and vitamin B12) and in its transsulfuration to cysteine (Cys) (vitamin B6). It is believed that the increase in the concentration of Hcy in PD can affect genetic polymorphisms of the folate metabolic pathway genes, such as MTHFR (C677T, A1298C and G1793A), MTR (A2756G), and MTHFD1 (G1958A), whose frequencies tend to increase in PD patients, as well as the reduced concentration of B vitamins. In PD, increased levels of Hcy may lead to dementia, depression and progression of the disease. PMID:24532985

Rozycka, Agata; Jagodzinski, Pawel P; Kozubski, Wojciech; Lianeri, Margarita; Dorszewska, Jolanta

2013-12-01

75

Minor allele of the APOA4 gene T347S polymorphism predisposes to obesity in postmenopausal Turkish women.  

PubMed

The aim of this study was to examine the relationship between APOA4 gene T347S polymorphism with obesity measures and serum lipids in Turkish adults. Randomly selected sample of 1,554 adults (754 men, mean age 50.4 ± 11.9 years and 800 women, mean age 49.6 ± 11.8 years) were included in the study. 346 Women (43.2 %) were postmenopausal. Genotyping was performed by using hybridization probes in real-time PCR. Not men but postmenopausal women, carrying the S347 allele, were associated with 1.5 kg/m(2) higher BMI (P = 0.016) and 3.6 cm wider waist circumference (P = 0.005) than postmenopausal T347 homozygotes, controlled for covariates. Logistic regression analyses of this polymorphism, adjusted for age, fasting triglyceride, smoking status, alcohol consumption and physical activity disclosed the rare allele to be associated with obesity in postmenopausal women at an odds of 1.80 (95 % CI 1.09-2.97; P = 0.021). Serum apoB level was lower in S347 allele carriers (110.9 ± 2.9 mg/dL) than in T347 homozygotes (119.0 ± 2.4 mg/dL; P = 0.035) in men but not women. APOA4 T347S polymorphism was unrelated to lipids and other lipoproteins in either gender. The APOA4 S347 allele predisposes to obesity and high waist circumference in Turkish postmenopausal women. ApoB levels are lower only in men in S347 allele carriers. PMID:23096082

Guclu-Geyik, Filiz; Onat, Altan; Coban, Neslihan; Komurcu-Bayrak, Evrim; Sansoy, Vedat; Can, Günay; Erginel-Unaltuna, Nihan

2012-12-01

76

A Second Genetic Polymorphism in Methylenetetrahydrofolate Reductase (MTHFR) Associated with Decreased Enzyme Activity  

Microsoft Academic Search

A common mutation in methylenetetrahydrofolate reductase (MTHFR), C677T, results in a thermolabile variant with reduced activity. Homozygous mutant individuals (approximately 10% of North Americans) are predisposed to mild hyperhomocysteinemia, when their folate status is low. This genetic–nutrient interactive effect is believed to increase the risk for neural tube defects and vascular disease. In this communication, we characterize a second common

Ilan Weisberg; Pamela Tran; Benedicte Christensen; Sahar Sibani; Rima Rozen

1998-01-01

77

Association between Hcy levels and the CBS844ins68 and MTHFR C677T polymorphisms with essential hypertension  

PubMed Central

The aim of the present study was to investigate the association between the homocysteine (Hcy) levels and polymorphisms of the CBS844ins68 and MTHFR C677T genes in essential hypertension (EH). The effects of the MTHFR C677T and CBS844ins68 haploid genotypes and the combined genotypes on EH and levels of Hcy were further explored. The polymorphisms of CBS844ins68 and MTHFR C677T genes in 200 EH and 200 normal tensive (NT) patients were detected using polymerase chain reaction-restriction fragment length polymorphism and analysis of the distribution of genotypes. An automated biochemical analyzer was used to measure the plasma Hcy levels and the clinical biochemistry data. The plasma Hcy levels in EH were significantly higher than those of the NT group (P<0.05). There were no significant differences (P>0.05) between males and females. Two genotypes, deletion/deletion (DD) and deletion/insertion (DI), of the CBS844ins68 polymorphism were found in two groups with no clear differences in two genotypes and allele frequency distribution (P>0.05). There were significant differences in the three genotype frequencies (?2=6.658, ?2=4.410, P<0.05) for MTHFR C677T locus genotypes CC, CT and TT. The Hcy levels in genotypes DD and DI had no significant differences (P>0.05) and the CT and TT types were significantly higher compared to the CC genotype (P<0.05). The CC/DD combined genotype in the two groups was significantly different (P<0.05), and the odds ratio (OR), 0.569 showed that the CC/DD genotype may be a protective factor of hypertension. In the two groups, the Hcy levels for combined genotypes CC/DD, CT/DD, TT/DD and TT/DI were significantly different (P<0.05). The SHEsis software analysis linkage disequilibrium coefficient=0.216, indicates that there is probably a weak linkage for MTHFR C677T and CBS844ins68. Haplotype analysis suggested that the C-D haplotype was negatively correlated with EH (OR, 0.727) and that there was a positive correlation between T-D haplotype and EH (OR, 1.376). MTHFR C677T and CBS844ins68 polymorphisms were present in the populations studied and the CBS844ins68 homozygous mutation was not present. Therefore, there is a correlation between the polymorphisms of the MTHFR C677T gene and EH, and allele T may be one of the predisposing factors. MTHFR C677T and CBS844ins68 may exist with a certain linkage and the T-D haplotype may be a risk factor for EH. PMID:25279160

CAI, WEIJUAN; YIN, LIANG; YANG, FANG; ZHANG, LEI; CHENG, JIANG

2014-01-01

78

Increased susceptibility to mild neonatal stress in MTHFR deficient mice.  

PubMed

Early life stress is shown to have a life-span outcome on human and animal behavior, increasing the risk for psychopathology. The gene methylenetetrahydrofolate reductase (MTHFR), which encodes for a key enzyme in one carbon metabolism, shows a high prevalence of polymorphism in patients with developmental disorders. Here we examined the hypothesis that MTHFR deficiency results in an increased susceptibility of the developing brain to mild neonatal stress (NS). Mild NS failed to alter corticosterone levels in young and adult Wt mice. However, an elevated level of corticosterone was found in the MTHFR deficient-NS female, exemplifying enhanced sensitivity to NS. Behavioral phenotyping of Wt and MTHFR deficient mice provides evidence that the effect of mild NS may be amplified by the MTHFR deficient genotype. Distinct behavioral characteristics were altered in male and female mice. In general, three patterns of influence on mice behavior were observed: (1) an additive suppressive effect of NS and MTHFR deficiency on exploration and activity was evident in females; (2) stress related parameters were significantly sensitive to genotype in females, presenting an interaction between genotype and sex; (3) various aspects of behavior in a social setting were modified preferably in males by genotype, NS and the interaction between the two, while females exhibited a smaller effect that was restricted to NS with no genotype effect. Overall, our results support an interaction between mild NS, the MTHFR genotype and sex. We suggest using this animal model to study the molecular mechanism linking these two risk factors and their involvement in neurodevelopmental disorders such as schizophrenia and autism. PMID:23896051

Kezurer, N; Galron, D; Golan, H M

2013-09-15

79

Genome-wide association analysis and fine mapping of NT-proBNP level provide novel insight into the role of the MTHFR-CLCN6-NPPA-NPPB gene cluster  

PubMed Central

High blood concentration of the N-terminal cleavage product of the B-type natriuretic peptide (NT-proBNP) is strongly associated with cardiac dysfunction and is increasingly used for heart failure diagnosis. To identify genetic variants associated with NT-proBNP level, we performed a genome-wide association analysis in 1325 individuals from South Tyrol, Italy, and followed up the most significant results in 1746 individuals from two German population-based studies. A genome-wide significant signal in the MTHFR-CLCN6-NPPA-NPPB gene cluster was replicated, after correction for multiple testing (replication one-sided P-value = 8.4 × 10?10). A conditional regression analysis of 128 single-nucleotide polymorphisms in the region of interest identified novel variants in the CLCN6 gene as independently associated with NT-proBNP. In this locus, four haplotypes were associated with increased NT-proBNP levels (haplotype-specific combined P-values from 8.3 × 10?03 to 9.3 × 10?11). The observed increase in the NT-proBNP level was proportional to the number of haplotype copies present (i.e. dosage effect), with an increase associated with two copies that varied between 20 and 100 pg/ml across populations. The identification of novel variants in the MTHFR-CLCN6-NPPA-NPPB cluster provides new insights into the biological mechanisms of cardiac dysfunction. PMID:21273288

Del Greco M., Fabiola; Pattaro, Cristian; Luchner, Andreas; Pichler, Irene; Winkler, Thomas; Hicks, Andrew A.; Fuchsberger, Christian; Franke, Andre; Melville, Scott A.; Peters, Annette; Wichmann, H. Erich; Schreiber, Stefan; Heid, Iris M.; Krawczak, Michael; Minelli, Cosetta; Wiedermann, Christian J.; Pramstaller, Peter P.

2011-01-01

80

MTHFR C677T and colorectal cancer risk: A meta-analysis of 25 populations.  

PubMed

The common functional methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism may influence the risk of colorectal cancer (CRC), but data from published studies with individually low statistical power are conflicting. To clarify the role of MTHFR C677T genotype in CRC, we considered all available studies in a meta-analysis. Studies reporting on MTHFR C677T genotype and CRC were searched in PubMed up to April 2006. The principle prior hypothesis was that homozygosity for MTHFR 677TT would be associated with reduced risk of CRC. Data were available for 29,931 subjects, including 12,243 with CRC, from 25 independent populations. Compared to the homozygous CC genotype, the MTHFR 677TT genotype was associated with a reduced risk of CRC (odds ratio (OR): 0.83; 95% confidence interval (CI): 0.75-0.93; p = 0.001). There was some heterogeneity among the results of individual studies, but this was not statistically significant (heterogeneity p = 0.12; I2 = 25.8%). Heterozygosity for MTHFR 677 did not influence CRC risk (OR: 0.99; 95% CI: 0.94-1.04). These findings indicate that individuals homozygous for the MTHFR 677TT genotype are at moderately reduced risk of CRC, and support the proposal that common genetic variation in the MTHFR gene contributes to CRC susceptibility, probably accounting for at least 9% of the total incidence. PMID:17131337

Hubner, Richard A; Houlston, Richard S

2007-03-01

81

Univariate and multiple linear regression analyses for 23 single nucleotide polymorphisms in 14 genes predisposing to chronic glomerular diseases and IgA nephropathy in Han Chinese.  

PubMed

Immunoglobulin A nephropathy (IgAN) is a complex trait regulated by the interaction among multiple physiologic regulatory systems and probably involving numerous genes, which leads to inconsistent findings in genetic studies. One possibility of failure to replicate some single-locus results is that the underlying genetics of IgAN nephropathy is based on multiple genes with minor effects. To learn the association between 23 single nucleotide polymorphisms (SNPs) in 14 genes predisposing to chronic glomerular diseases and IgAN in Han males, the 23 SNPs genotypes of 21 Han males were detected and analyzed with a BaiO gene chip, and their associations were analyzed with univariate analysis and multiple linear regression analysis. Analysis showed that CTLA4 rs231726 and CR2 rs1048971 revealed a significant association with IgAN. These findings support the multi-gene nature of the etiology of IgAN and propose a potential gene-gene interactive model for future studies. PMID:25193896

Wang, Hui; Sui, Weiguo; Xue, Wen; Wu, Junyong; Chen, Jiejing; Dai, Yong

2014-09-01

82

Factors Predisposing Drug Abuse.  

ERIC Educational Resources Information Center

The exact nature of the events which may predispose a person to substance abuse is not known. This paper provides a theoretical discussion and review which emphasizes three contexts which have been shown to predispose on individual to drug abuse: (1) prenatal exposure to a given substance; (2) environmental conditions present upon first exposure…

Cheney, Carl D.; Phelps, Brady J.

83

A case report of two male siblings with autism and duplication of Xq13-q21, a region including three genes predisposing for autism.  

PubMed

Autism spectrum disorder, severe behaviour problems and duplication of the Xq12 to Xq13 region have recently been described in three male relatives. To describe the psychiatric comorbidity and dysmorphic features, including craniosynostosis, of two male siblings with autism and duplication of the Xq13 to Xq21 region, and attempt to narrow down the number of duplicated genes proposed to be leading to global developmental delay and autism. We performed DNA sequencing of certain exons of the TWIST1 gene, the FGFR2 gene and the FGFR3 gene. We also performed microarray analysis of the DNA. In addition to autism, the two male siblings exhibited severe learning disability, self-injurious behaviour, temper tantrums and hyperactivity, and had no communicative language. Chromosomal analyses were normal. Neither of the two siblings showed mutations of the sequenced exons known to produce craniosynostosis. The microarray analysis detected an extra copy of a region on the long arm of chromosome X, chromosome band Xq13.1-q21.1. Comparison of our two cases with previously described patients allowed us to identify three genes predisposing for autism in the duplicated chromosomal region. Sagittal craniosynostosis is also a new finding linked to the duplication. PMID:23974867

Wentz, Elisabet; Vujic, Mihailo; Kärrstedt, Ewa-Lotta; Erlandsson, Anna; Gillberg, Christopher

2014-05-01

84

MTHFR A1298C polymorphism is associated with cardiovascular risk in end stage renal disease in North Indians.  

PubMed

The methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism has been shown to be associated with cardiovascular disease and in patients with end-stage renal disease (ESRD). However, the relationship between MTHFR polymorphisms and cardiovascular disease (CVD) in patients on hemodialysis has not been examined. The aim of this study was to assess the association of polymorphisms of MTHFR gene with homocysteine (Hcy) and intimal medial thickness (IMT) in patients on hemodialysis. We performed case-control study involving107 patients with ESRD and 103 healthy controls. Plasma Hcy was measured in all the subjects and these subjects were genotyped for three MTHFR polymorphisms (C677T, A1298C, and G1793A). We observed significantly higher Hcy levels in patients as compared to controls. The frequency of MTHFR 1298CC genotype was significantly higher in ESRD patients than in controls (21.4% vs. 2.9%); the frequency of the MTHFR C677T genotypes did not differ between groups (26.1% vs. 17.4%). Compound heterozygous MTHFR 677CT/1298AC genotypes showed maximum association with the risk of ESRD (OR: 12.8; 5%CI: 1.64-10.01, P < 0.05). Concurrent occurrence of MTHFR 677CC wild genotype with either 1298CC or 1793GA significantly increased the risk of disease (OR: 7.20; 95%CI: 2.06-2.51, P < 0.001 and OR: 7.60; 95%CI: 1.68-34.35; P < 0.05, respectively). MTHFR 1298CC genotype was associated with higher Hcy levels. IMT was also significantly higher in patients with the 1298CC genotype (P < 0.05). Thus, A1298C polymorphism of MTHFR gene appears to be associated with the severity of carotid atherosclerosis and co-occurrence of MTHFR polymorphisms may be a risk factor for CVD in patients on hemodialysis. PMID:17899317

Poduri, Aruna; Mukherjee, Debabrata; Sud, Kamal; Kohli, Harbir Singh; Sakhuja, Vinay; Khullar, Madhu

2008-01-01

85

Polymorphism at the C-reactive protein locus influences gene expression and predisposes to systemic lupus erythematosus  

Microsoft Academic Search

Relative deficiency of pentraxin proteins is implicated in the pathogenesis of systemic lupus erythematosus. The C-reactive protein (CRP) response is defective in patients with acute flares of disease, and mice with targeted deletions of the serum amyloid P component gene (Sap) develop a lupus-like illness. In humans, the genes for CRP (CRP) and SAP (APCS) map to 1q23.2 within an

Andrew I. Russell; Deborah S. Cunninghame Graham; Christopher Shepherd; Cheri A. Roberton; John Whittaker; John Meeks; Richard J. Powell; David A. Isenberg; Mark J. Walport; Timothy J. Vyse

2004-01-01

86

Genotype and haplotype distributions of MTHFR 677C>T and 1298A>C single nucleotide polymorphisms: a meta-analysis  

Microsoft Academic Search

.  ?Common single nucleotide polymorphisms (SNPs; 677C>T and 1298A>C) in the methylenetetrahydrofolate reductase gene (MTHFR) decrease the activity of the enzyme, leading to hyperhomocysteinemia, particularly in folate-deficient states. We calculate\\u000a herein the haplotype frequencies of the MTHFR 677 and 1298 polymorphisms in pooled general populations derived from published data. We selected 16 articles that provided\\u000a reliable data on combined MTHFR genotypes

Shuji Ogino; Robert B. Wilson

2003-01-01

87

Role of polymorphisms in factor V (FV Leiden), prothrombin, plasminogen activator inhibitor type-1 (PAI-1), methylenetetrahydrofolate reductase (MTHFR) and cystathionine ?-synthase (CBS) genes as risk factors for thrombophilias.  

PubMed

Thrombophilias are defined as a predisposition to thrombosis due to hematological changes which induce blood hypercoagulability; they can be inherited or acquired. They are individually characterized by a large phenotypic variability, even when they occur within the same family. Hereditary thrombophilias are, in most cases, due to changes related to physiological coagulation inhibitors or mutations in the genes of coagulation factors. High levels of plasma homocysteine may also be responsible for vaso-occlusive episodes and may have acquired (nutritional deficiencies of folate and vitamins B6 and B12) and/or genetic causes (mutations in the genes responsible for expression of enzymes involved in the intracellular metabolism of homocysteine). Considering that: (1) thromboses are events of multigenic and multifactorial etiopathology; (2) the presence of mutations in several genes significantly increases the risk of their occurrence; (3) the vascular territory (venous and/or arterial) affected involves different pathophysiological mechanisms and treatments, knowledge of genetic variants that may contribute to the risk and variability of the phenotypic manifestations of these diseases is extremely important. This understanding may provide support for a more individualized and therefore more effective treatment for thrombophilia carriers. Thus, this mini-review aims to address a comprehensive summary of thrombophilias and thrombosis, and discuss the role of polymorphisms in Factor V (FV Leiden), Prothrombin, Plasminogen activator inhibitor type-1 (PAI-1), Methylenetetrahydrofolate reductase (MTHFR) and Cystathionine ?-synthase (CBS) genes as risk factors for thrombophilias. PMID:22512572

Miranda-Vilela, A L

2012-09-01

88

Polymorphism at the C-reactive protein locus influences gene expression and predisposes to systemic lupus erythematosus  

PubMed Central

Relative deficiency of pentraxin proteins is implicated in the pathogenesis of systemic lupus erythematosus. The C-reactive protein (CRP) response is defective in patients with acute flares of disease, and mice with targeted deletions of the serum amyloid P component gene (Sap) develop a lupus-like illness. In humans, the genes for CRP (CRP) and SAP (APCS) map to 1q23.2 within an interval linked with SLE. We have investigated the candidate genes CRP and APCS in two cohorts totalling 586 UK simplex SLE families. The inheritance of an intronic dinucleotide repeat and seven single nucleotide polymorphisms in the CRP and APCS genes was examined by application of family-based tests of association and linkage. Basal levels of CRP were influenced independently by two polymorphisms at the CRP locus, CRP 2 and CRP 4. Furthermore, the latter polymorphism was linked/associated with SLE and antinuclear autoantibody production. Thus, the polymorphism associated with reduced basal CRP was also associated with the development of SLE. These data support the hypothesis that defective disposal of potentially immunogenic material is a contributory factor in lupus pathogenesis. The identification of polymorphisms that determine basal CRP levels has implications in ischaemic heart disease, where CRP level is an important predictor of risk. PMID:14645206

Russell, Andrew I.; Graham, Deborah S. Cunninghame; Shepherd, Christopher; Roberton, Cheri A.; Whittaker, John; Meeks, John; Powell, Richard J.; Isenberg, David A.; Walport, Mark J.; Vyse, Timothy J.

2013-01-01

89

Polymorphism at the C-reactive protein locus influences gene expression and predisposes to systemic lupus erythematosus.  

PubMed

Relative deficiency of pentraxin proteins is implicated in the pathogenesis of systemic lupus erythematosus. The C-reactive protein (CRP) response is defective in patients with acute flares of disease, and mice with targeted deletions of the serum amyloid P component gene (Sap) develop a lupus-like illness. In humans, the genes for CRP (CRP) and SAP (APCS) map to 1q23.2 within an interval linked with SLE. We have investigated the candidate genes CRP and APCS in two cohorts totalling 586 UK simplex SLE families. The inheritance of an intronic dinucleotide repeat and seven single nucleotide polymorphisms in the CRP and APCS genes was examined by application of family-based tests of association and linkage. Basal levels of CRP were influenced independently by two polymorphisms at the CRP locus, CRP 2 and CRP 4. Furthermore, the latter polymorphism was linked/associated with SLE and antinuclear autoantibody production. Thus, the polymorphism associated with reduced basal CRP was also associated with the development of SLE. These data support the hypothesis that defective disposal of potentially immunogenic material is a contributory factor in lupus pathogenesis. The identification of polymorphisms that determine basal CRP levels has implications in ischaemic heart disease, where CRP level is an important predictor of risk. PMID:14645206

Russell, Andrew I; Cunninghame Graham, Deborah S; Shepherd, Christopher; Roberton, Cheri A; Whittaker, John; Meeks, John; Powell, Richard J; Isenberg, David A; Walport, Mark J; Vyse, Timothy J

2004-01-01

90

Pregnancy-associated osteoporosis with a heterozygous deactivating LDL receptor-related protein 5 (LRP5) mutation and a homozygous methylenetetrahydrofolate reductase (MTHFR) polymorphism.  

PubMed

Pregnancy-associated osteoporosis (PAO) is a rare, idiopathic disorder that usually presents with vertebral compression fractures (VCFs) within 6 months of a first pregnancy and delivery. Spontaneous improvement is typical. There is no known genetic basis for PAO. A 26-year-old primagravida with a neonatal history of unilateral blindness attributable to hyperplastic primary vitreous sustained postpartum VCFs consistent with PAO. Her low bone mineral density (BMD) seemed to respond to vitamin D and calcium therapy, with no fractures after her next successful pregnancy. Investigation of subsequent fetal losses revealed homozygosity for the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism associated both with fetal loss and with osteoporosis (OP). Because her neonatal unilateral blindness and OP were suggestive of loss-of-function mutation(s) in the gene that encodes LDL receptor-related protein 5 (LRP5), LRP5 exon and splice site sequencing was also performed. This revealed a unique heterozygous 12-bp deletion in exon 21 (c.4454_4465del, p.1485_1488del SSSS) in the patient, her mother and sons, but not her father or brother. Her mother had a normal BMD, no history of fractures, PAO, ophthalmopathy, or fetal loss. Her two sons had no ophthalmopathy and no skeletal issues. Her osteoporotic father (with a family history of blindness) and brother had low BMDs first documented at ages ?40 and 32 years, respectively. Serum biochemical and bone turnover studies were unremarkable in all subjects. We postulate that our patient's heterozygous LRP5 mutation together with her homozygous MTHFR polymorphism likely predisposed her to low peak BMD. However, OP did not cosegregate in her family with the LRP5 mutation, the homozygous MTHFR polymorphism, or even the combination of the two, implicating additional genetic or nongenetic factors in her PAO. Nevertheless, exploration for potential genetic contributions to PAO may explain part of the pathogenesis of this enigmatic disorder and identify some at-risk women. PMID:24014470

Cook, Fiona J; Mumm, Steven; Whyte, Michael P; Wenkert, Deborah

2014-04-01

91

A genetic association study of maternal and fetal candidate genes that predispose to preterm prelabor rupture of membranes (PROM)  

PubMed Central

Objective To determine whether maternal/fetal SNPs in candidate genes are associated with preterm prelabor rupture of membranes (pPROM). Study Design A case-control study was conducted in patients with pPROM (225 mothers and 155 fetuses) and 599 mothers and 628 fetuses with a normal pregnancy; 190 candidate genes and 775 SNPs were studied. Single locus/haplotype association analyses were performed; FDR was used to correct for multiple testing (q*=0.15)]. Results 1) A SNP in TIMP2 in mothers was significantly associated with pPROM(OR=2.12 95% CI [1.47-3.07], p = 0.000068), and this association remained significant after correction for multiple comparisons; 2) Haplotypes for COL4A3 in the mother were associated with pPROM (global p = 0.003); 3) Multilocus analysis identified a three locus model, which included maternal SNPs in COL1A2, DEFA5, and EDN1. Conclusion DNA variants in a maternal gene involved in extracellular matrix metabolism doubled the risk of pPROM. PMID:20673868

ROMERO, Roberto; FRIEL, Lara A.; EDWARDS, Digna R. VELEZ; KUSANOVIC, Juan Pedro; HASSAN, Sonia S.; MAZAKI-TOVI, Shali; VAISBUCH, Edi; KIM, Chong Jai; EREZ, Offer; CHAIWORAPONGSA, Tinnakorn; PEARCE, Brad D.; BARTLETT, Jacquelaine; SALISBURY, Benjamin A.; ANANT, Madan Kumar; VOVIS, Gerald F.; LEE, Min Seob; GOMEZ, Ricardo; BEHNKE, Ernesto; OYARZUN, Enrique; TROMP, Gerard; WILLIAMS, Scott M.; MENON, Ramkumar

2010-01-01

92

Association of the MTHFR A1298C Variant with Unexplained Severe Male Infertility  

PubMed Central

The methylenetetrahydrofolate reductase (MTHFR) gene is one of the main regulatory enzymes involved in folate metabolism, DNA synthesis and remethylation reactions. The influence of MTHFR variants on male infertility is not completely understood. The objective of this study was to analyze the distribution of the MTHFR C677T and A1298C variants using PCR-Restriction Fragment Length Polymorphism (RFLP) in a case group consisting of 344 men with unexplained reduced sperm counts compared to 617 ancestry-matched fertile or normozoospermic controls. The Chi square test was used to analyze the genotype distributions of MTHFR polymorphisms. Our data indicated a lack of association of the C677T variant with infertility. However, the homozygous (C/C) A1298C polymorphism of the MTHFR gene was present at a statistically high significance in severe oligozoospermia group compared with controls (OR?=?3.372, 95% confidence interval CI?=?1.27–8.238; p?=?0.01431). The genotype distribution of the A1298C variants showed significant deviation from the expected Hardy-Weinberg equilibrium, suggesting that purifying selection may be acting on the 1298CC genotype. Further studies are necessary to determine the influence of the environment, especially the consumption of diet folate on sperm counts of men with different MTHFR variants. PMID:22457816

Eloualid, Abdelmajid; Abidi, Omar; Charif, Majida; El houate, Brahim; Benrahma, Houda; Louanjli, Noureddine; Chadli, Elbakkay; Ajjemami, Maria; Barakat, Abdelhamid; Bashamboo, Anu; McElreavey, Ken; Rhaissi, Houria; Rouba, Hassan

2012-01-01

93

Association of MTHFR and PICALM polymorphisms with Alzheimer's disease.  

PubMed

Alzheimer's disease (AD) is a complex neurodegenerative disorder and the primary cause of dementia in the elderly and causes a decrease in cognition, functionality, and behaviour. Genetic risk factors play an important role in the pathogenesis of AD. In this case-control study, we aimed to investigate whether single nucleotide polymorphisms in MTHFR (rs1801133), PICALM (3851719), CLU (rs11136000), and CR1 (rs6701713) are associated with AD. Genotype frequencies were evaluated in 82 late-onset AD patients and 161 elderly healthy controls matched by age and gender. We detected a significant association of the MTHFR rs1801133 and PICALM rs3851179 polymorphisms with AD. The results of this study support the hypothesis that several genes are involved in the aetiology of AD. PMID:25359311

Belcavello, Luciano; Camporez, Daniela; Almeida, Leila D; Morelato, Renato L; Batitucci, Maria C P; de Paula, Flavia

2015-03-01

94

Frequency of APOE, MTHFR and ACE polymorphisms in the Zambian population  

PubMed Central

Background Polymorphisms within the apolipoprotein-E (APOE), Methylenetetrahydrofolate reductase (MTHFR) and Angiotensin I-converting enzyme (ACE) genes has been associated with cardiovascular and cerebrovascular disorders, Alzheimer’s disease and other complex diseases in various populations. The aim of the study was to analyze the allelic and genotypic frequencies of APOE, MTHFR C677T and ACE I/D gene polymorphisms in the Zambian population. Results The allele frequencies of APOE polymorphism in the Zambian populations were 13.8%, 59.5% and 26.7% for the ?2, ?3 and ?4 alleles respectively. MTHFR C677T and ACE I/D allele frequencies were 8.6% and 13.8% for the T and D minor alleles respectively. The ?2?2 genotype and TT genotype were absent in the Zambian population. The genetic distances between Zambian and other African and non-African major populations revealed an independent variability of these polymorphisms. Conclusion We found that the APOE ?3 allele and the I allele of the ACE were significantly high in our study population while there were low frequencies observed for the MTHFR 677 T and ACE D alleles. Our analysis of the APOE, MTHFR and ACE polymorphisms may provide valuable insight into the understanding of the disease risk in the Zambian population. PMID:24679048

2014-01-01

95

Methylation loss at H19 imprinted gene correlates withmethylenetetrahydrofolate reductase gene promoter hypermethylation in semen samples from infertile males  

PubMed Central

Aberrant methylation at the H19 paternal imprinted gene has been identified in different cohorts of infertile males. The causes of H19 methylation errors are poorly understood. In this study, we investigated the methylation status of the H19 gene in semen DNA samples from infertile males affected by MTHFR gene promoter hypermethylation. DNA from normal and abnormal semen samples harbouring MTHFR gene promoter hypermethylated, hmMTHFR-nor and hmMTHFR-abn, and without MTHFR methylation, MTHFR-nor and MTHFR-abn, were investigated for methylation status in the H19 locus using bisulfite-treated DNA PCR, followed by cloning and sequencing. The prevalence of H19 hypomethylated clones was 20% in hmMTHFR-nor and 0% in MTHFR-nor semen samples (p < 0.05), and 28% in hmMTHFR-abn compared with 16% in MTHFR-abn semen samples (p > 0.05). These results underscore the association between H19 methylation defects and hypermethylation of the MTHFR gene promoter in normal semen samples and suggest that aberrant methylation at H19 may occur in the normal sperm of infertile males affected by MTHFR gene dysfunction. These findings provide new insights into the mechanisms causing abnormal methylation in imprinted genes and, in turn, male infertility. PMID:23975186

Rotondo, John C; Selvatici, Rita; Di Domenico, Maura; Marci, Roberto; Vesce, Fortunato; Tognon, Mauro; Martini, Fernanda

2013-01-01

96

High folic acid consumption leads to pseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in mice12345  

PubMed Central

Background: Increased consumption of folic acid is prevalent, leading to concerns about negative consequences. The effects of folic acid on the liver, the primary organ for folate metabolism, are largely unknown. Methylenetetrahydrofolate reductase (MTHFR) provides methyl donors for S-adenosylmethionine (SAM) synthesis and methylation reactions. Objective: Our goal was to investigate the impact of high folic acid intake on liver disease and methyl metabolism. Design: Folic acid–supplemented diet (FASD, 10-fold higher than recommended) and control diet were fed to male Mthfr+/+ and Mthfr+/? mice for 6 mo to assess gene-nutrient interactions. Liver pathology, folate and choline metabolites, and gene expression in folate and lipid pathways were examined. Results: Liver and spleen weights were higher and hematologic profiles were altered in FASD-fed mice. Liver histology revealed unusually large, degenerating cells in FASD Mthfr+/? mice, consistent with nonalcoholic fatty liver disease. High folic acid inhibited MTHFR activity in vitro, and MTHFR protein was reduced in FASD-fed mice. 5-Methyltetrahydrofolate, SAM, and SAM/S-adenosylhomocysteine ratios were lower in FASD and Mthfr+/? livers. Choline metabolites, including phosphatidylcholine, were reduced due to genotype and/or diet in an attempt to restore methylation capacity through choline/betaine-dependent SAM synthesis. Expression changes in genes of one-carbon and lipid metabolism were particularly significant in FASD Mthfr+/? mice. The latter changes, which included higher nuclear sterol regulatory element-binding protein 1, higher Srepb2 messenger RNA (mRNA), lower farnesoid X receptor (Nr1h4) mRNA, and lower Cyp7a1 mRNA, would lead to greater lipogenesis and reduced cholesterol catabolism into bile. Conclusions: We suggest that high folic acid consumption reduces MTHFR protein and activity levels, creating a pseudo-MTHFR deficiency. This deficiency results in hepatocyte degeneration, suggesting a 2-hit mechanism whereby mutant hepatocytes cannot accommodate the lipid disturbances and altered membrane integrity arising from changes in phospholipid/lipid metabolism. These preliminary findings may have clinical implications for individuals consuming high-dose folic acid supplements, particularly those who are MTHFR deficient. PMID:25733650

Christensen, Karen E; Mikael, Leonie G; Leung, Kit-Yi; Lévesque, Nancy; Deng, Liyuan; Wu, Qing; Malysheva, Olga V; Best, Ana; Caudill, Marie A; Greene, Nicholas DE

2015-01-01

97

Gender-Specific Effect of Mthfr Genotype and Neonatal Vigabatrin Interaction on Synaptic Proteins in Mouse Cortex  

PubMed Central

The enzyme methylenetetrahydrofolate reductase (MTHFR) is a part of the homocysteine and folate metabolic pathways, affecting the methylations of DNA, RNA, and proteins. Mthfr deficiency was reported as a risk factor for neurodevelopmental disorders such as autism spectrum disorder and schizophrenia. Neonatal disruption of the GABAergic system is also associated with behavioral outcomes. The interaction between the epigenetic influence of Mthfr deficiency and neonatal exposure to the GABA potentiating drug vigabatrin (GVG) in mice has been shown to have gender-dependent effects on mice anxiety and to have memory impairment effects in a gender-independent manner. Here we show that Mthfr deficiency interacts with neonatal GABA potentiation to alter social behavior in female, but not male, mice. This impairment was associated with a gender-dependent enhancement of proteins implicated in excitatory synapse plasticity in the female cortex. Reelin and fragile X mental retardation 1 protein (FMRP) levels and membrane GluR1/GluR2 ratios were elevated in wild-type mice treated neonatally with GVG and in Mthfr+/? mice treated with saline, but not in Mthfr+/? mice treated with GVG, compared with control groups (wild type treated with saline). A minor influence on the levels of these proteins was observed in male mice cortices, possibly due to high basal protein levels. Interaction between gender, genotype, and treatment was also observed in the GABA pathway. In female mice, GABA A?2/gephyrin ratios were suppressed in all test groups; in male mice, a genotype-specific enhancement of GABA A?2/gephyrin was observed. The lack of an effect on either reln or Fmr1 transcription suggests post-transcriptional regulation of these genes. Taken together, these findings suggest that Mthfr deficiency may interact with neonatal GABA potentiation in a gender-dependent manner to interrupt synaptic function. This may illustrate a possible mechanism for the epigenetic involvement of Mthfr deficiency in neurodevelopmental disorders. PMID:21490592

Blumkin, Elinor; Levav-Rabkin, Tamar; Melamed, Osnat; Galron, Dalia; Golan, Hava M

2011-01-01

98

A potential interaction between COMT and MTHFR genetic variants in Han Chinese patients with bipolar II disorder  

PubMed Central

Bipolar II disorder (BP-II), characterized by recurrent dysregulation of mood, is a serious and chronic psychiatric illness. However, BP-II is commonly under-recognized, even in psychiatric settings. Because dopaminergic disturbance is thought to be involved in the development of bipolar disorder (BPD), it seems essential to investigate dopamine-related genes like the catechol-O-methyltransferase (COMT) gene, which are involved in dopamine metabolism, and the methylenetetrahydrofolate reductase (MTHFR) gene, which may affect COMT methylation and COMT function. The current study examined the association and interaction of the COMT Val158Met and MTHFR C677T variants with BP-II. Nine hundred seventy-eight participants were recruited: 531 with BP-II and 447 healthy controls. The genotypes of the COMT and MTHFR polymorphisms were determined using a polymerase chain reaction-restriction fragment length polymorphism analysis. Logistic regression analysis showed a significant interaction effect of the COMT Val158Met Val/Val genotype and the MTHFR C677T C/T + T/T genotype (P = 0.039) for the protective effect on the odds of developing BP-II. Our findings support preliminary evidence that the COMT and MTHFR genes interact in BP-II, and they imply the connection of both dopaminergic pathways and methylation pathways in the pathogenesis of BP-II. PMID:25744938

Wang, Liang-Jen; Lee, Sheng-Yu; Chen, Shiou-Lan; Chang, Yun-Hsuan; Chen, Po See; Huang, San-Yuan; Tzeng, Nian-Sheng; Chen, Kao Chin; Lee, I. Hui; Wang, Tzu-Yun; Yang, Yen Kuang; Lu, Ru-Band

2015-01-01

99

A potential interaction between COMT and MTHFR genetic variants in Han Chinese patients with bipolar II disorder.  

PubMed

Bipolar II disorder (BP-II), characterized by recurrent dysregulation of mood, is a serious and chronic psychiatric illness. However, BP-II is commonly under-recognized, even in psychiatric settings. Because dopaminergic disturbance is thought to be involved in the development of bipolar disorder (BPD), it seems essential to investigate dopamine-related genes like the catechol-O-methyltransferase (COMT) gene, which are involved in dopamine metabolism, and the methylenetetrahydrofolate reductase (MTHFR) gene, which may affect COMT methylation and COMT function. The current study examined the association and interaction of the COMT Val158Met and MTHFR C677T variants with BP-II. Nine hundred seventy-eight participants were recruited: 531 with BP-II and 447 healthy controls. The genotypes of the COMT and MTHFR polymorphisms were determined using a polymerase chain reaction-restriction fragment length polymorphism analysis. Logistic regression analysis showed a significant interaction effect of the COMT Val158Met Val/Val genotype and the MTHFR C677T C/T + T/T genotype (P = 0.039) for the protective effect on the odds of developing BP-II. Our findings support preliminary evidence that the COMT and MTHFR genes interact in BP-II, and they imply the connection of both dopaminergic pathways and methylation pathways in the pathogenesis of BP-II. PMID:25744938

Wang, Liang-Jen; Lee, Sheng-Yu; Chen, Shiou-Lan; Chang, Yun-Hsuan; Chen, Po See; Huang, San-Yuan; Tzeng, Nian-Sheng; Chen, Kao Chin; Lee, I Hui; Wang, Tzu-Yun; Yang, Yen Kuang; Lu, Ru-Band

2015-01-01

100

Association of Genetic polymorphism of PPAR?-2, ACE, MTHFR, FABP-2 and FTO genes in risk prediction of type 2 diabetes mellitus  

PubMed Central

Type 2 diabetes mellitus (T2DM) is a non-autoimmune, complex, heterogeneous and polygenic metabolic disease condition characterized by persistent elevated blood glucose levels (hyperglycemia). India as said to be the diabetic capital of the world is likely to experience the largest increase in T2DM and a greater number of diabetic individuals in the world by the year 2030. Identification of specific genetic variations in a particular ethnic group has a critical role in understanding the risk of developing T2DM in a much efficient way in future. These genetic variations include numerous types of polymorphisms among which single nucleotide polymorphisms (SNPs) is the most frequent. SNPs are basically located within the regulatory elements of several gene sequences. There are scores of genes interacting with various environmental factors affecting various pathways and sometimes even the whole signalling network that cause diseases like T2DM. This review discusses the biomarkers for early risk prediction of T2DM. Such predictions could be used in order to understand the pathogenesis of T2DM and to better diagnostics, treatment, and eventually prevention. PMID:24156506

2013-01-01

101

Association of genetic polymorphism of PPAR?-2, ACE, MTHFR, FABP-2 and FTO genes in risk prediction of type 2 diabetes mellitus.  

PubMed

Type 2 diabetes mellitus (T2DM) is a non-autoimmune, complex, heterogeneous and polygenic metabolic disease condition characterized by persistent elevated blood glucose levels (hyperglycemia). India as said to be the diabetic capital of the world is likely to experience the largest increase in T2DM and a greater number of diabetic individuals in the world by the year 2030. Identification of specific genetic variations in a particular ethnic group has a critical role in understanding the risk of developing T2DM in a much efficient way in future. These genetic variations include numerous types of polymorphisms among which single nucleotide polymorphisms (SNPs) is the most frequent. SNPs are basically located within the regulatory elements of several gene sequences. There are scores of genes interacting with various environmental factors affecting various pathways and sometimes even the whole signalling network that cause diseases like T2DM. This review discusses the biomarkers for early risk prediction of T2DM. Such predictions could be used in order to understand the pathogenesis of T2DM and to better diagnostics, treatment, and eventually prevention. PMID:24156506

Abbas, Shania; Raza, Syed Tasleem; Ahmed, Faisal; Ahmad, Absar; Rizvi, Saliha; Mahdi, Farzana

2013-01-01

102

Prevalence of MTHFR C677T Polymorphism in North Indian Mothers Having Babies with Trisomy 21 Down Syndrome  

ERIC Educational Resources Information Center

Recent studies have evaluated possible links between polymorphisms in maternal folate metabolism genes and Down syndrome. Some of these studies show a significantly increased prevalence of the C677T polymorphism of the 5,10-methylene tetrahydrofolate reductase (NADPH) gene (MTHFR) among mothers who have had babies with Down syndrome. This study…

Kohli, Utkarsh; Arora, Sadhna; Kabra, Madhulika; Ramakrishnan, Lakshmy; Gulati, Sheffali; Pandey, Ravindra

2008-01-01

103

Comparing techniques for the identification of the MTHFR A1298C polymorphism.  

PubMed

The restriction fragment length polymorphism (RFLP) technique with the MboII enzyme is used by a number of researchers as a methodology for the identification of the genetic polymorphism MTHFR A1298C. However, the reliability of this enzyme for genotyping this polymorphism has been questioned, since the silent polymorphism T1317C, located close to the polymorphic region A1298C on gene MTHFR, also has a recognition site for MboII. Thus, the fragments formed by the digestion of MboII present similar sizes, making it difficult to differentiate the allele MTHFR 1298A in the presence of the allele MTHFR 1317C. Hence, we investigated the A1298C polymorphism in a Brazilian population of renal transplant patients, using the RFLP technique with digestion by Mbo II and using sequencing, in order to examine the concordance between the two techniques. Our results showed an 8.6% difference in genotyping between RFLP and sequencing, but the statistical concordance test presented a kappa coefficient equal to 0.81 (CI 95% 0.74-88), which indicates a virtually perfect concordance, according to the criterion of Landis and Koch. Therefore, we concluded that the RFLP technique is concordant with automated sequencing in the detection of polymorphism A1298C under our laboratory conditions. PMID:19137091

de Alvarenga, Maria Paula Sanches; Pavarino-Bertelli, Erika Cristina; Goloni-Bertollo, Eny Maria

2008-04-01

104

Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: epidemiology, metabolism and the associated diseases.  

PubMed

The Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is associated with various diseases (vascular, cancers, neurology, diabetes, psoriasis, etc) with the epidemiology of the polymorphism of the C677T that varies dependent on the geography and ethnicity. The 5,10-Methylenetetrahydrofolate reductase (MTHFR) locus is mapped on chromosome 1 at the end of the short arm (1p36.6). This enzyme is important for the folate metabolism which is an integral process for cell metabolism in the DNA, RNA and protein methylation. The mutation of the MTHFR gene which causes the C677T polymorphism is located at exon 4 which results in the conversion of valine to alanine at codon 222, a common polymorphism that reduces the activity of this enzyme. The homozygous mutated subjects have higher homocysteine levels while the heterozygous mutated subjects have mildly raised homocysteine levels compared with the normal, non-mutated controls. Hyperhomocysteinemia is an emerging risk factor for various cardiovascular diseases and with the increasing significance of this polymorphism in view of the morbidity and mortality impact on the patients, further prevention strategies and nutritional recommendations with the supplementation of vitamin B12 and folic acid which reduces plasma homocysteine level would be necessary as part of future health education. This literature review therefore focuses on the recent evidence-based reports on the associations of the MTHFR C677T polymorphism and the various diseases globally. PMID:25449138

Liew, Siaw-Cheok; Gupta, Esha Das

2015-01-01

105

Enrichment of MTHFR 677?T in a Chinese long-lived cohort and its association with lipid modulation  

PubMed Central

Background Variants in the Methylenetetrahydrofolate reductase (MTHFR) gene may result in a lowered catalytic activity and associate with subsequent elevated serum homocysteine (Hcy) concentration, abnormal DNA synthesis and methylation, cardiovascular risk, and unhealthy aging. Several investigations on the relationship of MTHFR C677T polymorphism with serum lipid profile and longevity have been conducted in some populations, but the findings remain mixed. Herein, we sought to look at the association between MTHFR C677T and lipid profile in a longevous cohort in Bama, a well-known home of longevity in China. Methods Genotyping of MTHFR C677T was undertaken in 516 long-lived inhabitants (aged 90 and older, long-lived group, LG) and 493 healthy controls (aged 60–75, non-long-lived group, non-LG) recruited from Bama area. Correlation between MTHFR genotypes and lipids was then evaluated. Results T allele and TT genotype were significantly more prevalent in LG (P?=?0.001 and 0.002, respectively), especially in females, than in non-LG. No difference in the tested lipid measures among MTHFR C677T genotypes was observed in LG, non-LG and total population (P?>?0.05 for all). However, female but not male T carriers exhibited higher TC and LDL-C levels than did T noncarriers in the total population and in LG after stratification by sex (P?MTHFR 677?T genotypes and its modest unfavorable impact on lipids in Bama long-lived individuals may imply an existence of other protective genotypes which require further determination. PMID:24968810

2014-01-01

106

The Association of the MTHFR c.1625A>C Genetic Variant with the Risk of Congenital Heart Diseases in the Chinese  

PubMed Central

The purpose of this study is to investigate the association of methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms with the risk of congenital heart diseases (CHD). The genotypes of the MTHFR genetic variant were determined by the polymerase chain reaction–restriction fragment length polymorphism and DNA sequencing methods. Our data suggested that the allelic and genotypic frequencies of CHD patients were significantly different from non-CHD controls. The MTHFR c.1625A>C genetic variant was significantly associated with the increased risk of CHD (CC vs. AA: odds ratio [OR]=2.29, 95% confidence interval [CI] 1.15–4.53, p=0.016; C vs. A: OR=1.47, 95% CI 1.11–1.96, p=0.008). Results from this study indicate that the MTHFR c.1625A>C genetic variant influences the risk of CHD in the studied population. PMID:25494855

Wang, Yuting; Sun, Lei; Du, Weina; Song, Shuang; Wang, Shuo; Jiang, Weiju; Huang, Tianchu

2015-01-01

107

The association of the MTHFR c.1625A>C genetic variant with the risk of congenital heart diseases in the Chinese.  

PubMed

The purpose of this study is to investigate the association of methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms with the risk of congenital heart diseases (CHD). The genotypes of the MTHFR genetic variant were determined by the polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing methods. Our data suggested that the allelic and genotypic frequencies of CHD patients were significantly different from non-CHD controls. The MTHFR c.1625A>C genetic variant was significantly associated with the increased risk of CHD (CC vs. AA: odds ratio [OR]=2.29, 95% confidence interval [CI] 1.15-4.53, p=0.016; C vs. A: OR=1.47, 95% CI 1.11-1.96, p=0.008). Results from this study indicate that the MTHFR c.1625A>C genetic variant influences the risk of CHD in the studied population. PMID:25494855

Wang, Yuting; Sun, Lei; Du, Weina; Song, Shuang; Wang, Shuo; Jiang, Weiju; Huang, Tianchu; Li, Hui

2015-01-01

108

MTHFR polymorphisms C677T and A1298C and associations with IVF outcomes in Brazilian women.  

PubMed

The aim of this study was to investigate the association between MTHFR gene polymorphisms and IVF outcomes in Brazilian women undergoing assisted reproduction treatment. A prospective study was conducted in the Human Reproduction Department at the ABC University School of Medicine and the Ideia Fertility Institute between December 2010 and April 2012. The patient population was 82 women undergoing assisted reproduction cycles. The MTHFR polymorphisms C677T and A1298C were evaluated and compared with laboratory results and pregnancy rates. The C677T variant was associated with proportions of mature (P=0.006) and immature (P=0.003) oocytes whereas the A1298C variant was associated with number of oocytes retrieved (P=0.044). The polymorphisms, whether alone or in combination, were not associated with normal fertilization, good-quality embryo or clinical pregnancy rates. This study suggests that the number and maturity of oocytes retrieved may be related to the MTHFR polymorphisms C677T and A1298C. It is believed that folate has a crucial function in human reproduction and that folate deficiency can compromise the function of the metabolic pathways it is involved in, leading to an accumulation of homocysteine. The gene MTHFR encodes the 5-MTHFR enzyme, which is involved in folate metabolism, and C677T/A1298C polymorphisms of this gene are related to decreased enzyme activity and consequent changes in homocysteine concentration. Folate deficiency and hyperhomocysteinaemia can also compromise fertility and lead to pregnancy complications by affecting the development of oocytes, preparation of endometrial receptivity, implantation of the embryo and pregnancy. In folliculogenesis, hyperhomocysteinaemia can activate apoptosis, leading to follicular atresia and affecting the maturity of oocytes and the quality of embryos cultured in vitro. This study was performed to investigate the association between MTHFR polymorphisms and IVF outcomes in women undergoing assisted reproduction treatment. PMID:24746944

D'Elia, Priscila Queiroz; dos Santos, Aline Amaro; Bianco, Bianca; Barbosa, Caio Parente; Christofolini, Denise Maria; Aoki, Tsutomu

2014-06-01

109

The MTHFR C677T Variant is Associated with Responsiveness to Disulfiram Treatment for Cocaine Dependency  

PubMed Central

Objective: Disulfiram is a one of the few pharmacotherapies for cocaine addiction that shows promise. Since disulfiram and cocaine both affect levels of global methylation we hypothesized the MTHFR gene, whose product is involved in supplying methyl groups for DNA and protein methylation, may be associated with responsiveness to disulfiram in cocaine-dependent individuals. Methods: Sixty-seven cocaine-dependent patients were stabilized on methadone for 2?weeks and then randomized into disulfiram (250?mg/day, N?=?32) and placebo groups (N?=?35) for 10?weeks. Patients were genotyped for the MTHFR (rs1801133, also known as C677T) polymorphism and the data was evaluated for association with cocaine-free urines in the disulfiram or placebo groups. Data from patients that completed all 10?weeks of the study (N?=?56) were analyzed using repeated measures analysis of variance (ANOVA), corrected for population structure. Results: The CT or TT MTHFR genotype group (N?=?32) dropped from 73 to 52% cocaine-positive urines on disulfiram (p?=?0.0001), while the placebo group showed no treatment effect. The CC MTHFR genotype group (N?=?24) showed a smaller, but still significant, reduction in cocaine-positive urines on disulfiram compared to placebo; 81–69% (p?=?0.007). Conclusion: This study indicates that a patient’s MTHFR genotype may be used to identify individuals who might show improved response to disulfiram treatment for cocaine dependence. Clinical Trial: Pharmacogenetics of Disulfiram for Cocaine, clinicaltrials.gov/ct2/show/NCT00149630, NIDA-18197-2, NCT00149630. PMID:23335901

Spellicy, Catherine J.; Kosten, Thomas R.; Hamon, Sara C.; Harding, Mark J.; Nielsen, David A.

2013-01-01

110

Polymorphisms in the pituitary growth hormone gene and its receptor associated with coronary artery disease in a predisposed cohort from India  

Microsoft Academic Search

We investigated the promoter polymorphisms of the pituitary growth hormone gene (GH1) and exon 3 deletion polymorphism (GHRd3) in its receptor gene (GHR) in 299 angiographically proven patients with coronary artery disease (CAD) and 231 asymptomatic controls enrolled in the\\u000a ongoing Indian Atherosclerosis Research Study. Real time PCR based analysis of the GHR variant showed significant association of the GHRd3

Arindam Maitra; Jayashree Shanker; Debabrata Dash; Prathima R. Sannappa; Shibu John; Pratibha Siwach; Veena S. Rao; H. Sridhara; Vijay V. Kakkar

2010-01-01

111

Capturing the biological impact of CDKN2A and MC1R genes as an early predisposing event in melanoma and non melanoma skin cancer  

PubMed Central

Germline mutations in CDKN2A and/or red hair color variants in MC1R genes are associated with an increased susceptibility to develop cutaneous melanoma or non melanoma skin cancer. We studied the impact of the CDKN2A germinal mutation p.G101W and MC1R variants on gene expression and transcription profiles associated with skin cancer. To this end we set-up primary skin cell co-cultures from siblings of melanoma prone-families that were later analyzed using the expression array approach. As a result, we found that 1535 transcripts were deregulated in CDKN2A mutated cells, with over-expression of immunity-related genes (HLA-DPB1, CLEC2B, IFI44, IFI44L, IFI27, IFIT1, IFIT2, SP110 and IFNK) and down-regulation of genes playing a role in the Notch signaling pathway. 3570 transcripts were deregulated in MC1R variant carriers. In particular, genes related to oxidative stress and DNA damage pathways were up-regulated as well as genes associated with neurodegenerative diseases such as Parkinson’s, Alzheimer and Huntington. Finally, we observed that the expression signatures indentified in phenotypically normal cells carrying CDKN2A mutations or MC1R variants are maintained in skin cancer tumors (melanoma and squamous cell carcinoma). These results indicate that transcriptome deregulation represents an early event critical for skin cancer development. PMID:24742402

Puig-Butille, Joan Anton; Escámez, María José; Garcia-Garcia, Francisco; Tell-Marti, Gemma; Fabra, Àngels; Martínez-Santamaría, Lucía; Badenas, Celia; Aguilera, Paula; Pevida, Marta; Dopazo, Joaquín; del Río, Marcela; Puig, Susana

2014-01-01

112

A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity.  

PubMed

A common mutation in methylenetetrahydrofolate reductase (MTHFR), C677T, results in a thermolabile variant with reduced activity. Homozygous mutant individuals (approximately 10% of North Americans) are predisposed to mild hyperhomocysteinemia, when their folate status is low. This genetic-nutrient interactive effect is believed to increase the risk for neural tube defects and vascular disease. In this communication, we characterize a second common variant in MTHFR (A1298C), an E to A substitution. Homozygosity was observed in approximately 10% of Canadian individuals. This polymorphism was associated with decreased enzyme activity; homozygotes had approximately 60% of control activity in lymphocytes. Heterozygotes for both the C677T and the A1298C mutation, approximately 15% of individuals, had 50-60% of control activity, a value that was lower than that seen in single heterozygotes for the C677T variant. No individuals were homozygous for both mutations. Additional studies of the A1298C mutation, in the absence and presence of the C677T mutation, are warranted, to adequately address the role of this new genetic variant in complex traits. A silent genetic variant, T1317C, was identified in the same exon. It was relatively infrequent (allele frequency 5%) in our study group, but was quite common in a small sample of African individuals (allele frequency 39%). PMID:9719624

Weisberg, I; Tran, P; Christensen, B; Sibani, S; Rozen, R

1998-07-01

113

High-resolution array CGH profiling identifies Na/K transporting ATPase interacting 2 (NKAIN2) as a predisposing candidate gene in neuroblastoma.  

PubMed

Neuroblastoma (NB), the most common solid cancer in early childhood, usually occurs sporadically but also its familial occurance is known in 1-2% of NB patients. Germline mutations in the ALK and PHOX2B genes have been found in a subset of familial NBs. However, because some individuals harbouring mutations in these genes do not develop this tumor, additional genetic alterations appear to be required for NB pathogenesis. Herein, we studied an Italian family with three NB patients, two siblings and a first cousin, carrying an ALK germline-activating mutation R1192P, that was inherited from their unaffected mothers and with no mutations in the PHOX2B gene. A comparison between somatic and germline DNA copy number changes in the two affected siblings by a high resolution array-based Comparative Genomic Hybridization (CGH) analysis revealed a germline gain at NKAIN2 (Na/K transporting ATPase interacting 2) locus in one of the sibling, that was inherited from the parent who does not carry the ALK mutation. Surprisingly, NKAIN2 was expressed at high levels also in the affected sibling that lacks the genomic gain at this locus, clearly suggesting the existance of other regulatory mechanisms. High levels of NKAIN2 were detected in the MYCN-amplified NB cell lines and in the most aggressive NB lesions as well as in the peripheral blood of a large cohort of NB patients. Consistent with a role of NKAIN2 in NB development, NKAIN2 was down-regulated during all-trans retinoic acid differentiation in two NB cell lines. Taken together, these data indicate a potential role of NKAIN2 gene in NB growth and differentiation. PMID:24205241

Romania, Paolo; Castellano, Aurora; Surace, Cecilia; Citti, Arianna; De Ioris, Maria Antonietta; Sirleto, Pietro; De Mariano, Marilena; Longo, Luca; Boldrini, Renata; Angioni, Adriano; Locatelli, Franco; Fruci, Doriana

2013-01-01

114

Genetic basis of Creutzfeldt-Jakob disease in the United Kingdom: a systematic analysis of predisposing mutations and allelic variation in the PRNP gene  

Microsoft Academic Search

Creutzfeldt-Jakob disease (CJD) is a transmissible neurodegenerative disorder characterized by the accumulation of aggregates\\u000a of a cellular protein, PrP, in the brain. In both human and animals, genetic alterations to the gene encoding PrP (PRNP in human) modulate susceptiblity to CJD. The recent epidemic of bovine spongiform encephalopathy in the UK has raised the\\u000a possibility of transmission from animal produce

Otto Windl; Maureen Dempster; J. Peter Estibeiro; Richard Lathe; Rajith de Silva; Thomas Esmonde; Robert Will; Anthea Springbett; Tracy A. Campbell; Katie C. L. Sidle; Mark S. Palmer; John Collinge

1996-01-01

115

MTHFR 677C>T Polymorphism Increases the Male Infertility Risk: A Meta-Analysis Involving 26 Studies  

PubMed Central

Background and Objectives Methylenetetrahydrofolate reductase (MTHFR) polymorphism may be a risk factor for male infertility. However, the epidemiologic studies showed inconsistent results regarding MTHFR polymorphism and the risk of male infertility. Therefore, we performed a meta-analysis of published case-control studies to re-examine the controversy. Methods Electronic searches of PubMed, EMBASE, Google Scholar and China National Knowledge Infrastructure (CNKI) were conducted to select eligible literatures for this meta-analysis (updated to June 19, 2014). According to our inclusion criteria and the Newcastle-Ottawa Scale (NOS), only high quality studies that observed the association between MTHFR polymorphism and male infertility risk were included. Crude odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of association between the MTHFR polymorphism and male infertility risk. Results Twenty-six studies involving 5,575 cases and 5,447 controls were recruited. Overall, MTHFR 677C>T polymorphism showed significant associations with male infertility risk in both fixed effects (CT+TT vs. CC: OR = 1.34, 95% CI: 1.23–1.46) and random effects models (CT+TT vs. CC: OR = 1.39, 95% CI: 1.19–1.62). Further, when stratified by ethnicity, sperm concentration and control sources, the similar results were observed in Asians, Caucasians, Azoo or OAT subgroup and both in population-based and hospital-based controls. Nevertheless, no significant association was only observed in oligo subgroup. Conclusions Our results indicated that the MTHFR polymorphism is associated with an increased risk of male infertility. Further well-designed analytical studies are necessary to confirm our conclusions and evaluate gene-environment interactions with male infertility risk. PMID:25793386

Gong, Mancheng; Dong, Wenjing; He, Tingyu; Shi, Zhirong; Huang, Guiying; Ren, Rui; Huang, Sichong; Qiu, Shaopeng; Yuan, Runqiang

2015-01-01

116

Polymorphisms in the pituitary growth hormone gene and its receptor associated with coronary artery disease in a predisposed cohort from India.  

PubMed

We investigated the promoter polymorphisms of the pituitary growth hormone gene (GH1) and exon 3 deletion polymorphism (GHRd3) in its receptor gene (GHR) in 299 angiographically proven patients with coronary artery disease (CAD) and 231 asymptomatic controls enrolled in the ongoing Indian Atherosclerosis Research Study. Real time PCR based analysis of the GHR variant showed significant association of the GHRd3 deletion allele with CAD (OR 0.48, 95% CI: 0.30-0.76, P = 0.0014) and a dominant model of inheritance (Akaike information criterion = 482). The deletion allele showed significant association with high plasma HDL-c levels (P = 0.001). Sequencing of the proximal promoter region of GH1 revealed 12 novel polymorphisms and a TAGA haplotype constituted by the functional SNPs rs2005171, rs11568828, rs2005172 and rs6171, that showed significant association with CAD alone (adjusted OR of 3.31 (95% CI = 1.33-8.29, P = 0.011) and in CAD patients with diabetes (P = 0.019). Mean standardized height was associated with three of the four haplotype-tagging SNPs in the cohort (P ? 0.03). Eleven of the 12 polymorphic promoter SNPs contributed to 14.7% of variation in height in females in the whole dataset (P = 0.029). CAD patients with history of stroke exhibited marginally significantly lower mean height as compared to rest of the cohort (P < 0.006). In conclusion, genetic polymorphisms in the GHR gene and its ligand, GH1, may modulate the risk of CAD in the Asian Indian population. PMID:21273694

Maitra, Arindam; Shanker, Jayashree; Dash, Debabrata; Sannappa, Prathima R; John, Shibu; Siwach, Pratibha; Rao, Veena S; Sridhara, H; Kakkar, Vijay V

2010-12-01

117

Contribution of GSTM1, GSTT1, and MTHFR polymorphisms to end-stage renal disease of unknown etiology in Mexicans  

PubMed Central

Oxidative stress is increased in chronic kidney disease, owing to an imbalance between the oxidative and antioxidant pathways as well as a state of persistent hyperhomocysteinemia. The enzymes glutathione S-transferases (GSTs) and methylenetetrahydrofolate reductase (MTHFR) are implicated in the regulation of these pathways. This study investigates the association between polymorphisms in the Glutathione S-transferase Mu 1 (GSTM1), glutathione S-transferase theta 1 (GSTT1), and MTHFR genes and end-stage renal disease (ESRD) of unknown etiology in patients in Mexico. A Case-control study included 110 ESRD patients and 125 healthy individuals. GSTM1 and GSTT1 genotypes were determined using the multiplex polymerase chain reaction (PCR). The MTHFR C677T polymorphism was studied using a PCR/restriction fragment length polymorphism method. In ESRD patients, GSTM1 and GSTT1 null genotype frequencies were 61% and 7% respectively. GSTM1 genotype frequencies differed significantly between groups, showing that homozygous deletion of the GSTM1 gene was associated with susceptibility to ESRD of unknown etiology (P = 0.007, odds ratios = 2.05, 95% confidence interval 1.21-3.45). The MTHFR C677T polymorphism genotype and allele distributions were similar in both groups (P > 0.05), and the CT genotype was the most common genotype in both groups (45.5% and 46.6%). Our findings suggest that the GSTM1 null polymorphism appears to be associated with the ESRD of unknown etiology in patients in Mexico. PMID:24339523

Gutiérrez-Amavizca, B. E.; Orozco-Castellanos, R.; Ortíz-Orozco, R.; Padilla-Gutiérrez, J.; Valle, Y.; Gutiérrez-Gutiérrez, N.; García-García, G.; Gallegos-Arreola, M.; Figuera, L. E.

2013-01-01

118

Association of the Maternal MTHFR C677T Polymorphism with Susceptibility to Neural Tube Defects in Offsprings: Evidence from 25 Case-Control Studies  

PubMed Central

Background Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in folate metabolism and is involved in DNA methylation, DNA synthesis, and DNA repair. In addition, it is a possible risk factor in neural tube defects (NTDs). The association of the C677T polymorphism in the MTHFR gene and NTD susceptibility has been widely demonstrated, but the results remain inconclusive. In this study, we performed a meta-analysis with 2429 cases and 3570 controls to investigate the effect of the MTHFR C677T polymorphism on NTDs. Methods An electronic search of PubMed and Embase database for papers on the MTHFR C677T polymorphism and NTD risk was performed. All data were analysed with STATA (version 11). Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association. Sensitivity analysis, test of heterogeneity, cumulative meta-analysis, and assessment of bias were performed in our meta-analysis. Results A significant association between the MTHFR C677T polymorphism and NTD susceptibility was revealed in our meta-analysis ( TT versus CC: OR ?=?2.022, 95% CI: 1.508, 2.712; CT+TT versus CC: OR ?=?1.303, 95% CI: 1.089, 1.558; TT versus CC+CT: OR ?=?1.716, 95% CI: 1.448, 2.033; 2TT+CT versus 2CC+CT: OR ?=?1.330, 95% CI: 1.160, 1.525). Moreover, an increased NTD risk was found after stratification of the MTHFR C677T variant data by ethnicity and source of controls. Conclusion The results suggested the maternal MTHFR C677T polymorphism is a genetic risk factor for NTDs. Further functional studies to investigate folate-related gene polymorphisms, periconceptional multivitamin supplements, complex interactions, and the development of NTDs are warranted. PMID:23056169

Zou, Peng; Ji, Guixiang; Gu, Aihua; Zhao, Peng

2012-01-01

119

A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration  

PubMed Central

Age-related macular degeneration (AMD) is the most frequent cause of irreversible blindness in the elderly in developed countries. Our previous studies implicated activation of complement in the formation of drusen, the hallmark lesion of AMD. Here, we show that factor H (HF1), the major inhibitor of the alternative complement pathway, accumulates within drusen and is synthesized by the retinal pigmented epithelium. Because previous linkage analyses identified chromosome 1q25-32, which harbors the factor H gene (HF1/CFH), as an AMD susceptibility locus, we analyzed HF1 for genetic variation in two independent cohorts comprised of ?900 AMD cases and 400 matched controls. We found association of eight common HF1 SNPs with AMD; two common missense variants exhibit highly significant associations (I62V, ?2 = 26.1 and P = 3.2 × 10-7 and Y402H, ?2 = 54.4 and P = 1.6 × 10-13). Haplotype analysis reveals that multiple HF1 variants confer elevated or reduced risk of AMD. One common at-risk haplotype is present at a frequency of 50% in AMD cases and 29% in controls [odds ratio (OR) = 2.46, 95% confidence interval (1.95-3.11)]. Homozygotes for this haplotype account for 24% of cases and 8% of controls [OR = 3.51, 95% confidence interval (2.13-5.78)]. Several protective haplotypes are also identified (OR = 0.44-0.55), further implicating HF1 function in the pathogenetic mechanisms underlying AMD. We propose that genetic variation in a regulator of the alternative complement pathway, when combined with a triggering event, such as infection, underlie a major proportion of AMD in the human population. PMID:15870199

Hageman, Gregory S.; Anderson, Don H.; Johnson, Lincoln V.; Hancox, Lisa S.; Taiber, Andrew J.; Hardisty, Lisa I.; Hageman, Jill L.; Stockman, Heather A.; Borchardt, James D.; Gehrs, Karen M.; Smith, Richard J. H.; Silvestri, Giuliana; Russell, Stephen R.; Klaver, Caroline C. W.; Barbazetto, Irene; Chang, Stanley; Yannuzzi, Lawrence A.; Barile, Gaetano R.; Merriam, John C.; Smith, R. Theodore; Olsh, Adam K.; Bergeron, Julie; Zernant, Jana; Merriam, Joanna E.; Gold, Bert; Dean, Michael; Allikmets, Rando

2005-01-01

120

Association between MTHFR C677T polymorphism and congenital heart disease : A family-based meta-analysis.  

PubMed

Congenital heart disease (CHD) is the most common type of birth defect. It is suspected that polymorphisms in folate metabolism are associated with an increased risk of CHD, but the conclusion remains unclear. Studies have reported that the MTHFR C677T polymorphism was associated with the development of structural congenital heart malformations. The objective of this study was to conduct a meta-analysis of available studies to identify common polymorphisms in the MTHFR gene in children with CHD and their mothers and to test for an association between genotype and disease. In all, 19 eligible studies comprising 4,219 cases and 20,123 controls were included in this meta-analysis. A significant association was found between the MTHFR C677T polymorphism and CHD risk (OR: 1.26; 95?% CI =?1.06-1.51; p?=?0.009) with no strong evidence of heterogeneity (I(2)?=?39?%) in the fetal analysis. In the maternal analysis, the MTHFR C677T polymorphism was significantly associated with CHD risk (OR =?1.52; 95?% CI =? 1.09-2.11; p?=?0.01) with significant heterogeneity (I(2)?=?63?%). PMID:25256053

Li, Z; Jun, Y; Zhong-Bao, R; Jie, L; Jian-Ming, L

2014-09-27

121

Prevalence of MTHFR C677T and MS A2756G polymorphisms in major depressive disorder, and their impact on response to fluoxetine treatment  

Technology Transfer Automated Retrieval System (TEKTRAN)

To examine the prevalence of the C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene and the A2756G polymorphism of methionine synthase (MS), and their impact on antidepressant response. We screened 224 subjects (52% female, mean age 39 +/- 11 years) with SCID-diagnosed major...

122

Evaluation of the MTHFR A1298C variant in leukoaraiosis.  

PubMed

Vascular demyelinization of the white matter of the brain is referred to as leukoaraiosis (LA). This very frequent entity is associated with a cognitive decline, thereby resulting in a deteriorating quality of life. Besides poorly controlled hypertension and aging, its development is reported to be associated with an elevated serum homocysteine level. Although the methylenetetrahydrofolate reductase (MTHFR) C677T genetic variant is associated with an elevated serum homocysteine level, it has not been proved to be an independent risk factor for LA. The aim of the present study was to examine whether the MTHFR A1298C genetic variant, which is also believed to be unfavorable, is associated with the presence of LA. The clinical and genetic data on 198 LA patients and 235 neuroimaging alteration-free controls were analyzed. The presence of the A1298C or the 1298CC variant was calculated to be a risk factor for LA, as compared with the absence of both of them. The clustering of the heterozygous A1298C and C677T variants was proved to involve the risk of LA. Our results suggest that the MTHFR A1298C variant confers an independent genetic risk of LA, and this pathological role may be amplified by the MTHFR C677T variant. PMID:21845428

Szolnoki, Zoltan; Szaniszlo, Istvan; Szekeres, Marta; Hitri, Krisztina; Kondacs, Andras; Mandi, Yvette; Nedo, Erika; Somogyvari, Ferenc

2012-03-01

123

Association of methylenetetrahytrofolate reductase (MTHFR) C677T and A1298C polymorphisms with the susceptibility of childhood acute lymphoblastic leukaemia (ALL) in Chinese population  

PubMed Central

Background The aim of this study was to investigate the relationship between the polymorphisms of the methylenetetrahytrofolate reductase (MTHFR) gene and susceptibility to childhood acute lymphoblastic leukemia (ALL). Methods A case–control study was conducted among 98 children with ALL and 93 age- and sex- matched non-ALL controls. Genotyping of MTHFR C677T and A1298C polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The odds ratios (ORs) of MTHFR genotypes were used to assess the associations of these polymorphisms with childhood ALL susceptibility. Results No significant differences were observed for frequencies of the 677CC, 677CT and 677TT genotypes between patients and controls. Frequencies of the 1298AA, 1298 AC and 1298CC genotypes between the two groups were significantly different. The risk of ALL with the 1298C allele carriers (AC?+?CC) was elevated by 1.1 times compared with the AA genotype [OR?=?2.100; 95% CI (1.149; 3.837); P?=?0.015]. Conclusions The MTHFR A1298C polymorphism is associated with susceptibility to childhood ALL in the Chinese population. PMID:24476575

2014-01-01

124

Association between MTHFR polymorphisms and congenital heart disease: a meta-analysis based on 9,329 cases and 15,076 controls.  

PubMed

The aim of our study was to evaluate the association between polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene and the risk for congenital heart disease (CHD). Electronic literature databases were searched to identify eligible studies published before Jun, 2014. The association was assessed by the odds ratio (OR) with a 95% confidence interval (CI). The publication bias was explored using Begg's test. Sensitivity analysis was performed to evaluate the stability of the crude results. A total of 35 studies were included in this meta-analysis. For the MTHFR C677T polymorphism, we detected significant association in all genetic models for Asian children and the maternal population. Significant association was also detected in T vs. C for a Caucasian paediatric population (OR = 1.163, 95% CI: 1.008-1.342) and in both T vs. C (OR = 1.125, 95% CI: 1.043-1.214) and the dominant model (OR = 1.216, 95% CI:b1.096-1.348) for a Caucasian maternal population. For the MTHFR A1298C polymorphism, the association was detected in CC vs. AC for the Caucasian paediatric population (OR = 1.484, 95% CI: 1.035-2.128). Our results support the MTHFR -677T allele as a susceptibility factor for CHD in the Asian maternal population and the -1298 C allele as a risk factor in the Caucasian paediatric population. PMID:25472587

Xuan, Chao; Li, Hui; Zhao, Jin-Xia; Wang, Hong-Wei; Wang, Yi; Ning, Chun-Ping; Liu, Zhen; Zhang, Bei-Bei; He, Guo-Wei; Lun, Li-Min

2014-01-01

125

Association Between MTHFR Polymorphisms and Congenital Heart Disease: A Meta-analysis based on 9,329 cases and 15,076 controls  

PubMed Central

The aim of our study was to evaluate the association between polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene and the risk for congenital heart disease (CHD). Electronic literature databases were searched to identify eligible studies published before Jun, 2014. The association was assessed by the odds ratio (OR) with a 95% confidence interval (CI). The publication bias was explored using Begg's test. Sensitivity analysis was performed to evaluate the stability of the crude results. A total of 35 studies were included in this meta-analysis. For the MTHFR C677T polymorphism, we detected significant association in all genetic models for Asian children and the maternal population. Significant association was also detected in T vs. C for a Caucasian paediatric population (OR = 1.163, 95% CI: 1.008–1.342) and in both T vs. C (OR = 1.125, 95% CI: 1.043–1.214) and the dominant model (OR = 1.216, 95% CI:b1.096–1.348) for a Caucasian maternal population. For the MTHFR A1298C polymorphism, the association was detected in CC vs. AC for the Caucasian paediatric population (OR = 1.484, 95% CI: 1.035–2.128). Our results support the MTHFR -677T allele as a susceptibility factor for CHD in the Asian maternal population and the -1298C allele as a risk factor in the Caucasian paediatric population. PMID:25472587

Xuan, Chao; Li, Hui; Zhao, Jin-Xia; Wang, Hong-Wei; Wang, Yi; Ning, Chun-Ping; Liu, Zhen; Zhang, Bei-Bei; He, Guo-Wei; Lun, Li-Min

2014-01-01

126

Primer-engineered multiplex PCR-RFLP for detection of MTHFR C677T, prothrombin G20210A and factor V Leiden mutations.  

PubMed

Single-nucleotide polymorphisms in the genes that code for coagulation factors V (factor V Leiden) and II (prothrombin, G20210A), as well as the methylenetetrahydrofolate reductase (MTHFR, C677T) gene, have been implicated in the majority of cases of hereditary thrombophilia. We have developed a multiplex PCR-RFLP assay based on MnlI endonuclease digestion for the simultaneous detection of mutations in the FV, FII, and MTHFR genes. Digested amplification products were analyzed by gel electrophoresis in a single gel lane and visualized by ethidium bromide. This approach is a rapid and convenient method, hence economic, that alternate to others described for the detection of FVL, G20210A and C677T mutations. PMID:17275807

Koksal, Vedat; Baris, Ibrahim; Etlik, Ozdal

2007-08-01

127

FACTORS PREDISPOSING CALVES FOR E. COLI ENTERITIS  

E-print Network

FACTORS PREDISPOSING CALVES FOR E. COLI ENTERITIS L. PROHÁSZKA Vetevinavy Medical Reseavch outbreaks of E. coli enteritis were studied. It was found that in newborn calves the serum bicarbonate level rose/32-35 meq/l/at 2-5 days of age at the critical time of E. coli infection and normalized again/22

Boyer, Edmond

128

Macrolide antibiotics allosterically predispose the ribosome for translation arrest  

PubMed Central

Translation arrest directed by nascent peptides and small cofactors controls expression of important bacterial and eukaryotic genes, including antibiotic resistance genes, activated by binding of macrolide drugs to the ribosome. Previous studies suggested that specific interactions between the nascent peptide and the antibiotic in the ribosomal exit tunnel play a central role in triggering ribosome stalling. However, here we show that macrolides arrest translation of the truncated ErmDL regulatory peptide when the nascent chain is only three amino acids and therefore is too short to be juxtaposed with the antibiotic. Biochemical probing and molecular dynamics simulations of erythromycin-bound ribosomes showed that the antibiotic in the tunnel allosterically alters the properties of the catalytic center, thereby predisposing the ribosome for halting translation of specific sequences. Our findings offer a new view on the role of small cofactors in the mechanism of translation arrest and reveal an allosteric link between the tunnel and the catalytic center of the ribosome. PMID:24961372

Sothiselvam, Shanmugapriya; Liu, Bo; Han, Wei; Ramu, Haripriya; Klepacki, Dorota; Atkinson, Gemma Catherine; Brauer, Age; Remm, Maido; Tenson, Tanel; Schulten, Klaus; Vázquez-Laslop, Nora; Mankin, Alexander S.

2014-01-01

129

MAT2A mutations predispose individuals to thoracic aortic aneurysms.  

PubMed

Up to 20% of individuals who have thoracic aortic aneurysms or acute aortic dissections but who do not have syndromic features have a family history of thoracic aortic disease. Significant genetic heterogeneity is established for this familial condition. Whole-genome linkage analysis and exome sequencing of distant relatives from a large family with autosomal-dominant inheritance of thoracic aortic aneurysms variably associated with the bicuspid aortic valve was used for identification of additional genes predisposing individuals to this condition. A rare variant, c.1031A>C (p.Glu344Ala), was identified in MAT2A, which encodes methionine adenosyltransferase II alpha (MAT II?). This variant segregated with disease in the family, and Sanger sequencing of DNA from affected probands from unrelated families with thoracic aortic disease identified another MAT2A rare variant, c.1067G>A (p.Arg356His). Evidence that these variants predispose individuals to thoracic aortic aneurysms and dissections includes the following: there is a paucity of rare variants in MAT2A in the population; amino acids Glu344 and Arg356 are conserved from humans to zebrafish; and substitutions of these amino acids in MAT I? are found in individuals with hypermethioninemia. Structural analysis suggested that p.Glu344Ala and p.Arg356His disrupt MAT II? enzyme function. Knockdown of mat2aa in zebrafish via morpholino oligomers disrupted cardiovascular development. Co-transfected wild-type human MAT2A mRNA rescued defects of zebrafish cardiovascular development at significantly higher levels than mRNA edited to express either the Glu344 or Arg356 mutants, providing further evidence that the p.Glu344Ala and p.Arg356His substitutions impair MAT II? function. The data presented here support the conclusion that rare genetic variants in MAT2A predispose individuals to thoracic aortic disease. PMID:25557781

Guo, Dong-chuan; Gong, Limin; Regalado, Ellen S; Santos-Cortez, Regie L; Zhao, Ren; Cai, Bo; Veeraraghavan, Sudha; Prakash, Siddharth K; Johnson, Ralph J; Muilenburg, Ann; Willing, Marcia; Jondeau, Guillaume; Boileau, Catherine; Pannu, Hariyadarshi; Moran, Rocio; Debacker, Julie; Bamshad, Michael J; Shendure, Jay; Nickerson, Deborah A; Leal, Suzanne M; Raman, C S; Swindell, Eric C; Milewicz, Dianna M

2015-01-01

130

Hyperhomocysteinemia and MTHFR Polymorphisms as Antenatal Risk Factors of White Matter Abnormalities in Two Cohorts of Late Preterm and Full Term Newborns  

PubMed Central

Higher total homocysteine (tHcy) levels, and C677T and A1298C methylenetetrahydrofolate (MTHFR) polymorphisms, have been reported in preterm or full term newborns with neonatal encephalopathy following perinatal hypoxic-ischemic insult. This study investigated the causal role of tHcy and MTHFR polymorphisms together with other acquired risk factors on the occurrence of brain white matter abnormalities (WMA) detected by cranial ultrasound scans (cUS) in a population of late preterm and full term infants. A total of 171 newborns (81?M, 47.4%), 45 (26.3%) born <37?wks, and 126 (73.7%) born ?37?wks were recruited in the study. cUS detected predominant WMA pattern in 36/171 newborns (21.1%) mainly characterized by abnormal periventricular white matter signal and mild-to-moderate periventricular white matter volume loss with ventricular dilatation (6/36, 16.6%). WMA resulted in being depending on tHcy levels (P < 0.014), lower GA (P < 0.000), lower Apgar score at 1 minutes (P < 0.000) and 5 minutes (P < 0.000), and 1298AC and 677CT/1298AC genotypes (P < 0.000 and P < 0.000). In conclusion, both acquired and genetic predisposing antenatal factors were significantly associated with adverse neonatal outcome and WMA. The role of A1298C polymorphism may be taken into account for prenatal assessment and treatment counseling.

Marseglia, Lucia M.; Nicotera, Antonio; Salpietro, Vincenzo; Giaimo, Elisa; Cardile, Giovanna; Bonsignore, Maria; Alibrandi, Angela; Caccamo, Daniela; Manti, Sara; D'Angelo, Gabriella; Mamì, Carmelo; Di Rosa, Gabriella

2015-01-01

131

Homocysteine and nitrite levels are modulated by MTHFR 677C>T polymorphism in obese women treated with simvastatin.  

PubMed

Higher homocysteine (Hcy) levels are associated with cardiovascular risk. The aim of the present study was to evaluate the effect of simvastatin treatment on circulating Hcy levels in obese women without hypertension, diabetes or dyslipidaemia; and to determine whether the 677C>T polymorphism located in methylenetetrahydrofolate reductase (NAD(P)H) (MTHFR) gene modulates the effects of this treatment on Hcy and nitrite (as a biomarker of nitric oxide (NO) bioavailability). Twenty-five obese women (body mass index ? 30 kg/m(2) ) who had received 20 mg/day simvastatin for 6 weeks were enrolled in the study. Venous blood samples were collected to measure plasma biomarkers and gene polymorphisms. Simvastatin treatment significantly reduced total cholesterol, low-density lipoprotein-cholesterol, thiobarbituric acid-reactive substances, high-sensitivity C-reactive protein and Hcy, whereas nitrite levels were increased. The reduction in Hcy levels in carriers of the T allele was -20.3% compared with -9.4% in patients with the CC genotype. Importantly, before treatment, nitrite levels were significantly higher in patients with the CC genotype compared with T allele carriers, whereas after treatment these levels were similar between groups. Our findings demonstrate that obese women without comorbidities and carrying the T variant of the 677C>T polymorphism of MTHFR exhibit benefits with simvastatin treatment, mainly in terms of increased NO levels. PMID:25115547

Villela, Maria P; Andrade, Vanessa L; Eccard, Bryelle; Jordão, Alceu A; Sertório, Jonas T; Tanus-Santos, Jose E; Silva, Ieda F O; Silveira, Josianne N; Sandrim, Valéria C

2014-10-01

132

Meta-analysis on MTHFR polymorphism and lung cancer susceptibility in East Asian populations  

PubMed Central

Lung cancer is the most frequently occurring type of cancer worldwide and the leading cause of cancer mortality. Environmental and genetic factors play important roles in lung carcinogenesis. The aim of this meta-analysis was to investigate the association between methylenetetrahydrofolate reductase (MTHFR) polymorphism and the risk of lung cancer in East Asian populations. Related articles were identified through searching literature databases, such as PubMed, EMBASE, Web of Science, Chinese Biomedicine and CNKI. The odds ratio (OR) values in those studies were incorporated by meta-analysis to assess lung cancer susceptibility associated with the MTHFR mutation genotype. The MTHFR C677TT genotype exhibited a significantly increased risk of lung cancer compared to the MTHFR 677CC/CT genotype (OR=1.24; 95% CI, 1.01–1.52). No relationship was identified between the other MTHFR C677T genetic models and the risk of lung cancer and there was no significantly increased risk of lung cancer in A1298C genetic models. In a subgroup of hospital-based controls, according to the source of controls, the C677TT genotype exhibited a significantly increased risk of lung cancer, compared to the C677CC genotype (OR=3.01; 95% CI, 1.07–8.46). In the stratified analysis, the study indicated that the MTHFR 677TT genotype was associated with a significant increase in the risk of lung squamous carcinoma (OR=1.53; 95% CI, 1.09–2.14), whereas no association was observed between the MTHFR C677TT genotype and the risk of lung adenocarcinoma. No association was observed between MTHFR C677TT polymorphism and the risk of lung cancer when smoking was considered. In conclusion, the meta-analysis results suggested that MTHFR C677T polymorphisms exhibit a significantly increased risk of lung cancer and that the MTHFR 677TT genotype is associated with a significantly increased risk of lung squamous carcinoma. PMID:24648965

ZHANG, XUE-DE; LI, YAN-TING; YANG, SHUAN-YING; LI, WEI

2013-01-01

133

The effect of folic acid deficiency and MTHFR C677T polymorphism on chromosome damage in human lymphocytes in vitro.  

PubMed

We performed a comprehensive study on the genotoxic and cytotoxic effects of in vitro folic acid deficiency on primary human lymphocytes. Lymphocytes were cultured in medium containing 12-120 nM folic acid for 9 days in a novel cytokinesis-block micronucleus (CBMN) assay system (n = 20). Besides identifying optimal folic acid concentrations for in vitro genomic stability, we tested the hypothesis that lymphocytes from individuals homozygous for the C677T methylenetetrahydrofolate reductase (MTHFR) polymorphism (TTs, n = 10) are protected against chromosome damage relative to controls (CCs, n = 10) under conditions of folic acid deficiency. This hypothesis is based on the assumption that reduced MTHFR activity in TT lymphocytes causes a diversion of 5,10-methylene tetrahydrofolate toward thymidine synthesis, which minimizes uracil-induced double-stranded DNA breakage. Cells were scored for micronuclei, apoptosis, necrosis, nucleoplasmic bridges, and nuclear budding. The latter two endpoints are indicative of chromosome rearrangements and gene amplification, respectively, and to the best of our knowledge, this is the first report of their association with folic acid concentration. Folic acid concentration correlated significantly (P < 0.0001) and negatively (r, -0.63 to -0.74) with all markers of chromosome damage, which were minimized at 60-120 nM folic acid, much greater than concentrations assumed "normal," but not necessarily optimal in plasma. Two-way ANOVA revealed no effect of the MTHFR genotype on any of the endpoints. Results show that the C677T polymorphism does not affect the ability of a cell to resist chromosome damage induced by folic acid deficiency in this in vitro system. PMID:11588136

Crott, J W; Mashiyama, S T; Ames, B N; Fenech, M

2001-10-01

134

Deletion polymorphism in the angiotensin-converting enzyme gene as a thrombophilic risk factor after hip arthroplasty.  

PubMed

Despite thromboprophylaxis, deep vein thrombosis is a common complication of major orthopedic surgery. Predisposing genetic risk factors are unknown. In this case-control study, we investigated the association of the insertion (I)/deletion (D) angiotensin converting enzyme (ACE) gene polymorphism, Factor V Leiden (R506Q) mutation, and 5,10 methylenetetrahydrofolate reductase (MTHFR) gene polymorphism with post-operative venous thrombosis in 85 patients who underwent elective total hip arthroplasty. The odds of a thrombotic event following hip surgery among subjects with the DD genotype of the ACE gene was increased more than 10-fold compared to subjects with the II genotype (odds ratio 11.7 [95% confidence interval 2.3-84.5]); it was increased 5-fold in subjects with the ID genotype compared to the II genotype (odds ratio 5.0 [95% confidence interval 1.1-34.9]). Mean plasma ACE level in control subjects not on ACE inhibitors at the time of study (n=43) was lowest in persons homozygous for the I allele (18.9+/-7.95 U/l), intermediate in patients with the ID genotype (31.6+/-10.8 U/l) and highest in subjects homozygous for the D allele (44.0+/-7.14 U/l). Mean plasma ACE level among cases was higher (33.0 U/l, n=25) than among controls (29.4 U/l, n=43) but this difference was not statistically significant. Neither the Factor V Leiden mutation nor MTHFR gene polymorphism increased the risk of thrombosis following hip replacement. These results demonstrate that the I/D ACE gene polymorphism is a potent risk factor for thrombosis in subjects undergoing total hip arthroplasty. PMID:9869151

Philipp, C S; Dilley, A; Saidi, P; Evatt, B; Austin, H; Zawadsky, J; Harwood, D; Ellingsen, D; Barnhart, E; Phillips, D J; Hooper, W C

1998-12-01

135

What aspects of autism predispose to talent?  

PubMed

In this paper, we explore the question, why are striking special skills so much more common in autism spectrum conditions (ASC) than in other groups? Current cognitive accounts of ASC are briefly reviewed in relation to special skills. Difficulties in 'theory of mind' may contribute to originality in ASC, since individuals who do not automatically 'read other minds' may be better able to think outside prevailing fashions and popular theories. However, originality alone does not confer talent. Executive dysfunction has been suggested as the 'releasing' mechanism for special skills in ASC, but other groups with executive difficulties do not show raised incidence of talents. Detail-focused processing bias ('weak coherence', 'enhanced perceptual functioning') appears to be the most promising predisposing characteristic, or 'starting engine', for talent development. In support of this notion, we summarize data from a population-based twin study in which parents reported on their 8-year-olds' talents and their ASC-like traits. Across the whole sample, ASC-like traits, and specifically 'restricted and repetitive behaviours and interests' related to detail focus, were more pronounced in children reported to have talents outstripping older children. We suggest that detail-focused cognitive style predisposes to talent in savant domains in, and beyond, autism spectrum disorders. PMID:19528019

Happé, Francesca; Vital, Pedro

2009-05-27

136

MTHFR 677C>T effects on anterior cingulate structure and function during response monitoring in schizophrenia: a preliminary study  

PubMed Central

Patients with schizophrenia exhibit deficient response monitoring as indexed by blunted activation of the dorsal anterior cingulate cortex (dACC) and functionally related regions during error commission. This pattern may reflect heritable alterations of dACC function. We examined whether the hypofunctional 677C>T variant in MTHFR, a candidate schizophrenia risk gene, contributed to our previous findings of blunted error-related dACC activation and reduced microstructural integrity of dACC white matter. Eighteen medicated outpatients with schizophrenia underwent diffusion tensor imaging and performed an antisaccade paradigm during functional magnetic resonance imaging (fMRI). T allele carriers exhibited significantly less error-related activation than C/C patients in bilateral dACC and substantia nigra, regions that are thought to mediate dopamine-dependent error-based reinforcement learning. T carrier patients also showed significantly lower fractional anisotropy in bilateral dACC. These findings suggest that the MTHFR 677T allele blunts response monitoring in schizophrenia, presumably via effects on dopamine signaling and dACC white matter microstructural integrity. PMID:21190096

Brohawn, David G.; Friedman, Jesse S.; Dyckman, Kara A.; Thakkar, Katharine N.; Agam, Yigal; Vangel, Mark G.; Goff, Donald C.; Manoach, Dara S.

2014-01-01

137

Sequence variation of the methylene tetrahydrofolate reductase gene (677C>T and 1298?A>C) and traditional risk factors in a South Indian population.  

PubMed

Methylene tetrahydrofolate reductase (MTHFR) plays a significant role in the metabolism of methionine. MTHFR deficiency is an autosomal recessive trait that could be a significant risk factor for a number of defects, for example, vascular events, due to lower dietary folate intake among South Indians. To find the incidence of 677 C>T and 1298?A>C in MTHFR gene single nucleotide polymorphisms (SNPs) among the south Indian population, polymerase chain reaction and restriction fragment length polymorphism were employed among 152 patients with myocardial infarction and 167 controls. The MTHFR 677CT genotype was found among 35 (22.4%) cases and 08 (4.8%) controls, the MTHFR 677CC allele was found among 115 (73.7%) cases and 159 (94.6%) controls. Also, the analysis of the MTHFR 1298A>C SNP identified the MTHFR 1298CC genotype among 16 (10.3%) cases and 01 (0.6%) control, the MTHFR 1298AC genotype was found in 56 (35.9%) cases and 27 (16.2%) controls, and the MTHFR 1298AA genotype was observed in 80 (51.3%) cases and 139 (82.6%) controls. The C vs. A allele also showed significantly higher frequency among the patients in comparison with the controls (p<0.0001). The results of this study indicate that the MTHFR A1298C SNP is more prevalent among south Indians compared with the MTHFR C677T SNP, suggesting a possible role of MTHFR A1298C in the pathogenesis of heart diseases. PMID:21749215

Dayakar, Seetha; Goud, Kalal Iravathy; Reddy, Thavanati Parvathi Kumara; Rao, Seshagiri P; Sesikeran, Shyamala B; Sadhnani, Muralidhar

2011-11-01

138

Methylenetetrahydrofolate reductase (MTHFR) polymorphism susceptibility to schizophrenia and bipolar disorder: an updated meta-analysis.  

PubMed

Previous studies examining the possible role of the methylenetetrahydrofolate reductase (MTHFR) polymorphisms in the development of schizophrenia (SZ) and bipolar disorder (BPD) have provided inconclusive findings, this meta-analysis was therefore designed to get a more reliable assessment. A total of 38 articles were identified through a search of electronic databases, up to 27 February 2014. Odds ratios (ORs) with 95 % confidence interval (CIs) were calculated using random effects models. Meta-analysis showed that MTHFR C677T was significantly associated with SZ, the highest OR was found for the recessive model (for TT vs. CT + CC: OR = 1.34, 95 % CI: 1.18-1.53); a marginal association of MTHFR C677T with increased risk of BPD has also been found for the recessive model (OR = 1.26, 95 % CI: 1.00-1.59). Subgroup analysis by ethnicity indicated that the significant association with SZ and BPD existed among Asian and African populations, but not for the white. MTHFR A1298C was significant associated with SZ, the highest OR for the dominant model (OR = 1.13, 95 % CI: 1.03-1.24). Subgroup analysis indicated a significant association with SZ existed in Asian populations, not among the white populations and no significant association was detected between the MTHFR A1298C and BPD in all groups. We conclude that MTHFR polymorphism is associated with SZ and BPD among Asian, African populations, but not the white. PMID:24938371

Hu, Cai-Yun; Qian, Zhen-Zhong; Gong, Feng-Feng; Lu, Shan-Shan; Feng, Fang; Wu, Yi-Le; Yang, Hui-Yun; Sun, Ye-Huan

2015-02-01

139

Methylenetetrahydrofolate reductase (MTHFR) polymorphism A1298C (Glu429Ala) predicts decline in renal function over time in the African-American Study of Kidney Disease and Hypertension (AASK) Trial and Veterans Affairs Hypertension Cohort (VAHC)  

PubMed Central

Background. Hyperhomocysteinemia is associated with increased venous thrombosis and cardiovascular disease (CVD). Mutations in the human methylenetetrahydrofolate reductase (MTHFR) gene have been associated with increased homocysteine levels and risks of CVD in various populations including those with kidney disease. Here, we evaluated the influence of MTHFR variants on progressive loss of kidney function. Methods. We analyzed 821 subjects with hypertensive nephrosclerosis from the longitudinal National Institute of Diabetes and Digestive and Kidney Diseases African-American Study of Kidney Disease and Hypertension (AASK) Trial to determine whether decline in glomerular filtration rate (GFR) over ?4.2 years was predicted by common genetic variation within MTHFR at non-synonymous positions C677T (Ala222Val) and A1298C (Glu429Ala) or by MTHFR haplotypes. The effect on GFR decline was then supported by a study of 1333 subjects from the San Diego Veterans Affairs Hypertension Cohort (VAHC), followed over ?4.5 years. Linear effect models were utilized to determine both genotype [single-nucleotide polymorphism (SNP)] and genotype (SNP)-by-time interactions. Results. In AASK, the polymorphism at A1298C predicted the rate of GFR decline: A1298/A1298 major allele homozygosity resulted in a less pronounced decline of GFR, with a significant SNP-by-time interaction. An independent follow-up study in the San Diego VAHC subjects supports that A1298/A1298 homozygotes have the greatest estimated GFR throughout the study. Haplotype analysis with C677T yielded concurring results. Conclusion. We conclude that the MTHFR-coding polymorphism at A1298C is associated with renal decline in African-Americans with hypertensive nephrosclerosis and is supported by a veteran cohort with a primary care diagnosis of hypertension. Further investigation is needed to confirm such findings and to determine what molecular mechanism may contribute to this association. PMID:21613384

Salem, Rany M.; Lipkowitz, Michael S.; Bhatnagar, Vibha; Pandey, Braj; Schork, Nicholas J.; O’Connor, Daniel T.

2012-01-01

140

Methotrexate use, MTHFR polymorphisms and traditional risk factors in predicting cardiovascular events in elderly males with rheumatoid arthritis (RA)  

Microsoft Academic Search

ObjectiveThe enzyme methylenetetrahydrofolate reductase (MTHFR) has been implicated in the metabolism of methotrexate (MTX) – the most common disease modifying antirheumatic drug used to treat rheumatoid arthritis (RA). MTHFR C677T and A1298C polymorphisms have been associated with increased cardiovascular (CV) events in non-RA populations. We explored the potential associations of MTHFR C677T, A1298C and MTX with decreased time-to-CV event in

Lisa A Davis; Grant W Cannon; Lauren M Pointer; Roger K Wolff; Ted R Mikuls; Leah Haverhals; Andreas M Reimold; Gail S Kerr; J Steuart Richards; Dannette S Johnson; Liron Caplan

2011-01-01

141

Genetic Factors Predisposing to Systemic Lupus Erythematosus and Lupus Nephritis  

PubMed Central

Systemic Lupus Erythematosus (SLE) is a chronic inflammatory disease characterized by a loss of tolerance to self-antigens and the production of high titers of serum autoantibodies. Lupus nephritis can affect up to 74% of SLE patients, particularly those of Hispanic and African ancestries, and remains a major cause of morbidity and mortality. A genetic etiology in SLE is now well substantiated. Thanks to extensive collaborations, extraordinary progress has been made in the last few years and the number of confirmed genes predisposing to SLE has catapulted to approximately 30. Studies of other forms of genetic variation, such as CNVs and epigenetic alterations, are emerging and promise to revolutionize our knowledge about disease mechanisms. However, to date little progress has been made on the identification of genetic factors specific to lupus nephritis. On the near horizon, two large-scale efforts, a collaborative meta-analysis of lupus nephritis based on all genome-wide association data in Caucasians and parallel scans in four other ethnicities, are poised to make fundamental discoveries in the genetics of lupus nephritis. Collectively, these findings will demonstrate that a broad array of pathways underlines the genetic heterogeneity of SLE and lupus nephritis, and provide potential avenues for the development of novel therapies. PMID:20347645

Ramos, Paula S.; Brown, Elisabeth E.; Kimberly, Robert P.; Langefeld, Carl D.

2010-01-01

142

Plasma folate, methylenetetrahydrofolate reductase (MTHFR), and colorectal cancer risk in three large nested case-control studies  

Technology Transfer Automated Retrieval System (TEKTRAN)

Few prospective studies have examined the associations between blood levels of folate, in conjunction with methylenetetrahydrofolate reductase (MTHFR) polymorphisms, and colorectal cancer. We evaluated the associations between plasma folate, MTHFR C677T, and A1298C, and colorectal cancer in three la...

143

Gender-Specific Effect of Mthfr Genotype and Neonatal Vigabatrin Interaction on Synaptic Proteins in Mouse Cortex  

Microsoft Academic Search

The enzyme methylenetetrahydrofolate reductase (MTHFR) is a part of the homocysteine and folate metabolic pathways, affecting the methylations of DNA, RNA, and proteins. Mthfr deficiency was reported as a risk factor for neurodevelopmental disorders such as autism spectrum disorder and schizophrenia. Neonatal disruption of the GABAergic system is also associated with behavioral outcomes. The interaction between the epigenetic influence of

Elinor Blumkin; Tamar Levav-Rabkin; Osnat Melamed; Dalia Galron; Hava M Golan

2011-01-01

144

Interaction between the MTHFR C677T polymorphism and traumatic childhood events predicts depression  

PubMed Central

Childhood trauma is associated with the onset and recurrence of major depressive disorder (MDD). The thermolabile T variant of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism (rs1801133) is associated with a limited (oxidative) stress defense. Therefore, C677T MTHFR could be a potential predictor for depressive symptomatology and MDD recurrence in the context of traumatic stress during early life. We investigated the interaction between the C677T MTHFR variant and exposure to traumatic childhood events (TCEs) on MDD recurrence during a 5.5-year follow-up in a discovery sample of 124 patients with recurrent MDD and, in an independent replication sample, on depressive symptomatology in 665 healthy individuals from the general population. In the discovery sample, Cox regression analysis revealed a significant interaction between MTHFR genotype and TCEs on MDD recurrence (P=0.017). Over the 5.5-year follow-up period, median time to recurrence was 191 days for T-allele carrying patients who experienced TCEs (T+ and TCE+); 461 days for T? and TCE+ patients; 773 days for T+ and TCE? patients and 866 days for T? and TCE? patients. In the replication sample, a significant interaction was present between the MTHFR genotype and TCEs on depressive symptomatology (P=0.002). Our results show that the effects of TCEs on the prospectively assessed recurrence of MDD and self-reported depressive symptoms in the general population depend on the MTHFR genotype. In conclusion, T-allele carriers may be at an increased risk for depressive symptoms or MDD recurrence after exposure to childhood trauma. PMID:23900311

Lok, A; Bockting, C L H; Koeter, M W J; Snieder, H; Assies, J; Mocking, R J T; Vinkers, C H; Kahn, R S; Boks, M P; Schene, A H

2013-01-01

145

Methylenetetrahydrofolate Reductase Gene Polymorphisms in Children with Attention Deficit Hyperactivity Disorder  

PubMed Central

Objective: The purpose of this study was to evaluate the relationship between 5,10- methylenetetrahydrofolate reductase (MTHFR) polymorphisms and Attention Deficit Hyperactivity Disorder (ADHD) in a sample of Turkish children. Study Design: MTHFR gene polymorphisms were assessed in 40 patients with ADHD and 30 healty controls. Two mutations in the MTHFR gene were investigated using polymerase chain reactions and restriction fragment length polymorphisms. Results: Although there were no statistically significant differences in genotype distributions of the C677T alleles between the ADHD and the control groups (p=0,678) but the genotypic pattern of the distributions of the A1298C alleles was different between the ADHD patients and the controls (p=0,033). Conclusions: Preliminary data imply a possible relationship between A1298C MTHFR polymorphisms and the ADHD. PMID:21897766

Gokcen, Cem; Kocak, Nadir; Pekgor, Ahmet

2011-01-01

146

Correlations of MTHFR 677C>T Polymorphism with Cardiovascular Disease in Patients with End-Stage Renal Disease: A Meta-Analysis  

PubMed Central

Objective This meta-analysis was conducted to evaluate the correlations of a common polymorphism (677C>T) in the methylenetetrahydrofolate reductase (MTHFR) gene with risk of cardiovascular disease (CVD) in patients with end-stage renal disease (ESRD). Method The following electronic databases were searched without language restrictions: Web of Science (1945?2013), the Cochrane Library Database (Issue 12, 2013), MEDLINE (1966?2013), EMBASE (1980?2013), CINAHL (1982?2013) and the Chinese Biomedical Database (CBM) (1982?2013). Meta-analysis was performed using STATA statistical software. Odds ratios (ORs) with their 95% confidence intervals (95%CIs) were calculated. Results Eight cohort studies met all inclusion criteria and were included in this meta-analysis. A total of 2,292 ESRD patients with CVD were involved in this meta-analysis. Our meta-analysis results revealed that the MTHFR 677C>T polymorphism might increase the risk of CVD in ESRD patients (TT vs. CC: OR?=?2.75, 95%CI?=?1.35?5.59, P?=?0.005; CT+TT vs. CC: OR?=?1.39, 95%CI?=?1.09?1.78, P?=?0.008; TT vs. CC+CT: OR?=?2.52, 95%CI?=?1.25?5.09, P?=?0.010; respectively). Further subgroup analysis by ethnicity suggested that the MTHFR 677C>T polymorphism was associated with an elevated risk for CVD in ESRD patients among Asians (TT vs. CC: OR?=?3.38, 95%CI?=?1.11?10.28, P?=?0.032; CT+TT vs. CC: OR?=?1.44, 95%CI?=?1.05?1.97, P?=?0.022; TT vs. CC+CT: OR?=?3.15, 95%CI?=?1.02?9.72, P?=?0.046; respectively), but not among Africans or Caucasians (all P>0.05). Conclusion Our findings indicate that the MTHFR 677C>T polymorphism may be associated with an elevated risk for CVD in ESRD patients, especially among Asians. PMID:25050994

Gao, Xian-Hui; Zhang, Guo-Yi; Wang, Ying; Zhang, Hui-Ying

2014-01-01

147

Detecting disease-predisposing variants: The haplotype method  

SciTech Connect

For many HLA-associated diseases, multiple alleles - and, in some cases, multiple loci - have been suggested as the causative agents. The haplotype method for identifying disease-predisposing amino acids in a genetic region is a stratification analysis. We show that, for each haplotype combination containing all the amino acid sites involved in the disease process, the relative frequencies of amino acid variants at sites not involved in disease but in linkage disequilibrium with the disease-predisposing sites are expected to be the same in patients and controls. The haplotype method is robust to mode of inheritance and penetrance of the disease and can be used to determine unequivocally whether all amino acid sites involved in the disease have not been identified. Using a resampling technique, we developed a statistical test that takes account of the nonindependence of the sites sampled. Further, when multiple sites in the genetic region are involved in disease, the test statistic gives a closer fit to the null expectation when some - compared with none - of the true predisposing factors are included in the haplotype analysis. Although the haplotype method cannot distinguish between very highly correlated sites in one population, ethnic comparisons may help identify the true predisposing factors. The haplotype method was applied to insulin-dependent diabetes mellitus (IDDM) HLA class II DQA1-DQB1 data from Caucasian, African, and Japanese populations. Our results indicate that the combination DQA1 No. 52 (Arg predisposing) DQB1 No. 57 (Asp protective), which has been proposed as an important IDDM agent, does not include all the predisposing elements. With rheumatoid arthritis HLA class H DRB1 data, the results were consistent with the shared-epitope hypothesis. 35 refs., 2 figs., 6 tabs.

Valdes, A.M.; Thomson, G. [Univ. of California, Berkeley, CA (United States)

1997-03-01

148

Association of PHB 1630 C>T and MTHFR 677 C>T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study  

PubMed Central

Background: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. Methods: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively. Results: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95%CI 1.10–2.04 and HR 2.16, 95%CI 1.24–3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. Conclusion: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers. PMID:22669161

Jakubowska, A; Rozkrut, D; Antoniou, A; Hamann, U; Scott, R J; McGuffog, L; Healy, S; Sinilnikova, O M; Rennert, G; Lejbkowicz, F; Flugelman, A; Andrulis, I L; Glendon, G; Ozcelik, H; Thomassen, M; Paligo, M; Aretini, P; Kantala, J; Aroer, B; von Wachenfeldt, A; Liljegren, A; Loman, N; Herbst, K; Kristoffersson, U; Rosenquist, R; Karlsson, P; Stenmark-Askmalm, M; Melin, B; Nathanson, K L; Domchek, S M; Byrski, T; Huzarski, T; Gronwald, J; Menkiszak, J; Cybulski, C; Serrano, P; Osorio, A; Cajal, T R; Tsitlaidou, M; Benítez, J; Gilbert, M; Rookus, M; Aalfs, C M; Kluijt, I; Boessenkool-Pape, J L; Meijers-Heijboer, H E J; Oosterwijk, J C; van Asperen, C J; Blok, M J; Nelen, M R; van den Ouweland, A M W; Seynaeve, C; van der Luijt, R B; Devilee, P; Easton, D F; Peock, S; Frost, D; Platte, R; Ellis, S D; Fineberg, E; Evans, D G; Lalloo, F; Eeles, R; Jacobs, C; Adlard, J; Davidson, R; Eccles, D; Cole, T; Cook, J; Godwin, A; Bove, B; Stoppa-Lyonnet, D; Caux-Moncoutier, V; Belotti, M; Tirapo, C; Mazoyer, S; Barjhoux, L; Boutry-Kryza, N; Pujol, P; Coupier, I; Peyrat, J-P; Vennin, P; Muller, D; Fricker, J-P; Venat-Bouvet, L; Johannsson, O Th; Isaacs, C; Schmutzler, R; Wappenschmidt, B; Meindl, A; Arnold, N; Varon-Mateeva, R; Niederacher, D; Sutter, C; Deissler, H; Preisler-Adams, S; Simard, J; Soucy, P; Durocher, F; Chenevix-Trench, G; Beesley, J; Chen, X; Rebbeck, T; Couch, F; Wang, X; Lindor, N; Fredericksen, Z; Pankratz, V S; Peterlongo, P; Bonanni, B; Fortuzzi, S; Peissel, B; Szabo, C; Mai, P L; Loud, J T; Lubinski, J

2012-01-01

149

MTHFR 677C 3 T genotype disrupts prefrontal function in schizophrenia through an interaction  

E-print Network

function during working memory. Within the dorsolateral prefrontal cortex (DLPFC), a region critical associated with abnormal dopamine signaling in the prefrontal cortex, which is likely under complex geneticMTHFR 677C 3 T genotype disrupts prefrontal function in schizophrenia through an interaction

Manoach, Dara S.

150

Are There Inherited Behavioral Traits That Predispose to Substance Abuse?  

Microsoft Academic Search

Research findings suggest that alcoholism and drug abuse may be predisposed by inherited behavioral propensities or temperaments. These inherited predispositions, through interaction with the physical and social environments, shape the development of personality. As discussed herein, there is strong evidence linking certain personality characteristics, specifically antisocial and neurotic traits, with the risk for substance abuse. Thus, personality and its precursor,

Ralph E. Tarter

1988-01-01

151

Predisposing factors for delirium in the surgical intensive care unit  

Microsoft Academic Search

BACKGROUND: Delirium is a sign of deterioration in the homeostasis and physical status of the patient. The objective of our study was to investigate the predisposing factors for delirium in a surgical intensive care unit (ICU) setting. METHOD: Between January 1996 and 1997, we screened prospectively 818 patients who were consecutive applicants to the general surgery service of Dicle-University Hospital

Mustafa Aldemir; Sakir Özen; Ismail H Kara; Bilsel Baç

2001-01-01

152

Methylenetetrahydrofolate Reductase (MTHFR) Polymorphisms and Susceptibility for Cervical Lesions: A Meta-Analysis  

PubMed Central

Background The association between the methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C polymorphisms and the susceptibility to cervical lesions was unclear. This study was designed to investigate their precise association using a large-scale meta-analysis. Methods The previous 16 studies were identified by searching PubMed, Embase and CBM databases. The crude odds ratios and their corresponding 95% confidence intervals (CIs) were used to estimate the association between the MTHFR C677T/A1298C polymorphisms and the susceptibility to the cervical lesions. The subgroup analyses were made on the following: pathological history, geographic region, ethnicity, source of controls and source of DNA for genotyping. Results Neither of the polymorphisms had a significant association with the susceptibility to the cervical lesions in all genetic models. Similar results were found in the subgroup analyses. No association was found between the MTHFR C677T polymorphism and the cervical lesions in the Asia or the America populations though a significant inverse association was found in the Europe population (additive model: P?=?0.006, OR?=?0.83, 95% CI?=?0.72–0.95; CT vs. CC: P?=?0.05, OR?=?0.83, 95% CI?=?0.69–1.00; TT vs. CC: P?=?0.05, OR?=?0.73, 95% CI?=?0.53–1.00). Interestingly, women with the MTHFR A1298C polymorphisms had a marginally increased susceptibility to invasive cancer (ICC) when compared with no carriers but no statistically significant difference in the dominant model (P?=?0.06, OR?=?1.21, 95% CI?=?0.99–1.49) and AC vs. AA (P?=?0.09, OR?=?1.21, 95% CI?=?0.97–1.51). Conclusions The MTHFR C677T and A1298C polymorphisms may not increase the susceptibility to cervical lesions. However, the meta-analysis reveals a negative association between the MTHFR C677T polymorphisms and the cervical lesions, especially in the European populations. The marginal association between the MTHFR A1298C polymorphisms and the susceptibility to cervical cancer requires a further study. PMID:23285018

Liu, Xiaojiao; Yang, Pei

2012-01-01

153

Screening for C677T and A1298C MTHFR polymorphisms in patients with epilepsy and risk of hyperhomocysteinemia  

Microsoft Academic Search

Hyperhomocysteinemia can result from decreased methylenetetrahydrofolate reductase (MTHFR) enzyme activity, owing to genetic\\u000a polymorphisms and\\/or inadequate folate intake. This study was aimed at investigating the prevalence of C677T and A1298C MTHFR\\u000a polymorphisms, and their impact on hyperhomocysteinemia in 95 epileptic patients and 98 controls. Double gradient-denaturing\\u000a gradient gel electrophoresis screening revealed that the frequency of T677 polymorphic allele was similar

D. Caccamo; S. Condello; G. Gorgone; G. Crisafulli; V. Belcastro; S. Gennaro; P. Striano; F. Pisani; R. Ientile

2004-01-01

154

Possible Predisposing Factors for the Second Hip Fracture  

Microsoft Academic Search

.   Among 1685 patients who sustained a hip fracture at the island of Crete (Greece) in a 4-year period we found 106 patients\\u000a with bilateral noncontemporary hip fractures. Pathologic hip fractures and fractures that emerged from high energy trauma\\u000a were excluded. To investigate the possible factors predisposing to the later fracture in the sound hip, we studied these 106\\u000a patients

K. E. Dretakis; E. K. Dretakis; E. F. Papakitsou; S. Psarakis; K. Steriopoulos

1998-01-01

155

Celiac Disease in a Predisposed Subject (HLA-DQ2.5) with Coexisting Graves' Disease.  

PubMed

Celiac disease is an intestinal autoimmune disorder, triggered by ingestion of a gluten-containing diet in genetically susceptible individuals. The genetic predisposition is related to human leukocyte antigen (HLA) class II genes, especially HLA-DQ2-positive patients. The prevalence of celiac disease has been estimated to be ~1% in Europe and the USA, but it is rarer and/or underdiagnosed in Asia. We report a case of celiac disease in a predisposed patient, with a HLA-DQ2 heterodimer, and Graves' disease that was treated successfully with a gluten-free diet. A 47-year-old woman complained of persistent chronic diarrhea and weight loss over a 9 month period. Results of all serological tests and stool exams were negative. However, the patient was found to carry the HLA DQ2 heterodimer. Symptoms improved after a gluten-free diet was initiated. The patient has been followed and has suffered no recurrence of symptoms while on the gluten-free diet. An overall diagnosis of celiac disease was made in a genetically predisposed patient (HLA-DQ2 heterodimer) with Graves' disease. PMID:25325278

Hwang, In Kyoung; Kim, Seon Hye; Lee, Unjoo; Chin, Sang Ouk; Rhee, Sang Youl; Oh, Seungjoon; Woo, Jeong Taek; Kim, Sung Woon; Kim, Young Seol; Chon, Suk

2015-03-27

156

Celiac Disease in a Predisposed Subject (HLA-DQ2.5) with Coexisting Graves' Disease  

PubMed Central

Celiac disease is an intestinal autoimmune disorder, triggered by ingestion of a gluten-containing diet in genetically susceptible individuals. The genetic predisposition is related to human leukocyte antigen (HLA) class II genes, especially HLA-DQ2-positive patients. The prevalence of celiac disease has been estimated to be ~1% in Europe and the USA, but it is rarer and/or underdiagnosed in Asia. We report a case of celiac disease in a predisposed patient, with a HLA-DQ2 heterodimer, and Graves' disease that was treated successfully with a gluten-free diet. A 47-year-old woman complained of persistent chronic diarrhea and weight loss over a 9 month period. Results of all serological tests and stool exams were negative. However, the patient was found to carry the HLA DQ2 heterodimer. Symptoms improved after a gluten-free diet was initiated. The patient has been followed and has suffered no recurrence of symptoms while on the gluten-free diet. An overall diagnosis of celiac disease was made in a genetically predisposed patient (HLA-DQ2 heterodimer) with Graves' disease. PMID:25325278

Hwang, In Kyoung; Kim, Seon Hye; Lee, Unjoo; Chin, Sang Ouk; Rhee, Sang Youl; Oh, Seungjoon; Woo, Jeong-Taek; Kim, Sung-Woon; Kim, Young Seol

2015-01-01

157

Effect of MTHFR Polymorphisms on Hyperhomocysteinemia in Levodopa-treated Parkinsonian Patients  

Microsoft Academic Search

High plasma homocysteine levels have been observed in Parkinson’s disease (PD) patients treated with levodopa. In this study,\\u000a we investigated the effects of C677T and A1298C MTHFR polymorphisms, in association with l-DOPA daily dose and vitamin status, on hyperhomocysteinemia development in PD patients. Plasma homocysteine and folate\\/vitamin\\u000a B12 levels were assayed in 49 l-DOPA-treated PD patients, and compared with those

D. Caccamo; G. Gorgone; M. Currò; G. Parisi; W. Di Iorio; C. Menichetti; V. Belcastro; L. Parnetti; A. Rossi; F. Pisani; R. Ientile; P. Calabresi

2007-01-01

158

Association between MTHFR Polymorphisms and Acute Myeloid Leukemia Risk: A Meta-Analysis  

PubMed Central

Previous observational studies investigating the association between methylenetetrahydrofolate reductase (MTHFR) polymorphisms and acute myeloid leukemia risk (AML) have yielded inconsistent results. The aim of this study is to derive a more precise estimation of the association between MTHFR (C677T and A1298C) polymorphisms and acute myeloid leukemia risk. PubMed and Embase databases were systematically searched to identify relevant studies from their inception to August 2013. Odds ratios (ORs) with 95% confidence intervals (CIs) were the metric of choice. Thirteen studies were selected for C677T polymorphism (1838 cases and 5318 controls) and 9 studies (1335 patients and 4295 controls) for A1298C polymorphism. Overall, pooled results showed that C677T polymorphism was not significant associated with AML risk(OR, 0.98–1.04; 95% CI, 0.86–0.92 to 1.09–1.25). Similar results were observed for the A1298C polymorphism and in subgroup analysis. All comparisons revealed no substantial heterogeneity nor did we detect evidence of publication bias. In summary, this meta-analysis provides evidence that MTHFR polymorphisms were not associated with AML risk. Further investigations are needed to offer better insight into the role of these polymorphisms in AML carcinogenesis. PMID:24586405

Su, Yan; Lu, Ge-Ning; Wang, Ren-Sheng

2014-01-01

159

Signaling pathway genes for blood pressure, folate and cholesterol levels among hypertensives: an epistasis analysis.  

PubMed

Irregular atrial pressure, defective folate and cholesterol metabolism contribute to the pathogenesis of hypertension. However, little is known about the combined roles of the methylenetetrahydrofolate reductase (MTHFR), apolipoprotein-E (ApoE) and angiotensin-converting enzyme (ACE) genes, which are involved in metabolism and homeostasis. The objective of this study is to investigate the association of the MTHFR 677 C>T and 1298A>C, ACE insertion-deletion (I/D) and ApoE genetic polymorphisms with hypertension and to further explore the epistasis interactions that are involved in these mechanisms. A total of 594 subjects, including 348 normotensive and 246 hypertensive ischemic stroke subjects were recruited. The MTHFR 677 C>T and 1298A>C, ACE I/D and ApoEpolymorphisms were genotyped and the epistasis interaction were analyzed. The MTHFR 677 C>T and ApoE polymorphisms demonstrated significant associations with susceptibility to hypertension in multiple logistic regression models, multifactor dimensionality reduction and a classification and regression tree. In addition, the logistic regression model demonstrated that significant interactions between the ApoE E3E3, E2E4, E2E2 and MTHFR 677 C>T polymorphisms existed. In conclusion, the results of this epistasis study indicated significant association between the ApoE and MTHFR polymorphisms and hypertension. PMID:25055800

Wei, L K; Menon, S; Griffiths, L R; Gan, S H

2015-02-01

160

Earwax Impaction: Symptoms, Predisposing Factors and Perception among Nigerians  

PubMed Central

Background and Aim: Earwax impaction is a common ear disorder with presentation worldwide. This study aimed at determining the clinical presentation, patients’ perception of earwax, and its predisposing factors among Nigerians. Materials and Methods: This prospective study was conducted on consented patients with diagnosis of earwax impaction at the Ear, Nose, and Throat Clinic of the University Teaching Hospital, Ado Ekiti, Ekiti state, south west, Nigeria. The research was carried out over a period of one year (April 2008 and March 2009). All consented patients were told about the aim and scope of the study and their biodata were taken. Detailed history of the presenting complaints and otological complaints were taken and all data entered into structured questionnaires. Full-ear examination and otoscopy were performed and our findings were documented. From all these exercise, data obtained were collated and statistically analyzed. Results: A total of 437 patients were diagnosed with earwax impaction and prevalence of 20.1% was found. There was 52.2% male preponderance with male to female ratio of 1:1. Bimodal peak age distribution of patients was found at the extreme ages of life. Most common sources of our patients referrals were 39.6% general medical practitioners with least from 6.2% self-reporting. Common presentations were 277 (63.3%) hearing loss, 268 (61.3%) earache (otalgia), and 234 (53.5%) tiinitus. Unilateral earwax impaction, 75.1% was more common than bilateral earwax impaction. Right ear was more affected than left ear. Recurrent earwax impaction of 66.1% was found in our study. About 382 (87.4%) believed earwax was due to dirt or dust. Most common predisposing factors among our patients were self-ear cleaning. Conclusion: Common predisposing factor of this high recurrent earwax impaction were wrong perception and preventable self-ear cleaning with indiscriminate objects including cotton tip swab. This condition could be reduced by health education of the community. PMID:25657947

Adegbiji, Waheed Atilade; Alabi, Biodun Sulyman; Olajuyin, Oyebanji Anthony; Nwawolo, C.C.

2014-01-01

161

The maize brown midrib2 (bm2) gene encodes a methylenetetrahydrofolate reductase that contributes to lignin accumulation  

PubMed Central

The midribs of maize brown midrib (bm) mutants exhibit a reddish-brown color associated with reductions in lignin concentration and alterations in lignin composition. Here, we report the mapping, cloning, and functional and biochemical analyses of the bm2 gene. The bm2 gene was mapped to a small region of chromosome 1 that contains a putative methylenetetrahydrofolate reductase (MTHFR) gene, which is down-regulated in bm2 mutant plants. Analyses of multiple Mu-induced bm2-Mu mutant alleles confirmed that this constitutively expressed gene is bm2. Yeast complementation experiments and a previously published biochemical characterization show that the bm2 gene encodes a functional MTHFR. Quantitative RT-PCR analyses demonstrated that the bm2 mutants accumulate substantially reduced levels of bm2 transcript. Alteration of MTHFR function is expected to influence accumulation of the methyl donor S-adenosyl-l-methionine (SAM). Because SAM is consumed by two methyltransferases in the lignin pathway (Ye et al., 1994), the finding that bm2 encodes a functional MTHFR is consistent with its lignin phenotype. Consistent with this functional assignment of bm2, the expression patterns of genes in a variety of SAM-dependent or -related pathways, including lignin biosynthesis, are altered in the bm2 mutant. Biochemical assays confirmed that bm2 mutants accumulate reduced levels of lignin with altered composition compared to wild-type. Hence, this study demonstrates a role for MTHFR in lignin biosynthesis. PMID:24286468

Tang, Ho Man; Liu, Sanzhen; Hill-Skinner, Sarah; Wu, Wei; Reed, Danielle; Yeh, Cheng-Ting; Nettleton, Dan; Schnable, Patrick S

2014-01-01

162

Genetic variation in GPBAR1 predisposes to quantitative changes in colonic transit and bile acid excretion.  

PubMed

The pathobiology of irritable bowel syndrome (IBS) is multifaceted. We aimed to identify candidate genes predisposing to quantitative traits in IBS. In 30 healthy volunteers, 30 IBS-constipation, and 64 IBS-diarrhea patients, we measured bowel symptoms, bile acid (BA) synthesis (serum 7?-hydroxy-4-cholesten-3-one and FGF19), fecal BA and fat, colonic transit (CT by scintigraphy), and intestinal permeability (IP by 2-sugar excretion). We assessed associations of candidate genes controlling BA metabolism (KLB rs17618244 and FGFR4 rs351855), BA receptor (GPBAR1 rs11554825), serotonin (5-HT) reuptake (SLC6A4 through rs4795541 which encodes for the 44-bp insert in 5HTTLPR), or immune activation (TNFSF15 rs4263839) with three primary quantitative traits of interest: colonic transit, BA synthesis, and fecal BA excretion. There were significant associations between fecal BA and CT at 48 h (r = 0.43; P < 0.001) and IP (r = 0.23; P = 0.015). GPBAR1 genotype was associated with CT48 (P = 0.003) and total fecal BA [P = 0.030, false detection rate (FDR) P = 0.033]. Faster CT48 observed with both CC and TT GPBAR1 genotypes was due to significant interaction with G allele of KLB, which increases BA synthesis and excretion. Other univariate associations (P < 0.05, without FDR correction) observed between GPBAR1 and symptom phenotype and gas sensation ratings support the role of GPBAR1 receptor. Associations between SLC6A4 and stool consistency, ease of passage, postprandial colonic tone, and total fecal BA excretion provide data in support of future hypothesis-testing studies. Genetic control of GPBAR1 receptor predisposing to pathobiological mechanisms in IBS provides evidence from humans in support of the importance of GPBAR1 to colonic motor and secretory functions demonstrated in animal studies. PMID:25012842

Camilleri, Michael; Shin, Andrea; Busciglio, Irene; Carlson, Paula; Acosta, Andres; Bharucha, Adil E; Burton, Duane; Lamsam, Jesse; Lueke, Alan; Donato, Leslie J; Zinsmeister, Alan R

2014-09-01

163

No association between MTHFR A1298C and MTRR A66G polymorphisms, and MS in an Australian cohort.  

PubMed

Multiple sclerosis (MS) is a complex neurological disease that affects the central nervous system (CNS) resulting in debilitating neuropathology. Pathogenesis is primarily defined by CNS inflammation and demyelination of nerve axons. Methionine synthase reductase (MTRR) is an enzyme that catalyzes the remethylation of homocysteine (Hcy) to methionine via cobalamin and folate dependant reactions. Cobalamin acts as an intermediate methyl carrier between methylenetetrahydrofolate reductase (MTHFR) and Hcy. MTRR plays a critical role in maintaining cobalamin in an active form and is consequently an important determinant of total plasma Hcy (pHcy) concentrations. Elevated intracellular pHcy levels have been suggested to play a role in CNS dysfunction, neurodegenerative, and cerebrovascular diseases. Our investigation entailed the genotyping of a cohort of 140 cases and matched controls for MTRR and MTHFR, by restriction length polymorphism (RFLP) techniques. Two polymorphisms: MTRR A66G and MTHFR A1298C were investigated in an Australian age and gender matched case-control study. No significant allelic frequency difference was observed between cases and controls at the alpha = 0.05 level (MTRR chi2 = 0.005, P = 0.95, MTHFR chi2 = 1.15, P = 0.28). Our preliminary findings suggest no association between the MTRR A66G and MTHFR A1298C polymorphisms and MS. PMID:17113603

Szvetko, A L; Fowdar, J; Nelson, J; Colson, N; Tajouri, L; Csurhes, P A; Pender, M P; Griffiths, L R

2007-01-15

164

Predisposing Factors Associated With Chronic and Recurrent Rhinosinusitis in Childhood  

PubMed Central

Purpose There is currently no information regarding predisposing factors for chronic and recurrent rhinosinusitis (RS), although these are considered to be multifactorial in origin, and allergic diseases contribute to their pathogenesis. We evaluated the predisposing factors that may be associated with chronic and recurrent RS. Methods In this prospective study, we examined patients with RS younger than 13 years of age, diagnosed with RS at six tertiary referral hospitals in Korea between October and December, 2006. Demographic and clinical data related to RS were recorded and analyzed. Results In total, 296 patients were recruited. Acute RS was the most frequent type: 56.4% of the patients had acute RS. The prevalences of other types of RS, in descending order, were chronic RS (18.9%), subacute RS (13.2%), and recurrent RS (11.5%). Factors associated with recurrent RS were similar to those of chronic RS. Patients with chronic and recurrent RS were significantly older than those with acute and subacute RS. The prevalences of allergic rhinitis, atopy, and asthma were significantly higher in patients with chronic and recurrent RS than those with acute and subacute RS. Conclusions An association between atopy and chronic/recurrent RS, compared to acute and subacute RS, suggests a possible causal link. PMID:22379602

Choi, Sun-Hee; Han, Man-Yong; Ahn, Young-Min; Park, Yong-Mean; Kim, Chang-Keun; Kim, Hyun-Hee; Koh, Young-Yull

2012-01-01

165

TPMT and MTHFR genotype is not associated with altered risk of thioguanine-related sinusoidal obstruction syndrome in pediatric acute lymphoblastic leukemia: a report from the Children's Oncology Group.  

PubMed

Sinusoidal obstruction syndrome is a complication of therapy for pediatric ALL and may be modified by thiopurine methyltransferase activity as well as by MTHFR genotype. We assessed TPMT *3A, *3B, *3C, and MTHFR C677T and A1298C germline genetic polymorphisms among 351 patients enrolled in the thioguanine treatment arm of CCG-1952 clinical trial. TPMT and MTHFR C677T genotypes were not associated with SOS risk. The combination of MTHFR and TPMT variant genotypes was not associated with SOS risk. These suggest that germline genetic variation in TPMT and MTHFR do not significantly alter SOS risk in patients exposed to thioguanine. PMID:24737678

Wray, Lisa; Vujkovic, Marijana; McWilliams, Thomas; Cannon, Shannon; Devidas, Meenakshi; Stork, Linda; Aplenc, Richard

2014-11-01

166

Adaptive developmental plasticity in methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism limits its frequency in South Indians.  

PubMed

Methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism shows considerable heterogeneity in its distribution in humans worldwide. The current study was conducted to investigate whether this polymorphism exhibited adaptive developmental plasticity in the control of the TT-genotype frequency. We screened 1,818 South Indian subjects (895 males and 923 females) for MTHFR C677T polymorphism using PCR-restriction fragment length polymorphism approach. MTHFR 677T-allele frequency in males and females was 9.1 and 11.0%, respectively. Compared to females, males had lower frequency of TT-genotype [odds ratio 0.31, 95% confidence interval (CI) 0.08-1.01]. The frequency of MTHFR 677T-allele was highest in the age group of 20-40 years and it gradually decreased from 40-60 to 60-80 years (P trend<0.0001). MTHFR 677TT-genotype was associated with 7.02-folds (95% CI: 2.12-25.63, P<0.0001) cumulative risk for recurrent pregnancy loss (RPL), neural tube defects (NTDs) and deep vein thrombosis (DVT). Linear regression model suggested that male gender exhibited increased homocysteine levels by 9.35 ?mol/L while each MTHFR 677T-allele contributed to 4.63 ?mol/L increase in homocysteine. Plasma homocysteine showed inverse correlation with dietary folate (r=-0.17, P<0.0001), B2 (r=-0.14, P<0.0001) and B6 (r=-0.07, P=0.03). Examination of the spontaneously aborted fetuses (n=35) showed no significant association of fetal genotype on its in utero viability. From the current study, it was concluded that C677T seemed to have acquired adaptive developmental plasticity among South Indians due to environmental influences thus contributing to hyperhomocysteinemia and its associated complications such as RPL, NTDs, DVT, etc. PMID:24449370

Naushad, Shaik Mohammad; Krishnaprasad, Chintakindi; Devi, Akella Radha Rama

2014-05-01

167

Subclinical Mastitis in Dairy Animals: Incidence, Economics, and Predisposing Factors  

PubMed Central

A study was conducted to assess the incidence and economics of subclinical form of bovine mastitis in Central Region of India. Daily milk records of 187 animals during three seasons were collected and subjected to analysis. The economic loss due to reduction in yield, clinical expenses, and additional resources used were quantified and aggregated. The losses due to mastitis in monetary terms were estimated to be INR1390 per lactation, among which around 49% was owing to loss of value from milk and 37% on account of veterinary expenses. Higher losses were observed in crossbred cows due to their high production potential that was affected during mastitis period. The cost of treating an animal was estimated to be INR509 which includes cost of medicine (31.10%) and services (5.47%). Inadequate sanitation, hygiene, and veterinary services were the main predisposing factors for incidence and spread of mastitis as perceived by the respondents. PMID:25093203

Sinha, Mukesh Kr.; Thombare, N. N.; Mondal, Biswajit

2014-01-01

168

Otomycosis; clinical features, predisposing factors and treatment implications  

PubMed Central

Objectives : The aim of this study was to determine the frequency of otomycosis, the clinical presentation, predisposing factors and treatment outcomes. Methods: This observational study was conducted at ENT department of Combined Military Hospital Attock, from October, 2010 to September, 2012. Convenient sample comprising 180 patients of both sexes and all age groups were selected from ENT OPD. The frequency, predisposing factors and most common symptoms of otomycosis were recorded. The response to different antifungal agents was also observed. Results were recorded in percentages. Results: There were 180 patients with documented diagnosis of otomycosis. There were 107 (59%) males and 73 (41%) females. The age of patients ranged from 1½ years to 75 years with a mean age of 38.5 years. Mean follow up time was 2 years. Most common presenting symptom was hearing loss (77.7%) followed by pruritis (68.8%) and otalgia (40%). We prescribed 1% clotrimazole drops or lotion in 58% patients and 2% salicylic acid in 31% cases. Both of these agents are effective. Topical 1% clotrimazole drops yielded highest resolution rate with lowest recurrent rate. Overall 149 (83%) patients were improved with initial treatment and 31 (17%) did not respond to initial treatment. Eight (4.4%) patients had a history of otological procedures. Four (2.2%) patients had canal wall down procedures that resulted in mastoid cavity. To analyse the efficacy of 1% clotrimazole and 2% salicylic acid we applied Z-Test to calculate the difference between 2 proportions of patients before treatment with those patients who remained uncured after treatment. Conclusion: Otomycosisis commonly presented with decreased hearing, pruritis, otalgia & otorrhoea. It usually resolves with local toilet of ear and instillation of antifungal agents. Eradication of disease is difficult in presence of a mastoid cavity and metabolic diseases like diabetes mellitus. PMID:24948980

Anwar, Khurshid; Gohar, Muhammad Shahid

2014-01-01

169

Association between the methylene tetrahydrofolate reductase gene C677T mutation and colchicine unresponsiveness in Behcet’s disease  

PubMed Central

Purpose Behcet’s disease (BD) is a multisystemic immunoinflammatory disorder characterized by mucocutaneous, ocular, vascular, and central nervous system manifestations. The common methylene tetrahydrofolate reductase (MTHFR) gene C677T mutation is a known risk factor for thrombosis. The aim of this study was to investigate the MTHFR gene C677 mutation in patients with BD and evaluate if there was an association with clinical features, especially thrombosis, in a relatively large cohort of patients with BD. Methods The study included 318 patients with BD and 207 healthy controls. Genomic DNA was isolated and genotyped using PCR-based restriction fragment length polymorphism assay for the MTHFR gene C677T mutation. Results The genotype and allele frequencies of the C677T mutation showed a statistically significant difference between BD patients and controls (p=0.003 and p=0.001, respectively). There was also a significant association between C677T alteration and response to colchicine in BD patients (p=0.046). Conclusions The results of this study showed that there was a high association between the MTHFR gene C677T mutation and BD. Stratification analysis according to clinical features for this disease did not reveal an association except response to colchicine that was shown to be influenced by the MTHFR C677T mutation. PMID:22773907

Yigit, Serbulent; Kalkan, Goknur; Rustemoglu, Aydin; Inanir, Ahmet; Gul, Ulker; Pancar, Gunseli Sefika; Akkanet, Songul; Ates, Omer

2012-01-01

170

Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility  

E-print Network

, Leeds, LS2 9JT, United Kingdom Edited by Philip W. Majerus, Washington University School of Medicine, St. Louis, MO, and approved August 10, 1999 (received for review June 11, 1999) Reduction of 5 located at nucleotide 677 of the MTHFR gene results in an alanine-to-valine substitution. Up to 15

California at Berkeley, University of

171

Microarray-based detection of CYP1A1, CYP2C9, CYP2C19, CYP2D6, GSTT1, GSTM1, MTHFR, MTRR, NQO1, NAT2, HLA-DQA1, and AB0 allele frequencies in native Russians.  

PubMed

Xenobiotic-metabolizing genes (e.g., Cytochromes P450, GST, NAT2, and NQO1), folate metabolism genes (e.g., MTHFR and MTRR), and major histocompatibility complex genes (e.g., HLA-DQA1) play multiple roles in the organism functioning. In addition, AB0 is the most clinically significant high-polymorphic gene in transfusion and transplantation medicine. Epidemiological data show that allele frequencies of these genes exhibit ethnic and geographic diversity. Besides, little is known about frequency distribution of the major polymorphic variants in native Russians. We developed biological microchips that allow us to analyze a spectrum of allelic variants in 12 different genes: CYP1A1, CYP2D6, CYP2C9, CYP2C19, GSTT1, GSTM1, MTHFR, MTRR, NQO1, NAT2, HLA-DQA1, and AB0. Using this composite methodological platform we have studied 352 DNA samples from healthy native Russian volunteers. The allelic frequencies of gene polymorphisms obtained are close to allelic frequencies observed in some European populations, as published earlier. These data were used in comparative studies to determine predisposition to tuberculosis, lymphoma, and leukemia in adults and to childhood acute leukemia. The HLA-DQA1 and AB0 allele frequencies were used to estimate forensic population parameters for these loci. PMID:20373852

Gra, Olga; Mityaeva, Olga; Berdichevets, Iryna; Kozhekbaeva, Zhanna; Fesenko, Denis; Kurbatova, Olga; Goldenkova-Pavlova, Irina; Nasedkina, Tatyana

2010-06-01

172

The Effect of MTHFR Ala222Val Polymorphism on Open-angle Glaucoma: A Meta-analysis.  

PubMed

Abstract Glaucoma is the second leading cause of irreversible blindness worldwide, among which primary open-angle glaucoma (POAG) is the most common form of glaucoma in some populations. To date, published data on the association between MTHFR (Ala222Val) polymorphism and POAG risk are still inconclusive. In this work, we performed a meta-analysis of available case-control study in order to assess the association between MTHFR (Ala222Val) polymorphism and POAG susceptibility. In total we compiled 13 studies (1970 POAG patients and 1712 control subjects) into the meta-analysis. Overall, no obvious associations between MTHFR (Ala222Val) polymorphism and POAG susceptibility was found under all four genetic models (Val/Val versus Ala/Ala: OR?=?1.05, 95% CI?=?0.77-1.43; Ala/Val versus Ala/Ala: OR?=?1.05, 95% CI?=?0.86-1.26; Ala/Val + Val/Val versus Ala/Ala: OR?=?1.08, 95% CI?=?0.87-1.34; Val/Val versus Ala/Val + Ala/Ala: OR?=?1.14, 95% CI?=?0.67-1.92). In the stratified analysis by ethnicity, significant associations were still not observed in all genetic models. In conclusion, based on 13 eligible studies, the result provided strong evidences that MTHFR Ala222Val polymorphism is not associated with POAG. PMID:25317717

Zhao, Rong; Yin, Dongchen; Wang, Enpu; Si, Bingxin

2015-03-01

173

A Hypomethylating Variant of MTHFR, 677C.T, Blunts the Neural Response to Errors in Patients with  

E-print Network

A Hypomethylating Variant of MTHFR, 677C.T, Blunts the Neural Response to Errors in Patients Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, United States of America Abstract Background: Responding to errors is a critical first step

Manoach, Dara S.

174

Infection with human metapneumovirus predisposes mice to severe pneumococcal pneumonia.  

PubMed

Human metapneumovirus (hMPV) is a recently described paramyxovirus that causes respiratory tract infections. Prior clinical studies have highlighted the importance of respiratory viruses, such as influenza virus, in facilitating secondary bacterial infections and increasing host immunopathology. The objective of the present work was to evaluate the effects of initial viral infection with hMPV or influenza A virus followed by Streptococcus pneumoniae superinfection 5 days later in a murine model. Both groups of superinfected mice demonstrated significant weight loss (mean of 15%) and higher levels of airway obstruction (mean enhanced pause value of 2.7) compared to those of mice infected with hMPV, influenza virus, or pneumococcus alone. Bacterial counts increased from 5 x 10(2) CFU/lung in mice infected with pneumococcus only to 10(7) and 10(9) CFU/lung in mice with prior infections with hMPV and influenza A virus, respectively. A more pronounced interstitial and alveolar inflammation correlated with higher levels of inflammatory cytokines and chemokines such as interleukin-1alpha (IL-1alpha), IL-1beta, IL-6, IL-12, monocyte chemotactic protein 1, macrophage inflammatory protein 1alpha, KC, and granulocyte colony-stimulating factor, as well as greater expression of Toll-like receptor 2 (TLR2), TLR6, TLR7, and TLR13 in the lungs of superinfected animals compared to results for single infections, with similar immunological effects seen in both coinfection models. Prior infection with either hMPV or influenza A virus predisposes mice to severe pneumococcus infection. PMID:19019962

Kukavica-Ibrulj, Irena; Hamelin, Marie-Eve; Prince, Gregory A; Gagnon, Constance; Bergeron, Yves; Bergeron, Michel G; Boivin, Guy

2009-02-01

175

Genome-wide association study identifies novel loci predisposing to cutaneous melanoma†  

PubMed Central

We performed a multistage genome-wide association study of melanoma. In a discovery cohort of 1804 melanoma cases and 1026 controls, we identified loci at chromosomes 15q13.1 (HERC2/OCA2 region) and 16q24.3 (MC1R) regions that reached genome-wide significance within this study and also found strong evidence for genetic effects on susceptibility to melanoma from markers on chromosome 9p21.3 in the p16/ARF region and on chromosome 1q21.3 (ARNT/LASS2/ANXA9 region). The most significant single-nucleotide polymorphisms (SNPs) in the 15q13.1 locus (rs1129038 and rs12913832) lie within a genomic region that has profound effects on eye and skin color; notably, 50% of variability in eye color is associated with variation in the SNP rs12913832. Because eye and skin colors vary across European populations, we further evaluated the associations of the significant SNPs after carefully adjusting for European substructure. We also evaluated the top 10 most significant SNPs by using data from three other genome-wide scans. Additional in silico data provided replication of the findings from the most significant region on chromosome 1q21.3 rs7412746 (P = 6 × 10?10). Together, these data identified several candidate genes for additional studies to identify causal variants predisposing to increased risk for developing melanoma. PMID:21926416

Amos, Christopher I.; Wang, Li-E; Lee, Jeffrey E.; Gershenwald, Jeffrey E.; Chen, Wei V.; Fang, Shenying; Kosoy, Roman; Zhang, Mingfeng; Qureshi, Abrar A.; Vattathil, Selina; Schacherer, Christopher W.; Gardner, Julie M.; Wang, Yuling; Tim Bishop, D.; Barrett, Jennifer H.; MacGregor, Stuart; Hayward, Nicholas K.; Martin, Nicholas G.; Duffy, David L.; Mann, Graham J.; Cust, Anne; Hopper, John; Brown, Kevin M.; Grimm, Elizabeth A.; Xu, Yaji; Han, Younghun; Jing, Kaiyan; McHugh, Caitlin; Laurie, Cathy C.; Doheny, Kim F.; Pugh, Elizabeth W.; Seldin, Michael F.; Han, Jiali; Wei, Qingyi

2011-01-01

176

Relationship of the FKBP5 C/T polymorphism with dysfunctional attitudes predisposing to depression.  

PubMed

FK506-binding protein 51 (FKBP5) is a co-chaperone of the glucocorticoid receptor, and plays an important role in the negative feedback regulation of the hypothalamic-pituitary-adrenal axis. The C/T single nucleotide polymorphism in the intron 2 of the FKBP5 gene affects cortisol secretion, and has been implicated in the pathophysiology of depression. In this study, the relationship of the FKBP5 C/T polymorphism with dysfunctional attitudes predisposing to depression was examined. The subjects were 300 healthy Japanese. The FKBP5 genotypes were determined by a real-time PCR and cycling probe technology for SNP typing. Dysfunctional attitudes were assessed by the 24-item version of the Dysfunctional Attitude Scale (DAS-24), which has the Achievement, Self-control, and Dependency subscales. DAS-24 total scores were significantly higher in the group with the T allele than in that without this allele (p=0.001). Regarding the subscales, scores of the Achievement (p=0.003) and Self-control (p=0.009) subscales, but not those of the Dependency subscale, were significantly higher in the former group than in the latter group. The present study suggests that the FKBP5 C/T polymorphism is implicated in formation of dysfunctional attitudes, especially those about achievement and self-control. PMID:24889341

Suzuki, Akihito; Matsumoto, Yoshihiko; Sadahiro, Ryoichi; Enokido, Masanori; Goto, Kaoru; Otani, Koichi

2014-08-01

177

Deletions of NRXN1 (Neurexin-1) Predispose to a Wide Spectrum of Developmental Disorders  

PubMed Central

Research has implicated mutations in the gene for neurexin-1 (NRXN1) in a variety of conditions including autism, schizophrenia, and nicotine dependence. To our knowledge, there have been no published reports describing the breadth of the phenotype associated with mutations in NRXN1. We present a medical record review of subjects with deletions involving exonic sequences of NRXN1. We ascertained cases from 3,540 individuals referred clinically for comparative genomic hybridization testing from March 2007 to January 2009. Twelve subjects were identified with exonic deletions. The phenotype of individuals with NRXN1 deletion is variable and includes autism spectrum disorders, mental retardation, language delays, and hypotonia. There was a statistically significant increase in NRXN1 deletion in our clinical sample compared to control populations described in the literature (P = 8.9 × 10?7). Three additional subjects with NRXN1 deletions and autism were identified through the Homozygosity Mapping Collaborative for Autism, and this deletion segregated with the phenotype. Our study indicates that deletions of NRXN1 predispose to a wide spectrum of developmental disorders. © 2010 Wiley-Liss, Inc. PMID:20468056

Ching, Michael SL; Shen, Yiping; Tan, Wen-Hann; Jeste, Shafali S; Morrow, Eric M; Chen, Xiaoli; Mukaddes, Nahit M; Yoo, Seung-Yun; Hanson, Ellen; Hundley, Rachel; Austin, Christina; Becker, Ronald E; Berry, Gerard T; Driscoll, Katherine; Engle, Elizabeth C; Friedman, Sandra; Gusella, James F; Hisama, Fuki M; Irons, Mira B; Lafiosca, Tina; LeClair, Elaine; Miller, David T; Neessen, Michael; Picker, Jonathan D; Rappaport, Leonard; Rooney, Cynthia M; Sarco, Dean P; Stoler, Joan M; Walsh, Christopher A; Wolff, Robert R; Zhang, Ting; Nasir, Ramzi H; Wu, Bai-Lin

2010-01-01

178

An autosomal locus predisposing to multiple deletions of mtDNA on chromosome 3p  

SciTech Connect

Autosomal dominant progressive external ophthalmoplegia (adPEO) is a disorder characterized by ptosis, progressive weakness of the external eye muscles, and general muscle weakness. The patients have multiple deletions of mtDNA on Southern blots or in PCR analysis of muscle DNA and a mild deficiency of one or more respiratory-chain enzymes carrying mtDNA-encoded subunits. The pattern of inheritance indicates a nuclear gene defect predisposing to secondary mtDNA deletions. Recently, in one Finnish family, we assigned an adPEO locus to chromosome 10q23.3-24.3 but also excluded linkage to this same locus in two Italian adPEO families with a phenotype closely resembling the Finnish one. We applied a random mapping approach to informative non-10q-linked Italian families to assign the second locus for adPEO and found strong evidence for linkage on chromosome 3p14.1-21.2 in three Italian families, with a maximum two-point lod score of 4.62 at a recombination fraction of .0. However, in three additional families, linkage to the same chromosomal region was clearly absent, indicating further genetic complexity of the adPEO trait. 19 refs., 3 figs., 2 tabs.

Kaukonen, J.A.; Suomalainen, A.; Peltonen, L. [National Public Health Inst., Helsinki (Finland); Amati, P.; Zeviani, M. [Univ. of Milano, Milan (Italy)] [and others

1996-04-01

179

Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders.  

PubMed

Research has implicated mutations in the gene for neurexin-1 (NRXN1) in a variety of conditions including autism, schizophrenia, and nicotine dependence. To our knowledge, there have been no published reports describing the breadth of the phenotype associated with mutations in NRXN1. We present a medical record review of subjects with deletions involving exonic sequences of NRXN1. We ascertained cases from 3,540 individuals referred clinically for comparative genomic hybridization testing from March 2007 to January 2009. Twelve subjects were identified with exonic deletions. The phenotype of individuals with NRXN1 deletion is variable and includes autism spectrum disorders, mental retardation, language delays, and hypotonia. There was a statistically significant increase in NRXN1 deletion in our clinical sample compared to control populations described in the literature (P = 8.9 x 10(-7)). Three additional subjects with NRXN1 deletions and autism were identified through the Homozygosity Mapping Collaborative for Autism, and this deletion segregated with the phenotype. Our study indicates that deletions of NRXN1 predispose to a wide spectrum of developmental disorders. PMID:20468056

Ching, Michael S L; Shen, Yiping; Tan, Wen-Hann; Jeste, Shafali S; Morrow, Eric M; Chen, Xiaoli; Mukaddes, Nahit M; Yoo, Seung-Yun; Hanson, Ellen; Hundley, Rachel; Austin, Christina; Becker, Ronald E; Berry, Gerard T; Driscoll, Katherine; Engle, Elizabeth C; Friedman, Sandra; Gusella, James F; Hisama, Fuki M; Irons, Mira B; Lafiosca, Tina; LeClair, Elaine; Miller, David T; Neessen, Michael; Picker, Jonathan D; Rappaport, Leonard; Rooney, Cynthia M; Sarco, Dean P; Stoler, Joan M; Walsh, Christopher A; Wolff, Robert R; Zhang, Ting; Nasir, Ramzi H; Wu, Bai-Lin

2010-06-01

180

COMPARATIVE EVALUATION OF RISK FACTORS FOR CARDIOVASCULAR DISEASE (CVD) IN GENETICALLY PREDISPOSED RATS  

EPA Science Inventory

Rodent CVD models are increasingly used for understanding individual differences in susceptibility to environmental stressors such as air pollution. We characterized pathologies and a number of known human risk factors of CVD in genetically predisposed, male young adult Spontaneo...

181

Etiological agents and predisposing factors of intracranial abscesses in a Greek university hospital  

Microsoft Academic Search

Summary The bacteriology for 21 patients with brain abscesses is presented and correlated with their predisposing conditions. Chronic otomastoiditis was the most common predisposing factor, and the overall most frequent infected sites were the frontal and temporal regions. Gram-negative non-sporeforming anaerobes of the genusBacteroides andFusobacterium followed by aerobic streptococci were the predominant pathogens. Enterobacteria were only identified in postcraniotomy abscesses,

D. Sofianou; A. Tsakris; P. Selviarides; G. Foroglou; E. Sofianos

1996-01-01

182

Genetic Association Analyses of Nitric Oxide Synthase Genes and Neural Tube Defects Vary by Phenotype  

PubMed Central

Neural tube defects (NTDs) are caused by improper neural tube closure during the early stages of embryonic development. NTDs are hypothesized to have a complex genetic origin and numerous candidate genes have been proposed. The nitric oxide synthase 3 (NOS3) G594T polymorphism has been implicated in risk for spina bifida, and interactions between that single nucleotide polymorphism (SNP) and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism have also been observed. To evaluate other genetic variation in the NO pathway in the development of NTDs, we examined all three NOS genes: NOS1, NOS2, and NOS3. Using 3109 Caucasian samples in 745 families, we evaluated association in the overall dataset and within specific phenotypic subsets. Haplotype tagging SNPs in the NOS genes were tested for genetic association with NTD subtypes, both for main effects as well as for the presence of interactions with the MTHFR C677T polymorphism. Nominal main effect associations were found with all subtypes, across all three NOS genes, and interactions were observed between SNPs in all three NOS genes and MTHFR C677T. Unlike the previous report, the most significant associations in our dataset were with cranial subtypes and the AG genotype of rs4795067 in NOS2 (p = 0.0014) and the interaction between the rs9658490 G allele in NOS1 and MTHFR 677TT genotype (p = 0.0014). Our data extend the previous findings by implicating a role for all three NOS genes, independently and through interactions with MTHFR, in risk not only for spina bifida, but all NTD subtypes. PMID:24323870

Soldano, Karen L.; Garrett, Melanie E.; Cope, Heidi L.; Rusnak, J. Michael; Ellis, Nathen J.; Dunlap, Kaitlyn L.; Speer, Marcy C.; Gregory, Simon G.; Ashley-Koch, Allison E.

2014-01-01

183

Prediction of Methotrexate Clinical Response in Portuguese Rheumatoid Arthritis Patients: Implication of MTHFR rs1801133 and ATIC rs4673993 Polymorphisms  

PubMed Central

Objective. Methotrexate (MTX), the most used drug in rheumatoid arthritis (RA) treatment, showing variability in clinical response, is often associated with genetic polymorphisms. This study aimed to elucidate the role of methylenetetrahydrofolate reductase (MTHFR) C677T and aminoimidazole carboxamide adenosine ribonucleotide transformylase (ATIC) T675C polymorphisms and clinicopathological variables in clinical response to MTX in Portuguese RA patients. Methods. Study included 233 RA patients treated with MTX for at least six months. MTHFR C677T and ATIC T675C polymorphisms were genotyped and clinicopathological variables were collected. Statistical analyses were performed and binary logistic regression method adjusted to possible confounding variables. Results. Multivariate analyses demonstrated that MTHFR 677TT (OR = 4.63; P = 0.013) and ATIC 675T carriers (OR = 5.16; P = 0.013) were associated with over 4-fold increased risk for nonresponse. For clinicopathological variables, noncurrent smokers (OR = 7.98; P = 0.001), patients positive to anti-cyclic citrullinated peptide (OR = 3.53; P = 0.004) and antinuclear antibodies (OR = 2.28; P = 0.045), with higher health assessment questionnaire score (OR = 2.42; P = 0.007), and nonsteroidal anti-inflammatory drug users (OR = 2.77; P = 0.018) were also associated with nonresponse. Contrarily, subcutaneous administration route (OR = 0.11; P < 0.001) was associated with response. Conclusion. Our study suggests that MTHFR C677T and ATIC T675C genotyping combined with clinicopathological data may help to identify patients whom will not benefit from MTX treatment and, therefore, assist clinicians in personalizing RA treatment. PMID:24967362

Lima, Aurea; Monteiro, Joaquim; Bernardes, Miguel; Sousa, Hugo; Azevedo, Rita; Seabra, Vitor; Medeiros, Rui

2014-01-01

184

[Clinical course of acute coronary syndrome in dependence on containing of homozystein and ?677? methylenetetrahydrofolate reductase gene polymorphism].  

PubMed

Nowadays to a numerous factors of IHD development risks hyperhomocysteinemia (HHc), C-reactive protein, fibrogen, as well as genetic disorders are relating. With development of IHD and its complications associated methylentetrahudrofolate reductase gene mutation of ?677? polymorphism. The purpose of the investigation was studying the connection between acute coronary syndrome severity (ACS) in dependence on plasma homocysteine containing and genotype by ?677? polymorphism MTHFR gene. Examined: 161 patients with ACS and 87 almost healthy people. Identification of 4th exon allelic polymorphism MTHFR ?677? gene (rs1801133) was conducted with method of polymerase chain reaction, the investigation of homocysteine containing with immunoenzymated method. The statistic analyze was performed with using of SPSS - 17 programme. According to results of study patients with ACS of homozygote by minor allele T ?677? MTHFR gene polymorphism by main allele C and heterozygote were associated with high homocysteine containing in plasma. While frequencies of T/T genotype was reliably higher in patients with ACS with segment ST elevation and complicated course compare with patients with ACS with segment ST elevation and non-complicated course and ACS without climbs of segment ST. Also, statistically reliable difference in genotypes distribution by C677T MTHFR gene polymorphism in dependence on homocysteine plasma level and clinical course of ACS severity were established. PMID:25693213

Prystupa, L; Grek, A; Ataman, Y; Orlovskiy, A; Opolonska, N

2015-01-01

185

Why are women predisposed to autoimmune rheumatic diseases?  

Microsoft Academic Search

The majority of autoimmune diseases predominate in females. In searching for an explanation for this female excess, most attention has focused on hormonal changes - both exogenous changes (for example, oral contraceptive pill) and fluctuations in endogenous hormone levels particularly related to menstruation and pregnancy history. Other reasons include genetic differences, both direct (influence of genes on sex chromosomes) and

Jacqueline E Oliver; Alan J Silman

2009-01-01

186

Rate of T alleles and TT genotype at MTHFR 677C->T locus or C alleles and CC genotype at MTHFR 1298A->C locus among healthy subjects in Turkey: impact on homocysteine and folic acid status and reference intervals.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) is important for folate and homocysteine (Hcy) metabolism. MTHFR 677C->T and 1298A->C MTHFR are two most common mutations which can affect folate and total homocysteine (tHcy) status. This study was designed to determine the rate of MTHFR 677C->T and 1298A->C mutations, and their influence on serum folate, Hcy and vitamin B12 status and the reference intervals in 402 healthy Turkish adults. The rate of MTHFR 677C->T or 1298A->C mutations was 50.7% or 54.7%, respectively. The MTHFR 677C->T mutation-specific reference intervals for serum folate and tHcy were characterized by marked shifts in their upper limits. In homozygote subjects for MTHFR 677C->T serum folate concentration was lower and serum tHcy concentration was higher than those in the wild genotype; all subjects had lower serum folate and 54% of the subjects had higher tHcy concentrations than the cutoff values of or=12 micromol/L, respectively. Serum vitamin B12 status was similar in all genotypes. Serum tHcy concentrations were inversely correlated with serum folate and vitamin B12 concentrations in all genotypes. These data show that the rate of MTHFR 677C->T and 1298A->C mutations is very high in Turks and serum folate and tHcy status are impaired by these mutations. PMID:19764044

Ozarda, Yesim; Sucu, Derya Kaynak; Hizli, Banu; Aslan, Diler

2009-12-01

187

Prevalence of thromogenic gene mutations in women with recurrent miscarriage: A retrospective study of 1,507 patients  

PubMed Central

Objective Thromogenic gene mutations has been thought to be associated with recurrent pregnancy loss in women in Turkey. The aim of this study was to investigate the prevalence of thromogenic gene mutations such as factor V Leiden (FVL, G1691T), prothrombin (G20210A), and the methylene tetrahydrofolate reductase (MTHFR, C677T) mutation in women with recurrent pregnancy loss. Methods This descriptive study was carried out in the Department of Obstetrics and Gynaecology, Harran University School of Medicine, and included a total of 1,507 women with histories of recurrent pregnancy loss between January 2010 and June 2013. The mutations were assessed by using the polymerase chain reaction. Results The homozygous mutation frequencies of FVL, prothrombin, and MTHFR were found to be 3 (0.20%), 0 and 125 (8.29%), and the heterozygous mutation frequencies were 83 (5.51%), 61 (4.05%), and 612 (40.61%), respectively. Among the 86 FVL mutation patients, 38 also had accompanying prothrombin and MTHFR mutations. Conclusion Since the homozygous forms of the FVL-prothrombin gene mutations have low incidences and MTHFR mutation is similar to a healthy population, preconceptional thromogenic gene mutations screening seems to be controversial. PMID:25469341

Hilali, Nese Gul; Camuzcuoglu, Aysun; Camuzcuoglu, Hakan; Akbas, Halit; Kilic, Avni; Vural, Mehmet

2014-01-01

188

Association of Transforming Growth Factor Alpha and Methylenetetrahydrofolate reductase gene variants with nonsyndromic cleft lip and palate in the Indian population  

PubMed Central

Objectives: The aim was to evaluate the relationship of the K-primer variant of the transforming growth factor-alpha (TGF-?) gene and C677T variant of the methylenetetrahydrofolate reductase (MTHFR) gene with nonsyndromic cleft lip and palate (CL/P) in the Indian population. Setting and Sample Population: The study group consisted of DNA samples of 25 subjects with nonsyndromic CL with or without cleft palate and 25 unrelated controls, already existing in the Department of Orthodontics, D.A.P.M.R.V. Dental College, Bengaluru, Karnataka, India. Materials and Methods: The DNA samples were divided into two categories: Group A which included the 25 subjects with nonsyndromic CL/P; and Group B, which consisted of the 25 unrelated controls. The polymerase chain reaction (PCR) test was done for amplification of the region of interest from the DNA samples. Restriction digestion was then performed on the amplified product using the restriction enzyme HinfI, separately for each of the variants. The digested PCR products were separated into channels on a 1.5% agarose gel containing ethidium bromide in an electrophoretic chamber. A U.V. transilluminator was used to see the specific bands of base pairs of the digested PCR products. Results: In Group A, the TGF-? gene variant was present in 16 subjects (P = 0.001) and MTHFR gene variant was present in 8 subjects (P = 0.185). A combination of both gene variants were present in seven subjects, which was an interesting finding. In Group B, four subjects tested positive for the TGF-? and MTHFR gene variants. Conclusions: The TGF-? gene variant and a combination of TGF-? + MTHFR gene variants significantly contribute to the development of nonsyndromic CL/P and can be considered as genetic markers for Indian population. The MTHFR gene variant, though a minor risk factor, cannot be considered as a genetic marker. PMID:25191068

Desai, Asavari L.; Dinesh, M. R.; Amarnath, B. C.; Dharma, R. M.; Akshai, K. R.; Prashanth, C. S.

2014-01-01

189

Association between MTHFR C677T and A1298C Polymorphisms and NSCL/P Risk in Asians: A Meta-Analysis  

PubMed Central

Objective Several studies have reported the association between methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and nonsyndromic cleft lip with or without palate (NSCL/P) in Asian populations. However, findings have been conflicting. In order to investigate the association, a meta-analysis was performed. Methods We searched Pubmed, MedLine and EmBase database to selected eligible studies. The pooled odds ratios (ORs) with 95% confidence intervals (95%CIs) were calculated using fixed effects model or random effects model to assess the association between MTHFR polymorphisms and NSCL/P in both Asian children and mothers. Results Finally, nine case-control studies were included. Overall, the MTHFR C677T polymorphism and NSCL/P showed pooled ORs (95%CI) of 1.41(1.23–1.61) in Asian children, and 1.70(1.19–2.42) in Asian mothers. Subgroup analyses by geographical locations further identified the association in Eastern Asian children, Western/Central Asian children and mothers, but not in Eastern Asian mothers. However, no significant relationship between MTHFR A1298C polymorphism and NSCL/P was found in this meta-analysis. Conclusions The MTHFR 677T allele was associated with an increased risk of NSCL/P in Asian populations. PMID:24658649

Zhao, Mengmeng; Ren, Yangwu; Shen, Li; Zhang, Yue; Zhou, Baosen

2014-01-01

190

Combined folate gene MTHFD and TC polymorphisms as maternal risk factors for Down syndrome in China.  

PubMed

We examined whether polymorphisms in the methylenetetrahydrofolate dehydrogenase (MTHFD) and transcobalamin (TC) genes, which are involved in folate metabolism, affect maternal risk for Down syndrome. We investigated 76 Down syndrome mothers and 115 control mothers from Bengbu, China. Genomic DNA was isolated from the peripheral lymphocytes. Polymerase chain reaction and restriction fragment length polymorphism were used to examine the polymorphisms of MTHFD G1958A and TC C776G. The frequencies of the polymorphic alleles were 24.3 and 19.1% for MTHFD 1958A, 53.9 and 54.2% for TC 776G, in the case and control groups, respectively. No significant differences were found between two groups in relation to either the allele or the genotype frequency for both polymorphisms. However, when gene-gene interactions between these two polymorphisms together with previous studied C677T and A1298C polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene were analyzed, the combined MTHFR 677CT/TT and MTHFD 1958AA/GA genotype was found to be significantly associated with the risk of having a Down syndrome child [odds ratio (OR) = 3.11; 95% confidence interval (95%CI) = 1.07-9.02]. In addition, the combined TC 776CG and MTHFR 677TT genotype increased the risk of having a child with Down syndrome 3.64-fold (OR = 3.64; 95%CI = 1.28-10.31). In conclusion, neither MTHFD G1958A nor TC C776G polymorphisms are an independent risk factor for Down syndrome. However, the combined MTHFD/MTHFR, TC/MTHFR genotypes play a role in the risk of bearing a Down syndrome child in the Chinese population. PMID:24668664

Liao, Y P; Zhang, D; Zhou, W; Meng, F M; Bao, M S; Xiang, P; Liu, C Q

2014-01-01

191

Atherosclerosis in male patients with ankylosing spondylitis: the relation with methylenetetrahydrofolate reductase (C677T) gene polymorphism and plasma homocysteine levels.  

PubMed

The aim of this study was to determine the intima-media thickness (IMT) in carotid arteries and to assess the relation of these values with plasma homocysteine (pHcy) levels and methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism in patients with Ankylosing spondylitis (AS). Serum lipids, vitamin B12, folic acid, pHcy and acute phase protein levels were measured in all cases. MTHFR C677T gene polymorphisms were determined, and IMT of main carotid artery were evaluated ultrasonographically in all subjects. Bath Ankylosing Spondylitis Disease Activity Index, Ankylosing Spondylitis Disease Activity score and Bath Ankylosing Spondylitis Metrology Index were used to assess disease activity and spinal mobility. Fifty AS patients (mean age of 36.6 ± 4.79 years) and 50 control subjects (36.34 ± 4.72 years) were included in the study. Plasma homocysteine levels of AS patients and control group were also similar (14.26 ± 9.96 vs. 11.81 ± 5.53 ?mol/L). Hyperhomocysteinemia was present in 11 subjects in patient group (22.0 %), while it was seen in 5 subjects in the control group (10.0 %). The MTHFR C677T genotype distribution was as follows: CC 31 (62 %), CT 14 (28 %), TT 5 (10 %) in AS patients. The mean carotid IMT values were also found to be similar between the groups. The most important factor influencing pHcy level was found as MTHFR 677TT genotype. We indicated no difference of atherosclerosis indices revealed by IMT values and pHcy levels AS patients and control subjects. But an association between MTHFR 677 gene polymorphism and pHcy levels was concluded, which may suggest that MTHFR 677 TT polymorphism may be a potential prognostic factor for cardiovascular disease in patients with AS. PMID:23247802

Geçene, Muharrem; Tuncay, Figen; Borman, P?nar; Yücel, Dogan; Senes, Mehmet; Y?lmaz, Behice Kaniye

2013-06-01

192

CTCF haploinsufficiency destabilizes DNA methylation and predisposes to cancer.  

PubMed

Epigenetic alterations, particularly in DNA methylation, are ubiquitous in cancer, yet the molecular origins and the consequences of these alterations are poorly understood. CTCF, a DNA-binding protein that regulates higher-order chromatin organization, is frequently altered by hemizygous deletion or mutation in human cancer. To date, a causal role for CTCF in cancer has not been established. Here, we show that Ctcf hemizygous knockout mice are markedly susceptible to spontaneous, radiation-, and chemically induced cancer in a broad range of tissues. Ctcf(+/-) tumors are characterized by increased aggressiveness, including invasion, metastatic dissemination, and mixed epithelial/mesenchymal differentiation. Molecular analysis of Ctcf(+/-) tumors indicates that Ctcf is haploinsufficient for tumor suppression. Tissues with hemizygous loss of CTCF exhibit increased variability in CpG methylation genome wide. These findings establish CTCF as a prominent tumor-suppressor gene and point to CTCF-mediated epigenetic stability as a major barrier to neoplastic progression. PMID:24794443

Kemp, Christopher J; Moore, James M; Moser, Russell; Bernard, Brady; Teater, Matt; Smith, Leslie E; Rabaia, Natalia A; Gurley, Kay E; Guinney, Justin; Busch, Stephanie E; Shaknovich, Rita; Lobanenkov, Victor V; Liggitt, Denny; Shmulevich, Ilya; Melnick, Ari; Filippova, Galina N

2014-05-22

193

Polymorphisms in genes involved in folate metabolism and colorectal neoplasia: a HuGE review.  

PubMed

Epidemiologic and mechanistic evidence suggests that folate is involved in colorectal neoplasia. Some polymorphic genes involved in folate metabolism--methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), methionine synthase (MTR A2756G), methionine synthase reductase (MTRR A66G), cystathionine beta-synthase (CBS exon 8, 68-base-pair insertion), and thymidylate synthase (TS enhancer region and 3' untranslated region)--have been investigated in colorectal neoplasia. For MTHFR C677T and A1298C, the variant allele is associated with reduced enzyme activity in vitro. For the other polymorphisms, functional data are limited and/or inconsistent. Genotype frequencies for all of the polymorphisms show marked ethnic and geographic variation. In most studies, MTHFR 677TT (10 studies, >4,000 cases) and 1298CC (four studies, >1,500 cases) are associated with moderately reduced colorectal cancer risk. In four of five genotype-diet interaction studies, 677TT subjects who had higher folate levels (or a "high-methyl diet") had the lowest cancer risk. In two studies, 677TT homozygote subjects with the highest alcohol intake had the highest cancer risk. Findings from six studies of MTHFR C677T and adenomatous polyps are inconsistent. There have been only one or two studies of the other polymorphisms; replication is needed. Overall, the roles of folate-pathway genes, folate, and related dietary factors in colorectal neoplasia are complex. Research priorities are suggested. PMID:14977639

Sharp, Linda; Little, Julian

2004-03-01

194

Genetic interactions between MTHFR (C677T), methionine synthase (A2756G, C2758G) variants with vitamin B12 and folic acid determine susceptibility to premature coronary artery disease in Indian population  

PubMed Central

Background: Researchers have determined that Indians face a higher risk of heart disease, despite the fact that nearly half of them are vegetarians and lack many of the other traditional risk factors. In the below-30 age group, coronary artery disease mortality among Indians is three-fold higher than in the whites in United Kingdom and ten-fold higher than the Chinese in Singapore. High levels of homocysteine have been widely linked to the early onset of heart diseases in other populations, although a definite proof among Indians is lacking, which needs to be investigated by way of screening for factors responsible for high homocysteine levels. Objective: To screen for genetic factors responsible for hyperhomocysteinemia and the risk for premature coronary artery disease. Materials and Methods: A total of 100 individuals with proven premature coronary artery disease and 200 age-and-sex matched controls were screened for polymorphisms in Methylenetetrahydrofolate reductase (MTHFR) (C677T) Methionine synthase (MS) genes (A2756G, C2758G), and the B12 and Folate levels were estimated. Results: Results from the mutational analysis revealed that in the study group, seven individuals had a polymorphism for the C677T allele in the MTHFR gene (one homozygous and six heterozygous) (Fischer's Exact test P > 0.046) (OR: 0.2711 95% CI 0.0774 to 0.9491). Six were heterozygous for the A2756G polymorphism in the MS gene (Fischer's Exact test P > 0.0012). None showed a polymorphism at the C2758G allele in the MS gene. Four controls showed heterozygosity for the C677T polymorphism and none for the MS gene. The B12 and Folate levels were significantly lower in the study group as compared to the controls. Conclusions: It is important to know which factors determine the total homocysteine concentrations. In the general population, the most important modifiable determinants of tHcy are folate intake and coffee consumption. Smoking and alcohol consumption are also associated with the total homocysteine concentrations, but more research is necessary to elucidate whether these relations are not originating from residual confounding due to other lifestyle factors. PMID:22022143

Kanth, V. V. Ravi; Golla, Jaya Prakash; Sastry, B. K. S; Naik, Sudhir; Kabra, Nitin; Sujatha, Madireddi

2011-01-01

195

Assessing predictive capacity and conditional independence of landslide predisposing factors for shallow landslides susceptibility models  

NASA Astrophysics Data System (ADS)

The aim of this study is to identify the landslide predisposing factors combination, using a bivariate statistical model that best predict landslide susceptibility. The best predictive model should have a good performance in terms of suitability and predictive power, and should be based on landslide predisposing factors that are conditionally independent. The study area is the Santa Marta de Penaguião council (70 km2) located in the Northern Portugal. Several destructive landslides occurred in this area in the last decades promoting landscape degradation and other negative human and economic impacts. A landslide inventory was built in 2005-2009 using aerial photo-interpretation (1/5.000 scale) and field work validation. This inventory contains 767 shallow translational slides. The landslide density is 11 events/square kilometre, and each landslide has, on average, 136 m2 and the depth of the slip surface typically ranges from 1 to 1.5 m. The landslide layer was crossed individually with seven landslide predisposing factors (Aspect; Curvature; Slope Angle; Geomorphological Units; Land Use; Inverse Wetness Index; Lithology) and each class within each predisposing theme was weighted using the Information Value Method. In order to identify the best combination of landslide predisposing factors, all possible combinations were tested which resulted in 120 predictive models. The goodness of fit of each landslide susceptibility model was evaluated by constructing the Success Rate Curves and by computing the Area Under the Curve (AUC). The best landslide susceptibility model was selected according to the model degree of fitness and on the basis of a conditional independence criterion. Two tests were performed to the entire dataset to assess conditional independence: the Overall Conditional Independence (OCI) and the Agterberg & Cheng Conditional Independence Test (ACCIT) (Agterberg and Cheng, 2002). The best landslide susceptibility model was constructed with only three landslide predisposing factors (slope angle, inverse wetness index and land use) and was compared with a model developed using the total set of landslide predisposing factors. Finally, the predictive capacity of the selected landslide susceptibility model was evaluated by computing Prediction Rate Curves based on the partitioning of landslide inventory using temporal, spatial and random criteria. The same procedure was applied to the seven-factors model for comparison purposes. Results showed that the model of spatial distribution of landslide susceptibility built with three factors is not significantly different from the one produced with the total set of factors. Therefore, it is shown that it is possible to produce a reliable landslide susceptibility model using only a few landslides predisposing factors and fulfilling the conditional independence hypothesis.

Pereira, S.; Zêzere, J. L.; Bateira, C.

2012-04-01

196

The chosen genes : Jews, genetics, and the future of ethnic medicine  

E-print Network

All humans have certain genes that cause or predispose them to various diseases. In the ideal medical future, scientists will have hyperfast gene analyzers able to sequence anyone's DNA in a matter of minutes. In that ...

Anthes, Emily Kennedy

2006-01-01

197

Vronique Deroche-Gamonet High novelty preference rats are predisposed to compulsive cocaine self-administration  

E-print Network

Véronique Deroche-Gamonet High novelty preference rats are predisposed to compulsive cocaine self ­ France. Running title: novelty preference predicts cocaine addiction Correspondence to : Véronique/novelty seeking is amongst the best markers of cocaine addiction in humans. However, its implication

Paris-Sud XI, Université de

198

Family and Past History of Mental Illness as Predisposing Factors in Post-Traumatic Stress Disorder  

Microsoft Academic Search

Background: Family studies of post-traumatic stress disorder (PTSD) have given inconsistent results to date. Identifying predisposing factors in PTSD compared to anxiety disorders may help to clarify the classification of PTSD as a diagnostic entity. Method: Retrospective case note study of 87 PTSD patients who participated in an RCT, and 51 PTSD patients and 87 agoraphobics treated routinely in outpatients.

Nigel McKenzie; Isaac Marks; Sheena Liness

2001-01-01

199

Assessing Factors That May Predispose Minnesota Farms To Wolf Depredation on Cattle  

NSDL National Science Digital Library

The Northern Prairie Wildlife Research Center (NPWRC) has posted several more resources online. This article, by David Mech and others, attempts to "detect factors that might predispose farms in Minnesota to wolf depredations;" this paper was first published in 2000 in the Wildlife Society Bulletin [28(3):623-629]. The resource may be browsed online or downloaded as a .zip file.

Harper, Elizabeth K.

200

The role of pollen in chalkbrood disease in Apis mellifera: transmission and predisposing conditions  

Microsoft Academic Search

Chalkbrood in honeybees (Apis mellifera L. Himenoptera: Apidae) is a fungal disease caused by Ascosphaera apis (Maassen ex Claussen) Olive and Spiltoir. This disease requires the presence of fungal spores and a predisposing condition in the suscepti- ble brood for the disease to develop. In this study we examined the role of pollen in the development of chalkbrood disease under

J. M. Flores; I. Gutierrez; R. Espejo

2005-01-01

201

Electrophysiologic parameters and predisposing factors in the generation of drug-induced Torsade de Pointes arrhythmias  

Microsoft Academic Search

When a new (cardiovascular) drug shows signs of QT interval prolongation on the ECG (delay in repolarization time), the regulatory agencies demand screening of its possible proarrhythmic potential before approving it for clinical practice. In this review, identified predisposing factors have been related to specific electrophysiological parameters, allowing quantification of their contribution to Torsade de Pointes arrhythmias. In addition, arrhythmogenic

Marc A. Vos; Jurren M. van Opstal; Jet D. M. Leunissen; S. Cora Verduyn

2001-01-01

202

Regional differences in ulnar nerve excitability may predispose to the development of entrapment neuropathy  

Microsoft Academic Search

ObjectiveTo assess whether there are differences in nerve excitability properties between proximal and distal stimulation sites in the ulnar nerve in healthy controls, which may provide information on whether alteration in ion channel function predisposes to the development of ulnar neuropathy at the elbow.

Arun V. Krishnan; Susanna B. Park; Mike Payne; Cindy S.-Y. Lin; Steve Vucic; Matthew C. Kiernan

2011-01-01

203

The Influence of Predisposing, Enabling and Need Factors on Condom Use in Ivory Coast  

ERIC Educational Resources Information Center

The main objective of this study was to identify key determinants of condom use in Ivory Coast. Data stem from Ivory Coast Demographic Health Survey (DHS) conducted by ORC Macro in 2005 among a representative sample of 9,686 persons aged 15 - 49. Following the behavioral model, we use logistic regression to assess the effect of predisposing

Ngamini Ngui, Andre

2010-01-01

204

Association Study between Folate Pathway Gene Single Nucleotide Polymorphisms and Gastric Cancer in Koreans.  

PubMed

Gastric cancer is ranked as the most common cancer in Koreans. A recent molecular biological study about the folate pathway gene revealed the correlation with a couple of cancer types. In the folate pathway, several genes are involved, including methylenetetrahydrofolate reductase (MTHFR), methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR), and methyltetrahydrofolate-homocysteine methyltransferase (MTR). The MTHFR gene has been reported several times for the correlation with gastric cancer risk. However, the association of the MTRR or MTR gene has not been reported to date. In this study, we investigated the association between the single nucleotide polymorphisms (SNPs) of the MTHFR, MTRR, and MTR genes and the risk of gastric cancer in Koreans. To identify the genetic association with gastric cancer, we selected 17 SNPs sites in folate pathway-associated genes of MTHFR, MTR, and MTRR and tested in 1,261 gastric cancer patients and 375 healthy controls. By genotype analysis, estimating odds ratios and 95% confidence intervals (CI), rs1801394 in the MTRR gene showed increased risk for gastric cacner, with statistical significance both in the codominant model (odds ratio [OR], 1.39; 95% CI, 1.04 to 1.85) and dominant model (OR, 1.34; 95% CI, 1.02 to 1.75). Especially, in the obese group (body mass index ? 25 kg/m(2)), the codominant (OR, 9.08; 95% CI, 1.01 to 94.59) and recessive model (OR, 3.72; 95% CI, 0.92 to 16.59) showed dramatically increased risk (p < 0.05). In conclusion, rs1801394 in the MTRR gene is associated with gastric cancer risk, and its functional significance need to be validated. PMID:23166529

Yoo, Jae-Young; Kim, Sook-Young; Hwang, Jung-Ah; Hong, Seung-Hyun; Shin, Aesun; Choi, Il Ju; Lee, Yeon-Su

2012-09-01

205

Association Study between Folate Pathway Gene Single Nucleotide Polymorphisms and Gastric Cancer in Koreans  

PubMed Central

Gastric cancer is ranked as the most common cancer in Koreans. A recent molecular biological study about the folate pathway gene revealed the correlation with a couple of cancer types. In the folate pathway, several genes are involved, including methylenetetrahydrofolate reductase (MTHFR), methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR), and methyltetrahydrofolate-homocysteine methyltransferase (MTR). The MTHFR gene has been reported several times for the correlation with gastric cancer risk. However, the association of the MTRR or MTR gene has not been reported to date. In this study, we investigated the association between the single nucleotide polymorphisms (SNPs) of the MTHFR, MTRR, and MTR genes and the risk of gastric cancer in Koreans. To identify the genetic association with gastric cancer, we selected 17 SNPs sites in folate pathway-associated genes of MTHFR, MTR, and MTRR and tested in 1,261 gastric cancer patients and 375 healthy controls. By genotype analysis, estimating odds ratios and 95% confidence intervals (CI), rs1801394 in the MTRR gene showed increased risk for gastric cacner, with statistical significance both in the codominant model (odds ratio [OR], 1.39; 95% CI, 1.04 to 1.85) and dominant model (OR, 1.34; 95% CI, 1.02 to 1.75). Especially, in the obese group (body mass index ? 25 kg/m2), the codominant (OR, 9.08; 95% CI, 1.01 to 94.59) and recessive model (OR, 3.72; 95% CI, 0.92 to 16.59) showed dramatically increased risk (p < 0.05). In conclusion, rs1801394 in the MTRR gene is associated with gastric cancer risk, and its functional significance need to be validated. PMID:23166529

Yoo, Jae-Young; Kim, Sook-Young; Hwang, Jung-Ah; Hong, Seung-Hyun; Shin, Aesun; Choi, Il Ju; Lee, Yeon-Su

2012-01-01

206

Predisposing genes and increased chromosome aberrations in lung cancer cigarette smokers  

Microsoft Academic Search

Genotoxic effects linking cigarette smoking with lung cancer have not been consistently demonstrated, therefore claims for the cause–effect relationships are vigorously contested. Using matched populations of 22 lung cancer patients who have been cigarette smokers (LCP), 22 non-cancerous cigarette smokers (SC) and 13 non-smokers (NSC), we have applied the fluorescence in situ hybridization (FISH) tandem probe assay to elucidate the

Nivea Conforti-Froes; Randa El-Zein; Sherif Z Abdel-Rahman; Joseph B Zwischenberger; William W Au

1997-01-01

207

Search for a gene predisposing to manic-depression on chromosome 21  

SciTech Connect

Six kindreds containing multiple cases of manic-depressive illness (MDI) were genotyped with seven highly polymorphic microsatellite loci used in the construction of an index map for chromosome 21. The kindreds were also genotyped with a microsatellite polymorphism for PFKL, a chromosome 21 locus that has shown suggestive linkage to MDI in one pedigree. Evidence of linkage was not found assuming either autosomal dominant or recessive inheritance. The nonparametric affected sib pair test did not yield significant evidence of linkage. 11 refs., 1 fig., 3 tabs.

Byerley, W.; Holik, J.; Hoff, M.; Coon, H. [Univ. of Utah Medical Center, Salt Lake City, UT (United States)

1995-06-19

208

Initial genetic analysis reveals tzi predisposed to cardiovascular disease Scientific magazine "Nature Communications" publishes new findings about physiognomy,  

E-print Network

Initial genetic analysis reveals Ã?tzi predisposed to cardiovascular disease Scientific magazine was genetically predisposed to cardiovascular diseases, according to recent studies carried out by the team of cardiovascular disease. He was not overweight and no stranger to exercise. "The evidence that such a genetic

Tübingen, Universität

209

The Alu-Rich Genomic Architecture of SPAST Predisposes to Diverse and Functionally Distinct Disease-Associated CNV Alleles  

PubMed Central

Intragenic copy-number variants (CNVs) contribute to the allelic spectrum of both Mendelian and complex disorders. Although pathogenic deletions and duplications in SPAST (mutations in which cause autosomal-dominant spastic paraplegia 4 [SPG4]) have been described, their origins and molecular consequences remain obscure. We mapped breakpoint junctions of 54 SPAST CNVs at nucleotide resolution. Diverse combinations of exons are deleted or duplicated, highlighting the importance of particular exons for spastin function. Of the 54 CNVs, 38 (70%) appear to be mediated by an Alu-based mechanism, suggesting that the Alu-rich genomic architecture of SPAST renders this locus susceptible to various genome rearrangements. Analysis of breakpoint Alus further informs a model of Alu-mediated CNV formation characterized by small CNV size and potential involvement of mechanisms other than homologous recombination. Twelve deletions (22%) overlap part of SPAST and a portion of a nearby, directly oriented gene, predicting novel chimeric genes in these subjects’ genomes. cDNA from a subject with a SPAST final exon deletion contained multiple SPAST:SLC30A6 fusion transcripts, indicating that SPAST CNVs can have transcriptional effects beyond the gene itself. SLC30A6 has been implicated in Alzheimer disease, so these fusion gene data could explain a report of spastic paraplegia and dementia cosegregating in a family with deletion of the final exon of SPAST. Our findings provide evidence that the Alu genomic architecture of SPAST predisposes to diverse CNV alleles with distinct transcriptional—and possibly phenotypic—consequences. Moreover, we provide further mechanistic insights into Alu-mediated copy-number change that are extendable to other loci. PMID:25065914

Boone, Philip M.; Yuan, Bo; Campbell, Ian M.; Scull, Jennifer C.; Withers, Marjorie A.; Baggett, Brett C.; Beck, Christine R.; Shaw, Christine J.; Stankiewicz, Pawel; Moretti, Paolo; Goodwin, Wendy E.; Hein, Nichole; Fink, John K.; Seong, Moon-Woo; Seo, Soo Hyun; Park, Sung Sup; Karbassi, Izabela D.; Batish, Sat Dev; Ordóñez-Ugalde, Andrés; Quintáns, Beatriz; Sobrido, María-Jesús; Stemmler, Susanne; Lupski, James R.

2014-01-01

210

Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency  

SciTech Connect

5-Methyltetrahydrofolate, the major form of folate in plasma, is a carbon donor for the remethylation of homocysteine to methionine. This form of folate is generated from 5,10-methylenetetrahydrofolate through the action of 5,10-methylenetetrahydrofolate reductase (MTHFR), a cytosolic flavoprotein. Patients with an autosomal recessive severe deficiency of MTHFR have homocystinuria and a wide range of neurological and vascular disturbances. We have recently described the isolation of a cDNA for MTHFR and the identification of two mutations in patients with severe MTHFR deficiency. We report here the characterization of seven novel mutations in this gene: six missense mutations and a 5{prime} splice-site defect that activates a cryptic splice in the coding sequence. We also present a preliminary analysis of the relationship between genotype and phenotype for all nine mutations identified thus far in this gene. A nonsense mutation and two missense mutations (proline to leucine and threonine to methionine) in the homozygous state are associated with extremely low activity (0%-3%) and onset of symptoms within the 1st year of age. Other missense mutations (arginine to cysteine and arginine to glutamine) are associated with higher enzyme activity and later onset of symptoms. 19 refs., 4 figs., 2 tabs.

Goyette, P.; Frosst, P.; Rosenblatt, D.S.; Rozen. R. [McGill Univ., Montreal (Canada)

1995-05-01

211

Association of neural tube defects in children of mothers with MTHFR 677TT genotype and abnormal carbohydrate metabolism risk: a case-control study.  

PubMed

Abnormalities in maternal folate and carbohydrate metabolism have both been shown to induce neural tube defects (NTD) in humans and animal models. However, the relationship between these two factors in the development of NTDs remains unclear. Data from mothers of children with spina bifida seen at the Unidad de Espina Bífida del Hospital Infantil Virgen del Rocío (case group) were compared to mothers of healthy children with no NTD (control group) who were randomly selected from patients seen at the outpatient ward in the same hospital. There were 25 individuals in the case group and 41 in the control group. Analysis of genotypes for the methylenetetrahydrofolate reductase (MTHFR) 677CT polymorphism in women with or without risk factors for abnormal carbohydrate metabolism revealed that mothers who were homozygous for the MTHFR 677TT polymorphism and at risk of abnormal carbohydrate metabolism were more likely to have offspring with spina bifida and high levels of homocysteine, compared to the control group. The increased incidence of NTDs in mothers homozygous for the MTHFR 677TT polymorphism and at risk of abnormal carbohydrate metabolism stresses the need for careful metabolic screening in pregnant women, and, if necessary, determination of the MTHFR 677CT genotype in those mothers at risk of developing abnormal carbohydrate metabolism. PMID:24737468

Cadenas-Benitez, N M; Yanes-Sosa, F; Gonzalez-Meneses, A; Cerrillos, L; Acosta, D; Praena-Fernandez, J M; Neth, O; Gomez de Terreros, I; Ybot-González, P

2014-01-01

212

Association between MTHFR C677T Polymorphism and Risk of Acute Lymphoblastic Leukemia: A Meta-Analysis Based on 51 Case-Control Studies  

PubMed Central

Background Studies and systematic reviews have reached inconsistent conclusions on the role of 5, 10-methylenetetrahydrofolate reductase (MTHFR) polymorphism C677T in acute lymphoblastic leukemia (ALL) risk. Material/Methods The present meta-analysis comprising of 51 case-control studies, including 7892 cases and 14 280 controls was performed to reevaluate the association between MTHFR C677T polymorphism and ALL risk. Results Statistical differences were found in the dominant model (TT+CT vs. CC, odd ratio (OR)=0.89, 95% CI, 0.79–1.00, P=0.04) and the CT vs. CC (OR=0.89, 95% CI, 0.80–1.00, P=0.05), but not in the allele contrast model (T vs. C, OR=0.92, 95% CI, 0.84–1.01, P=0.08), additive model (TT vs. CC, OR=0.87, 95% CI, 0.73–1.05, P=0.15), or recessive model (TT vs. CT+CC, OR=0.94, 95% CI, 0.81–1.10, P=0.44) in overall populations. In the subgroup analyses stratified by age (children and adults) and ethnicity (Asian and Caucasian), no significant associations between MTHFR C677T polymorphism and ALL risk were observed. Conclusions The current study found no sufficient evidence of a protective role of MTHFR C677T polymorphism in ALL susceptibility. PMID:25761797

Li, Su-yi; Ye, Jie-yu; Liang, En-yu; Zhou, Li-xia; Yang, Mo

2015-01-01

213

Association between MTHFR C677T Polymorphism and Risk of Acute Lymphoblastic Leukemia: A Meta-Analysis Based on 51 Case-Control Studies.  

PubMed

Background Studies and systematic reviews have reached inconsistent conclusions on the role of 5, 10-methylenetetrahydrofolate reductase (MTHFR) polymorphism C677T in acute lymphoblastic leukemia (ALL) risk. Material and Methods The present meta-analysis comprising of 51 case-control studies, including 7892 cases and 14 280 controls was performed to reevaluate the association between MTHFR C677T polymorphism and ALL risk. Results Statistical differences were found in the dominant model (TT+CT vs. CC, odd ratio (OR)=0.89, 95% CI, 0.79-1.00, P=0.04) and the CT vs. CC (OR=0.89, 95% CI, 0.80-1.00, P=0.05), but not in the allele contrast model (T vs. C, OR=0.92, 95% CI, 0.84-1.01, P=0.08), additive model (TT vs. CC, OR=0.87, 95% CI, 0.73-1.05, P=0.15), or recessive model (TT vs. CT+CC, OR=0.94, 95% CI, 0.81-1.10, P=0.44) in overall populations. In the subgroup analyses stratified by age (children and adults) and ethnicity (Asian and Caucasian), no significant associations between MTHFR C677T polymorphism and ALL risk were observed. Conclusions The current study found no sufficient evidence of a protective role of MTHFR C677T polymorphism in ALL susceptibility. PMID:25761797

Li, Su-Yi; Ye, Jie-Yu; Liang, En-Yu; Zhou, Li-Xia; Yang, Mo

2015-01-01

214

Meta-analyses of blood homocysteine levels for gender and genetic association studies of the MTHFR C677T polymorphism in schizophrenia.  

PubMed

Previous studies suggest that elevated blood homocysteine levels and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism are risk factors for schizophrenia. However, the effects of gender and MTHFR C677T genotypes on blood homocysteine levels in schizophrenia have not been consistent. We first investigated whether plasma total homocysteine levels were higher in patients with schizophrenia than in controls with stratification by gender and by the MTHFR C677T genotypes in a large cohort (N = 1379). Second, we conducted a meta-analysis of association studies between blood homocysteine levels and schizophrenia separately by gender (N = 4714). Third, we performed a case-control association study between the MTHFR C677T polymorphism and schizophrenia (N = 4998) and conducted a meta-analysis of genetic association studies based on Japanese subjects (N = 10 378). Finally, we assessed the effect of plasma total homocysteine levels on schizophrenia by a mendelian randomization approach. The ANCOVA after adjustment for age demonstrated a significant effect of diagnosis on the plasma total homocysteine levels in all strata, and the subsequent meta-analysis for gender demonstrated elevated blood homocysteine levels in both male and female patients with schizophrenia although antipsychotic medication might influence the outcome. The meta-analysis of the Japanese genetic association studies demonstrated a significant association between the MTHFR C677T polymorphism and schizophrenia. The mendelian randomization analysis in the Japanese populations yielded an OR of 1.15 for schizophrenia per 1-SD increase in plasma total homocysteine. Our study suggests that increased plasma total homocysteine levels may be associated with an increased risk of schizophrenia. PMID:24535549

Nishi, Akira; Numata, Shusuke; Tajima, Atsushi; Kinoshita, Makoto; Kikuchi, Kumiko; Shimodera, Shinji; Tomotake, Masahito; Ohi, Kazutaka; Hashimoto, Ryota; Imoto, Issei; Takeda, Masatoshi; Ohmori, Tetsuro

2014-09-01

215

Predisposing Factors Associated With Delirium Among Demented Long-Term Care Residents  

Microsoft Academic Search

This was a cross-sectional study to investigate predisposing factors associated with delirium among demented long-term-care residents and to assess the cumulative effect of these factors on the likelihood of having delirium. Of the 155 participants, 109 (70.3%) were found delirious according to the confusion assessment method. Among these individuals, age (OR = 1.07; 95% CI = 1.05-1.10) and severity of

Philippe Voyer; Sylvie Richard; Lise Doucet; Pierre-Hugues Carmichael

2009-01-01

216

Ingested gastrointestinal foreign bodies: predisposing factors for complications in children having surgical or endoscopic removal  

Microsoft Academic Search

A retrospective study was performed to determine the predisposing factors associated with the complications of ingested gastrointestinal\\u000a (GI) tract foreign bodies (FBs) in children who had surgical or endoscopic removal. The study was performed in 161 children\\u000a who had endoscopic or surgical removal. The clinical data were evaluated in two groups. In groups I and II, respectively,\\u000a 135 patients with

Baran Tokar; Alper A. Cevik; Huseyin Ilhan

2007-01-01

217

Peritoneal Perforation of Liver Hydatid Cysts: Clinical Presentation, Predisposing Factors, and Surgical Outcome  

Microsoft Academic Search

The aim of this study was to evaluate the clinical presentation of, predisposing factors in, and early and long-term outcome\\u000a of patients treated surgically for intraperitoneal ruptured liver hydatid cysts. Medical records of 27 patients with traumatic\\u000a rupture of hydatid cysts were evaluated retrospectively, as were records of 347 patients with nonperforated hydatid cysts.\\u000a The ratio of perforation cases to

Alper Akcan; Hizir Akyildiz; Tarik Artis; Ahmet Ozturk; Mehmet Ali Deneme; Engin Ok; Erdogan Sozuer

2007-01-01

218

Aspergillus citrinoterreus, a new species of section Terrei isolated from samples of patients with nonhematological predisposing conditions.  

PubMed

The use of molecular identification techniques has revealed an increasing number of new species within Aspergillus section Terrei. We phenotyped a set of 26 clinical isolates that showed genetic differences from Aspergillus terreus sensu stricto by analyzing sequences from PCR-amplified ?-tubulin and calmodulin genes and the internal transcribed spacer region. Since the isolates were phylogenetically and morphologically different from all of the members of Aspergillus section Terrei, they are described here as a new species, Aspergillus citrinoterreus, so named because it produces a diffusible yellowish pigment in agar. A. citrinoterreus isolates were significantly more susceptible to itraconazole, voriconazole, and posaconazole than A. terreus sensu stricto isolates were; in contrast, the amphotericin B MICs for both species were high. A. citrinoterreus was found in clinical samples from patients with proven or probable invasive aspergillosis and colonized patients, none of whom had hematological malignancies as predisposing conditions. However, they did have other underlying conditions such as chronic obstructive pulmonary disease, cirrhosis, and cancer or had received a solid organ transplants and presented not only with invasive pulmonary aspergillosis but also with mediastinitis. A. citrinoterreus isolates were detected for the first time in 2002. In all cases of invasive aspergillosis, A. citrinoterreus was found to be a copathogen, mostly with A. fumigatus. PMID:25502530

Guinea, Jesús; Sandoval-Denis, Marcelo; Escribano, Pilar; Peláez, Teresa; Guarro, Josep; Bouza, Emilio

2015-02-01

219

Developmental androgen excess programs sympathetic tone and adipose tissue dysfunction and predisposes to a cardiometabolic syndrome in female mice  

PubMed Central

Among women, the polycystic ovarian syndrome (PCOS) is considered a form of metabolic syndrome with reproductive abnormalities. Women with PCOS show increased sympathetic tone, visceral adiposity with enlarged adipocytes, hypoadiponectinemia, insulin resistance, glucose intolerance, increased inactive osteocalcin, and hypertension. Excess fetal exposure to androgens has been hypothesized to play a role in the pathogenesis of PCOS. Previously, we showed that neonatal exposure to the androgen testosterone (NT) programs leptin resistance in adult female mice. Here, we studied the impact of NT on lean and adipose tissues, sympathetic tone in cardiometabolic tissues, and the development of metabolic dysfunction in mice. Neonatally androgenized adult female mice (NTF) displayed masculinization of lean tissues with increased cardiac and skeletal muscle as well as kidney masses. NTF mice showed increased and dysfunctional white adipose tissue with increased sympathetic tone in both visceral and subcutaneous fat as well as increased number of enlarged and insulin-resistant adipocytes that displayed altered expression of developmental genes and hypoadiponectinemia. NTF exhibited dysfunctional brown adipose tissue with increased mass and decreased energy expenditure. They also displayed decreased undercarboxylated and active osteocalcin and were predisposed to obesity during chronic androgen excess. NTF showed increased renal sympathetic tone associated with increased blood pressure, and they developed glucose intolerance and insulin resistance. Thus, developmental exposure to testosterone in female mice programs features of cardiometabolic dysfunction, as can be observed in women with PCOS, including increased sympathetic tone, visceral adiposity, insulin resistance, prediabetes, and hypertension. PMID:23612996

Nohara, Kazunari; Waraich, Rizwana S.; Liu, Suhuan; Ferron, Mathieu; Waget, Aurélie; Meyers, Matthew S.; Karsenty, Gérard; Burcelin, Rémy

2013-01-01

220

Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas  

PubMed Central

Constitutional SMARCB1 mutations at 22q11.23 have been found in ~50% of familial and <10% of sporadic schwannomatosis cases1. We sequenced highly conserved regions along 22q from eight individuals with schwannomatosis whose schwannomas involved somatic loss of one copy of 22q, encompassing SMARCB1 and NF2, with a different somatic mutation of the other NF2 allele in every schwannoma but no mutation of the remaining SMARCB1 allele in blood and tumor samples. LZTR1 germline mutations were identified in seven of the eight cases. LZTR1 sequencing in 12 further cases with the same molecular signature identified 9 additional germline mutations. Loss of heterozygosity with retention of an LZTR1 mutation was present in all 25 schwannomas studied. Mutations segregated with disease in all available affected first-degree relatives, although four asymptomatic parents also carried an LZTR1 mutation. Our findings identify LZTR1 as a gene predisposing to an autosomal dominant inherited disorder of multiple schwannomas in ~80% of 22q-related schwannomatosis cases lacking mutation in SMARCB1. PMID:24362817

Piotrowski, Arkadiusz; Xie, Jing; Liu, Ying F; Poplawski, Andrzej B; Gomes, Alicia R; Madanecki, Piotr; Fu, Chuanhua; Crowley, Michael R; Crossman, David K; Armstrong, Linlea; Babovic-Vuksanovic, Dusica; Bergner, Amanda; Blakeley, Jaishri O; Blumenthal, Andrea L; Daniels, Molly S; Feit, Howard; Gardner, Kathy; Hurst, Stephanie; Kobelka, Christine; Lee, Chung; Nagy, Rebecca; Rauen, Katherine A; Slopis, John M; Suwannarat, Pim; Westman, Judith A; Zanko, Andrea; Korf, Bruce R; Messiaen, Ludwine M

2015-01-01

221

Innate immunity alone is not sufficient for chronic rejection but predisposes healed allografts to T cell-mediated pathology1  

PubMed Central

Background Acute allograft rejection is dependent on adaptive immunity, but it is unclear whether the same is true for chronic rejection. Here we asked whether innate immunity alone is sufficient for causing chronic rejection of mouse cardiac allografts. Methods We transplanted primarily vascularized cardiac grafts to recombinase activating gene-knockout (RAG?/?) mice that lack T and B cells but have an intact innate immune system. Recipients were left unmanipulated, received adjuvants that stimulate innate immunity, or were reconstituted with B-1 lymphocytes to generate natural IgM antibodies. In a second model, we transplanted cardiac allografts to mice that lack secondary lymphoid tissues (splenectomized aly/aly recipients) and studied the effect of NK cell inactivation on T cell-mediated chronic rejection. Results Acute cardiac allograft rejection was not observed in any of the recipients. Histological analysis of allografts harvested 50 to 90 days after transplantation to RAG?/? mice failed to identify chronic vascular or parenchymal changes beyond those observed in control syngeneic grafts. Chronic rejection of cardiac allografts parked in splenectomized aly/aly mice was observed only after the transfer of exogenously activated T cells. NK inactivation throughout the experiment, or during the parking period alone, reduced the severity of T cell- dependent chronic rejection. Conclusions The innate immune system alone is not sufficient for causing chronic rejection. NK cells predispose healed allografts to T cell-dependent chronic rejection and may contribute to chronic allograft pathology. PMID:22226941

Zecher, Daniel; Li, Qi; Williams, Amanda L.; Walters, John T.; Baddoura, Fady K.; Chalasani, Geetha; Rothstein, David M.; Shlomchik, Warren D.; Demetris, Anthony J.; Lakkis, Fadi G.

2012-01-01

222

Methylenetetrahydrofolate Reductase gene polymorphism in patients receiving hemodialysis.  

PubMed

Methylenetetrahydrofolate Reductase (MTHFR) is key enzyme in metabolism of homocysteine. Homozygotes for mutation (TT genotype) have hyperhomocysteinemia, risk factor for atherosclerosis development. The aim of the study was to find out distribution of genotype frequencies of C677T MTHFR among patients on maintenance hemodialysis. Possible association of alleles and genotypes of C677T polymorphism of the MTHFR gene with age of onset, duration of dialysis and cause of kidney failure was studied also. Cross-sectional study includes 80 patients from Clinic of Hemodialysis KUCS in Sarajevo. In order to perform genotyping, isolated DNA was analyzed by RFLP-PCR and gel-electrophoresis. From total of 80 patients, 42.5% (n=24) were female, 57.5% (n=46) were male, mean age 54.59+/-1.78 years and duration of dialysis 79.92+/-6.32 months. Genotype distribution was: CC 51.2% (n=41), CT 37.5% (n=30) and TT 11.2% (n=9). Patients with wild-type genotype have longer duration of dialysis in month (87.1 +/- 63.93) comparing to TT genotype patients (67.06 +/- 39.3), with no statistical significance. T allele frequency was significantly higher in group of vascular and congenital cause of kidney failure (Pearson X2 =6.049, P<0.05) comparing to inflammation etiology group. Genotype distribution results are within the results other studies in Europe. Obtained results indicate that C677T polymorphism is not associated with onset, duration and cause of kidney failure in our hemodialysis population. There is an association of T allele of the MTHFR gene and vascular and congenital cause kidney failure. PMID:20433440

Kiseljakovi?, Emina; Resi?, Halima; Kapur, Lejla; Hasi?, Sabaheta; Jadri?, Radivoj

2010-04-01

223

Genes  

NSDL National Science Digital Library

Illustration of the placement of genes in a chromosome. A gene can be defined as a region of DNA that controls a hereditary characteristic. It usually corresponds to a sequence used in the production of a specific protein or RNA. A gene carries biological information in a form that must be copied and transmitted from each cell to all its progeny. This includes the entire functional unit: coding DNA sequences, non-coding regulatory DNA sequences, and introns. Genes can be as short as 1000 base pairs or as long as several hundred thousand base pairs. It can even be carried by more than one chromosome. The estimate for the number of genes in humans has decreased as our knowledge has increased. As of 2001, humans are thought to have between 30,000 and 40,000 genes.

BEGIN:VCARD VERSION:2.1 FN:Access Excellence N:Excellence; Access REV:2005-03-12 END:VCARD

2005-03-12

224

The tRNA(Gln) 4336 mitochondrial DNA variant is not a high penetrance mutation which predisposes to dementia before the age of 75 years.  

PubMed Central

The genetic factors that predispose to Alzheimer's disease (AD) are heterogeneous. Two recent reports have suggested that a mitochondrial DNA mutation within the tRNAGln gene, located at position 4336, may be a risk factor for AD, as it was found in 10/256 (3.9%) cases with AD confirmed by necropsy. Although low prevalences of this mutation were detected in non-demented subjects in both of these studies, the controls were not carefully matched with the AD cases. We have investigated the frequency of this mutation in two community based elderly cohorts in Cambridgeshire, who have participated in longitudinal studies of cognitive function. The 4336 mitochondrial mutation was detected in 8/ 443 people examined. These people were found to be non-demented at ages 74, 81, 84, 86, 89, 90, 91, and 102 years, in contrast to the previously described cases whose onset of dementia occurred between 60 and 76 years (mean 68). Accordingly, we believe that this mitochondrial variant is not a high penetrance mutation which predisposes to dementia before the age of 76 years. Images PMID:9004131

Tysoe, C; Robinson, D; Brayne, C; Dening, T; Paykel, E S; Huppert, F A; Rubinsztein, D C

1996-01-01

225

MTHFR-1298 A>C (rs1801131) is a predictor of survival in two cohorts of stage II/III colorectal cancer patients treated with adjuvant fluoropyrimidine chemotherapy with or without oxaliplatin.  

PubMed

Adjuvant treatment based on fluoropyrimidines (FL) improves the prognosis of stage II/III colorectal cancer (CRC). Validated predictive/prognostic biomarkers would spare therapy-related morbidity in patients with a good prognosis. We compared the impact of a set of 22 FL-related polymorphisms with the prognosis of two cohorts of CRC patients treated with adjuvant FL with or without OXA, including a total of 262 cases. 5,10-Methylentetrahydrofolate reductase (MTHFR) MTHFR-1298 A>C (rs1801131) polymorphism had a concordant effect: MTHFR-rs1801131-1298CC genotype carriers had a worse disease free survival (DFS) in both the cohorts. In the pooled population MTHFR-rs1801131-1298CC carriers had also a worse overall survival. We computed a clinical score related to DFS including MTHFR-rs1801131, tumor stage, sex and tumor location, where rs1801131 is the most detrimental factor (hazard ratio=5.3, 95% confidence interval=2.2-12.9; P-value=0.0006). MTHFR-rs1801131 is a prognostic factor that could be used as an additional criteria for the choice of the proper adjuvant regimen in stage II/III colorectal cancer patients.The Pharmacogenomics Journal advance online publication, 21 October 2014; doi:10.1038/tpj.2014.64. PMID:25331073

Cecchin, E; Perrone, G; Nobili, S; Polesel, J; De Mattia, E; Zanusso, C; Petreni, P; Lonardi, S; Pella, N; D'Andrea, M; Errante, D; Rizzolio, F; Mazzei, T; Landini, I; Mini, E; Toffoli, G

2014-10-21

226

Maternal air pollution exposure induces fetal neuroinflammation and predisposes offspring to obesity in aduthood in a sex-specific manner  

EPA Science Inventory

Emerging evidence suggests environmental chemical exposures during critical windows of development may contribute to the escalating prevalence of obesity. We tested the hypothesis that prenatal air pollution exposure would predispose the offspring to weight gain in adulthood. Pre...

227

Polymorphisms in folate-metabolizing genes and risk of non-Hodgkin's lymphoma  

Microsoft Academic Search

We investigated the role of single nucleotide polymorphisms (SNPs) in the folate-metabolizing genes MTHFR, MTR, MTRR, MTHFD, CBS and SHMT in regulating genetic susceptibility to Non-Hodgkin's lymphoma (NHL). We determined the allele and genotype frequencies in the case group (146 patients with NHL) and the control group (540 blood donors). A significant association with NHL was observed only for MTHFD1

Alexandra S. Weiner; Olga V. Beresina; Elena N. Voronina; Elena N. Voropaeva; Uljana A. Boyarskih; Tatiana I. Pospelova; Maxim L. Filipenko

2011-01-01

228

Identifying multiple causative genes at a single GWAS locus.  

PubMed

Genome-wide association studies (GWAS) are useful for nominating candidate genes, but typically are unable to establish disease causality or differentiate between the effects of variants in linkage disequilibrium (LD). Additionally, some GWAS loci might contain multiple causative variants or genes that contribute to the overall disease susceptibility at a single locus. However, the majority of current GWAS lack the statistical power to test whether multiple causative genes underlie the same locus, prompting us to adopt an alternative approach to testing multiple GWAS genes empirically. We used gene targeting in a disease-susceptible rat model of genetic hypertension to test all six genes at the Agtrap-Plod1 locus (Agtrap, Mthfr, Clcn6, Nppa, Nppb, and Plod1) for blood pressure (BP) and renal phenotypes. This revealed that the majority of genes at this locus (five out of six) can impact hypertension by modifying BP and renal phenotypes. Mutations of Nppa, Plod1, and Mthfr increased disease susceptibility, whereas Agtrap and Clcn6 mutations decreased hypertension risk. Reanalysis of the human AGTRAP-PLOD1 locus also implied that disease-associated haplotype blocks with polygenic effects were not only possible, but rather were highly plausible. Combined, these data demonstrate for the first time that multiple modifiers of hypertension can cosegregate at a single GWAS locus. PMID:24006081

Flister, Michael J; Tsaih, Shirng-Wern; O'Meara, Caitlin C; Endres, Bradley; Hoffman, Matthew J; Geurts, Aron M; Dwinell, Melinda R; Lazar, Jozef; Jacob, Howard J; Moreno, Carol

2013-12-01

229

Folate/homocysteine phenotypes and MTHFR 677C>T genotypes are associated with serum levels of monocyte chemoattractant protein-1  

PubMed Central

Monocyte chemoattractant protein-1 (MCP-1) is a chemokine that recruits monocytes into the subendothelial cell layer in atherosclerotic lesions. Elevated homocysteine (hyper-homocysteinemia), which is usually associated with low-folate status, is a known risk factor for many pathologies with inflammatory etiologies. The present study was undertaken to examine whether there are associations between MCP-1 concentrations and folate/Hcy phenotype or methylenetetrahydrofolate reductase (MTHFR) 677C>T genotype in healthy young adults. In females, MCP-1 concentrations were positively correlated with Hcy and negatively correlated with both serum and red blood cell folate; female smokers and MTHFR 677T carriers had particularly elevated MCP-1 concentrations. Similar relationships were not seen in males. These findings may have implications for understanding the female predominance observed for a range of autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis. PMID:19625220

Hammons, Andrea L.; Summers, Carolyn M.; Woodside, Jayne V.; McNulty, Helene; Strain, J.J.; Young, Ian S.; Murray, Liam; Boreham, Colin A.; Scott, John M.; Mitchell, Laura E.; Whitehead, Alexander S.

2014-01-01

230

MTHFR 677T Is a Strong Determinant of the Degree of Hearing Loss Among Polish Males with Postlingual Sensorineural Hearing Impairment  

PubMed Central

Hearing impairment (HI) is the most common sensory handicap. Congenital HI often has a genetic basis, whereas the etiology of nonsyndromic postlingual HI (npHI) usually remains unidentified. Our purpose was to test whether the MTHFR C677T (rs1801133) polymorphism affecting folate metabolism is associated with the occurrence or severity of npHI. We studied rs1801133 genotypes in 647 npHI patients (age <40, sudden sensorineural loss excluded, HI characterized as mean of better ear hearing thresholds for 0.5–8 kHz) and 3273 adult controls from the background population. Genotype distribution among patients and controls was similar, but among male cases (n=302) we found a dose-dependent correlation of MTHFR 677T with the degree of HI (mean thresholds in dB: 38.8, 44.9, and 53.3, for CC, CT, and TT genotypes, respectively; p=0.0013, pcor.=0.017). Among male patients rs1801133 TT significantly increased the risk of severe/profound HI (odds ratio=4.88, p=0.001). Among controls the known effect of MTHFR 677T on plasma total homocysteine was more pronounced in men than in women (p<0.00004 for genotype-sex interaction) suggesting that in Poland folate deficiency is more prevalent in males. In conclusion, we report a novel strong effect of MTHFR 677T among males with npHI. The functional significance of rs1801133 suggests that these patients may benefit from folate supplementation—an intervention which is simple, cheap, and devoid of side effects. PMID:22424391

Pollak, Agnieszka; Mueller-Malesinska, Malgorzata; Lechowicz, Urszula; Skorka, Agata; Korniszewski, Lech; Sobczyk-Kopciol, Agnieszka; Waskiewicz, Anna; Broda, Grazyna; Iwanicka-Pronicka, Katarzyna; Oldak, Monika; Skarzynski, Henryk

2012-01-01

231

Fluorescence resonance energy transfer-based real-time polymerase chain reaction method without DNA extraction for the genotyping of F5, F2, F12, MTHFR, and HFE.  

PubMed

Blood samples are extensively used for the molecular diagnosis of many hematological diseases. The daily practice in a clinical laboratory of molecular diagnosis in hematology involves using a variety of techniques, based on the amplification of nucleic acids. Current methods for polymerase chain reaction (PCR) use purified genomic DNA, mostly isolated from total peripheral blood cells or white blood cells (WBC). In this paper we describe a real-time fluorescence resonance energy transfer-based method for genotyping directly from blood cells. Our strategy is based on an initial isolation of the WBCs, allowing the removal of PCR inhibitors, such as the heme group, present in the erythrocytes. Once the erythrocytes have been lysed, in the LightCycler(®) 2.0 Instrument, we perform a real-time PCR followed by a melting curve analysis for different genes (Factors 2, 5, 12, MTHFR, and HFE). After testing 34 samples comparing the real-time crossing point (CP) values between WBC (5×10(6) WBC/mL) and purified DNA (20 ng/?L), the results for F5 Leiden were as follows: CP mean value for WBC was 29.26±0.566 versus purified DNA 24.79±0.56. Thus, when PCR was performed from WBC (5×10(6) WBC/mL) instead of DNA (20 ng/?L), we observed a delay of about 4 cycles. These small differences in CP values were similar for all genes tested and did not significantly affect the subsequent analysis by melting curves. In both cases the fluorescence values were high enough, allowing a robust genotyping of all these genes without a previous DNA purification/extraction. PMID:25028568

Martinez-Serra, Jordi; Robles, Juan; Nicolàs, Antoni; Gutierrez, Antonio; Ros, Teresa; Amat, Juan Carlos; Alemany, Regina; Vögler, Oliver; Abelló, Aina; Noguera, Aina; Besalduch, Joan

2014-01-01

232

Assessing factors that may predispose Minnesota farms to wolf predation on cattle  

USGS Publications Warehouse

Wolf (Canis lupus) depredations on livestock cause considerable conflict and expense in Minnesota. Furthermore, claims are made that such depredations are fostered by the type of animal husbandry practiced. Thus, we tried to detect factors that might predispose farms in Minnesota to wolf depredations. We compared results of interviews with 41 cattle farmers experiencing chronic cattle losses to wolves (chronic farms) with results from 41 nearby matched farms with no wolf losses to determine farm characteristics or husbandry practices that differed and that therefore might have affected wolf depredations. We also used a Geographic Information System (GIS) to detect any habitat differences between the 2 types of farms. We found no differences between chronic and matched farms in the 11 farm characteristics and management practices that we surveyed, except that farms with chronic losses were larger, had more cattle, and had herds farther from human dwellings. Habitat types were the same around farms with and without losses. The role of proper carcass disposal as a possible factor predisposing farms to wolf depredations remains unclear

Mech, L.D.; Harper, E.K.; Meier, T.J.; Paul, W.J.

2000-01-01

233

Primary Otomycosis in the Indian Subcontinent: Predisposing Factors, Microbiology, and Classification  

PubMed Central

Objective. To define otomycosis and determine the predisposing factors and microbiology in primary otomycosis. Study Design. Prospective study of two years and review of the literature. Setting. Academic Department of Otolaryngology in a coastal city in India. Patients. 150 immunocompetent individuals of whom 100 consecutive patients with a clinical diagnosis of otomycosis are considered as the study group and 50 consecutive patients with no otomycosis are considered as the control group. Results and Observations. Instillation of coconut oil (42%), use of topical antibiotic eardrops (20%), and compulsive cleaning of external ear with hard objects (32%) appeared to be the main predisposing factors in otomycosis. Aspergilli were the most common isolates (80%) followed by Penicillium (8%), Candida albicans (4%), Rhizopus (1%), and Chrysosporium (1%), the last being reported for the first time in otomycosis. Among aspergilli, A. niger complex (38%) was the most common followed by A. fumigatus complex (27%) and A. flavus complex (15%). Bacterial isolates associated with fungi in otomycosis were S. aureus, P. aeruginosa, and Proteus spp. In 42% of healthy external ears fungi were isolated. Conclusion. Aspergillus spp. were the most common fungi isolated, followed by Penicillium. Otomycotic ears are often associated with bacterial isolates when compared to normal ears. Fungi are also present in a significant number of healthy external auditory canals and their profiles match those in cases of otomycosis. The use of terms “primary” and “secondary” otomycosis is important to standardize reporting. PMID:24949016

Kotigadde, Subbannayya; Shekhar, Manisha; Thada, Nikhil Dinaker; Prabhu, Prashanth; D' Souza, Tina; Prasad, Kishore Chandra

2014-01-01

234

A new predisposing factor for trigemino-cardiac reflex during subdural empyema drainage: a case report  

PubMed Central

Introduction The trigemino-cardiac reflex is defined as the sudden onset of parasympathetic dysrhythmia, sympathetic hypotension, apnea, or gastric hypermotility during stimulation of any of the sensory branches of the trigeminal nerve. Clinically, trigemino-cardiac reflex has been reported to occur during neurosurgical skull-base surgery. Apart from the few clinical reports, the physiological function of this brainstem reflex has not yet been fully explored. Little is known regarding any predisposing factors related to the intraoperative occurrence of this reflex. Case presentation We report the case of a 70-year-old Caucasian man who demonstrated a clearly expressed form of trigemino-cardiac reflex with severe bradycardia requiring intervention that was recorded during surgical removal of a large subdural empyema. Conclusion To the best of our knowledge, this is the first report of an intracranial infection leading to perioperative trigemino-cardiac reflex. We therefore add a new predisposing factor for trigemino-cardiac reflex to the existing literature. Possible mechanisms are discussed in the light of the relevant literature. PMID:21118536

2010-01-01

235

Drought predisposes piñon-juniper woodlands to insect attacks and mortality.  

PubMed

To test the hypothesis that drought predisposes trees to insect attacks, we quantified the effects of water availability on insect attacks, tree resistance mechanisms, and mortality of mature piñon pine (Pinus edulis) and one-seed juniper (Juniperus monosperma) using an experimental drought study in New Mexico, USA. The study had four replicated treatments (40 × 40 m plot/replicate): removal of 45% of ambient annual precipitation (H2 O-); irrigation to produce 125% of ambient annual precipitation (H2 O+); a drought control (C) to quantify the impact of the drought infrastructure; and ambient precipitation (A). Piñon began dying 1 yr after drought initiation, with higher mortality in the H2 O- treatment relative to other treatments. Beetles (bark/twig) were present in 92% of dead trees. Resin duct density and area were more strongly affected by treatments and more strongly associated with piñon mortality than direct measurements of resin flow. For juniper, treatments had no effect on insect resistance or attacks, but needle browning was highest in the H2 O- treatment. Our results provide strong evidence that ? 1 yr of severe drought predisposes piñon to insect attacks and increases mortality, whereas 3 yr of the same drought causes partial canopy loss in juniper. PMID:23421561

Gaylord, Monica L; Kolb, Thomas E; Pockman, William T; Plaut, Jennifer A; Yepez, Enrico A; Macalady, Alison K; Pangle, Robert E; McDowell, Nate G

2013-04-01

236

Nipple candidiasis among breastfeeding mothers. Case-control study of predisposing factors.  

PubMed Central

OBJECTIVE: To investigate factors that predispose breastfeeding mothers to nipple candidiasis. DESIGN: A retrospective case-control study of women attending the Calgary Breastfeeding Clinic. SETTING: Ambulatory breastfeeding referral centre. PARTICIPANTS: All women (105) who attended the clinic during a 3.5-month study period. All were referred for problems with breastfeeding; 27 (the case group) had positive diagnostic criteria for nipple candidiasis. The other 78 formed a control group. MAIN OUTCOME MEASURE: A patient information sheet, completed while taking a medical history, recorded the presence or absence of four possible predisposing factors. Two infant variables were also noted on physical examination. Patients were diagnosed as having or not having nipple candidiasis on the basis of specific clinical criteria, and statistics on other variables were compared for those with positive and with negative diagnoses. RESULTS: A statistically significant correlation (P < 0.05) was found between nipple candidiasis and three factors: vaginal candidiasis (P = 0.001), previous antibiotic use (P = 0.036), and nipple trauma (P = 0.001). CONCLUSIONS: Further research is required to establish clear causality. However, we recommend that physicians be suspicious of nipple candidiasis; avoid antibiotics or use the shortest effective course; treat yeast vaginitis during the third trimester and after delivery aggressively; and treat mothers for nipple yeast if babies have oral or diaper candidiasis. Breastfeeding mothers can also be counseled in preventive measures. PMID:8081120

Tanguay, K. E.; McBean, M. R.; Jain, E.

1994-01-01

237

The Menin Gene  

Microsoft Academic Search

\\u000a Multiple endocrine neoplasia type I (MEN-1) is an autosomal dominant syndrome featuring tumors of endocrine origin. Heterozygous\\u000a germline mutations in the MEN-1 tumor suppressor gene predispose MEN-1 patients to tumor development, mainly in parathyroid, pancreatic islet cells, and\\u000a the anterior pituitary gland. Since the MEN-1-encoded protein, menin, is ubiquitously expressed, the endocrine-specific nature\\u000a in MEN-1 patients remains unexplained. This chapter

Hsin-Chieh Jennifer Shen; Steven K. Libutti

238

The MET13 Methylenetetrahydrofolate Reductase Gene Is Essential for Infection-Related Morphogenesis in the Rice Blast Fungus Magnaporthe oryzae  

PubMed Central

Methylenetetrahydrofolate reductases (MTHFRs) play a key role in the biosynthesis of methionine in both prokaryotic and eukaryotic organisms. In this study, we report the identification of a novel T-DNA-tagged mutant WH672 in the rice blast fungus Magnaporthe oryzae, which was defective in vegetative growth, conidiation and pathogenicity. Analysis of the mutation confirmed a single T-DNA insertion upstream of MET13, which encodes a 626-amino-acid protein encoding a MTHFR. Targeted gene deletion of MET13 resulted in mutants that were non-pathogenic and significantly impaired in aerial growth and melanin pigmentation. All phenotypes associated with ?met13 mutants could be overcome by addition of exogenous methionine. The M. oryzae genome contains a second predicted MTHFR-encoding gene, MET12. The deduced amino acid sequences of Met13 and Met12 share 32% identity. Interestingly, ?met12 mutants produced significantly less conidia compared with the isogenic wild-type strain and grew very poorly in the absence of methionine, but were fully pathogenic. Deletion of both genes resulted in ?met13?met12 mutants that showed similar phenotypes to single ?met13 mutants. Taken together, we conclude that the MTHFR gene, MET13, is essential for infection-related morphogenesis by the rice blast fungus M. oryzae. PMID:24116181

Wang, Hong; Wang, Congcong; Li, Ya; Yue, Xiaofeng; Ma, Zhonghua; Talbot, Nicholas J.; Wang, Zhengyi

2013-01-01

239

TLR9 2848 GA Heterozygotic Status Possibly Predisposes Fetuses and Newborns to Congenital Infection with Human Cytomegalovirus  

PubMed Central

Background Some single nucleotide polymorphisms (SNP), located in Toll-like receptor (TLR) genes, were reported to be associated with human cytomegalovirus (HCMV) infections. The study was aimed to assess the correlation of SNPs at TLR4 and TLR9 genes with the occurrence of congenital cytomegaly, based on available samples. Methods Reported case-control study included both HCMV infected and non-infected fetuses and newborns. The specimens were classified to the molecular analyses, based on serological features of the recent infection and HCMV DNAemia in body fluids. TLR SNPs were studied, using multiplex nested PCR-RFLP assay, and determined genotypes were confirmed by sequencing. Hardy-Weinberg equilibrium was assessed for the identified genotypes. The linkage disequilibrium was also estimated for TLR4 SNPs. A relationship between the status of TLR genotypes and congenital cytomegaly development was estimated, using a logistic regression model. Results Hardy Weinberg equilibrium was observed for almost all SNPs, both infected and non-infected patients, with exception of TLR4 896 A>G polymorphism in the control group (P?0.050). TLR4 896 A>G and 1196 C>T SNPs were found in linkage disequilibrium in both study groups (P?0.050). The CC genotype at TLR4 1196 SNP and the GA variant at TLR9 2848 G>A SNP were significantly associated with HCMV infection (P?0.050). The risk of congenital cytomegaly was higher in heterozygotes at TLR9 SNP than in the carriers of other genotypic variants at the reported locus (OR 4.81; P?0.050). The GC haplotype at TLR4 SNPs and GCA variants at TLR4 and TLR9 SNPs were significantly associated with HCMV infection (P?0.0001). The ACA variants were more frequent among fetuses and neonates with symptomatic, rather than asymptomatic cytomegaly (P?0.0001). Conclusions TLR4 and TLR9 polymorphisms may contribute to the development of congenital infection with HCMV in fetuses and neonates. The TLR9 2848 GA heterozygotic status possibly predisposes to HCMV infection, increasing the risk of congenital cytomegaly development. PMID:25844529

Wujcicka, Wioletta; Paradowska, Edyta; Studzi?ska, Miros?awa; Gaj, Zuzanna; Wilczy?ski, Jan; Le?nikowski, Zbigniew; Nowakowska, Dorota

2015-01-01

240

The epidemiology of bovine respiratory disease: What is the evidence for predisposing factors?  

PubMed Central

Bovine respiratory disease (BRD) is the most costly disease of beef cattle in North America. It is multi-factorial, with a variety of physical and physiological stressors combining to predispose cattle to pneumonia. However, efforts to discern which factors are most important have frequently failed to establish definitive answers. Calves are at highest risk shortly after transport. Risk factors include purchasing from sale barns and commingling. It is unclear whether or not these practices increase susceptibility, increase exposure, or are proxies for poor management. Lighter-weight calves appear to be at greater risk, although this has not been consistent. Persistent infection (PI) with bovine virus diarrhea virus increases BRD occurrence, but it is unclear if PI calves affect other cattle in the feedlot. The complexity of BRD has made it difficult to define involvement of individual factors. Stressors may play a role as “necessary but not sufficient” components, requiring additive effects to cause disease. PMID:21197200

Taylor, Jared D.; Fulton, Robert W.; Lehenbauer, Terry W.; Step, Douglas L.; Confer, Anthony W.

2010-01-01

241

IL-9– and mast cell–mediated intestinal permeability predisposes to oral antigen hypersensitivity  

PubMed Central

Previous mouse and clinical studies demonstrate a link between Th2 intestinal inflammation and induction of the effector phase of food allergy. However, the mechanism by which sensitization and mast cell responses occurs is largely unknown. We demonstrate that interleukin (IL)-9 has an important role in this process. IL-9–deficient mice fail to develop experimental oral antigen–induced intestinal anaphylaxis, and intestinal IL-9 overexpression induces an intestinal anaphylaxis phenotype (intestinal mastocytosis, intestinal permeability, and intravascular leakage). In addition, intestinal IL-9 overexpression predisposes to oral antigen sensitization, which requires mast cells and increased intestinal permeability. These observations demonstrate a central role for IL-9 and mast cells in experimental intestinal permeability in oral antigen sensitization and suggest that IL-9–mediated mast cell responses have an important role in food allergy. PMID:18378796

Forbes, Elizabeth E.; Groschwitz, Katherine; Abonia, J. Pablo; Brandt, Eric B.; Cohen, Elizabeth; Blanchard, Carine; Ahrens, Richard; Seidu, Luqman; McKenzie, Andrew; Strait, Richard; Finkelman, Fred D.; Foster, Paul S.; Matthaei, Klaus I.; Rothenberg, Marc E.; Hogan, Simon P.

2008-01-01

242

High stocking density as a predisposing factor for necrotic enteritis in broiler chicks.  

PubMed

Stocking density is a management factor which has critical implications for the poultry industry. The aim of the present study was to investigate the effect of high stocking density as a predisposing factor in an experimental model of necrotic enteritis in broiler chicks. The experimental challenge model included an oral inoculation with 10-fold dose of attenuated anticoccidial vaccine and multiple oral inoculations with a specific strain of Clostridium perfringens. Two hundred and forty as hatched day-old broiler chicks were randomly allocated to four treatment groups according to the following experimental design: group N, with normal stocking density (15 birds/m(2)) and no challenge; group D, with high stocking density (30 birds/m(2)) and no challenge; group P, with normal stocking density and positive challenge; and group DP, with high stocking density and positive challenge. From each bird, the intestine, gizzard and liver were collected and scored for gross lesions. The intestinal digesta was collected for pH and viscosity determination. One caecum from each bird was taken for microbiological analysis. The statistical analysis and evaluation of the experimental data revealed significant interaction effects between "stocking density" and "challenge", regarding gross lesion scores in intestine and liver, pH values in jejunum, ileum and caeca as well as C. perfringens counts in the caeca (P ? 0.05). High stocking density in challenged birds increased the gross lesion score in the intestine (P ? 0.05), contrary to unchallenged birds. It can be concluded that high stocking density affects unfavourably the welfare and gut health of broiler chicks, predisposes to necrotic enteritis in a subclinical experimental model and increases further its importance as a management factor for the poultry industry. PMID:25563065

Tsiouris, V; Georgopoulou, I; Batzios, C; Pappaioannou, N; Ducatelle, R; Fortomaris, P

2015-04-01

243

Estrogen treatment predisposes to severe and persistent vaginal candidiasis in diabetic mice  

PubMed Central

Background Increased levels of estrogen and diabetes mellitus separately predispose to vaginal candidiasis (VC). However, the compounding effect of estrogen on the severity and persistence of VC in diabetic females is not clear. Methods To address this issue, a diabetic mouse model with estrogen-maintained VC was developed and evaluated for vaginal fungal burden (VFB) and immune competence at different time points throughout the study period. Results Blood glucose levels in estrogen-treated diabetic mice were consistently lower than that in untreated counterparts. Estrogen-treated C. albicans-infected non-diabetic mice experienced persistent episodes of VC as compared with naïve controls (P?predispose to severe and persistent VC on the other. The later outcome could be related to the immunosuppressed status of the host. PMID:24401317

2014-01-01

244

Oblique Bile Duct Predisposes to the Recurrence of Bile Duct Stones  

PubMed Central

Background and Study Aims Bile stones represent a highly prevalent condition and abnormalities of the biliary tree predispose to stone recurrence due to development of biliary stasis. In our study, we assessed the importance of an altered bile duct course for stone formation. Patients and Methods 1,307 patients with choledocholithiasis in the absence of any associated hepatobiliary disease who underwent endoscopic retrograde cholangiopancreatography (ERCP) between 2002 and 2009 were analysed. The angle enclosed between the horizontal portion of the common bile duct (CBD) and the horizontal plane was measured (angle ?). Oblique common bile duct (OCBD) was defined as a CBD with angle ?<45°. Results 103 patients (7.9%) were found to harbour OCBD and these were compared to 104 randomly selected control subjects. Compared to controls, OCBD patients were (i) significantly older (72±13 vs. 67±13, p<0.00001); (ii) more frequently underwent a cholecystectomy (p?=?0.02) and biliary surgery (p?=?0.003) prior to the diagnosis and (iii) more often developed chronic pancreatitis (p?=?0.04) as well as biliary fistulae (p?=?0.03). Prior to and after ERCP, OCBD subjects displayed significantly elevated cholestatic parameters and angle ? negatively correlated with common bile duct diameter (r?=?-0.29, p?=?0.003). OCBD subjects more often required multiple back-to-back ERCP sessions to remove bile stones (p?=?0.005) as well as more ERCPs later on due to recurrent stone formation (p<0.05). Conclusion OCBD defines a novel variant of the biliary tree, which is associated with chronic cholestasis, hampers an efficient stone removal and predisposes to recurrence of bile duct stones. PMID:23365676

Strnad, Pavel; von Figura, Guido; Gruss, Regina; Jareis, Katja-Marlen; Stiehl, Adolf; Kulaksiz, Hasan

2013-01-01

245

Predisposing, enabling, and need factors as predictors of low and high psychotherapy utilization in veterans.  

PubMed

This study used national administrative data from the Veterans Health Administration (VHA) to examine predisposing, enabling, and need factors related to multiple levels of psychotherapy utilization in a sample of veterans with posttraumatic stress disorder (PTSD), depression, or anxiety. The database was queried for all veterans who were newly diagnosed with PTSD, depression, or anxiety during the 2010 fiscal year and received at least 1 outpatient psychotherapy session in the year following diagnosis (N = 130,331). Veterans were classified as low (51.0%; 1-3 sessions), moderate (38.3%; 4-18 sessions), high (8.7%; 19-51 sessions), or very high (1.9%; 52 or more sessions) psychotherapy users based on the total number of psychotherapy visits during the 1-year follow-up period. Multinomial logistic regression was used to examine predictors of utilization level. Predisposing factors of gender and marital status were modestly associated with utilization. Several need factors were strongly associated with utilization; very high users had higher rates of PTSD and substance use disorders, more comorbid psychiatric diagnoses, and more inpatient psychiatric visits. Very high users were also more likely to demonstrate enabling factors, including living closer to a VHA facility and seeking care at more complex facilities. Overall, need factors appeared to be most strongly linked to psychotherapy utilization. These results suggest many patients may not receive a clinically optimal dose of psychotherapy, highlighting the need to enhance retention in therapy for low utilizers and examine whether very high utilizers are benefitting from extensive courses of treatment. PMID:24841513

Hundt, Natalie E; Barrera, Terri L; Mott, Juliette M; Mignogna, Joseph; Yu, Hong-Jen; Sansgiry, Shubhada; Stanley, Melinda A; Cully, Jeffrey A

2014-08-01

246

Congenital anomaly of the inferior vena cava and factor V Leiden mutation predisposing to deep vein thrombosis  

PubMed Central

A previously healthy 21-year-old man presented with back pain, bilateral extremity pain, and right lower extremity weakness, paresthesias, and swelling. Sonographic examination revealed diffuse deep vein thrombosis (DVT) in the femoral and popliteal venous system. CT imaging revealed hypoplasia of the hepatic inferior vena cava (IVC) segment with formation of multiple varices and collateral veins around the kidneys. Hematologic workup also discovered a factor V Leiden mutation, further predisposing the patient to DVT. The rare, often overlooked occurrence of attenuated IVC, especially in the setting of hypercoagulable state, can predispose patients to significant thrombosis. PMID:25395858

Lamparello, Brooke M; Erickson, Cameron R; Kulthia, Arun; Virparia, Vasudev; Thet, Zeyar

2014-01-01

247

Thermolabile methylenetetrahydrofolate reductase gene and the risk of cognitive impairment in those over 85  

PubMed Central

OBJECTIVES—Previous reports have shown raised plasma concentrations of homocysteine in older persons with cognitive impairment. This may be caused by environmental and genetic factors. The relation between cognitive function and a common ala/val mutation in the methylenetetrahydrofolate reductase (MTHFR) gene was studied in those over 85. Homozygous carriers of this mutation are characterised by a lifelong exposure to moderately raised plasma concentrations of homocysteine.?METHODS—In the Leiden 85-plus Study, a population based study of persons aged 85 years and over, the score on the mini mental state examination (MMSE) and the presence of dementia dependent on the MTHFR genotypes were compared in 641 participants (456 women, 185 men) at baseline. In addition, the association between the MTHFR genotype and cognitive decline was studied by re-examining cognitive function of 172 participants without dementia at baseline after a median follow up of 4.0years.?RESULTS—At baseline, carriers of the ala/ala genotype had a median MMSE score of 27 points (interquartile range (IQR) 21.5-29), for the ala/val genotype it was 26 points (IQR 20-29), and for the val/val genotype it was 27 points (IQR 20-28.3) (p=0.3). The prevalence of dementia was also not significantly different for the various genotypes (ala/ala 22%, ala/val 28%, val/val 27%; p=0.4). None of the carriers of the val/val genotype without cognitive impairment at baseline developed dementia during the follow up.?CONCLUSIONS—Although previous studies have shown that older persons with cognitive impairment have raised plasma concentrations of homocysteine, homozygosity for the ala to val mutation in the MTHFR gene is not a genetic risk factor for cognitive impairment in persons aged 85 years and over.?? PMID:10486408

Gussekloo, J; Heijmans, B; Slagboom, P; Lagaay, A; Knook, D; Westendorp, R

1999-01-01

248

A cross-ethnicity investigation of genes previously implicated in primary angle closure glaucoma  

PubMed Central

Purpose To investigate the underlying genetic variation between candidate genes and primary angle closure glaucoma (PACG) in both Nepalese and Australian populations. Methods A total of 213 patients with PACG (106 Nepalese and 107 Australian) and 492 age and sex matched controls (204 Nepalese and 288 Australian) were included in the current study. Three candidate genes were selected; methyl-tetrahydrofolate reductase (MTHFR), calcitonin receptor-like receptor gene (CALCRL), and membrane frizzled-related protein (MFRP). Tag single nucleotide polymorphisms (SNPs) were selected and genotyped to capture the majority of common variation across each locus. Allele and haplotype analyses were conducted using PLINK. Results SNPs in the nanophthalmos gene MFRP were found to be nominally associated with PACG under the allelic model. Two SNPs were associated in the Australian cohort (rs948414; p=0.02 and rs36015759; p=0.02), and a single SNP in the Nepalese cohort (rs10790289; p=0.03), however these SNPs failed to remain significant after adjustment for sex and age. A haplotype at the CALCRL gene (AATACAGAT) was associated in the Australian cohort (corrected p-value=0.024). No association was observed in either cohort for MTHFR. Conclusions This study implicates genetic variation at the CALCRL gene in the pathogenesis of PACG in an Australian Caucasian cohort. Additionally, the MFRP gene shows tendency to be associated with PACG in both the Australian and Nepalese cohorts. Further investigation in a larger cohort is warranted to confirm these findings. No statistically significant associations were identified between MTHFR and PACG in either population. PMID:22933837

Burdon, Kathryn P.; Thapa, Suman S.; Hewitt, Alex W.; Craig, Jamie E.

2012-01-01

249

No association between MTHFR C677T and serum uric acid levels among Japanese with ABCG2 126QQ and SLC22A12 258WW.  

PubMed

Several genome-wide association studies (GWAS) have revealed that single nucleotide polymorphisms (SNPs) of ABCG2 and SLC22A12 were strongly associated with serum uric acid (SUA), but those of methylene tetrahydrofolate reductase (MTHFR) were not. However, there were several studies indicating the association with MTHFR C677T polymorphism. This study examined the association with the polymorphism, taking into account the genotypes of ABCG2 Q126X and SLC22A12 W258X. Subjects were 5,028 health checkup examinees of Seirei Preventive Health Care Center (3,416 males and 1,612 females) aged 35 to 69 years, who participated in the Japan Multi-Institutional Collaborative Cohort Study (J-MICC Study). Hyperuricemia was defined as SUA equal to 7 mg/dL or over. The genotype frequency was 35.9% for CC, 48.1% for CT, and 16.0% for TT, being in Hardy-Weinberg equilibrium (p=0.90). Among 4,425 participants with ABCG2 126QQ and SLC22A12 258WW who were not under medication for hyperuricemia, the mean SUA was 5.6 mg/dL, 5.6 mg/dL, and 5.7 mg/dL, respectively. When 114 participants with ABCG2 126QQ and SLC22A12 258WW under medication for hyperuricemia were included in hyperuricemia cases, the sex-age adjusted odds ratio (OR) of hyperuricemia was not significant; OR=1.00 (95% confidence interval, 0.89-1.24) for CT genotype and OR=0.98 (0.84-1.32) for TT genotype, relative to CC genotype. The present study indicated no association between SUA and MTHFR C677T genotype, after the influences of ABCG2 Q126X and SLC22A12 W258X were removed. PMID:23544272

Hinohara, Yukako; Naito, Mariko; Okada, Rieko; Yin, Guan; Higashibata, Takahiro; Tamura, Takashi; Kawai, Sayo; Morita, Emi; Wakai, Kenji; Matsuo, Hirotaka; Mori, Atsuyoshi; Hamajima, Nobuyuki

2013-02-01

250

Genes and primary headaches: discovering new potential therapeutic targets  

PubMed Central

Genetic studies have clearly shown that primary headaches (migraine, tension-type headache and cluster headache) are multifactorial disorders characterized by a complex interaction between different genes and environmental factors. Genetic association studies have highlighted a potential role in the etiopathogenesis of these disorders for several genes related to vascular, neuronal and neuroendocrine functions. A potential role as a therapeutic target is now emerging for some of these genes. The main purpose of this review is to describe new advances in our knowledge regarding the role of MTHFR, KCNK18, TRPV1, TRPV3 and HCRTR genes in primary headache disorders. Involvement of these genes in primary headaches, as well as their potential role in the therapy of these disorders, will be discussed. PMID:23848401

2013-01-01

251

Population Testing for Cancer Predisposing BRCA1/BRCA2 Mutations in the Ashkenazi-Jewish Community: A Randomized Controlled Trial  

PubMed Central

Background: Technological advances raise the possibility of systematic population-based genetic testing for cancer-predisposing mutations, but it is uncertain whether benefits outweigh disadvantages. We directly compared the psychological/quality-of-life consequences of such an approach to family history (FH)–based testing. Methods: In a randomized controlled trial of BRCA1/2 gene-mutation testing in the Ashkenazi Jewish (AJ) population, we compared testing all participants in the population screening (PS) arm with testing those fulfilling standard FH-based clinical criteria (FH arm). Following a targeted community campaign, AJ participants older than 18 years were recruited by self-referral after pretest genetic counseling. The effects of BRCA1/2 genetic testing on acceptability, psychological impact, and quality-of-life measures were assessed by random effects regression analysis. All statistical tests were two-sided. Results: One thousand, one hundred sixty-eight AJ individuals were counseled, 1042 consented, 1034 were randomly assigned (691 women, 343 men), and 1017 were eligible for analysis. Mean age was 54.3 (SD = 14.66) years. Thirteen BRCA1/2 carriers were identified in the PS arm, nine in the FH arm. Five more carriers were detected among FH-negative FH-arm participants following study completion. There were no statistically significant differences between the FH and PS arms at seven days or three months on measures of anxiety, depression, health anxiety, distress, uncertainty, and quality-of-life. Contrast tests indicated that overall anxiety (P = .0001) and uncertainty (P = .005) associated with genetic testing decreased; positive experience scores increased (P = .0001); quality-of-life and health anxiety did not change with time. Overall, 56% of carriers did not fulfill clinical criteria for genetic testing, and the BRCA1/2 prevalence was 2.45%. Conclusion: Compared with FH-based testing, population-based genetic testing in Ashkenazi Jews doesn’t adversely affect short-term psychological/quality-of-life outcomes and may detect 56% additional BRCA carriers. PMID:25435541

Manchanda, Ranjit; Loggenberg, Kelly; Sanderson, Saskia; Burnell, Matthew; Wardle, Jane; Gessler, Sue; Side, Lucy; Balogun, Nyala; Desai, Rakshit; Kumar, Ajith; Dorkins, Huw; Wallis, Yvonne; Chapman, Cyril; Taylor, Rohan; Jacobs, Chris; Tomlinson, Ian; McGuire, Alistair; Beller, Uziel; Menon, Usha

2015-01-01

252

Association between Maternal MTHFR Polymorphisms and Nonsyndromic Cleft Lip with or without Cleft Palate in Offspring, A Meta-Analysis Based on 15 Case-Control Studies  

PubMed Central

Background The methylenetetrahydrofolate reductase (MTHFR) is thought to be involved in the development of nonsyndromic cleft lip with or without cleft palate (NSCL/P). However, conflicting results have been obtained when evaluating the association between maternal MTHFR C677T and A1298C polymorphisms and the risk of NSCL/P. In light of this gap, a meta-analysis of all eligible case-control studies was conducted in the present study. Materials and Methods A total of 15 case-control studies were ultimately identified after a comprehensive literature search and Hardy-Weinberg equilibrium (HWE) examination. Cochrane’s Q test and index of heterogeneity (I2) indicated no obvious heterogeneity among studies. Results Fixed or random-effects models were used to calculate the pooled odds ratios (ORs). The results showed that the TT genotype in mothers increased the likelihood of having NSCL/P offspring 1.25 times (95% CI: 1.047-1.494) more than the CC homozygotes. Meanwhile, maternal TT genotype increased the risk of producing NSCL/P offspring in recessive model (OR=1.325, 95% CI: 1.124-1.562). However, the CT heterozygote and the CT+TT dominant models had no association with NSCL/P offspring compared with the CC wild-type homozygote model. Subgroup analyses based on ethnicity indicated that maternal TT genotype increased the likelihood of having NSCL/P offspring in Whites (OR=1.308, 95% CI: 1.059-1.617) and Asians (OR=1.726, 95% CI: 1.090-2.733) in recessive model. Also, subgroup analyses based on source of control showed that mothers with the 677TT genotype had a significantly increased susceptibility of having NSCL/P children in hospital based population (HB) when compared with CC homozygotes (OR=1.248, 95% CI: 1.024-1.520) and un- der the recessive model (OR=1.324, 95% CI: 1.104-1.588). Furthermore, maternal A1298C polymorphism had no significant association with producing NSCL/P offspring (dominant model OR=0.952, 95% CI: 0.816-1.111, recessive model OR=0.766, 95% CI: 0.567-1.036). Conclusion MTHFR C677T polymorphism is associated with the risk of generating NSCL/P offspring, and being a 677TT homozygote is a risk factor. MTHFR A1298C polymorphism was not associated with generating NSCL/P offspring. However, further work should be performed to confirm these findings. PMID:25780529

Pan, Xinjuan; Wang, Ping; Yin, Xinjuan; Liu, Xiaozhuan; Li, Di; Li, Xing; Wang, Yongchao; Li, Hongle; Yu, Zengli

2015-01-01

253

Predisposing, enabling, and need factors associated with high service use in a public mental health system.  

PubMed

The purpose of this study was twofold: (1) To investigate the individual- and system-level characteristics associated with high utilization of acute mental health services according to a widely-used theory of service use-Andersen's Behavioral Model of Health Service Use -in individuals enrolled in a large, public-funded mental health system; and (2) To document service utilization by high use consumers prior to a transformation of the service delivery system. We analyzed data from 10,128 individuals receiving care in a large public mental health system from fiscal years 2000-2004. Subjects with information in the database for the index year (fiscal year 2000-2001) and all of the following 3 years were included in this study. Using logistic regression, we identified predisposing, enabling, and need characteristics associated with being categorized as a single-year high use consumer (HU: >3 acute care episodes in a single year) or multiple-year HU (>3 acute care episodes in more than 1 year). Thirteen percent of the sample met the criteria for being a single-year HU and an additional 8% met the definition for multiple-year HU. Although some predisposing factors were significantly associated with an increased likelihood of being classified as a HU (younger age and female gender) relative to non-HUs, the characteristics with the strongest associations with the HU definition, when controlling for all other factors, were enabling and need factors. Homelessness was associated with 115% increase in the odds of ever being classified as a HU compared to those living independently or with family and others. Having insurance was associated with increased odds of being classified as a HU by about 19% relative to non-HUs. Attending four or more outpatient visits was an enabling factor that decreased the chances of being defined as a HU. Need factors, such as having a diagnosis of schizophrenia, bipolar disorder or other psychotic disorder or having a substance use disorder increased the likelihood of being categorized as a HU. Characteristics with the strongest association with heavy use of a public mental health system were enabling and need factors. Therefore, optimal use of public mental services may be achieved by developing and implementing interventions that address the issues of homelessness, insurance coverage, and substance use. This may be best achieved by the integration of mental health, intensive case management, and supportive housing, as well as other social services. PMID:21533848

Lindamer, Laurie A; Liu, Lin; Sommerfeld, David H; Folsom, David P; Hawthorne, William; Garcia, Piedad; Aarons, Gregory A; Jeste, Dilip V

2012-05-01

254

Exploring the Effects of Methylenetetrahydrofolate Reductase Gene Variants C677T and A1298C on the Risk of Orofacial Clefts in 261 Norwegian Case-Parent Triads  

Microsoft Academic Search

Folic acid and the methylenetetrahydrofolate reductase (MTHFR) gene have both been implicated in the etiology of orofacial clefts. The authors selected 261 case-parent triads (173 cases with cleft lip with or without cleft palate (CL\\/P) and 88 cases with cleft palate only (CPO)) from a Norwegian population-based study of orofacial clefts (May 1996-1998). A case-parent triad design was used to

Astanand Jugessur; Allen J. Wilcox; Rolv T. Lie; Jeffrey C. Murray; Jack A. Taylor

2003-01-01

255

Prothrombotic gene variants as risk factors of acute myocardial infarction in young women  

PubMed Central

Background Acute myocardial infarction (AMI) in young women represent an extreme phenotype associated with a higher mortality compared with similarly aged men. Prothrombotic gene variants could play a role as risk factors for AMI at young age. Methods We studied Factor V Leiden, FII G20210A, MTHFR C677T and beta-fibrinogen -455G>A variants by real-time PCR in 955 young AMI (362 females) and in 698 AMI (245 females) patients. The data were compared to those obtained in 909 unrelated subjects (458 females) from the general population of the same geographical area (southern Italy). Results In young AMI females, the allelic frequency of either FV Leiden and of FII G20210A was significantly higher versus the general population (O.R.: 3.67 for FV Leiden and O.R.: 3.84 for FII G20210A; p<0.001). Among AMI patients we showed only in males that the allelic frequency of the MTHFR C677T variant was significantly higher as compared to the general population. Such difference was due to a significantly higher frequency in AMI males of the MTHFR C677T variant homozygous genotype (O.R. 3.05). Discussion and conclusion Our data confirm that young AMI in females is a peculiar phenotype with specific risk factors as the increased plasma procoagulant activity of FV and FII. On the contrary, the homozygous state for the 677T MTHFR variant may cause increased levels of homocysteine and/or an altered folate status and thus an increased risk for AMI, particularly in males. The knowledge of such risk factors (that may be easily identified by molecular analysis) may help to improve prevention strategies for acute coronary diseases in specific risk-group subjects. PMID:23171482

2012-01-01

256

Exacerbated Mechanical Hyperalgesia in Rats with Genetically Predisposed Depressive Behavior: Role of Melatonin and NMDA Receptors  

PubMed Central

A connection between pain and depression has long been recognized in the clinical setting; however, its mechanism remains unclear. In this study, we showed that mechanical hyperalgesia induced by unilateral temporomandibular joint (TMJ) inflammation was exacerbated in Wistar-Kyoto (WKY) rats with genetically predisposed depressive behavior. Reciprocally, TMJ inflammation enhanced depressive behavior such that a lower nociceptive threshold correlated with a higher score of depressive behavior in the same WKY rats. As compared with Wistar rats, WKY rats exhibited a lower plasma melatonin level, downregulation of the melatonin MT1 receptor, but upregulation of the NR1 subunit of the NMDA receptor in the ipsilateral trigeminal subnucleus caudalis (Sp5C). Intracisternal administration of 6-chloromelatonin (250?g, twice daily × 7 days) concurrently attenuated mechanical hyperalgesia and depressive behavior in WKY rats as well as downregulated the NR1 expression in the ipsilateral Sp5C. In patch-clamp recordings, melatonin dose-dependently decreased NMDA-induced currents in spinal cord dorsal horn substantia gelatinosa neurons. These results demonstrate a reciprocal relationship between TMJ inflammation-induced mechanical hyperalgesia and depressive behavior and suggest that the central melatoninergic system, through modulation of the NMDA receptor expression and activity, may play a role in the mechanisms of the comorbidity between pain and depression. PMID:23046768

Wang, Shuxing; Tian, Yinghong; Song, Li; Lim, Grewo; Tan, Yonghui; You, Zerong; Chen, Lucy; Mao, Jianren

2012-01-01

257

Induced resistance in tomato by SAR activators during predisposing salinity stress  

PubMed Central

Plant activators are chemicals that induce disease resistance. The phytohormone salicylic acid (SA) is a crucial signal for systemic acquired resistance (SAR), and SA-mediated resistance is a target of several commercial plant activators, including Actigard (1,2,3-benzothiadiazole-7-thiocarboxylic acid-S-methyl-ester, BTH) and Tiadinil [N-(3-chloro-4-methylphenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide, TDL]. BTH and TDL were examined for their impact on abscisic acid (ABA)-mediated, salt-induced disease predisposition in tomato seedlings. A brief episode of salt stress to roots significantly increased the severity of disease caused by Pseudomonas syringae pv. tomato (Pst) and Phytophthora capsici relative to non-stressed plants. Root treatment with TDL induced resistance to Pst in leaves and provided protection in both non-stressed and salt-stressed seedlings in wild-type and highly susceptible NahG plants. Non-stressed and salt-stressed ABA-deficient sitiens mutants were highly resistant to Pst. Neither TDL nor BTH induced resistance to root infection by Phytophthora capsici, nor did they moderate the salt-induced increment in disease severity. Root treatment with these plant activators increased the levels of ABA in roots and shoots similar to levels observed in salt-stressed plants. The results indicate that SAR activators can protect tomato plants from bacterial speck disease under predisposing salt stress, and suggest that some SA-mediated defense responses function sufficiently in plants with elevated levels of ABA. PMID:23653630

Pye, Matthew F.; Hakuno, Fumiaki; MacDonald, James D.; Bostock, Richard M.

2013-01-01

258

Assessment of Fatty Liver Syndrome and Its Predisposing Factors in a Dairy Herd from Venezuela  

PubMed Central

The present on-farm research evaluated the occurrence of fatty liver syndrome and its predisposing risk factors for multiparous dairy cows from a commercial herd in Venezuela. Liver biopsy samples were collected at 35 days (d) prepartum (Holstein, n = 14; Holstein × Carora crossbred, n = 17) as well as 1 to 7?d (Holstein, n = 8; Holstein × Carora crossbred, n = 11) and 28 to 35?d (Holstein, n = 6; Holstein × Carora crossbred, n = 14) postpartum in order to analyse hepatic triacylglycerols (TAG, % wet basis) and glycogen concentrations. At postpartum, an occurrence of 72.0% for severe fatty liver along with 73.5% of subclinical ketosis (SCK) was found. The multiple regression model that best explained the association between milk production in the previous lactation (MYP) and TAG at first week postpartum was as follows: TAG, % = ?11.2 + 3.16 (prepartum body condition) + 0.0009176 (MYP) (R² = 0.36, P < 0.05). Logistic regression indicated that Holstein × Carora crossbred cows tended to have 27% higher relative risk than Holstein to experience SCK, whereas prepartum liver TAG greater than 3% tended to be associated with a higher relative risk for SCK compared to cows with TAG ?3%. PMID:23738138

Gonzalez, Clara I.

2013-01-01

259

Acute inflammation is exacerbated in mice genetically predisposed to a severe protein C deficiency  

PubMed Central

The anticoagulant, activated protein C (aPC), possesses antithrombotic, profibrinolytic, anti-inflammatory, and antiapoptotic properties, and the level of this protein is an important marker of acute inflammatory responses. Although infusion of aPC improves survival in a subset of patients with severe sepsis, evidence as to how aPC decreases mortality in these cases is limited. Because a total deficiency of PC shows complete neonatal lethality, no animal model currently exists to address the mechanistic relationships between very low endogenous aPC levels and inflammatory diseases. Here, we show for the first time that novel genetic dosing of PC strongly correlates with survival outcomes following endotoxin (LPS) challenge in mice. The data provide evidence that very low endogenous levels of PC predispose mice to early-onset disseminated intravascular coagulation, thrombocytopenia, hypotension, organ damage, and reduced survival after LPS challenge. Furthermore, evidence of an exacerbated inflammatory response is observed in very low PC mice but is greatly reduced in wild-type cohorts. Reconstitution of low-PC mice with recombinant human aPC improves hypotension and extends survival after LPS challenge. This study directly links host endogenous levels of PC with various coagulation, inflammation, and hemodynamic end points following a severe acute inflammatory challenge. PMID:17047151

Lay, Angelina J.; Donahue, Deborah; Tsai, Meng-Ju

2007-01-01

260

Does long-term treatment with Doxil® predispose patients to oral cancer?  

PubMed

We present a possible adverse reaction related to long-term use of Doxil(®) in female patients. We believe that long-term use of Doxil(®) may predispose female patients to oral squamous cell carcinoma. The patients in this report were not exposed to the common risk factors related to oral cancer formation such as smoking or alcohol consumption. Both patients were 59-year-old females. The first patient was diagnosed in 2001 with stage IIIC ovarian cancer. Seven years following treatment with Doxil(®), she was diagnosed with stage III squamous cell carcinoma of the right maxilla. The second patient was diagnosed with Kaposi's sarcoma with evidence of spread to the lungs. Four years following treatment with Doxil(®) she was diagnosed with stage I squamous cell carcinoma of the left maxilla. A literature review did not reveal any report on Doxil(®) and predisposition to oral cancer; however, we found an abstract that was presented at the last annual meeting of the American Society of Clinical Oncology (ASCO) by Cannon et al. When we combine the data from Cannon et al. and the data presented here, a total of six female patients developed an epithelial carcinoma of the oral cavity following long-term treatment with Doxil(®). We believe that a large-scale study should be initiated on patients that were treated with Doxil(®) for more than 3 years, since these patients might be at risk for developing secondary cancer of the oral cavity. PMID:22430199

Ben-David, Yehuda; Leiser, Yoav; Kachta, Orly; El-Naaj, Imad Abu

2013-06-01

261

Incisional Hernia in Women: Predisposing Factors and Management Where Mesh is not Readily Available  

PubMed Central

Background / Aim: Incisional hernia is still relatively common in our practice. The aim of the study was to identify risk factors associated with incisional hernia in our region. The setting is the Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Nigeria during a period when prosthetic mesh was not readily available. Patients and Methods: All the women who presented with incisional hernia between 1996 and 2005 were prospectively studied using a standard form to obtain information on pre-hernia (index) operations and possible predisposing factors. They all had open surgical repair and were followed up for 18–60 months. Results: Forty-four women were treated during study period. The index surgeries leading to the hernias were emergency caesarian section 26/44 (59.1%), emergency exploratory laparotomy 6/44 (13.6%), and elective surgeries 12/44 (27.3%). Major associated risk factors were the use of wrong suture materials for fascia repair, midline incisions, wound sepsis, and overweight. Conclusion: For elective surgeries, reduction of weight should be encouraged when appropriate, and transverse incisions are preferred. Absorbable sutures, especially chromic catgut, should be avoided in fascia closure. Antibiotics should be used for complicated obstetric cases. PMID:21483511

Agbakwuru, EA; Olabanji, JK; Alatise, OI; Okwerekwu, RO; Esimai, OA

2009-01-01

262

Predisposing factors for renal scarring in children with urinary tract infection.  

PubMed

This study was undertaken to determine the predisposing factors for renal scarring in children with urinary tract infection. In this prospective cohort study, 176 children with documented urinary tract infection were categorized into four groups: ?1 year old, 1-2 years old, 2-7 years and 7-14 years old. Ultrasonography and Technetium-99 m-DMSA scan were used to detect the possible abnormalities. Infants under 12 months old presented as the most common group for renal scarring (27 cases, 52.9%), and vesicoureteral reflux (VUR) was diagnosed in 29 cases (56.8%). Fifteen (41.67%) children between the ages of one and two years had renal scar, and VUR was detected in half of the patients. In the third group, 36.3%, and in fourth group, 41.6% of the patients had renal scar. Also, 38.6% in group three and 50% in the final group had VUR. A co-incidental finding that was observed in this study was the high incidence of pseudohypoaldesteronism (PHA) in our patients: in 39.2% of the children in group one, 22.2% in group two and 4% in group three. In group four however, none of the patients had PHA. Risk of scar formation with urinary tract infection (UTI) was higher in the younger age group and in those with recurrent UTIs. PMID:22569440

Beiraghdar, Fatemeh; Panahi, Yunes; Einollahi, Behzad; Moharamzad, Yashar; Nemati, Eghlim; Amirsalari, Susan

2012-05-01

263

Mechanisms Predisposing Penile Fracture and Long-Term Outcomes on Erectile and Voiding Functions  

PubMed Central

Purpose. To determine the mechanisms predisposing penile fracture as well as the rate of long-term penile deformity and erectile and voiding functions. Methods. All fractures were repaired on an emergency basis via subcoronal incision and absorbable suture with simultaneous repair of eventual urethral lesion. Patients' status before fracture and voiding and erectile functions at long term were assessed by periodic follow-up and phone call. Detailed history included cause, symptoms, and single-question self-report of erectile and voiding functions. Results. Among the 44 suspicious cases, 42 (95.4%) were confirmed, mean age was 34.5 years (range: 18–60), mean follow-up 59.3 months (range 9–155). Half presented the classical triad of audible crack, detumescence, and pain. Heterosexual intercourse was the most common cause (28 patients, 66.7%), followed by penile manipulation (6 patients, 14.3%), and homosexual intercourse (4 patients, 9.5%). “Woman on top” was the most common heterosexual position (n = 14, 50%), followed by “doggy style” (n = 8, 28.6%). Four patients (9.5%) maintained the cause unclear. Six (14.3%) patients had urethral injury and two (4.8%) had erectile dysfunction, treated by penile prosthesis and PDE-5i. No patient showed urethral fistula, voiding deterioration, penile nodule/curve or pain. Conclusions. “Woman on top” was the potentially riskiest sexual position (50%). Immediate surgical treatment warrants long-term very low morbidity. PMID:24822062

Reis, Leonardo O.; Cartapatti, Marcelo; Marmiroli, Rafael; de Oliveira Júnior, Eduardo Jeronimo; Saade, Ricardo Destro; Fregonesi, Adriano

2014-01-01

264

Perceptions of predisposing and protective factors for perinatal depression in same-sex parents.  

PubMed

Increasing numbers of women are choosing to have children in the context of same-sex relationships or as "out" lesbian or bisexual individuals. This study used qualitative methods to assess perceived predisposing and protective factors for perinatal depression in lesbian, gay, bisexual, and queer (LGBQ) women. Two focus groups with LGBQ women were conducted: 1) biological parents of young children and 2) nonbiological parents of young children or whose partners were currently pregnant. Three major themes emerged. Issues related to social support were primary, particularly related to disappointment with the lack of support provided by members of the family of origin. Participants also described issues related to the couple relationship, such as challenges in negotiating parenting roles. Finally, legal and policy barriers (e.g., second parent adoption) were identified as a significant source of stress during the transition to parenthood. Both lack of social support and relationship problems have previously been identified as risk factors for perinatal depression in heterosexual women, and legal and policy barriers may represent a unique risk factor for this population. Therefore, additional study of perinatal mental health among LGBQ women is warranted. PMID:16260356

Ross, Lori E; Steele, Leah; Sapiro, Beth

2005-01-01

265

Prevalence of Low Back Pain Among Nurses: Predisposing Factors and Role of Work Place Violence  

PubMed Central

Background: Ergonomic factors predispose nurses to low back pain (LBP). Few studies have clarified the role of workplace violence in LBP occurrence. Objectives: The present study was designed to investigate acute and chronic LBP in Iranian nurses and its association with exposure to physical violence as well as its personal and ergonomic risk factors. Materials and Methods: In this analytic cross sectional study, the rate of acute and chronic LBP and contributing factors were investigated among 1246 nurses using a validated questionnaire. Statistical analysis was performed by chi square, student t-test, and logistic regression, to determine the association between independent variables and LBP. Results: In total, 1246 nurses, consisting of 576 (46.23%) males and 670 (53.77%) females, were included. The mean age and the mean years of employment were 31.23 ± 5.33 and 16.18 ± 7.05, respectively. Both acute low back pain (ALBP) and chronic low back pain (CLBP) were associated with physical violence experience. Moreover, acute and chronic LBP were predicted by positive past history of LBP as well as two ergonomic factors, frequent bending and frequent carrying of patients. Conclusions: Besides a history of low back pain and ergonomic factors, physical violence may be considered a contributing factor for acute low back injuries. Special attention to all personal, occupational, and psychological risk factors is recommended. PMID:25717449

Rezaee, Maryam; Ghasemi, Mohammad

2014-01-01

266

C677T mutation in methylenetetrahydrofolate reductase gene and neural tube defects: should Japanese women undergo gene screening before pregnancy?  

PubMed

We analyzed the role of maternal C677T mutation in methylenetetrahydrofolate reductase (MTHFR) gene on spina bifida development in newborns. A total of 115 mothers who had given birth to a spina bifida child (SB mothers) gave 10?mL of blood together with written informed consent. The genotype distribution of C677T mutation was assessed and compared with that of the 4517 control individuals. The prevalence of the homozygous genotype (TT) among SB mothers was not significantly different from that among the controls (odds ratio [OR]?=?0.65; 95% confidence interval [CI]?=?0.31-1.25; P?=?0.182), suggesting that MTHFR 677TT genotype in Japan is not associated with spina bifida development in newborns. The T allele frequency was not increased in SB mothers (34.8%) as compared to that of the control individuals (38.2%). Further, the internationally reported association between the two groups was found to be similar in all 15 countries studied except the Netherlands, where the TT genotype was found to be a genetic risk factor for spina bifida. For the prevention of affected pregnancy every woman planning to conceive has to take folic acid supplements 400??g a day and the government is asked to take action in implementing food fortification with folic acid in the near future. In conclusion, it is not necessary for Japanese women to undergo genetic screening C677T mutation of the MTHFR gene as a predictive marker for spina bifida prior to pregnancy, because the TT genotype is not a risk factor for having an affected infant. PMID:24588777

Kondo, Atsuo; Fukuda, Hiromi; Matsuo, Takuya; Shinozaki, Keiko; Okai, Ikuyo

2014-02-01

267

Correlation of Homocysteine Metabolic Enzymes Gene Polymorphism and Mild Cognitive Impairment in the Xinjiang Uygur Population  

PubMed Central

Background The aim of this study was to investigate the genetic polymorphisms in the homocysteine (HCY) metabolic enzymes in the Xinjiang Uygur population who have mild cognitive impairment (MCI). Material/Methods Based on the epidemiological investigation, 129 cases of diagnosed Uygur MCI patients and a matched control group with 131 cases were enrolled for analyzing the association between the polymorphisms in the HCY metabolism related genes (C677T, A1298C, and G1968A polymorphisms in MTHFR, as well as the A2756G polymorphism in MS) and MCI by using the SNaPshot method. We then determined the homocysteine level in patients. Results In Xinjiang Uygur subjects, the A1298C polymorphisms in MTHFR and the A2756G polymorphisms in the MS gene in the MCI group were different from those in the control group. However, the C677T and G1968A polymorphisms in the MTHFR gene in MCI patients were not different from those in the control group. Multivariate logistic regression showed that, in addition to the well-known risk factors, such as low education level, high cholesterol level, high level of low-density lipoprotein, and high homocysteine levels, the A>G mutation in the MS gene at the rs1805087 locus was another independent risk factor for MCI in the Uyghur MCI population. The risk of MCI in G allele carriers was 2.265 times higher than that in matched control individuals (95% CI: 1.205~4.256, P<0.05). Conclusions The genetic polymorphism of HCY metabolizing enzymes is correlated to the occurrence of MCI in the Xinjiang Uygur population. The A2756G polymorphism in the MS gene could be an independent risk factor for MCI in the Xinjiang Uygur population. PMID:25625218

Luo, Mei; Ji, Huihui; Zhou, Xiaohui; Liang, Jie; Zou, Ting

2015-01-01

268

Are effects of MTHFR (C677T) genotype on BMD confined to women with low folate and riboflavin intake? Analysis of food records from the Danish osteoporosis prevention study  

Microsoft Academic Search

We have previously found BMD and fracture risk to be significantly associated with the MTHFR (C677T) polymorphism in healthy postmenopausal women in the first years after menopause. Since then, other cohort studies have suggested that sufficient intake of riboflavin and\\/or folate may have the potential to prevent development of low BMD in women with the TT genotype. This could to

Bo Abrahamsen; Jonna Skov Madsen; Charlotte Landbo Tofteng; Lis Stilgren; Else Marie Bladbjerg; Søren Risom Kristensen; Kim Brixen; Leif Mosekilde

2005-01-01

269

Rapid Communication Are effects of MTHFR (C677T) genotype on BMD confined to women with low folate and riboflavin intake? Analysis of food records from the Danish osteoporosis prevention study  

Microsoft Academic Search

We have previously found BMD and fracture risk to be significantly associated with the MTHFR (C677T) polymorphism in healthy postmenopausal women in the first years after menopause. Since then, other cohort studies have suggested that sufficient intake of riboflavin and\\/or folate may have the potential to prevent development of low BMD in women with the TT genotype. This could to

Bo Abrahamsen; Jonna Skov Madsen; Charlotte Landbo Tofteng; Lis Stilgren

270

Pre-exposure to ozone predisposes oak leaves to attacks by Diplodia corticola and Biscogniauxia mediterranea.  

PubMed

One-year-old cork oak (Quercus suber) and turkey oak (Q. cerris) seedlings were exposed to ozone (110 ppb, 5 h day(-1), for 30 days) and were inoculated with Diplodia corticola and Biscogniauxia mediterranea, respectively, by spraying a suspension of spores on the leaves. Both fungi are endophytic and may act as weak parasites, contributing to oak decline. Ozone exposure stimulated leaf attacks after inoculation, although the physiological, visible, and structural responses of both oaks to O3 exposure were weak. In fact, steady-state gas exchange, leaf waxes, and wettability were not significantly affected by O3. In Q. cerris, O3 altered the structure of stomata, as observed by scanning microscopy, and reduced the leaf relative water content. No hyphal entry through stomata or growth towards stomata was, however, observed. Inoculations were performed in a humid chamber at low light; stomata were likely to be closed. When Q. cerris was inoculated in natural conditions, i.e., in a forest infected by B. mediterranea, seedlings pre-exposed to the enhanced O3 regime had a higher number of B. mediterranea isolates than the controls. This suggests that pre-exposure to O3 predisposed Q. cerris leaves to attacks by B. mediterranea independent of stomata. The hyphae of both fungi were able to enter the leaf through the cuticle, either by gradual in-growth into the cuticle or erosion of a hollow in the cuticle at the point of contact. The primary cause of increased leaf injury in O3-exposed seedlings appeared to be higher germination of spores than on control leaves. PMID:17450300

Paoletti, Elena; Anselmi, Naldo; Franceschini, Antonio

2007-01-01

271

Absence of stimulation of poly(ADP-ribose) polymerase activity in patients predisposed to colon cancer.  

PubMed Central

Poly(ADP-ribose)polymerase (PARP) has been implicated in DNA repair mechanisms and the associated activity shown to markedly increase after DNA damage in carcinogen-treated cells. A defective DNA repair has been associated to the aetiology of human cancers. In order to assess the potential role of this enzyme in cellular response to DNA damage by gamma-radiation, we studied the activity of PARP in patients with familial adenomatous polyposis (FAP). We compared poly(ADP-ribose)polymerase activity by the rate of incorporation of radioactivity from [3H]adenine-NAD+ into acid-insoluble material in permeabilized leucocytes from FAP patients and healthy volunteers. Concomitantly, the intracellular levels of NAD+--the substrate for the PARP--and the reduced counterpart NADH were determined using an enzymatic cycling assay 30 min after [60Co] gamma-ray cells irradiation. Our results demonstrate that a marked stimulation of PARP activity is produced upon radiation of the cells from healthy subjects but not in the FAP leucocytes, which concomitantly show a marked decrease in total NAD-/NADH content. Our observations point to a role of PARP in the repair of the gamma-radiation-induced DNA lesions through a mechanism that is impaired in the cells from FAP patients genetically predisposed to colon cancer. The differences observed in PARP activation by gamma-radiation in patients and healthy individuals could reflect the importance of PARP activity dependent on treatment with gamma-rays. The absence of this response in FAP patients would seem to suggest a possible defect in the role of PARP in radiation-induced DNA repair in this cancer-prone disease. PMID:9635838

Cristóvão, L.; Lechner, M. C.; Fidalgo, P.; Leitão, C. N.; Mira, F. C.; Rueff, J.

1998-01-01

272

Previous Burn Injury Predisposes Mice to Lipopolysaccharide (LPS) Induced Changes in Glucose Metabolism  

PubMed Central

In mice, it has been demonstrated that at 7 days after burn injury, injection of LPS is more lethal than the same dose at one day after injury. In the present study, we examined the effect of LPS injection to mice burned seven days previously on glucose metabolism (18FDG uptake) in vivo. CD-1 male mice (25-28 grams, Charles River breeding laboratories) were anesthetized, backs shaven, and subjected to dorsal full thickness burn on 25% total body surface area. Sham treated animals were used as controls. Six days after burn injury all mice were fasted overnight. One half of the burned and sham controls were subsequently injected i.p. with LPS (10 mg/kg, E. Coli). The remaining animals were injected with saline i.p. Two hours later all mice were injected i.v. with 50 ?Ci of 18F FDG. One hour later the animals were euthanized and biodistribution was measured. Tissues were weighed and radioactivity was measured with a well-type gamma counter. Results were expressed as %dose/gram tissue, mean ± SEM. The combination of burn 7 days previously and LPS significantly increased mortality compared animals with burn alone, LPS alone or sham controls. Burn injury seven days previously caused a significant reduction in 18FDG uptake by the brain compared to sham controls. The combination of LPS and burn injury seven days previously produced a significant increase in 18FDG uptake by brown adipose tissue (BAT) and heart compared with either treatment separately. LPS produced a significant increase in 18FDG uptake by lung, spleen and GI tract of the sham animals, changes that were different in mice burned 7 days previously and injected with LPS. The present results suggest that burn injury seven days previously predisposes mice to alterations in 18FDG uptake produced by LPS. These changes may relate in part, to the increased lethality of LPS injection in previously burned mice. PMID:22961012

Carter, Edward A.; Paul, Kasie; Barrow, Sandra A.; Fischman, Alan J.; Tompkins, Ronald G.

2012-01-01

273

Sexual activity does not predispose to reflux episodes in patients with gastroesophageal reflux disease  

PubMed Central

Background The role of sexual activity on gastroesophageal reflux disease (GERD) is an under-recognized concern of patients, and one rarely assessed by physicians. Objective The objective of this article is to determine the influence of sexual activity on the intraesophageal acid exposure and acid reflux events in GERD patients. Methods Twenty-one patients with the diagnosis of GERD were prospectively enrolled. Intraesophageal pH monitoring was recorded for 48 hours with a Bravo capsule. All patients were instructed to have sexual intercourse or abstain in a random order two hours after the same refluxogenic dinner within two consecutive nights. Patients were requested to have sex in the standard “missionary position” and women were warned to avoid abdominal compression. The patients completed a diary reporting the time of the sexual intercourse and GERD symptoms. The percentage of reflux time and acid reflux events were compared in two ways: within 30 and 60 minutes prior to and after sexual intercourse on the day of sexual intercourse and in the same time frame of the day without sexual intercourse. Results Fifteen of 21 GERD patients were analyzed. The percentage of reflux time and number of acid reflux events did not show a significant difference within the 30- and 60-minute periods prior to and after sexual intercourse on the day of sexual intercourse and on the day without sexual intercourse, as well. Conclusion Sexual activity does not predispose to increased intraesophageal acid exposure and acid reflux events. Larger studies are needed to confirm our findings in patients who define reflux symptoms during sexual intercourse. PMID:25452843

Bor, Serhat; Valytova, Elen; Yildirim, Esra; Vardar, Rukiye

2014-01-01

274

Exploring genetic variants predisposing to diabetes mellitus and their association with indicators of socioeconomic status  

PubMed Central

Background The relevance of disease-related genetic variants for the explanation of social inequalities in complex diseases is unclear and empirical analyses are largely missing. The aim of our study was to examine whether genetic variants predisposing to diabetes mellitus are associated with socioeconomic status in a population-based cohort. Methods We genotyped 11 selected diabetes-related single nucleotide polymorphisms in 4655 participants (age 45-75 years) of the Heinz Nixdorf Recall study. Diabetes status was self-reported or defined by blood glucose levels. Education, income and paternal occupation were assessed as indicators of socioeconomic status. Multiple regression analyses were used to examine the association of socioeconomic status and diabetes by estimating sex-specific and age-adjusted prevalence ratios and their corresponding 95%-confidence intervals. To explore the relationship between individual single nucleotide polymorphisms and socioeconomic status sex- and age-adjusted odds ratios were computed. We adjusted the alpha-level for multiple testing of 11 single nucleotide polymorphisms using Bonferroni’s method ( ? BF?~?0.005). In addition, we explored the association of a genetic risk score with socioeconomic status. Results Social inequalities in diabetes were observed for all indicators of socioeconomic status. However, there were no significant associations between individual diabetes-related risk alleles and socioeconomic status with odds ratios ranging from 0.87 to 1.23. Similarly, the genetic risk score analysis revealed no evidence for an association. Conclusions Our data provide no evidence for an association between 11 diabetes-related risk alleles and different indicators of socioeconomic status in a population-based cohort, suggesting that the explored genetic variants do not contribute to health inequalities in diabetes. PMID:24935819

2014-01-01

275

Obesity accentuates circadian variability in breathing during sleep in mice but does not predispose to apnea  

PubMed Central

Obesity is a primary risk factor for the development of obstructive sleep apnea in humans, but the impact of obesity on central sleep apnea is less clear. Given the comorbidities associated with obesity in humans, we developed techniques for long-term recording of diaphragmatic EMG activity and polysomnography in obese mice to assess breathing patterns during sleep and to determine the effect of obesity on apnea generation. We hypothesized that genetically obese ob/ob mice would exhibit less variability in breathing across the 24-h circadian cycle, be more prone to central apneas, and be more likely to exhibit patterns of increased diaphragm muscle activity consistent with obstructive apneas compared with lean mice. Unexpectedly, we found that obese mice exhibited a greater circadian impact on respiratory rate and diaphragmatic burst amplitude than lean mice, particularly during rapid eye movement (REM) sleep. Central apneas were more common in REM sleep (42 ± 17 h?1) than non-REM (NREM) sleep (14 ± 5 h?1) in obese mice (P < 0.05), but rates were not different between lean and obese mice in either sleep state. Even after experimentally enhancing central apnea generation by acute withdrawal of hypoxic chemoreceptor activation during sleep, central apnea rates remained comparable between lean and obese mice. Last, we were unable to detect patterns of diaphragmatic burst activity suggestive of obstructive apnea events in obese mice. In summary, obesity does not predispose mice to increased occurrence of central or obstructive apneas during sleep, but does lead to a more pronounced circadian variability in respiration. PMID:23722707

Locke, Landon W.; McDowell, Angela L.; Strollo, Patrick J.; O'Donnell, Christopher P.

2013-01-01

276

Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans  

Microsoft Academic Search

Identification of the genes underlying complex phenotypes and the definition of the evolutionary forces that have shaped eukaryotic genomes are among the current challenges in molecular genetics. Variation in gene copy number is increasingly recognized as a source of inter-individual differences in genome sequence and has been proposed as a driving force for genome evolution and phenotypic variation. Here we

Timothy J. Aitman; Rong Dong; Timothy J. Vyse; Penny J. Norsworthy; Michelle D. Johnson; Jennifer Smith; Jonathan Mangion; Cheri Roberton-Lowe; Amy J. Marshall; Enrico Petretto; Matthew D. Hodges; Gurjeet Bhangal; Sheetal G. Patel; Kelly Sheehan-Rooney; Mark Duda; Paul R. Cook; David J. Evans; Jan Domin; Jonathan Flint; Joseph J. Boyle; Charles D. Pusey; H. Terence Cook

2006-01-01

277

Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus  

Microsoft Academic Search

Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986

Z Su; LJ Gay; A Strange; C Palles; G Band; DC Whiteman; F Lescai; C Langford; M Nanji; S Edkins; A van der Winkel; D Levine; P Sasieni; C Bellenguez; K Howarth; C Freeman; N Trudgill; M Pirinen; MP Peppelenbosch; LJ van der Laan; EJ Kuipers; JP Drenth; WH Peters; JV Reynolds; DP Kelleher; R McManus; H Grabsch; H Prenen; R Bisschops; K Krishnadath; PD Siersema; JW van Baal; M Middleton; R Petty; R Gillies; N Burch; P Bhandari; S Paterson; C Edwards; I Penman; K Vaidya; Y Ang; I Murray; P Patel; W Ye; P Mullins; AH Wu; NC Bird; H Dallal; NJ Shaheen; LJ Murray; K Koss; L Bernstein; Y Romero; LJ Hardie; R Zhang; H Winter; DA Corley; S Panter; HA Risch; BJ Reid; I Sargeant; H Smart; A Dhar; H McMurtry; H Ali; G Liu; AG Casson; WH Chow; M Rutter; A Tawil; D Morris; C Nwokolo; P Isaacs; C Rodgers; K Ragunath; C MacDonald; C Haigh; D Monk; G Davies; S Wajed; D Johnston; M Gibbons; S Cullen; N Church; R Langley; M Griffin; D Alderson; P Deloukas; SE Hunt; E Gray; S Dronov; SC Potter; A Tashakkori-Ghanbaria; M Anderson; C Brooks; JM Blackwell; E Bramon; MA Brown; JP Casas; A Corvin; A Duncanson; HS Markus; CG Mathew; CN Palmer; R Plomin; A Rautanen; SJ Sawcer; RC Trembath; AC Viswanathan; N Wood; G Trynka; C Wijmenga; JB Cazier; P Atherfold; AM Nicholson; NL Gellatly; D Glancy; SC Cooper; D Cunningham; T Lind; J Hapeshi; D Ferry; B Rathbone; J Brown; S Love; S Attwood; S MacGregor; P Watson; S Sanders; W Ek; RF Harrison; P Moayyedi; J de Caestecker; H Barr; E Stupka; TL Vaughan; L Peltonen; CC Spencer; I Tomlinson; P Donnelly; JA Jankowski

2012-01-01

278

Loss of ALS2 Function Is Insufficient to Trigger Motor Neuron Degeneration in Knock-Out Mice But Predisposes Neurons to Oxidative Stress  

PubMed Central

Amyotrophic lateral sclerosis (ALS), the most common motor neuron disease, is caused by a selective loss of motor neurons in the CNS. Mutations in the ALS2 gene have been linked to one form of autosomal recessive juvenile onset ALS (ALS2). To investigate the pathogenic mechanisms of ALS2, we generated ALS2 knock-out (ALS2?/?) mice. Although ALS2?/? mice lacked obvious developmental abnormalities, they exhibited age-dependent deficits in motor coordination and motor learning. Moreover, ALS2?/? mice showed a higher anxiety response in the open-field and elevated plus-maze tasks. Although they failed to recapitulate clinical or neuropathological phenotypes consistent with motor neuron disease by 20 months of age, ALS2?/? mice or primary cultured neurons derived from these mice were more susceptible to oxidative stress compared with wild-type controls. These observations suggest that loss of ALS2 function is insufficient to cause major motor deficits or motor neuron degeneration in a mouse model but predisposes neurons to oxidative stress. PMID:16107644

Cai, Huaibin; Lin, Xian; Xie, Chengsong; Laird, Fiona M.; Lai, Chen; Wen, Hongjin; Chiang, Hsueh-Cheng; Shim, Hoon; Farah, Mohamed H.; Hoke, Ahmet; Price, Donald L.; Wong, Philip C.

2008-01-01

279

Acquired hypermethylation of the P16INK4A promoter in abdominal paraganglioma: relation to adverse tumor phenotype and predisposing mutation  

PubMed Central

Recurrent alterations in promoter methylation of tumor suppressor genes (TSGs) and LINE1 (L1RE1) repeat elements were previously reported in pheochromocytoma and abdominal paraganglioma. This study was undertaken to explore CpG methylation abnormalities in an extended tumor panel and assess possible relationships between metastatic disease and mutation status. CpG methylation was quantified by bisulfite pyrosequencing for selected TSG promoters and LINE1 repeats. Methylation indices above normal reference were observed for DCR2 (TNFRSF10D), CDH1, P16 (CDKN2A), RARB, and RASSF1A. Z-scores for overall TSG, and individual TSG methylation levels, but not LINE1, were significantly correlated with metastatic disease, paraganglioma, disease predisposition, or outcome. Most strikingly, P16 hypermethylation was strongly associated with SDHB mutation as opposed to RET/MEN2, VHL/VHL, or NF1-related disease. Parallel analyses of constitutional, tumor, and metastasis DNA implicate an order of events where constitutional SDHB mutations are followed by TSG hypermethylation and 1p loss in primary tumors, later transferred to metastatic tissue. In the combined material, P16 hypermethylation was prevalent in SDHB-mutated samples and was associated with short disease-related survival. The findings verify the previously reported importance of P16 and other TSG hypermethylation in an independent tumor series. Furthermore, a constitutional SDHB mutation is proposed to predispose for an epigenetic tumor phenotype occurring before the emanation of clinically recognized malignancy. PMID:23154831

Kiss, Nimrod B; Muth, Andreas; Andreasson, Adam; Juhlin, C Christofer; Geli, Janos; Bäckdahl, Martin; Höög, Anders; Wängberg, Bo; Nilsson, Ola; Ahlman, Håkan; Larsson, Catharina

2013-01-01

280

Vaginal colonization by papG allele II+ Escherichia coli isolates from pregnant and nonpregnant women as predisposing factor to pyelonephritis.  

PubMed

Vaginal (61) and fecal (61) Escherichia coli isolates from pregnant and nonpregnant women (18-45 years old) were surveyed for papG alleles by PCR technique. papG allele II was the most prevalent among both vaginal (32.7%) and fecal (3.2%) isolates, whereas other alleles were found only among vaginal isolates (1.6% for alleles I and III and 3.2% for alleles II + III). papG(+) pregnant women's isolates did not differ significantly from those of nonpregnant in possession of papG allele II (90% versus 73.3%), whereas both (32.7%) differed significantly (P ? 0.05) in comparison with fecal isolates (3.2%). The vast majority of papG allele II(+) vaginal isolates were clustered in group B2 (81.8%) and much less in group D (18.1%). Also, most of them were positive for fimH (100%), papC (100%), iucC (90.9%), and hly (72.7%), and about half of them were positive for sfa/foc (45.4%). In addition, the mean of VFs' gene possession was 3.5 (range from 2 to 5). It can be concluded that vaginal colonization by papG allele II(+) E. coli is possibly one of the predisposing factors of both pregnant and nonpregnant women to pyelonephritis, but its potential may be modified by other factors especially host factors. PMID:23861574

Al-Mayahie, Sareaa Maseer Gatya

2013-01-01

281

Combination of Thrombophilic Gene Polymorphisms as a Cause of Increased the Risk of Recurrent Pregnancy Loss  

PubMed Central

Background Recurrent pregnancy loss is (RPL) a heterogeneous condition. While the role of acquired thrombophilia has been accepted as an etiology for RPL, the contribution of specific inherited thrombophilic gene polymorphisms to the disorder has been remained controversial. Methods One hundred women with a history of two or more consecutive abortions and 100 women with at least two live births and no miscarriages were included in the study and evaluated for the presence of 11 thrombophilic gene polymorphisms (Factor V LEIDEN, Factor V 4070 A/G, Factor V 5279 A/G, Factor XIII 103 G/T, Factor XIII 614 A/T, Factor XIII 1694 C/T, PAI-1 -675 4G/5G, ITGB3 1565 T/C, ?-Fibrinogen -455G/A, MTHFR 677 C/T, MTHFR 1298 A/C) using PCR-RFLP technique. The data were statistically analyzed using Mann-Whitney test and logistic regression model. Results There was no relation between factor XIII 103G/T gene polymorphism with increased risk of RPL. However, the other 10 gene polymorphisms were found to be associated with increased/decreased risk of RPL. Multiple logistic regression model for analyzing the simultaneous effects of these polymorphisms on the risk of RPL showed that six of these 11 polymorphisms (Factor V 1691G/A, Factor V 5279A/G, Factor XIII 614A/T, ?-Fibrinogen -455G/A, ITGB3 1565T/C, and MTHFR 1298A/ C) were associated with RPL. Conclusion It is possible to calculate the risk of abortion in a patient with RPL by determining only six of the 10 polymorphisms that are individually associated with RPL. PMID:23926530

Torabi, Raheleh; Zarei, Saeed; Zeraati, Hojjat; Zarnani, Amir Hassan; Akhondi, Mohammad Mehdi; Hadavi, Reza; Shiraz, Elham Savadi; Jeddi-Tehrani, Mahmood

2012-01-01

282

Association of CVD Candidate Gene Polymorphisms with Ischemic Stroke and Cerebral Hemorrhage in Chinese Individuals  

PubMed Central

Background Contribution of cardiovascular disease related genetic risk factors for stroke are not clearly defined. We performed a genetic association study to assess the association of 56 previously characterized gene variants in 34 candidate genes from cardiovascular disease related biological pathways with ischemic stroke and cerebral hemorrhage in a Chinese population. Methods There were 1280 stroke patients (1101 with ischemic stroke and 179 with cerebral hemorrhage) and 1380 controls in the study. The genotypes for 56 polymorphisms of 34 candidate genes were determined by the immobilized probe approach and the associations of gene polymorphisms with ischemic stroke and cerebral hemorrhage were performed by logistic regression under an allelic model. Results After adjusting for age, sex, BMI and hypertension status by logistic regression analysis, we found that NPPA rs5063 was significantly associated with both ischemic stroke (odds ratio [OR] 0.69; 95% confidence interval [CI], 0.52 to 0.90; P?=?0.006) and cerebral hemorrhage(OR?=?0.39; 95%CI, 0.19 to 0.78; P?=?0.007). In addition, MTHFR rs1801133 also was associated with cerebral hemorrhage (OR?=?1.48; 95%CI, 1.16 to1.89; P?=?0.001) but not with ischemic stroke (OR?=?1.08; 95%CI, 0.96 to1.22; P?=?0.210). After false discovery rate (FDR) correction, the association of NPPA rs5063 and MTHFR rs1801133 with cerebral hemorrhage remained significant. Conclusions The NPPA rs5063 is associated with reduced risk for cerebral hemorrhage and MTHFR rs1801133 is associated with increased risk of cerebral hemorrhage in a Chinese population. PMID:25144711

Shen, Yue; Li, Jiana; He, Lingbin; Yuan, Yuan; Tan, Xuerui; Liu, Lisheng; Zhao, Jingbo; Wang, Xingyu

2014-01-01

283

C4 deficiency is a predisposing factor for Streptococcus pneumoniae-induced autoantibody production  

PubMed Central

Reductions in C4 levels may predispose individuals to infection with encapsulated bacteria as well as autoimmunity. In this study, we examined the role C4 has in protection against Streptococcus pneumoniae-induced autoimmunity. Mild respiratory infection with serotype 19F pneumococci selectively induced systemic anti-dsDNA IgA production in naïve C4-/- mice, but not C3-/- or wild type mice. Systemic challenge with virulent serotype 3 pneumococci also induced anti-dsDNA IgA production in immune C4-/- mice. Remarkably, pneumococcal polysaccharide (PPS) vaccination alone induced C4-/- mice to produce increased anti-dsDNA IgA levels that were maintained in some mice for months. These effects were most pronounced in female C4-/- mice. Importantly, immunization-induced increases in anti-dsDNA IgA levels were strongly associated with increased IgA deposition in kidneys. Cross-reactivity between pneumococcal antigens and dsDNA played a partial role in the induction of anti-dsDNA IgA, but a major role for PPS-associated TLR2 agonists was also revealed. Administration of the TLR2/4 antagonist, OxPAPC, at the time of PPS immunization completely blocked the production of anti-dsDNA IgA in C4-/- mice without suppressing PPS-specific Ab production. The TLR2 agonist, Pam3Csk4, similarly induced anti-dsDNA IgA production in C4-/- mice, which OxPAPC also prevented. LPS, a TLR4 agonist, had no effect. Pam3Csk4, but not LPS, also induced dsDNA-specific IgA production by C4-/- splenic IgA+ B cells in vitro, indicating TLR2 agonists can stimulate autoAb production via B cell-intrinsic mechanisms. Collectively, our results show an important role for C4 in suppressing autoAb production elicited by cross-reactive antigens and TLR2 agonists associated with S. pneumoniae. PMID:25339671

Yammani, Rama D.; Leyva, Marcela A.; Jennings, Ryan N.; Haas, Karen M.

2015-01-01

284

A POPULATION-SPECIFIC HTR2B STOP CODON PREDISPOSES TO SEVERE IMPULSIVITY  

PubMed Central

SUMMARY Impulsivity, describing action without foresight, is an important feature of several psychiatric diseases, suicidality and violent behavior. The complex origins of impulsivity hinder identification of the genes influencing both it and diseases with which it is associated. We performed exon-centric sequencing of impulsive individuals in a founder population, targeting fourteen genes belonging to the serotonin and dopamine domain. A stop codon in HTR2B that is common (MAF >1%) but exclusive to Finns was identified. Expression of the gene in the human brain was assessed, as well as the molecular functionality of the stop codon that was associated with psychiatric diseases marked by impulsivity in both population and family-based analyses. Knockout of Htr2b increased impulsive behaviors in mice, indicative of predictive validity. Our study shows the potential for identifying and tracing effects of rare alleles in complex behavioral phenotypes using founder populations, and suggests a role for HTR2B in impulsivity. PMID:21179162

Bevilacqua, Laura; Doly, Stéphane; Kaprio, Jaakko; Yuan, Qiaoping; Tikkanen, Roope; Paunio, Tiina; Zhou, Zhifeng; Wedenoja, Juho; Maroteaux, Luc; Diaz, Silvina; Belmer, Arnaud; Hodgkinson, Colin A.; Dell’Osso, Liliana; Suvisaari, Jaana; Coccaro, Emil; Rose, Richard J; Peltonen, Leena; Virkkunen, Matti; Goldman, David

2011-01-01

285

MTHFR 677C>T Polymorphism and the Risk of Breast Cancer: Evidence from an Original Study and Pooled Data for 28031 Cases and 31880 Controls  

PubMed Central

Background Methylenetetrahydrofolate reductase (MTHFR) acts at an important metabolic point in the regulation of cellular methylation reaction. It assists in the conversion of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. The latter aids in remethylation of homocysteine to de novo methionine that is required for DNA synthesis. The objective of this study was to examine the effect of MTHFR 677 C>T polymorphism on the risk of breast cancer in the Indian sub-continent. Methods and Results We genotyped 677 C>T locus in 1096 individuals that were classified into cases (N=588) and controls (N=508). Genotype data were analyzed using chi-square test. No significant difference was observed in the distribution of genotypes between cases and controls in north Indian (P = 0.932), south Indian (P = 0.865), and pooled data (P = 0.680). To develop a consensus regarding the impact of 677C>T polymorphism on breast cancer risk, we also conducted a meta-analysis on 28031 cases and 31880 controls that were pooled from sixty one studies. The overall summary estimate upon meta-analysis suggested no significant correlation between the 677C>T substitution and breast cancer in the dominant model (Fixed effect model: OR = 0.97, P=0.072, Random effects model: OR = 0.96, P = 0.084) or the recessive model (Fixed effect model: OR = 1.05, P = 0.089; Random effects model: OR= 1.08, P= 0.067). Conclusion 677 C>T substitution does not affect breast cancer risk in the Indo-European and Dravidian populations of India. Analysis on pooled data further ruled out association between the 677 C>T polymorphism and breast cancer. Therefore, 677 C>T substitution does not appear to influence the risk of breast cancer. PMID:25803740

Sekhar, Deepa; Francis, Amirtharaj; Gupta, Nishi; Konwar, Rituraj; Kumar, Sandeep; Kumar, Surender; Thangaraj, Kumarasamy; Rajender, Singh

2015-01-01

286

A Lower Degree of PBMC L1 Methylation in Women with Lower Folate Status May Explain the MTHFR C677T Polymorphism Associated Higher Risk of CIN in the US Post Folic Acid Fortification Era  

PubMed Central

Background Studies in populations unexposed to folic acid (FA) fortification have demonstrated that MTHFR C677T polymorphism is associated with increased risk of higher grades of cervical intraepithelial neoplasia (CIN 2+). However, it is unknown whether exposure to higher folate as a result of the FA fortification program has altered the association between MTHFR C677T and risk of CIN, or the mechanisms involved with such alterations. The current study investigated the following in a FA fortified population: 1) The association between MTHFR C677T polymorphism and risk of CIN 2+; 2) The modifying effects of plasma folate concentrations on this association; and 3) The modifying effects of plasma folate on the association between the polymorphism and degree of methylation of long interspersed nucleotide elements (L1s), in peripheral blood mononuclear cell (PBMC) DNA, a documented biomarker of CIN risk. Methods The study included 457 US women diagnosed with either CIN 2+ (cases) or ? CIN 1 (non-cases). Unconditional logistic regression models were used to test the associations after adjusting for relevant risk factors for CIN. Results The 677CT/TT MTHFR genotypes were not associated with the risk of CIN 2+. Women with CT/TT genotype with lower folate, however, were more likely to be diagnosed with CIN 2+ compared to women with CT/TT genotype with higher folate (OR?=?2.41, P?=?0.030). Women with CT/TT genotype with lower folate were less likely to have a higher degree of PBMC L1 methylation compared to women with CT/TT genotype with higher folate (OR?=?0.28, P?=?0.017). Conclusions This study provides the first evidence that the MTHFR 677CT/TT genotype-associated lower degree of PBMC L1 methylation increases the risk of CIN 2+ in women in the US post-FA fortification era. Thus, even in the post-FA fortification era, not all women have adequate folate status to overcome MTHFR 677CT/TT genotype-associated lower degree of L1 methylation. PMID:25302494

Badiga, Suguna; Johanning, Gary L.; Macaluso, Maurizio; Azuero, Andres; Chambers, Michelle M.; Siddiqui, Nuzhat R.; Piyathilake, Chandrika J.

2014-01-01

287

Two necrotic enteritis predisposing factors, dietary fishmeal and Eimeria infection, induce large changes in the caecal microbiota of broiler chickens.  

PubMed

It is widely established that a high-protein fishmeal supplemented starter diet and Eimeria infection can predispose birds to the development of clinical necrotic enteritis symptoms following Clostridium perfringens infection. However, it has not been clearly established what changes these treatments cause to predispose birds to succumb to necrotic enteritis. We analysed caecal microbiota of 4 groups of broilers (n=12) using deep pyrosequencing of 16S rDNA amplicons: (1) control chicks fed a control diet, (2) Eimeria infected chicks fed control diet, (3) chicks fed fishmeal supplemented diet and lastly (4) both fishmeal fed and Eimeria infected chicks. We found that the high-protein fishmeal diet had a strong effect on the intestinal microbiota similar to the previously reported effect of C. perfringens infection. We noted major changes in the prevalence of various lactobacilli while the total culturable Lactobacillus counts remained stable. The Ruminococcaceae, Lachnospiraceae, unknown Clostridiales and Lactobacillaceae families were most affected by fishmeal with increases in a number of operational taxonomic units (OTUs) that had previously been linked to Crohn's disease and reductions in OTUs known to be butyrate producers. Eimeria induced very different changes in microbiota; Ruminococcaceae groups were reduced in number and three unknown Clostridium species were increased in abundance. Additionally, Eimeria did not significantly influence changes in pH, formic, propionic or isobutyric acid while fishmeal induced dramatic changes in all these measures. Both fishmeal feeding and Eimeria infection induced significant changes in the gut microbiota; these changes may play an important role in predisposing birds to necrotic enteritis. PMID:24522272

Wu, Shu-Biao; Stanley, Dragana; Rodgers, Nicholas; Swick, Robert A; Moore, Robert J

2014-03-14

288

The X-files in immunity: sex-based differences predispose immune responses  

Microsoft Academic Search

Despite accumulating evidence in support of sex-based differences in innate and adaptive immune responses, in the susceptibility to infectious diseases and in the prevalence of autoimmune diseases, health research and clinical practice do not address these distinctions, and most research studies of immune responses do not stratify by sex. X-linked genes, hormones and societal context are among the many factors

Eleanor N. Fish

2008-01-01

289

Testicular germ cell tumours: predisposition genes and the male germ cell niche  

Microsoft Academic Search

Testicular germ cell tumours (TGCTs) of adults and adolescents are putatively derived from primordial germ cells or gonocytes. Recently reported genome-wide association studies implicate six gene loci that predispose to TGCT development. Remarkably, the functions of proteins encoded by genes within these regions bridge our understanding between the pathways involved in primordial germ cell physiology, male germ cell development and

Duncan Gilbert; Elizabeth Rapley; Janet Shipley

2011-01-01

290

Intercellular adhesion molecule 1 gene associations with immunologic subsets of inflammatory bowel disease  

Microsoft Academic Search

Background & Aims: Inflammatory bowel disease is characterized by a failure to down-regulate the usual self-limited gut inflammatory response, suggesting that one or more of the predisposing genes could be those that determine the level of the immune response along the inflammatory pathway. The aim of this study was to examine potential associations of intercellular adhesion molecule 1 (ICAM-1) gene

Huiying Yang; Devendra K. Vora; Stephan R. Targan; Hiroo Toyoda; Arthur L. Beaudet; Jerome I. Rotter

1995-01-01

291

Gene Expression Differences over a Critical Period of Afferent-Dependent  

E-print Network

Gene Expression Differences over a Critical Period of Afferent-Dependent Neuron SurvivalRNA expression of specific genes could predispose CN neurons to either death or survival after deafferentation 98195 ABSTRACT Deprivation of auditory nerve input in young mice results in dramatic neuron death

Rubel, Edwin

292

Genetic Modifiers Predisposing to Congenital Heart Disease in the Sensitized Down Syndrome Population  

PubMed Central

Background About half of people with Down syndrome (DS) exhibit some form of congenital heart disease (CHD). However, trisomy for human chromosome 21 (Hsa21) alone is insufficient to cause CHD as half of all people with DS have a normal heart, suggesting that genetic modifiers interact with dosage sensitive gene(s) on Hsa21 to result in CHD. We hypothesize that a threshold exists in both Down syndrome and euploid populations for the number of genetic perturbations that can be tolerated before CHD results. Methods and Results We ascertained a group of individuals with DS and complete atrioventricular septal defect (AVSD) and sequenced two candidate genes for CHD, CRELD1, which is associated with AVSD in people with or without DS, and HEY2, whose mouse ortholog produces septal defects when mutated. Several deleterious variants were identified but the frequency of these potential modifiers was low. We crossed mice with mutant forms of these potential modifiers to the Ts65Dn mouse model of Down syndrome. Crossing loss-of-function alleles of either Creld1 or Hey2 onto the trisomic background caused a significant increase in the frequency of CHD, demonstrating an interaction between the modifiers and trisomic genes. We showed further that although either of these mutant modifiers is benign by itself, they interact to affect heart development when inherited together. Conclusions Using mouse models of Down syndrome and of genes associated with congenital heart disease we demonstrate a biological basis for an interaction that supports a threshold hypothesis for additive effects of genetic modifiers in the sensitized trisomic population. PMID:22523272

Li, Huiqing; Cherry, Sheila; Klinedinst, Donna; DeLeon, Valerie; Redig, Jennifer; Reshey, Benjamin; Chin, Michael T.; Sherman, Stephanie L.; Maslen, Cheryl L.; Reeves, Roger H.

2012-01-01

293

Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma  

PubMed Central

Although CDKN2A is the most frequent high-risk melanoma susceptibility gene, the underlying genetic factors for most melanoma-prone families remain unknown. Using whole exome sequencing, we identified a rare variant that arose as a founder mutation in the telomere shelterin POT1 gene (g.7:124493086 C>T, Ser270Asn) in five unrelated melanoma-prone families from Romagna, Italy. Carriers of this variant had increased telomere length and elevated fragile telomeres suggesting that this variant perturbs telomere maintenance. Two additional rare POT1 variants were identified in all cases sequenced in two other Italian families, yielding a frequency of POT1 variants comparable to that of CDKN2A mutations in this population. These variants were not found in public databases or in 2,038 genotyped Italian controls. We also identified two rare recurrent POT1 variants in American and French familial melanoma cases. Our findings suggest that POT1 is a major susceptibility gene for familial melanoma in several populations. PMID:24686846

Shi, Jianxin; Yang, Xiaohong R.; Ballew, Bari; Rotunno, Melissa; Calista, Donato; Fargnoli, Maria Concetta; Ghiorzo, Paola; Paillerets, Brigitte Bressac-de; Nagore, Eduardo; Avril, Marie Francoise; Caporaso, Neil E.; McMaster, Mary L.; Cullen, Michael; Wang, Zhaoming; Zhang, Xijun; Bruno, William; Pastorino, Lorenza; Queirolo, Paola; Banuls-Roca, Jose; Garcia-Casado, Zaida; Vaysse, Amaury; Mohamdi, Hamida; Riazalhosseini, Yasser; Foglio, Mario; Jouenne, Fanélie; Hua, Xing; Hyland, Paula L.; Yin, Jinhu; Vallabhaneni, Haritha; Chai, Weihang; Minghetti, Paola; Pellegrini, Cristina; Ravichandran, Sarangan; Eggermont, Alexander; Lathrop, Mark; Peris, Ketty; Scarra, Giovanna Bianchi; Landi, Giorgio; Savage, Sharon A.; Sampson, Joshua N.; He, Ji; Yeager, Meredith; Goldin, Lynn R.; Demenais, Florence; Chanock, Stephen J.; Tucker, Margaret A.; Goldstein, Alisa M.; Liu, Yie; Landi, Maria Teresa

2014-01-01

294

An Overview of IAEA Activities to Support Pre-disposal Management of Radioactive Wastes in Member States - 12334  

SciTech Connect

The International Atomic Energy Agency (IAEA) promotes safe and effective management of radioactive waste and has suitable programmes in place to serve the needs of Member States in this area. These programmes cover the development and use of safety standards, planning, technologies and approaches needed for the management of different types of radioactive waste, resulting both from the nuclear fuel cycle and nuclear applications. In the pre-disposal area, the assistance to Members States covers a wide range of topics, including policy and strategy, inventory assessment, technologies and approaches for waste minimization, selection of technical options for waste processing and storage, improvement in operating practices at nuclear facilities, optimization of waste management capacity, etc. and is delivered through the publication of technical guidance documents, coordinated research projects, networks, technical cooperation projects and organization of training and technical review services. This report presents an overview of recent IAEA accomplishments aiming to support activities in pre-disposal management of radioactive waste with focus on technological aspects. (authors)

Kumar Samanta, Susanta; Drace, Zoran; Ojovan, Michael [Waste Technology Section, International Atomic Energy Agency, P.O. Box 100, Wagramerstasse, 1400 Vienna (Austria)

2012-07-01

295

Mild hyperhomocysteinemia and the common C677T polymorphism of methylene tetrahydrofolate reductase gene are not associated with the metabolic syndrome in Type 2 diabetes.  

PubMed

A moderate increase of total homocysteine (tHcy) plasma levels seems to increase cardiovascular disease (CVD) risk in Type 2 diabetic subjects, but its relationship with diabetes and insulin-resistance is still controversial. We examined whether mild hyperhomocysteinemia and its major genetic determinant would cluster with the metabolic syndrome (MS) in Type 2 diabetes. One hundred Type 2 diabetic subjects with and without MS were enrolled in the study. Fasting tHcy, vitamin B12, and folate plasma levels, insulin-resistance [assessed by homeostasis model assessment, (HOMAIR)] and the methylene tetrahydrofolate reductase (MTHFR) C677T genotype were assessed in all the participants. Geometric mean tHcy concentration and the prevalence of mild hyperhomocysteinemia, as commonly defined by tHcy >/=15 micromol/l, were comparable in diabetic subjects with and without MS, even after adjustment for age, sex, vitamin B12, folate and creatinine levels. In both groups, the MTHFR C677T genotype distribution was not significantly different from the Hardy-Weinberg equilibrium, with a TT homozygous frequency of 21% in subjects with and 18% in those without the syndrome (p=ns). tHcy plasma levels and the degree of insulin-resistance did not differ across MTHFR genotypes in both groups, even after multivariable adjustment. Overall, tHcy significantly correlated with creatinine (r=0.25; p=0.009) and trygliceride concentrations (r=0.24; p=0.02), but not with HOMAIR. At multivariate analysis, only creatinine was significantly correlated with tHcy levels (beta=0.42; p=0.001). In conclusion, hyperhomocysteinemia and the common C677T variant of MTHFR gene are not associated with MS in Type 2 diabetic subjects. PMID:16682831

Russo, G T; Di Benedetto, A; Alessi, E; Ientile, R; Antico, A; Nicocia, G; La Scala, R; Di Cesare, E; Raimondo, G; Cucinotta, D

2006-03-01

296

A Mutation in TNNC1-encoded Cardiac Troponin C, TNNC1-A31S, Predisposes to Hypertrophic Cardiomyopathy and Ventricular Fibrillation*  

PubMed Central

Defined as clinically unexplained hypertrophy of the left ventricle, hypertrophic cardiomyopathy (HCM) is traditionally understood as a disease of the cardiac sarcomere. Mutations in TNNC1-encoded cardiac troponin C (cTnC) are a relatively rare cause of HCM. Here, we report clinical and functional characterization of a novel TNNC1 mutation, A31S, identified in a pediatric HCM proband with multiple episodes of ventricular fibrillation and aborted sudden cardiac death. Diagnosed at age 5, the proband is family history-negative for HCM or sudden cardiac death, suggesting a de novo mutation. TnC-extracted cardiac skinned fibers were reconstituted with the cTnC-A31S mutant, which increased Ca2+ sensitivity with no effect on the maximal contractile force generation. Reconstituted actomyosin ATPase assays with 50% cTnC-A31S:50% cTnC-WT demonstrated Ca2+ sensitivity that was intermediate between 100% cTnC-A31S and 100% cTnC-WT, whereas the mutant increased the activation of the actomyosin ATPase without affecting the inhibitory qualities of the ATPase. The secondary structure of the cTnC mutant was evaluated by circular dichroism, which did not indicate global changes in structure. Fluorescence studies demonstrated increased Ca2+ affinity in isolated cTnC, the troponin complex, thin filament, and to a lesser degree, thin filament with myosin subfragment 1. These results suggest that this mutation has a direct effect on the Ca2+ sensitivity of the myofilament, which may alter Ca2+ handling and contribute to the arrhythmogenesis observed in the proband. In summary, we report a novel mutation in the TNNC1 gene that is associated with HCM pathogenesis and may predispose to the pathogenesis of a fatal arrhythmogenic subtype of HCM. PMID:22815480

Parvatiyar, Michelle S.; Landstrom, Andrew P.; Figueiredo-Freitas, Cicero; Potter, James D.; Ackerman, Michael J.; Pinto, Jose Renato

2012-01-01

297

The 19-bp deletion of dihydrofolate reductase (DHFR), methylenetetrahydrofolate reductase (MTHFR) C677T, Factor V Leiden, prothrombin G20210A polymorphisms in cancer patients with and without thrombosis  

Microsoft Academic Search

Venous thromboembolism (VTE) is a common complication in cancer patients. Several genetic risk factors related to thrombophilia\\u000a are known; however, their contributions to thrombotic tendency in cancer patients have conflicting results. In the present\\u000a study, we have focused on the prevalence of methylenetetrahydrofolate reductase (MTHFR) C677T, dihydrofolate reductase (DHFR)\\u000a 19-bp deletion within intron 1, factor V Leiden (FVL), and prothrombin

Aydan Eroglu; Yonca Egin; Ragip Çam; Nejat Akar

2009-01-01

298

Epigenetic Genes and Emotional Reactivity to Daily Life Events: A Multi-Step Gene-Environment Interaction Study  

PubMed Central

Recent human and animal studies suggest that epigenetic mechanisms mediate the impact of environment on development of mental disorders. Therefore, we hypothesized that polymorphisms in epigenetic-regulatory genes impact stress-induced emotional changes. A multi-step, multi-sample gene-environment interaction analysis was conducted to test whether 31 single nucleotide polymorphisms (SNPs) in epigenetic-regulatory genes, i.e. three DNA methyltransferase genes DNMT1, DNMT3A, DNMT3B, and methylenetetrahydrofolate reductase (MTHFR), moderate emotional responses to stressful and pleasant stimuli in daily life as measured by Experience Sampling Methodology (ESM). In the first step, main and interactive effects were tested in a sample of 112 healthy individuals. Significant associations in this discovery sample were then investigated in a population-based sample of 434 individuals for replication. SNPs showing significant effects in both the discovery and replication samples were subsequently tested in three other samples of: (i) 85 unaffected siblings of patients with psychosis, (ii) 110 patients with psychotic disorders, and iii) 126 patients with a history of major depressive disorder. Multilevel linear regression analyses showed no significant association between SNPs and negative affect or positive affect. No SNPs moderated the effect of pleasant stimuli on positive affect. Three SNPs of DNMT3A (rs11683424, rs1465764, rs1465825) and 1 SNP of MTHFR (rs1801131) moderated the effect of stressful events on negative affect. Only rs11683424 of DNMT3A showed consistent directions of effect in the majority of the 5 samples. These data provide the first evidence that emotional responses to daily life stressors may be moderated by genetic variation in the genes involved in the epigenetic machinery. PMID:24967710

Pishva, Ehsan; Drukker, Marjan; Viechtbauer, Wolfgang; Decoster, Jeroen; Collip, Dina; van Winkel, Ruud; Wichers, Marieke; Jacobs, Nele; Thiery, Evert; Derom, Catherine; Geschwind, Nicole; van den Hove, Daniel; Lataster, Tineke; Myin-Germeys, Inez; van Os, Jim

2014-01-01

299

Analysis of 30 Genes (355 SNPS) Related to Energy Homeostasis for Association with Adiposity in European-American and Yup’ik Eskimo Populations  

Microsoft Academic Search

Objective: Human adiposity is highly heritable, but few of the genes that predispose to obesity in most humans are known. We tested candidate genes in pathways related to food intake and energy expenditure for association with measures of adiposity. Methods: We studied 355 genetic variants in 30 candidate genes in 7 molecular pathways related to obesity in two groups of

Wendy K. Chung; Amit Patki; Naoki Matsuoka; Bert B. Boyer; Nianjun Liu; Solomon K. Musani; Anna V. Goropashnaya; Perciliz L. Tan; Nicholas Katsanis; Stephen B. Johnson; Peter K. Gregersen; David B. Allison; Rudolph L. Leibel; Hemant K. Tiwari

2009-01-01

300

PAGES: Clinical study for families with multiple cases of pancreatic cancer The PAncreatic Cancer GEnes Study (PAGES) is an ongoing study at Dana-Farber created  

E-print Network

PAGES: Clinical study for families with multiple cases of pancreatic cancer The PAncreatic Cancer GEnes Study (PAGES) is an ongoing study at Dana-Farber created to advance pancreatic cancer research of this study will be the identification of the gene(s) that predispose to pancreatic cancer, which will lead

Liu, Xiaole Shirley

301

Need, Enabling, Predisposing, and Behavioral Determinants of Access to Preventative Care in Argentina: Analysis of the National Survey of Risk Factors  

PubMed Central

Introduction Health care utilization is an important step to disease management, providing opportunities for prevention and treatment. Anderson’s Health Behavior Model has defined utilization by need, predisposing, and enabling determinants. We hypothesize that need, predisposing, and enabling, highlighting behavioral factors are associated with utilization in Argentina. Methods We performed a logistic regression analysis of the 2005 and 2009 Argentinean Survey of Risk Factors, a cohort of 41,392 and 34,732 individuals, to explore the association between need, enabling, predisposing, and behavioral factors to blood pressure measurement in the last year. Results In the 2005 cohort, blood pressure measurement was associated with perception of health, insurance coverage, basic needs met, and income. Additionally, female sex, civil state, household type, older age groups, education, and alcohol use were associated with utilization. The 2009 cohort showed similar associations with only minor differences between the models. Conclusions We explored the association between utilization of clinical preventive services with need, enabling, predisposing, and behavioral factors. While predisposing and need determinants are associated with utilization, enabling factors such as insurance coverage provides an area for public intervention. These are important findings where policies should be focused to improve utilization of preventive services in Argentina. PMID:22984608

Jahangir, Eiman; Irazola, Vilma; Rubinstein, Adolfo

2012-01-01

302

Cancer predisposing BARD1 mutations in breast–ovarian cancer families  

Microsoft Academic Search

The breast cancer susceptibility gene BARD1 (BRCA1-associated RING domain protein, MIM# 601593) acts with BRCA1 in DNA double-strand break (DSB) repair and also in apoptosis\\u000a initiation. We screened 109 BRCA1\\/2 negative high-risk breast and\\/or ovarian cancer patients from North-Eastern Poland for BARD1 germline mutations using a combination of denaturing high-performance liquid chromatography and direct sequencing. We identified\\u000a 16 different BARD1

Magdalena Ratajska; Ewelina Antoszewska; Anna Piskorz; Izabela Brozek; Åke Borg; Hanna Kusmierek; Wojciech Biernat; Janusz Limon

303

Genetic variants in the complement system predisposing to age-related macular degeneration: a review.  

PubMed

Age-related macular degeneration (AMD) is a major cause of visual impairment in the western world. It is characterized by the presence of lipoproteinaceous deposits (drusen) in the inner layers of the retina. Immunohistochemistry studies identified deposition of complement proteins in the drusen as well as in the choroid. In the last decade, genetic studies have linked both common and rare variants in genes of the complement system to increased risk of development of AMD. Here, we review the variants described to date and discuss the functional implications of dysregulation of the alternative pathway of complement in AMD. PMID:25034031

Schramm, Elizabeth C; Clark, Simon J; Triebwasser, Michael P; Raychaudhuri, Soumya; Seddon, Johanna M; Atkinson, John P

2014-10-01

304

The 3020insC Allele of NOD2 Predisposes to Cancers of Multiple Organs  

PubMed Central

The NOD2 gene has been associated with susceptibility to Crohn's disease and individuals with Crohn's disease are at increased risk for cancer at a number of organ sites. We studied the association between the 3020insC allele of the NOD2 gene and cancer among 2604 cancer patients and 1910 controls from Poland. Patients were diagnosed with one of twelve types of cancer in the Szczecin region between 1994 and 2004. Significant associations were found for colon cancer (OR = 1.8; 95% CI 1.2 to 2.6), for lung cancer (OR = 1.7; 95% CI = 1.1 to 2.5) and for ovarian cancer (OR = 1.6; 95% CI 1.1 to 2.3). In addition, a significant association was found for early-onset laryngeal cancer (OR = 2.9; 95% CI 1.4 to 6.2) and for breast cancer in the presence of DCIS (OR = 2.1 95% CI = 1.2 to 3.6). The NOD2 3020insC allele is relatively common (in Poland 7.3% of individuals) and may be responsible for an important fraction of cancer cases. We estimate that the lifetime cancer risk among carriers of this allele is 30% higher than that of individuals with two wild-type alleles. PMID:20223031

2005-01-01

305

Ectopic expression ofHOXC6 blocks myeloid differentiation and predisposes to malignant transformation  

PubMed Central

Insertional mutagenesis by retroviral vectors has led to the discovery of many oncogenes associated with leukemia. Here we investigated the role of HOXC6, identified by proximal retrovirus insertion a large animal stem cell gene therapy study, for a potential involvement in hematopoietic stem cell activity and hematopoietic fate decision. HOXC6 was overexpressed in the murine bone marrow transplantation model and tested in a competitive repopulation assay in comparison to the known hematopoietic stem cell expansion factor, HOXB4. We have identified HOXC6 as a factor that enhances competitive repopulation capacity in vivo and colony formation in vitro. Ectopic HOXC6 expression also induced strong myeloid differentiation and expansion of granulocyte-macrophage progenitors/common myeloid progenitors (GMPs/CMPs) in vivo, resulting in myeloid malignancies with low penetrance (3 out of 17 mice), likely in collaboration with Meis1 due to a provirus integration mapped to the 3' region in the malignant clone. We characterized the molecular basis of HOXC6-induced myeloid differentiation and malignant cell transformation with complementary DNA microarray analysis. Overexpression of HOXC6 induced a gene expression signature similar to several acute myeloid leukemia subtypes when compared to normal GMPs/CMPs. These results demonstrate HOXC6 as a regulator in hematopoiesis and its involvement in malignant transformation. PMID:24513167

Heckl, Dirk; Zhang, Xiao-Bing; Nelson, Veronica; Beard, Brian C.; Kiem, Hans-Peter

2014-01-01

306

Methylenetetrahydrofolate reductase C677T gene polymorphism and essential hypertension: A meta-analysis of 10,415 subjects  

PubMed Central

The methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism has been suggested to be associated with the risk of essential hypertension (EH), however, results remain inconclusive. To investigate this association, the present meta-analysis of 27 studies including 5,418 cases and 4,997 controls was performed. The pooled odds ratio (OR) and its corresponding 95% confidence interval were calculated using the random-effects model. A significant association between the MTHFR C677T gene polymorphism and EH was found under the allelic (OR, 1.32; 95% CI, 1.20–1.45; P=0.000), dominant (OR, 1.39; 95% CI, 1.25–1.55; P=0.000), recessive (OR, 1.38; 95% CI, 1.18–1.62; P=0.000), homozygote (OR, 1.59; 95% CI, 1.32–1.92; P=0.000), and heterozygote (OR, 1.32; 95% CI, 1.20–1.45; P=0.000) genetic models. A strong association was also revealed in subgroups, including Asian, Caucasian and Chinese. The Japanese subgroup did not show any significant association under all models. Meta-regression analyses suggested that the study design was a potential source of heterogeneity, whereas the subgroup analysis additionally indicated that the population origin may also be an explanation. Another subgroup analysis revealed that hospital-based studies have a stronger association than population-based studies, however, the former suffered a greater heterogeneity. Funnel plot and Egger’s test manifested no evidence of publication bias. In conclusion, the present study supports the evidence for the association between the MTHFR C677T gene polymorphism and EH in the whole population, as well as in subgroups, such as Asian, Caucasian and Chinese. The carriers of the 677T allele are susceptible to EH. PMID:25054014

YANG, KE-MING; JIA, JIAN; MAO, LI-NA; MEN, CHEN; TANG, KANG-TING; LI, YAN-YAN; DING, HAI-XIA; ZHAN, YI-YANG

2014-01-01

307

A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma.  

PubMed

So far, no common environmental and/or phenotypic factor has been associated with melanoma and renal cell carcinoma (RCC). The known risk factors for melanoma include sun exposure, pigmentation and nevus phenotypes; risk factors associated with RCC include smoking, obesity and hypertension. A recent study of coexisting melanoma and RCC in the same patients supports a genetic predisposition underlying the association between these two cancers. The microphthalmia-associated transcription factor (MITF) has been proposed to act as a melanoma oncogene; it also stimulates the transcription of hypoxia inducible factor (HIF1A), the pathway of which is targeted by kidney cancer susceptibility genes. We therefore proposed that MITF might have a role in conferring a genetic predisposition to co-occurring melanoma and RCC. Here we identify a germline missense substitution in MITF (Mi-E318K) that occurred at a significantly higher frequency in genetically enriched patients affected with melanoma, RCC or both cancers, when compared with controls. Overall, Mi-E318K carriers had a higher than fivefold increased risk of developing melanoma, RCC or both cancers. Codon 318 is located in a small-ubiquitin-like modifier (SUMO) consensus site (?KXE) and Mi-E318K severely impaired SUMOylation of MITF. Mi-E318K enhanced MITF protein binding to the HIF1A promoter and increased its transcriptional activity compared to wild-type MITF. Further, we observed a global increase in Mi-E318K-occupied loci. In an RCC cell line, gene expression profiling identified a Mi-E318K signature related to cell growth, proliferation and inflammation. Lastly, the mutant protein enhanced melanocytic and renal cell clonogenicity, migration and invasion, consistent with a gain-of-function role in tumorigenesis. Our data provide insights into the link between SUMOylation, transcription and cancer. PMID:22012259

Bertolotto, Corine; Lesueur, Fabienne; Giuliano, Sandy; Strub, Thomas; de Lichy, Mahaut; Bille, Karine; Dessen, Philippe; d'Hayer, Benoit; Mohamdi, Hamida; Remenieras, Audrey; Maubec, Eve; de la Fouchardière, Arnaud; Molinié, Vincent; Vabres, Pierre; Dalle, Stéphane; Poulalhon, Nicolas; Martin-Denavit, Tanguy; Thomas, Luc; Andry-Benzaquen, Pascale; Dupin, Nicolas; Boitier, Françoise; Rossi, Annick; Perrot, Jean-Luc; Labeille, Bruno; Robert, Caroline; Escudier, Bernard; Caron, Olivier; Brugières, Laurence; Saule, Simon; Gardie, Betty; Gad, Sophie; Richard, Stéphane; Couturier, Jérôme; Teh, Bin Tean; Ghiorzo, Paola; Pastorino, Lorenza; Puig, Susana; Badenas, Celia; Olsson, Hakan; Ingvar, Christian; Rouleau, Etienne; Lidereau, Rosette; Bahadoran, Philippe; Vielh, Philippe; Corda, Eve; Blanché, Hélène; Zelenika, Diana; Galan, Pilar; Aubin, François; Bachollet, Bertrand; Becuwe, Céline; Berthet, Pascaline; Bignon, Yves Jean; Bonadona, Valérie; Bonafe, Jean-Louis; Bonnet-Dupeyron, Marie-Noëlle; Cambazard, Fréderic; Chevrant-Breton, Jacqueline; Coupier, Isabelle; Dalac, Sophie; Demange, Liliane; d'Incan, Michel; Dugast, Catherine; Faivre, Laurence; Vincent-Fétita, Lynda; Gauthier-Villars, Marion; Gilbert, Brigitte; Grange, Florent; Grob, Jean-Jacques; Humbert, Philippe; Janin, Nicolas; Joly, Pascal; Kerob, Delphine; Lasset, Christine; Leroux, Dominique; Levang, Julien; Limacher, Jean-Marc; Livideanu, Cristina; Longy, Michel; Lortholary, Alain; Stoppa-Lyonnet, Dominique; Mansard, Sandrine; Mansuy, Ludovic; Marrou, Karine; Matéus, Christine; Maugard, Christine; Meyer, Nicolas; Nogues, Catherine; Souteyrand, Pierre; Venat-Bouvet, Laurence; Zattara, Hélène; Chaudru, Valérie; Lenoir, Gilbert M; Lathrop, Mark; Davidson, Irwin; Avril, Marie-Françoise; Demenais, Florence; Ballotti, Robert; Bressac-de Paillerets, Brigitte

2011-12-01

308

Who is predisposed to insomnia: a review of familial aggregation, stress-reactivity, personality and coping style.  

PubMed

Insomnia is a common health complaint world-wide. Insomnia is a risk factor in the development of other psychological and physiological disorders. Therefore understanding the mechanisms which predispose an individual to developing insomnia has great transdiagnostic value. However, whilst it is largely accepted that a vulnerable phenotype exists there is a lack of research which aims to systematically assess the make-up of this phenotype. This review outlines the research to-date, considering familial aggregation and the genetics and psychology of stress-reactivity. A model will be presented in which negative affect (neuroticism) and genetics (5HTTLPR) are argued to lead to disrupted sleep via an increase in stress-reactivity, and further that the interaction of these variables leads to an increase in learned negative associations, which further increase the likelihood of poor sleep and the development of insomnia. PMID:24480386

Harvey, Christopher-James; Gehrman, Phil; Espie, Colin A

2014-06-01

309

Allergy/hypersensitivity reactions as a predisposing factor to complex regional pain syndrome I in orthopedic patients.  

PubMed

Several predisposing conditions have been associated with complex regional pain syndrome I (CRPS I). The purpose of this study was to determine the relationship between a history of allergy/hypersensitivity reactions and CRPS I in orthopedic patients. Orthopedic patients with CRPS I (n=115) who experienced pain relief after a successful sympathetic nerve blockade were identified for study inclusion; a control group (n=115) matched to the CRPS I group by age, sex, and location of injury was also included. All patients in the study had an average age of 42 years. In the CRPS I group, all participants were Caucasian and the majority (80.8%) were women. The skin of patients with CRPS I was described as fair (57.7%), mottled (57.7%), or sensitive (80.8%). Of the patients with CRPS I, 78 (67.8%) reported a statistically significant history of allergies compared with the 39 (33.9%) patients in the control group (P<.0001). Patients with CRPS I who experienced complete pain relief for at least 1 month following a single sympathetic nerve block were asked to answer a questionnaire (n=35), and some then underwent immediate hypersensitivity testing using a skin puncture technique (n=26). Skin hypersensitivity testing yielded an 83.3% positive predictive value with an accuracy of 76.9%. Based on these results, a positive history for allergy/hypersensitivity reactions is a predisposing condition for CRPS I in this subset of orthopedic patients. These hypersensitivity reactions may prove important in gaining a better understanding in the pathophysiology of CRPS I as a regional pain syndrome. PMID:24762157

Li, Xinning; Kenter, Keith; Newman, Ashley; O'Brien, Stephen

2014-03-01

310

The Mycotoxin Deoxynivalenol Predisposes for the Development of Clostridium perfringens-Induced Necrotic Enteritis in Broiler Chickens  

PubMed Central

Both mycotoxin contamination of feed and Clostridium perfringens-induced necrotic enteritis have an increasing global economic impact on poultry production. Especially the Fusarium mycotoxin deoxynivalenol (DON) is a common feed contaminant. This study aimed at examining the predisposing effect of DON on the development of necrotic enteritis in broiler chickens. An experimental Clostridium perfringens infection study revealed that DON, at a contamination level of 3,000 to 4,000 µg/kg feed, increased the percentage of birds with subclinical necrotic enteritis from 20±2.6% to 47±3.0% (P<0.001). DON significantly reduced the transepithelial electrical resistance in duodenal segments (P<0.001) and decreased duodenal villus height (P?=?0.014) indicating intestinal barrier disruption and intestinal epithelial damage, respectively. This may lead to an increased permeability of the intestinal epithelium and decreased absorption of dietary proteins. Protein analysis of duodenal content indeed showed that DON contamination resulted in a significant increase in total protein concentration (P?=?0.023). Furthermore, DON had no effect on in vitro growth, alpha toxin production and netB toxin transcription of Clostridium perfringens. In conclusion, feed contamination with DON at concentrations below the European maximum guidance level of 5,000 µg/kg feed, is a predisposing factor for the development of necrotic enteritis in broilers. These results are associated with a negative effect of DON on the intestinal barrier function and increased intestinal protein availability, which may stimulate growth and toxin production of Clostridium perfringens. PMID:25268498

Antonissen, Gunther; Ducatelle, Richard; Haesebrouck, Freddy; Timbermont, Leen; Verlinden, Marc; Janssens, Geert Paul Jules; Eeckhaut, Venessa; Eeckhout, Mia; De Saeger, Sarah; Hessenberger, Sabine; Martel, An; Croubels, Siska

2014-01-01

311

Association between SNPs in genes involved in folate metabolism and preterm birth risk.  

PubMed

We investigated the association between 12 single nucleotide polymorphisms (SNPs) in 11 genes involved in folate metabolic and preterm birth. A subset of SNPs selected from 11 genes/loci involved in the folic acid metabolism pathway were subjected to SNaPshot analysis in a case-control study. Twelve SNPs (CBS-C699T, DHFR-c594+59del19, GST01-C428T, MTHFD-G1958A, MTHFR-C677T, MTHFR-A1298C, MTR-A2756G, MTRR-A66G, NFE2L2-ins1+C11108T, RFC1-G80A, TCN2-C776G, and TYMS-1494del6) in 503 DNA samples were simultaneously tested, and included 315 preterm births and 188 controls. None of the 12 SNP genotype distributions related to the folic acid metabolism pathway showed a significant difference between preterm and term babies. The frequency of the compound mutation genotype of MTHFD-G1958A, MTR-A2756G and RFC1-G80A in preterm babies was 7.3%, which was significantly higher than the 2.7% in term babies. Seven babies carried the compound mutation genotype of MTHFD-G1958A, MTR-A2756G, and CBS-C699T, but this was not observed in term babies. The frequency of the combined wild-type genotype of MTHFD-G1958A, MTR-A2756G, MTRR-A66G, MTHFR-A1298C, NFE2L2-ins1+C11108T, and RFC1- G80A in preterm babies was 3.17%, which was significantly lower than the 7.4% in term babies. The 12 SNPs screened in this study were not independent risk factors of preterm birth. Compound mutation genotypes, including MTHFD-G1958A, MTR-A2756G, and RFC1- G80A and MTHFD-G1958A, MTR-A2756G, and CBS-C699T, may increase the risk of preterm birth. The combined wild-type genotype MTHFD-G1958A, MTR-A2756G, MTRR-A66G, MTHFR-A1298C, NFE2L2-ins1+C11108T, and RFC1-G80A may decrease the risk of preterm birth. PMID:25730024

Wang, B J; Liu, M J; Wang, Y; Dai, J R; Tao, J Y; Wang, S N; Zhong, N; Chen, Y

2015-01-01

312

Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer.  

PubMed

Wnt signaling regulates embryonic pattern formation and morphogenesis of most organs. Aberrations of regulation of Wnt signaling may lead to cancer. Here, we have used positional cloning to identify the causative mutation in a Finnish family in which severe permanent tooth agenesis (oligodontia) and colorectal neoplasia segregate with dominant inheritance. Eleven members of the family lacked at least eight permanent teeth, two of whom developed only three permanent teeth. Colorectal cancer or precancerous lesions of variable types were found in eight of the patients with oligodontia. We show that oligodontia and predisposition to cancer are caused by a nonsense mutation, Arg656Stop, in the Wnt-signaling regulator AXIN2. In addition, we identified a de novo frameshift mutation 1994-1995insG in AXIN2 in an unrelated young patient with severe tooth agenesis. Both mutations are expected to activate Wnt signaling. The results provide the first evidence of the importance of Wnt signaling for the development of dentition in humans and suggest that an intricate control of Wnt-signal activity is necessary for normal tooth development, since both inhibition and stimulation of Wnt signaling may lead to tooth agenesis. Our findings introduce a new gene for hereditary colorectal cancer and suggest that tooth agenesis may be an indicator of cancer susceptibility. PMID:15042511

Lammi, Laura; Arte, Sirpa; Somer, Mirja; Jarvinen, Heikki; Lahermo, Paivi; Thesleff, Irma; Pirinen, Sinikka; Nieminen, Pekka

2004-05-01

313

Functional variations modulating PRKCA expression and alternative splicing predispose to multiple sclerosis.  

PubMed

The protein kinase C alpha (PRKCA) gene, encoding a Th17-cell-selective kinase, was repeatedly associated with multiple sclerosis (MS), but the underlying pathogenic mechanism remains unknown. We replicated the association in Italians (409 cases, 723 controls), identifying a protective signal in the PRKCA promoter (P = 0.033), and a risk haplotype in intron 3 (P = 7.7 × 10(-4); meta-analysis with previously published data: P = 4.01 × 10(-8)). Expression experiments demonstrated that the protective signal is associated with alleles conferring higher PRKCA expression levels, well fitting our observation that MS patients have significantly lower PRKCA mRNA levels in blood. The risk haplotype was shown to be driven by a GGTG ins/del polymorphism influencing the heterogeneous nuclear ribonucleoprotein H-dependent inclusion/skipping of a PRKCA alternative exon 3*. Indeed, exon 3* can be present in two different versions in PRKCA mRNAs (out-of-frame 61 bp or in-frame 66 bp long), and is preferentially included in transcripts generated through a premature polyadenylation event. The GGTG insertion downregulates 3* inclusion and shifts splicing towards the 66 bp isoform. Both events reduce the nonsense-mediated mRNA-decay-induced degradation of exon 3*-containing mRNAs. Since we demonstrated that the protein isoform produced through premature polyadenylation aberrantly localizes to the plasma membrane and/or in cytoplasmic clusters, dysregulated PRKCA 3* inclusion may represent an additional mechanism relevant to MS susceptibility. PMID:25080502

Paraboschi, Elvezia M; Rimoldi, Valeria; Soldà, Giulia; Tabaglio, Tommaso; Dall'Osso, Claudia; Saba, Elena; Vigliano, Marco; Salviati, Alessandro; Leone, Maurizio; Benedetti, Maria D; Fornasari, Diego; Saarela, Janna; De Jager, Philip L; Patsopoulos, Nikolaos A; D'Alfonso, Sandra; Gemmati, Donato; Duga, Stefano; Asselta, Rosanna

2014-12-20

314

Extracellular Matrix Defects in Aneurysmal Fibulin-4 Mice Predispose to Lung Emphysema  

PubMed Central

Background In this study we set out to investigate the clinically observed relationship between chronic obstructive pulmonary disease (COPD) and aortic aneurysms. We tested the hypothesis that an inherited deficiency of connective tissue might play a role in the combined development of pulmonary emphysema and vascular disease. Methods We first determined the prevalence of chronic obstructive pulmonary disease in a clinical cohort of aortic aneurysms patients and arterial occlusive disease patients. Subsequently, we used a combined approach comprising pathological, functional, molecular imaging, immunological and gene expression analysis to reveal the sequence of events that culminates in pulmonary emphysema in aneurysmal Fibulin-4 deficient (Fibulin-4R) mice. Results Here we show that COPD is significantly more prevalent in aneurysm patients compared to arterial occlusive disease patients, independent of smoking, other clinical risk factors and inflammation. In addition, we demonstrate that aneurysmal Fibulin-4R/R mice display severe developmental lung emphysema, whereas Fibulin-4+/R mice acquire alveolar breakdown with age and upon infectious stress. This vicious circle is further exacerbated by the diminished antiprotease capacity of the lungs and ultimately results in the development of pulmonary emphysema. Conclusions Our experimental data identify genetic susceptibility to extracellular matrix degradation and secondary inflammation as the common mechanisms in both COPD and aneurysm formation. PMID:25255451

Ramnath, Natasja W. M.; van de Luijtgaarden, Koen M.; van der Pluijm, Ingrid; van Nimwegen, Menno; van Heijningen, Paula M.; Swagemakers, Sigrid M. A.; van Thiel, Bibi S.; Ridwan, Ruziedi Y.; van Vliet, Nicole; Vermeij, Marcel; Hawinkels, Luuk J. A. C.; de Munck, Anne; Dzyubachyk, Oleh; Meijering, Erik; van der Spek, Peter; Rottier, Robbert; Yanagisawa, Hiromi; Hendriks, Rudi W.; Kanaar, Roland; Rouwet, Ellen V.; Kleinjan, Alex; Essers, Jeroen

2014-01-01

315

Germline SMARCE1 mutations predispose to both spinal and cranial clear cell meningiomas.  

PubMed

We recently reported SMARCE1 mutations as a cause of spinal clear cell meningiomas. Here, we have identified five further cases with non-NF2 spinal meningiomas and six with non-NF2 cranial meningiomas. Three of the spinal cases and three of the cranial cases were clear cell tumours. We screened them for SMARCE1 mutations and investigated copy number changes in all point mutation-negative samples. We identified two novel mutations in individuals with spinal clear cell meningiomas and three mutations in individuals with cranial clear cell meningiomas. Copy number analysis identified a large deletion of the 5' end of SMARCE1 in two unrelated probands with spinal clear cell meningiomas. Testing of affected and unaffected relatives of one of these individuals identified the same deletion in two affected female siblings and their unaffected father, providing further evidence of incomplete penetrance of meningioma disease in males. In addition, we found loss of SMARCE1 protein in three of 10 paraffin-embedded cranial clear cell meningiomas. Together, these results demonstrate that loss of SMARCE1 is relevant to cranial as well as spinal meningiomas. Our study broadens the spectrum of mutations in the SMARCE1 gene and expands the phenotype to include cranial clear cell meningiomas. PMID:25143307

Smith, Miriam J; Wallace, Andrew J; Bennett, Chris; Hasselblatt, Martin; Elert-Dobkowska, Ewelina; Evans, Linton T; Hickey, William F; van Hoff, Jack; Bauer, David; Lee, Amy; Hevner, Robert F; Beetz, Christian; du Plessis, Daniel; Kilday, John-Paul; Newman, William G; Evans, D Gareth

2014-12-01

316

Loci predisposing to autoimmunity in MRL-Fas lpr and C57BL/6-Faslpr mice.  

PubMed Central

Background genes determine the incidence and severity of lymphoaccumulation and histopathologic manifestations of systemic autoimmunity in mice homozygous for the apoptosis-defective Faslpr mutation. By interval mapping of 274 F2 mice intercrossed between MRL-Faslpr (severe disease) and C57BL/6-Faslpr (minimal disease), four loci were identified with significant linkage to lymphadenopathy and/ or splenomegaly on chromosomes 4, 5, 7, and 10, which were named lupus in (MRL-Faslpr x B6-Faslpr)F2 cross1-4 (Lmb1-4), respectively. Lmb1, -2, and -3 were also linked to the production of anti-dsDNA antibodies, but not glomerulonephritis, whereas Lmb4 was associated with glomerulonephritis. Lmb2, -3, and -4 were inherited from the MRL background, but interestingly, Lmb1 was derived from the C57BL16-Faslpr. Nevertheless, each locus, regardless of the strain of origin, appeared to act in an additive manner, although certain combinations were more effective. Only a single suggestive locus on chromosome 1 could be correlated with arthritis. The identification of loci with highly significant linkage to disease manifestations in Faslpr strains will make it possible to map and clone new genetic defects contributing to autoimmunity. PMID:9449705

Vidal, S; Kono, D H; Theofilopoulos, A N

1998-01-01

317

Factor V Leiden mutation is not a predisposing factor for acute coronary syndromes  

PubMed Central

Background The prevalence of Coronary artery disease (CAD) in India has increased considerably over the past few years and could become the number one killer disease if interventions are not done. Factor V Leiden (FVL) mutation and FII G20210A polymorphism are two recently described genetic factors with a propensity towards venous thrombosis. This warrants the investigations for thrombophilia in myocardial infarction patients in India. Methods The study cohort consisted of 51 patients aged below 50 years presenting with acute coronary syndromes. In both patient group and normal individuals the major risk factors Protein C deficiency, Protein S deficiency, anticardiolipin antibodies, Fibrinogen and Lipoprotein [a] were studied. Factor V Leiden (FVL) G1691A mutation in both control and patient group was looked by using Polymerase chain reaction (PCR) followed by sequencing of the PCR products. Results Our results indicated significantly higher levels of anticardiolipin antibodies and fibrinogen in the patients and absence of FVL (G1691A) mutation in our study cohort. One of the patients (H5) showed insertion of an extra A nucleotide in exon 10 of the Factor V gene resulting in frame shift mutation in this patient. Conclusion The results of present study showed absence of FVL mutation in our population. However, there is a need to confirm the above findings on patients from different populations from different parts of the country. The insertion of an extra A in exon 10 in the patient needs to be ascertained to confirm that it is one of its kinds or is prevalent in the population. PMID:23253409

Himabindu, G.; Rajasekhar, D.; Latheef, K.; Sarma, P.V.G.K.; Vanajakshamma, V.; Chaudhury, Abhijit; Bitla, Aparna R.

2012-01-01

318

Characterization of a naturally-occurring p27 mutation predisposing to multiple endocrine tumors  

PubMed Central

Background p27Kip1 (p27) is an important negative regulator of the cell cycle and a putative tumor suppressor. The finding that a spontaneous germline frameshift mutation in Cdkn1b (encoding p27) causes the MENX multiple endocrine neoplasia syndrome in the rat provided the first evidence that Cdkn1b is a tumor susceptibility gene for endocrine tumors. Noteworthy, germline p27 mutations were also identified in human patients presenting with endocrine tumors. At present, it is not clear which features of p27 are crucial for this tissue-specific tumor predisposition in both rats and humans. It was shown that the MENX-associated Cdkn1b mutation causes reduced expression of the encoded protein, but the molecular mechanisms are unknown. To better understand the role of p27 in tumor predisposition and to characterize the MENX animal model at the molecular level, a prerequisite for future preclinical studies, we set out to assess the functional properties of the MENX-associated p27 mutant protein (named p27fs177) in vitro and in vivo. Results In vitro, p27fs177 retains some properties of the wild-type p27 (p27wt) protein: it localizes to the nucleus; it interacts with cyclin-dependent kinases and, to lower extent, with cyclins. In contrast to p27wt, p27fs177 is highly unstable and rapidly degraded in every phase of the cell-cycle, including quiescence. It is in part degraded by Skp2-dependent proteasomal proteolysis, similarly to p27wt. Photobleaching studies showed reduced motility of p27fs177 in the nucleus compared to p27wt, suggesting that in this compartment p27fs177 is part of a multi-protein complex, likely together with the degradation machinery. Studies of primary rat newborn fibroblasts (RNF) established from normal and MENX-affected littermates confirmed the rapid degradation of p27fs177 in vivo which can be rescued by Bortezomib (proteasome inhibitor drug). Overexpression of the negative regulators microRNA-221/222 plays no role in regulating the amount of p27fs177 in RNFs and rat tissues. Conclusion Our findings show that reduced p27 levels, not newly acquired properties, trigger tumor formation in rats, similarly to what has been observed in mice. The molecular characteristics of p27fs177 establish MENX as a useful preclinical model to evaluate compounds that inhibit p27 degradation for their efficacy against endocrine tumors. PMID:20492666

2010-01-01

319

Predisposing and Enabling Factors Associated with Mammography Use among Hispanic and Non-Hispanic White Women Living in a Rural Area  

ERIC Educational Resources Information Center

Context: Women who do not receive regular mammograms are more likely than others to have breast cancer diagnosed at an advanced stage. Purpose: To examine predisposing and enabling factors associated with mammography use among Hispanic and non-Hispanic White women. Methods: Baseline data were used from a larger study on cancer prevention in rural…

Tejeda, Silvia; Thompson, Beti; Coronado, Gloria D.; Martin, Diane P.; Heagerty, Patrick J.

2009-01-01

320

An objective method to rank the importance of the factors predisposing to landslides with the GIS methodology: application to an area of the Apennines (Valnerina; Perugia, Italy)  

Microsoft Academic Search

The present work aims at contributing to further our knowledge on the predisposing factors to landslides as well as proposing a method that allows us to weigh up, as objectively as possible, the influence that the various factors have on landslides in order to construct a realistic map of potential landslide hazards. In order to assess the differential incidence of

L Donati; M. C Turrini

2002-01-01

321

Impact of predisposing, enabling, and need factors in accessing preventive medical care among U.S. children: results of the national survey of children's health  

Microsoft Academic Search

BACKGROUND: Preventive care in the United States has been a priority, especially for children under 18 years of age. The objective of this analysis was to determine which predisposing, enabling, and need factors affect access to preventive health care for children. METHODS: Data were obtained from the National Survey of Children's Health (NSCH), a cross-sectional study of children in the

Ka-Ming Lo; Kimberly G Fulda

2008-01-01

322

Examining the Diet of Post-Migrant Hispanic Males Using the Precede-Proceed Model: Predisposing, Reinforcing, and Enabling Dietary Factors  

ERIC Educational Resources Information Center

Objective: To examine socio-environmental, behavioral, and predisposing, reinforcing, and enabling (PRE) factors contributing to post-migration dietary behavior change among a sample of traditional Hispanic males. Design: In this descriptive study, semistructured interviews, a group interview, and photovoice, followed by group interviews, were…

Castellanos, Diana Cuy; Downey, Laura; Graham-Kresge, Susan; Yadrick, Kathleen; Zoellner, Jamie; Connell, Carol L.

2013-01-01

323

Methylenetetrahydrofolate reductase gene A1298C polymorphism in pediatric stroke--case-control and family-based study.  

PubMed

Moderate hyperhomocysteinemia is one of the risk factors of pediatric stroke. Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme, which regulates homocysteine metabolism, and some polymorphisms of gene encoding this enzyme are associated with a decreased activity of the enzyme. The aim of the study was to assess an association between the A1298C polymorphism and pediatric stroke. We also evaluated a possible synergistic effect of A1298C and C677T polymorphisms of this gene. The study group consisted of 88 children after ischemic stroke, 142 of their parents and 111 controls. The A1298C polymorphism was genotyped using the restriction fragment length polymorphism method. We used 2 study designs: a case-control model and a family-based association test. The Statistica 7.1 and EpiInfo 6 softwares were used in all analyses. We did not observe any statistically significant differences either in the transmission of the A allele in the family-based test or in the frequency of the A allele in the patients group compared with the controls. We also did not notice any significant additive or synergistic effects between the A1298C and C677T polymorphisms. An analysis of the results obtained in this study and a critical review of previously published studies indicate that the A1298C polymorphism of the MTHFR gene is not related to ischemic stroke in children. PMID:25440348

Balcerzyk, Anna; Niemiec, Pawe?; Kopyta, Ilona; Emich-Widera, Ewa; Pilarska, Ewa; Pienczk-R?c?awowicz, Karolina; Kaci?ski, Marek; Wendorff, Janusz; ?ak, Iwona

2015-01-01

324

Folate pathway gene alterations in patients with neural tube defects.  

PubMed

Periconceptional folate supplementation reduces the recurrence and occurrence risk of neural tube defects (NTD) by as much as 70%, yet the protective mechanism remains unknown. Inborn errors of folate and homocysteine metabolism may be involved in the aetiology of NTDs. Previous studies have demonstrated that both homozygosity for the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene, and combined heterozygosity for the C677T and for another mutation in the same gene, the A1298C polymorphism, represent genetic risk factors for NTDs. In an attempt to identify additional folate related genes that contribute to NTD pathogenesis, we performed molecular genetic analysis of folate receptors (FRs). We identified 4 unrelated patients out of 50 with de novo insertions of pseudogene (PS)-specific mutations in exon 7 and 3'UTR of the FRalpha gene, arising by microconversion events. All of the substitutions affect the carboxy-terminal amino acid membrane tail, or the GPI anchor region of the nascent protein. Furthermore, among 150 control individuals, we also identified one infant with a gene conversion event within the FRalpha coding region. This study, though preliminary, provides the first genetic association between molecular variations of the FRalpha gene and NTDs and suggests that this gene can act as a risk factor for human NTD. PMID:11102926

De Marco, P; Moroni, A; Merello, E; de Franchis, R; Andreussi, L; Finnell, R H; Barber, R C; Cama, A; Capra, V

2000-11-27

325

Compound heterozygosity for the C677T and A1298C mutations of the MTHFR gene in a case of hyperhomocysteinemia with recurrent deep thrombosis at young age.  

PubMed

We report a case of a young woman with an extensive, recurrent deep vein thrombosis (DVT) diagnosed by CT scan and duplex ultrasound examination. All blood investigations for etiology of recurrent DVT were normal except for serum homocysteine level, which was mildly increased. No other thrombophilic factors could be found. The three main causes of hyperhomocysteinemia are genetic defects, nutritional deficiencies and insufficient elimination. In our case a genetic defect for one of the key enzymes of homocysteine metabolism was found to be the underlying cause. Oral anticoagulation and supplementation with pyridoxine, cyanocobalamine and folate was recommended. Whether therapy with B vitamins and folate can substantially reduce the recurrence of venous thromboembolic disease remains to be established. PMID:19366086

Jurcu?, Ruxandra; Pop, Ioana; Coriu, D; Grasu, M; Zili?teanu, Diana; Giu?c?, S; Ginghin?, Carmen

2008-01-01

326

Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms.  

PubMed

Clonal proliferation in myeloproliferative neoplasms (MPN) is driven by somatic mutations in JAK2, CALR or MPL, but the contribution of inherited factors is poorly characterized. Using a three-stage genome-wide association study of 3,437 MPN cases and 10,083 controls, we identify two SNPs with genome-wide significance in JAK2(V617F)-negative MPN: rs12339666 (JAK2; meta-analysis P=1.27 × 10(-10)) and rs2201862 (MECOM; meta-analysis P=1.96 × 10(-9)). Two additional SNPs, rs2736100 (TERT) and rs9376092 (HBS1L/MYB), achieve genome-wide significance when including JAK2(V617F)-positive cases. rs9376092 has a stronger effect in JAK2(V617F)-negative cases with CALR and/or MPL mutations (Breslow-Day P=4.5 × 10(-7)), whereas in JAK2(V617F)-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic ?(2) P=7.3 × 10(-7)). Reduced MYB expression, previously linked to development of an ET-like disease in model systems, associates with rs9376092 in normal myeloid cells. These findings demonstrate that multiple germline variants predispose to MPN and link constitutional differences in MYB expression to disease phenotype. PMID:25849990

Tapper, William; Jones, Amy V; Kralovics, Robert; Harutyunyan, Ashot S; Zoi, Katerina; Leung, William; Godfrey, Anna L; Guglielmelli, Paola; Callaway, Alison; Ward, Daniel; Aranaz, Paula; White, Helen E; Waghorn, Katherine; Lin, Feng; Chase, Andrew; Joanna Baxter, E; Maclean, Cathy; Nangalia, Jyoti; Chen, Edwin; Evans, Paul; Short, Michael; Jack, Andrew; Wallis, Louise; Oscier, David; Duncombe, Andrew S; Schuh, Anna; Mead, Adam J; Griffiths, Michael; Ewing, Joanne; Gale, Rosemary E; Schnittger, Susanne; Haferlach, Torsten; Stegelmann, Frank; Döhner, Konstanze; Grallert, Harald; Strauch, Konstantin; Tanaka, Toshiko; Bandinelli, Stefania; Giannopoulos, Andreas; Pieri, Lisa; Mannarelli, Carmela; Gisslinger, Heinz; Barosi, Giovanni; Cazzola, Mario; Reiter, Andreas; Harrison, Claire; Campbell, Peter; Green, Anthony R; Vannucchi, Alessandro; Cross, Nicholas C P

2015-01-01

327

Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms  

PubMed Central

Clonal proliferation in myeloproliferative neoplasms (MPN) is driven by somatic mutations in JAK2, CALR or MPL, but the contribution of inherited factors is poorly characterized. Using a three-stage genome-wide association study of 3,437 MPN cases and 10,083 controls, we identify two SNPs with genome-wide significance in JAK2V617F-negative MPN: rs12339666 (JAK2; meta-analysis P=1.27 × 10?10) and rs2201862 (MECOM; meta-analysis P=1.96 × 10?9). Two additional SNPs, rs2736100 (TERT) and rs9376092 (HBS1L/MYB), achieve genome-wide significance when including JAK2V617F-positive cases. rs9376092 has a stronger effect in JAK2V617F-negative cases with CALR and/or MPL mutations (Breslow–Day P=4.5 × 10?7), whereas in JAK2V617F-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic ?2 P=7.3 × 10?7). Reduced MYB expression, previously linked to development of an ET-like disease in model systems, associates with rs9376092 in normal myeloid cells. These findings demonstrate that multiple germline variants predispose to MPN and link constitutional differences in MYB expression to disease phenotype. PMID:25849990

Tapper, William; Jones, Amy V.; Kralovics, Robert; Harutyunyan, Ashot S.; Zoi, Katerina; Leung, William; Godfrey, Anna L.; Guglielmelli, Paola; Callaway, Alison; Ward, Daniel; Aranaz, Paula; White, Helen E.; Waghorn, Katherine; Lin, Feng; Chase, Andrew; Joanna Baxter, E.; Maclean, Cathy; Nangalia, Jyoti; Chen, Edwin; Evans, Paul; Short, Michael; Jack, Andrew; Wallis, Louise; Oscier, David; Duncombe, Andrew S.; Schuh, Anna; Mead, Adam J.; Griffiths, Michael; Ewing, Joanne; Gale, Rosemary E.; Schnittger, Susanne; Haferlach, Torsten; Stegelmann, Frank; Döhner, Konstanze; Grallert, Harald; Strauch, Konstantin; Tanaka, Toshiko; Bandinelli, Stefania; Giannopoulos, Andreas; Pieri, Lisa; Mannarelli, Carmela; Gisslinger, Heinz; Barosi, Giovanni; Cazzola, Mario; Reiter, Andreas; Harrison, Claire; Campbell, Peter; Green, Anthony R.; Vannucchi, Alessandro; Cross, Nicholas C.P.

2015-01-01

328

A structural bioinformatics approach for identifying proteins predisposed to bind linear epitopes on pre-selected target proteins.  

PubMed

We have developed a protocol for identifying proteins that are predisposed to bind linear epitopes on target proteins of interest. The protocol searches through the protein database for proteins (scaffolds) that are bound to peptides with sequences similar to accessible, linear epitopes on the target protein. The sequence match is considered more significant if residues calculated to be important in the scaffold-peptide interaction are present in the target epitope. The crystal structure of the scaffold-peptide complex is then used as a template for creating a model of the scaffold bound to the target epitope. This model can then be used in conjunction with sequence optimization algorithms or directed evolution methods to search for scaffold mutations that further increase affinity for the target protein. To test the applicability of this approach we targeted three disease-causing proteins: a tuberculosis virulence factor (TVF), the apical membrane antigen (AMA) from malaria, and hemagglutinin from influenza. In each case the best scoring scaffold was tested, and binders with Kds equal to 37 ?M and 50 nM for TVF and AMA, respectively, were identified. A web server (http://rosettadesign.med.unc.edu/scaffold/) has been created for performing the scaffold search process with user-defined target sequences. PMID:23341643

Choi, Eun Jung; Jacak, Ron; Kuhlman, Brian

2013-04-01

329

Chronic stress exposure may affect the brain's response to high calorie food cues and predispose to obesogenic eating habits.  

PubMed

Exaggerated reactivity to food cues involving calorically-dense foods may significantly contribute to food consumption beyond caloric need. Chronic stress, which can induce palatable "comfort" food consumption, may trigger or reinforce neural pathways leading to stronger reactions to highly rewarding foods. We implemented functional magnetic resonance imaging (fMRI) to assess whether chronic stress influences activation in reward, motivation and executive brain regions in response to pictures of high calorie and low calorie foods in thirty women. On separate lab visits, we also assessed food intake from a snack food buffet and circulating cortisol. In women reporting higher chronic stress (HCS), pictures of high calorie foods elicited exaggerated activity in regions of the brain involving reward, motivation, and habitual decision-making. In response to pictures of high calorie food, higher chronic stress was also associated with significant deactivation in frontal regions (BA10; BA46) linked to strategic planning and emotional control. In functional connectivity analysis, HCS strengthened connectivity between amygdala and the putamen, while LCS enhanced connectivity between amygdala and the anterior cingulate and anterior prefrontal cortex (BA10). A hypocortisolemic signature and more consumption of high calorie foods from the snack buffet were observed in the HCS group. These results suggest that persistent stress exposure may alter the brain's response to food in ways that predispose individuals to poor eating habits which, if sustained, may increase risk for obesity. PMID:23954410

Tryon, Matthew S; Carter, Cameron S; Decant, Rashel; Laugero, Kevin D

2013-08-15

330

Druggable Protein Interaction Sites Are More Predisposed to Surface Pocket Formation than the Rest of the Protein Surface  

PubMed Central

Despite intense interest and considerable effort via high-throughput screening, there are few examples of small molecules that directly inhibit protein-protein interactions. This suggests that many protein interaction surfaces may not be intrinsically “druggable” by small molecules, and elevates in importance the few successful examples as model systems for improving our fundamental understanding of druggability. Here we describe an approach for exploring protein fluctuations enriched in conformations containing surface pockets suitable for small molecule binding. Starting from a set of seven unbound protein structures, we find that the presence of low-energy pocket-containing conformations is indeed a signature of druggable protein interaction sites and that analogous surface pockets are not formed elsewhere on the protein. We further find that ensembles of conformations generated with this biased approach structurally resemble known inhibitor-bound structures more closely than equivalent ensembles of unbiased conformations. Collectively these results suggest that “druggability” is a property encoded on a protein surface through its propensity to form pockets, and inspire a model in which the crude features of the predisposed pocket(s) restrict the range of complementary ligands; additional smaller conformational changes then respond to details of a particular ligand. We anticipate that the insights described here will prove useful in selecting protein targets for therapeutic intervention. PMID:23505360

Johnson, David K.; Karanicolas, John

2013-01-01

331

Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia  

Microsoft Academic Search

Autism spectrum disorder (ASD) and schizophrenia (SCZ) are two common neurodevelopmental syndromes that result from the combined effects of environmental and genetic factors. We set out to test the hypothesis that rare variants in many different genes, including de novo variants, could predispose to these conditions in a fraction of cases. In addition, for both disorders, males are either more

A Piton; J Gauthier; F F Hamdan; R G Lafrenière; Y Yang; E Henrion; S Laurent; A Noreau; P Thibodeau; L Karemera; D Spiegelman; F Kuku; J Duguay; L Destroismaisons; P Jolivet; M Côté; K Lachapelle; O Diallo; A Raymond; C Marineau; N Champagne; L Xiong; C Gaspar; J-B Rivière; J Tarabeux; P Cossette; M-O Krebs; J L Rapoport; A Addington; L E DeLisi; L Mottron; R Joober; E Fombonne; P Drapeau; G A Rouleau; GA Rouleau

2011-01-01

332

Quantification of key red blood cell folates from subjects with defined MTHFR 677C>T genotypes using stable isotope dilution liquid chromatography/mass spectrometry  

PubMed Central

Red blood cell (RBC) folate levels are established at the time of erythropoiesis and therefore provide a surrogate biomarker for the average folate status of an individual over the preceding four months. Folates are present as folylpolyglutamates, highly polar molecules that cannot be secreted from the RBCs, and must be converted into their monoglutamate forms prior to analysis. This was accomplished using an individual’s plasma pteroylpolyglutamate hydrolase by lysing the RBCs in whole blood at pH 5 in the presence of ascorbic acid. Quantitative conversion of formylated tetrahydrofolate derivatives into the stable 5,10-methenyltetrahydrofolate (5,10-MTHF) form was conducted at pH 1.5 in the presence of [13C5]-5-formyltetrahydrofolate. The resulting [13C5]-5,10-MTHF was then used as an internal standard for the formylated forms of tetrahydrofolate that had been converted into 5,10-MTHF as well any 5,10-MTHF that had been present in the original sample. A stable isotope dilution liquid chromatography-multiple reaction monitoring/mass spectrometry method was validated and then used for the accurate and precise quantification of RBC folic acid, 5-methyltetrahydrofolate (5-MTHF), tetrahydrofolate (THF), and 5,10-MTHF. The method was sensitive and robust and was used to assess the relationship between different methylenetetrahydrofolate reductase (MTHFR) 677C>T genotypes and RBC folate phenotypes. Four distinct RBC folate phenotypes could be identified. These were classified according to the relative amounts of individual RBC folates as type I (5-MTHF >95%; THF <5%; 5,10-MTHF <5%), type II (5-MTHF <95%; THF 5% to 20%; 5,10-MTHF <5%), type III (5-MTHF >55%; THF >20%; 5,10-MTHF >5%), and type IV (5-MTHF <55%; THF >20%; 5,10-MTHF >5%). PMID:18634122

Huang, Yuehua; Khartulyari, Stefanie; Morales, Megan E.; Stanislawska-Sachadyn, Anna; Von Feldt, Joan M.; Whitehead, Alexander S.; Blair, Ian A.

2014-01-01

333

A Systematic Review of Meta-Analyses on Gene Polymorphisms and Gastric Cancer Risk  

PubMed Central

Background Individual variations in gastric cancer risk have been associated in the last decade with specific variant alleles of different genes that are present in a significant proportion of the population. Polymorphisms may modify the effects of environmental exposures, and these gene-environment interactions could partly explain the high variation of gastric cancer incidence around the world. The aim of this report is to carry out a systematic review of the published meta-analyses of studies investigating the association between gene polymorphisms and gastric cancer risk, and describe their impact at population level. Priorities on the design of further primary studies are then provided. Methods A structured bibliographic search on Medline and EMBASE databases has been performed to identify meta-analyses on genetic susceptibility to gastric cancer, without restriction criteria. We report the main results of the meta-analyses and we describe the subgroup analyses performed, focusing on the detection of statistical heterogeneity. We investigated publication bias by pooling the primary studies included in the meta-analyses, and we computed the population attributable risk (PAR) for each polymorphism. Results Twelve meta-analyses and one pooled-analysis of community based genetic association studies were included, focusing on nine genes involved in inflammation (IL-1?, IL-1RN, IL-8), detoxification of carcinogens (GSTs, CYP2E1), folate metabolism (MTHFR), intercellular adhesion (E-cadherin) and cell cycle regulation (p53). According to their random-Odds Ratios, individuals carrying one of the IL-1RN *2, IL-1? -511T variant alleles or homozygotes for MTHFR 677T are significantly at higher risk of gastric cancer than those with the wild type homozygote genotypes, showing high PARs. The main sources of heterogeneity in the meta-analyses were ethnicity, quality of the primary study, and selected environmental co-exposures. Effect modification by Helicobacter pylori infection for subjects carrying the unfavourable variant of IL-1 polymorphisms and by low folate intake for individuals homozygotes for MTHFR 677T allele has been reported, while genes involved in the detoxification of carcinogens show synergistic interactions. Publication bias was observed (Egger test, p = 0.03). Discussion The published meta-analyses included in our systematic review focused on polymorphisms having a small effect in increasing gastric cancer risk per se. Nevertheless, the risk increase by interacting with environmental exposures and in combination with additional unfavourable polymorphisms. Unfortunately meta-analyses are underpowered for many subgroup analyses, so additional primary studies performed on larger population and collecting data on environmental and genetic co-exposures are demanded. PMID:19506726

Gianfagna, Francesco; De Feo, Emma; van Duijn, Cornelia M; Ricciardi, Gualtiero; Boccia, Stefania

2008-01-01

334

[Associations of human leukocyte antigen-A, B, DRB1 genes with leukemia patients in Anhui province of China].  

PubMed

This study was aimed to investigate the relation of human leukocyte antigen-A, B, DRB1 genes with the susceptibility of population to leukemia in Anhui province of China. The HLA genotypes were analyzed by PCR-SSP in 140 patients with chronic myelocytic leukemia (CML), 84 patients with acute lymphoblastic leukemia (ALL), 90 patients with acute nonlymphocytic leukemia (ANLL) and 916 healthy unrelated donors of hematopoietic stem cell as normal control admitted to Anhui provincial hospital. The gene frequencies of HLA-A, B, DRB1 between patients and normal controls were compared, chi² test was used for statistical analysis. The results showed that as compared with normal controls, the gene frequencies of A2, A11, B58 and DR9 in CML patients all obviously increased, and gene frequency of DR7 decreased; the gene frequencies of All and B13 in ALL patients were significantly higher than that in normal controls; the gene frequencies of A24, B58 and DR9 in ANLL patients were significantly higher than that in normal controls. It is concluded that HLA-A2, A11, B58 and DR9 are predisposing genes of CML patients, DR7 is an antagonistic gene, HLA-A11 and B13 are predisposing genes of ALL patients, HLA-A24, B58 and DR9 are predisposing genes of ANLL patients. PMID:20723328

Liao, Yan-Qiu; Zhu, Mei-Hong; Wang, Min; Jiang, Guang-Ming; Wang, Bao-Long

2010-08-01

335

Pitx2, an Atrial Fibrillation Predisposition Gene, Directly Regulates Ion Transport and Intercalated Disc Genes  

PubMed Central

Background Pitx2 is the homeobox gene located in proximity to the human 4q25 familial atrial fibrillation locus. When deleted in the mouse germline, Pitx2 haploinsufficiency predisposes to pacing induced atrial fibrillation indicating that reduced Pitx2 promotes an arrhythmogenic substrate. Previous work focused on Pitx2 developmental functions that predispose to atrial fibrillation. Although Pitx2 is expressed in postnatal left atrium, it is unknown whether Pitx2 has distinct postnatal and developmental functions. Methods and Results To investigate Pitx2 postnatal function, we conditionally inactivated Pitx2 in the postnatal atrium while leaving its developmental function intact. Unstressed adult Pitx2 homozygous mutant mice display variable R-R interval with diminished P-wave amplitude characteristic of sinus node dysfunction, an atrial fibrillation risk factor in human patients. An integrated genomics approach in the adult heart revealed Pitx2 target genes encoding cell junction proteins, ion channels, and critical transcriptional regulators. Importantly, many Pitx2 target genes have been implicated in human atrial fibrillation by genome wide association studies. Immunofluorescence and transmission electron microscopy studies in adult Pitx2 mutant mice revealed structural remodeling of the intercalated disc characteristic of human atrial fibrillation patients. Conclusions Our findings, revealing that Pitx2 has genetically separable postnatal and developmental functions, unveil direct Pitx2 target genes that include channel and calcium handling genes as well as genes that stabilize the intercalated disc in postnatal atrium. PMID:24395921

Tao, Ye; Zhang, Min; Li, Lele; Bai, Yan; Zhou, Yuefang; Moon, Anne M.; Kaminski, Henry J.; Martin, James F.

2014-01-01

336

Polymorphisms in folate-metabolizing genes and risk of non-Hodgkin's lymphoma.  

PubMed

We investigated the role of single nucleotide polymorphisms (SNPs) in the folate-metabolizing genes MTHFR, MTR, MTRR, MTHFD, CBS and SHMT in regulating genetic susceptibility to Non-Hodgkin's lymphoma (NHL). We determined the allele and genotype frequencies in the case group (146 patients with NHL) and the control group (540 blood donors). A significant association with NHL was observed only for MTHFD1 G1958A (allele G OR=1.382, P=0.05; genotype GA OR=2.316, P=0.01; genotype GG OR=2.153, P=0.03). After additional stratification of case and control groups according to sex and tumor type association of MTHFD1 G1958A with NHL was observed only in high-grade NHL subgroup (allele G OR=1.664, P=0.01) and in women subgroup (allele G OR=2.043, P=0.009). Meta-analysis for SNPs in the MTHFR, MTR, MTRR and SHMT revealed a reducing effect of the MTR 2756G allele on the risk of NHL (OR=0.902; 95% CI 0.821-0.991, P=0.03). PMID:21055808

Weiner, Alexandra S; Beresina, Olga V; Voronina, Elena N; Voropaeva, Elena N; Boyarskih, Uljana A; Pospelova, Tatiana I; Filipenko, Maxim L

2011-04-01

337

Genetic Association between Methylenetetrahydrofolate Reductase Gene Polymorphism and Risk of Osteonecrosis of the Femoral Head  

PubMed Central

Background. Methylenetetrahydrofolate reductase (MTHFR) SNP rs1801133 has been frequently investigated in recent years. Relevant candidate gene association studies with this SNP and osteonecrosis of the femoral head (ONFH) reported conflicting results. Meta-analysis provides a method to combine these data and to determine the association in a larger sample size. Method. We conducted a systematic search to identify possible studies. Four pooled ORs (odds ratios, T versus C, TT versus CC, TT/CT versus CC, and TT versus CT/CC), along with 95% confidence interval (CI), were calculated to evaluate the association between SNP rs1801133 and ONFH susceptibility. Both fixed effects model and random effects model were used. Findings. We eventually included twelve studies in this analysis, with results showing no overall association between ONFH susceptibility and SNP rs1801133 (T versus C: OR = 1.15, 95% CI = 0.97–1.38; TT versus CC: OR = 1.15, 95% CI = 0.91–1.46; TT/CT versus CC: OR = 1.09, 95% CI = 0.95–1.25; and TT versus CT/CC: OR = 1.16, 95% CI = 0.93–1.45). When stratified based on ethnicity, the results were still not significant. Conclusion. Our findings are generally supportive of no association between MTHFR SNP rs1801133 and the etiology of ONFH. PMID:25688352

Chai, Wei; Zhang, Zhendong; Ni, Ming; Geng, Peiliang; Lian, Zijian; Zhang, Guoqiang; Shi, Lewis L.; Chen, Jiying

2015-01-01

338

Genes and Gene Therapy  

MedlinePLUS

... correctly, a child can have a genetic disorder. Gene therapy is an experimental technique that uses genes to ... or prevent disease. The most common form of gene therapy involves inserting a normal gene to replace an ...

339

Predisposing trees to die during drought: How physiology and climate history influence mortality in southwestern U.S. piñon pine  

NASA Astrophysics Data System (ADS)

Detailed physical and chemical studies of trees that die and survive during drought provide insight into the historic conditions and physiological mechanisms that underpin episodes of tree mortality. We seek to deduce key physiological parameters that influenced the mortality and survival of piñon pine (Pinus edulis) during relatively warmer (2000's) and cooler (1950's) droughts in the southwestern U.S. Using recently sampled and archived tree-ring specimens of trees that died and survived during the 2000's and 1950's droughts, we constructed time series from two measurements that serve as integrated parameters of whole-tree physiological function: radial growth and stable carbon isotope ratios (?13C) in tree-ring cellulose. We focused our efforts on addressing two hypotheses: 1) piñon trees that died had hydraulic characteristics that predisposed them to succumb to drought and associated bark beetle outbreaks through either hydraulic failure or carbon starvation; 2) dead tree growth and ?13C should be more responsive to climate than surviving trees if drought and temperature driven stress are the ultimate drivers of tree death. We further hypothesize that if dying trees respond to drought by closing their stomata to avoid hydraulic failure, they limit their ability to photosynthesize and should exhibit lower growth and more positive ?13C than trees that survive. Conversely, if trees that died maintained relatively open stomata and succumbed to drought via hydraulic failure, they should exhibit more negative ?13C than trees that survive. Leading up to the 2000's drought, growth in trees that died was lower than in surviving trees, consistent with our expectation. ?13C in trees that died was more negative than in surviving trees but both growth and ?13C of trees that died were less responsive to climate than surviving trees, counter to our initial hypotheses. Our ?13C results are consistent with the hypothesis that the trees that died maintained higher stomatal conductance during drought and hence ran a greater risk of hydraulic failure than trees that survived. An alternative hypothesis is that trees that died had lower leaf area per unit root area, which could also explain higher growth in surviving trees. However, this explanation is inconsistent with previous published results on leaf area of piñon pines that died and survived during the 2000's drought. Notably, tree growth data extending back further in time reveals that growth of live and dead trees was similar until the 1950's drought, when growth trajectories diverged. The mechanism underlying this growth divergence is not yet clear, but this result suggests an important role of previous droughts in predisposing trees to die during subsequent droughts. This raises the possibility of increased future mortality if drought frequency increases even in the absence of changes in drought severity. We are currently expanding our analyses to trees that died and survived across multiple sites covering both the 2000's and the 1950's drought, which will allow us to compare mortality mechanisms across landscapes and between droughts of different magnitudes and temperature profiles.

Macalady, A. K.; English, N. B.; McDowell, N. G.; Swetnam, T. W.

2011-12-01

340

Molecular analysis of a family with three cases of first cousins with free trisomy 21 excludes the existence of a familial predisposing factor for nondisjunction  

SciTech Connect

We have studied a French family with three individuals, paternally related first cousins, that presented free and complete trisomy 21. Using short sequence repeat polymorphisms from chromosome 21, we analyzed the DNA of two of the three affected individuals that were available. We determined the parental origin of the supernumerary chromosome in both cases. The trisomy in these cases was found to be due to maternal meiotic errors. Since the individuals were related through their paternal grandparents (their fathers were siblings) we conclude that the recurrence of trisomy 21 in this family is a result of chance and is not due to any possible genetic predisposing factors. This is in accordance with previous results on recurrent trisomy 21 families, where predisposing factors were also often excluded through the same kind of analysis.

Girginoudis, P.; Avramopoulos, D. [Diagnostic Genetic Center, Athens (Greece); Robert, E. [Institut Europeen des Genomutations, Lyon (France)] [and others

1994-09-01

341

Hormonal regulation of energy-protein homeostasis in hemodialysis patients: an anorexigenic profile that may predispose to adverse cardiovascular outcomes  

PubMed Central

To assess whether endocrine dysfunction may cause derangement in energy homeostasis in patients undergoing hemodialysis (HD), we profiled hormones, during a 3-day period, from the adipose tissue and the gut and the nervous system around the circadian clock in 10 otherwise healthy HD patients and 8 normal controls. The protocol included a 40-h fast. We also measured energy-protein intake and output and assessed appetite and body composition. We found many hormonal abnormalities in HD patients: 1) leptin levels were elevated, due, in part, to increased production, and nocturnal surge in response to daytime feeding, exaggerated. 2) Peptide YY (PYY), an anorexigenic gut hormone, was markedly elevated and displayed an augmented response to feeding. 3) Acylated ghrelin, an orexigenic gut hormone, was lower and did not exhibit the premeal spike as observed in the controls. 4) neuropeptide Y (NPY), a potent orexigenic peptide, was markedly elevated and did not display any circadian variation. 5) Norepinephrine, marginally elevated, did not exhibit the normal nocturnal dip. By contrast, ?-melanocyte-stimulating hormone and glucagon-like peptide-1 were not different between the two groups. Despite these hormonal abnormalities, HD patients maintained a good appetite and had normal body lean and fat mass, and there was no evidence of increased energy expenditure or protein catabolism. We explain the hormonal abnormalities as well as the absence of anorexia on suppression of parasympathetic activity (vagus nerve dysfunction), a phenomenon well documented in dialysis patients. Unexpectedly, we noted that the combination of high leptin, PYY, and NPY with suppressed ghrelin may increase arterial blood pressure, impair vasodilatation, and induce cardiac hypertrophy, and thus could predispose to adverse cardiovascular events that are the major causes of morbidity and mortality in the HD population. This is the first report attempting to link hormonal abnormalities associated with energy homeostasis to adverse cardiovascular outcome in the HD patients. PMID:20959536

Suneja, Manish; Murry, Daryl J.; Stokes, John B.

2011-01-01

342

5?-Reductase type 1 deficiency or inhibition predisposes to insulin resistance, hepatic steatosis, and liver fibrosis in rodents.  

PubMed

5?-Reductase type 1 (5?R1) catalyses A-ring reduction of androgens and glucocorticoids in liver, potentially influencing hepatic manifestations of the metabolic syndrome. Male mice, homozygous for a disrupted 5?R1 allele (5?R1 knockout [KO] mice), were studied after metabolic (high-fat diet) and fibrotic (carbon tetrachloride [CCl4]) challenge. The effect of the 5?-reductase inhibitor finasteride on metabolism was investigated in male obese Zucker rats. While eating a high-fat diet, male 5?R1-KO mice demonstrated greater mean weight gain (21.6 ± 1.4 vs 16.2 ± 2.4 g), hyperinsulinemia (insulin area under the curve during glucose tolerance test 609 ± 103 vs. 313 ± 66 ng ? mL(-1) ? min), and hepatic steatosis (liver triglycerides 136.1 ± 17.0 vs. 89.3 ± 12.1 ?mol ? g(-1)). mRNA transcript profiles in liver were consistent with decreased fatty acid ?-oxidation and increased triglyceride storage. 5?R1-KO male mice were more susceptible to fibrosis after CCl4 administration (37% increase in collagen staining). The nonselective 5?-reductase inhibitor finasteride induced hyperinsulinemia and hepatic steatosis (10.6 ± 1.2 vs. 7.0 ± 1.0 ?mol ? g(-1)) in obese male Zucker rats, both intact and castrated. 5?R1 deficiency induces insulin resistance and hepatic steatosis, consistent with the intrahepatic accumulation of glucocorticoids, and predisposes to hepatic fibrosis. Hepatic steatosis is independent of androgens in rats. Variations in 5?R1 activity in obesity and with nonselective 5?-reductase inhibition in men with prostate disease may have important consequences for the onset and progression of metabolic liver disease. PMID:25239636

Livingstone, Dawn E W; Barat, Pascal; Di Rollo, Emma M; Rees, Georgina A; Weldin, Benjamin A; Rog-Zielinska, Eva A; MacFarlane, David P; Walker, Brian R; Andrew, Ruth

2015-02-01

343

Prevalence of prothrombin G20210A, factor V G1691A (Leiden), and methylenetetrahydrofolate reductase (MTHFR) C677T in seven different populations determined by multiplex allele-specific PCR.  

PubMed

Individuals belonging to six racial groups (African American, Asian Indian, Caucasian, Hispanic, Korean, Native American), and a seventh group comprised of referred patients with thrombosis were genotyped for the prothrombin G20210A mutation, the factor V G1691A (Leiden) mutation, and the methylenetetrahydrofolate reductase (MTHFR) C677T mutation by multiplexed allele-specific PCR. The prothrombin 20210A and factor V 1691A allele frequencies in the thrombosis patients, 3.2% and 9.5%, were significantly higher than those in the random Caucasians, 1.3% and 1.8%, (p = 0.043 and p <0.001, respectively). The relative risk of venous thrombosis was determined to be 2.4-fold for carriers of the prothrombin 20210A allele (odds ratio = 2.54; 95% confidence interval = 0.94, 6.82) and 4.5-fold for carriers of the factor V 1691A allele (odds ratio = 5.06; 95% confidence interval = 2.25, 11.36). Among the seven populations, significant differences were observed in the MTHFR 677T allele distribution, however this mutation was not determined to be a risk factor for venous thrombosis in the patient group studied, either alone or in combination with the prothrombin 20210A and/or the factor V 1691A allele(s). PMID:10365746

Hessner, M J; Luhm, R A; Pearson, S L; Endean, D J; Friedman, K D; Montgomery, R R

1999-05-01

344

Gene variations linked to lung cancer susceptibility in Asian women  

Cancer.gov

An international group of scientists has identified three genes that predispose Asian women who have never smoked to lung cancer. The discovery of specific genetic variations, which have not previously been associated with lung cancer risk in other populations, provides further evidence that risk of lung cancer among never-smokers, especially Asian women, may be associated with certain unique genetic characteristics that distinguishes it from lung cancer in smokers.

345

A candidate prostate cancer susceptibility gene at chromosome 17p  

Microsoft Academic Search

It is difficult to identify genes that predispose to prostate cancer due to late age at diagnosis, presence of phenocopies within high-risk pedigrees and genetic complexity. A genome-wide scan of large, high-risk pedigrees from Utah has provided evidence for linkage to a locus on chromosome 17p. We carried out positional cloning and mutation screening within the refined interval, identifying a

Jacques Simard; David H. F. Teng; Vicki Abtin; Michelle Baumgard; Audrey Beck; Nicola J. Camp; Arlene R. Carillo; Yang Chen; Priya Dayananth; Marc Desrochers; Martine Dumont; James M. Farnham; David Frank; Cheryl Frye; Siavash Ghaffari; Jamila S. Gupte; Rong Hu; Diana Iliev; Teresa Janecki; Edward N. Kort; Kirsten E. Laity; Amber Leavitt; Gilles Leblanc; Jodi McArthur-Morrison; Amy Pederson; Brandon Penn; Kelly T. Peterson; Julia E. Reid; Sam Richards; Marianne Schroeder; Richard Smith; Sarah C. Snyder; Brad Swedlund; Jeff Swensen; Alun Thomas; Martine Tranchant; Ann-Marie Woodland; Fernand Labrie; Mark H. Skolnick; Susan Neuhausen; Johanna Rommens; Lisa A. Cannon-Albright; Sean V. Tavtigian

2001-01-01

346

NF2 gene in neurofibromatosis type 2 patients  

Microsoft Academic Search

Neurofibromatosis type 2 (NF2) is an autosomal domi- nant disorder that predisposes to nervous system tu- mors. The schwannomin (also termed merlin) protein encoded by the NF2 gene shows a close relationship to the family of cytoskeleton-to-membrane proteins linkers ERM (ezrin-radixin-moesin proteins). Even though penetrance of the disease is >95% and no gen- etic heterogeneity has been described, point muta-

Jessica Zucman-Rossi; Patricia Legoix; Hera Der Sarkissian; Genevieve Cheret; Frederic Sor; Alberto Bernardi; Lucien Cazes; Sophie Giraud; Elisabeth Ollagnon; Gilbert Lenoir; Gilles Thomas

1998-01-01

347

Developmental regulation of expression of schizophrenia susceptibility genes in the primate hippocampal formation  

PubMed Central

The hippocampal formation is essential for normal memory function and is implicated in many neurodevelopmental, neurodegenerative and neuropsychiatric disorders. In particular, abnormalities in hippocampal structure and function have been identified in schizophrenic subjects. Schizophrenia has a strong polygenic component, but the role of numerous susceptibility genes in normal brain development and function has yet to be investigated. Here we described the expression of schizophrenia susceptibility genes in distinct regions of the monkey hippocampal formation during early postnatal development. We found that, as compared with other genes, schizophrenia susceptibility genes exhibit a differential regulation of expression in the dentate gyrus, CA3 and CA1, over the course of postnatal development. A number of these genes involved in synaptic transmission and dendritic morphology exhibit a developmental decrease of expression in CA3. Abnormal CA3 synaptic organization observed in schizophrenics might be related to some specific symptoms, such as loosening of association. Interestingly, changes in gene expression in CA3 might occur at a time possibly corresponding to the late appearance of the first clinical symptoms. We also found earlier changes in expression of schizophrenia susceptibility genes in CA1, which might be linked to prodromal psychotic symptoms. A number of schizophrenia susceptibility genes including APOE, BDNF, MTHFR and SLC6A4 are involved in other disorders, and thus likely contribute to nonspecific changes in hippocampal structure and function that must be combined with the dysregulation of other genes in order to lead to schizophrenia pathogenesis. PMID:23092977

Favre, G; Banta Lavenex, P; Lavenex, P

2012-01-01

348

Descriptive cross sectional study on prevalence, perceptions, predisposing factors and health seeking behaviour of women with stress urinary incontinence  

PubMed Central

Background Stress urinary incontinence (SUI) leads to considerable physical and psychological morbidity. The highest prevalence reported was found in Caucasian Americans (range 23% -67%) and the lowest in Singaporean females (4.8%). The study assessed the prevalence, perceptions, predisposing factors and health seeking behaviour of women with SUI in an Asian setting which may have different sociocultural implications. Methods 400 consecutive women >20 years of age attending the outpatient department of a tertiary care hospital in Sri Lanka, for non-urinary conditions were studied over a 3 week period using an interviewer administered questionnaire. SUI was diagnosed on clinical history alone when leakage of urine occurred either with coughing, sneezing, walking or lifting heavy objects. The severity was graded using the Finnish Gynaecological Society’s Urinary Incontinence Severity Score (UISS). Data were analysed using SPSS version 20. Odds ratios were calculated using univariate and multivariate analysis. Results Ninety three (23.33%) had SUI and only 12 (12.9%) had sought treatment. The prevalence among women >50 years of age was 34.71% ( n = 121) compared to 18.28% (n = 279) in those ?50 years. 25 (26.88%) had mild SUI, 66 (70.97%) moderate and 2 (2.15%) severe as per UISS. SUI was perceived as an illness by 210 (52.5%). SUI was significantly associated with pregnancy, parity, vaginal delivery, complicated labour, diabetes mellitus, chronic cough, constipation and faecal incontinence (p < 0.05). Among those affected main reasons for not seeking medical advice included; being embarrassed (n?=?27, 33.33%), not knowing that it is remediable (n?=?23, 28.40%), perceiving SUI to be a normal consequence of childbirth (n?=?19, 23.46%) and having to attend to needs of the family (n?=?12, 14.81%). None who had been pregnant (n?=?313) had received advice on postnatal pelvic floor exercises. SUI interfered with social activities (71;76.34%), sexual function (21; 22.58%) and resulted in despair (67; 72.09%). It was associated with clinically diagnosed candidiasis (50; 53.76%) and soreness in the perineal region (49; 52.69%). Conclusions SUI is a common and neglected gynaecological problem with poor healthcare seeking behaviour. Community based education may help to minimize the occurrence and improve the quality of life of those affected. PMID:24985068

2014-01-01

349

Somatic and germline mutation in GRIM19, a dual function gene involved in mitochondrial metabolism and cell death, is linked to mitochondrion-rich (Hürthle cell) tumours of the thyroid  

Microsoft Academic Search

Oxyphil or Hürthle cell tumours of the thyroid are characterised by their consistent excessive number of mitochondria. A recently discovered gene, GRIM-19 has been found to fulfil two roles within the cell: as a member of the interferon-? and retinoic acid-induced pathway of cell death, and as part of the mitochondrial Complex I assembly. In addition, a gene predisposing to

V Máximo; T Botelho; J Capela; P Soares; J Lima; A Taveira; T Amaro; A P Barbosa; A Preto; H R Harach; D Williams; M Sobrinho-Simões

2005-01-01

350

EFFECTS OF DIETARY FOLATE AND AGING ON GENE EXPRESSION IN THE COLONIC MUCOSA OF RATS: IMPLICATIONS FOR CARCINOGENESIS  

Technology Transfer Automated Retrieval System (TEKTRAN)

Folate depletion and aging are risk factors for human & rodent colorectal (CR) cancer. We investigated the effects of folate status and aging on gene expression patterns in the rat colon and hypothesized that folate depletion and advancing age cause deleterious changes in expression that predispose ...

351

Analysis of polymorphisms in 16 genes in type 1 diabetes that have been associated with other immune-mediated diseases  

E-print Network

, Whittaker J, Meeks J, Powell RJ, Isenberg DA, Walport MJ, Vyse TJ: Polymorphism at the C-reactive protein locus influences gene expression and predisposes to systemic lupus ery- thematosus. Hum Mol Genet 2004, 13:137-147. 15. Szalai AJ, McCrory MA, Cooper...

Smyth, Deborah J; Howson, Joanna M M; Payne, Felicity; Maier, Lisa M; Bailey, Rebecca; Holland, Kieran; Lowe, Christopher E; Cooper, Jason D; Hulme, John S; Vella, Adrian; Dalhman, Ingrid; Lam, Alex C; Nutland, Sarah; Walker, Neil M; Twells, Rebecca C J; Todd, John A

2006-03-06

352

Polymorphisms of Pyrimidine Pathway Enzymes Encoding Genes and HLA-B*40?01 Carriage in Stavudine-Associated Lipodystrophy in HIV-Infected Patients  

PubMed Central

Purpose To assess in a cohort of Caucasian patients exposed to stavudine (d4T) the association of polymorphisms in pyrimidine pathway enzymes and HLA-B*40?01 carriage with HIV/Highly active antiretroviral therapy (HAART)-associated lipodystrophy syndrome (HALS). Methods Three-hundred and thirty-six patients, 187 with HALS and 149 without HALS, and 72 uninfected subjects were recruited. The diagnosis of HALS was performed following the criteria of the Lipodystrophy Severity Grading Scale. Polymorphisms in the thymidylate synthase (TS) and methylene-tetrahydrofolate reductase (MTHFR) genes were determined by direct sequencing, HLA-B genotyping by PCR-SSOr Luminex Technology, and intracellular levels of stavudine triphosphate (d4T-TP) by a LC-MS/MS assay method. Results HALS was associated with the presence of a low expression TS genotype polymorphism (64.7% vs. 42.9%, OR?=?2.43; 95%CI: 1.53–3.88, P<0.0001). MTHFR gene polymorphisms and HLA-B*40?01 carriage were not associated with HALS or d4T-TP intracellular levels. Low and high expression TS polymorphisms had different d4T-TP intracellular levels (25.60 vs. 13.60 fmol/106 cells, P<0.0001). Independent factors associated with HALS were(OR [95%CI]: (a) Combined TS and MTHFR genotypes (p?=?0.006, reference category (ref.): ‘A+A’; OR for ‘A+B’ vs. ref.: 1.39 [0.69–2.80]; OR for ‘B+A’ vs. ref.: 2.16 [1.22–3.83]; OR for ‘B+B’ vs. ref.: 3.13, 95%CI: 1.54–6.35), (b) maximum viral load ?5 log10 (OR: 2.55, 95%CI: 1.56–4.14, P?=?0.001), (c) use of EFV (1.10 [1.00–1.21], P?=?0.008, per year of use). Conclusion HALS is associated with combined low-expression TS and MTHFR associated with high activity polymorphisms but not with HLA-B*40?01 carriage in Caucasian patients with long-term exposure to stavudine. PMID:23840581

Pruvost, Alain; Torres, Ferran; Salazar, Juliana; Gutierrez, Maria del Mar; Domingo, Joan Carles; Fernandez, Irene; Villarroya, Francesc; Vidal, Francesc; Baiget, Montserrat; de la Calle-Martín, Oscar

2013-01-01

353

Single-nucleotide polymorphisms in one-carbon metabolism genes, Mediterranean diet and breast cancer risk: a case-control study in the Greek-Cypriot female population.  

PubMed

Single-nucleotide polymorphisms (SNPs) within genes of the one-carbon metabolism pathway have been shown to interact with dietary folate intake to modify breast cancer (BC) risk. Our group has previously demonstrated that the Mediterranean dietary pattern, rich in beneficial one-carbon metabolism micronutrients, protects against BC in Greek-Cypriot women. We aimed to investigate whether SNPs in the MTHFR (rs1801133 and rs1801131) and MTR (rs1805087) genes modify the effect of the Mediterranean dietary pattern on BC risk. Dietary intake data were obtained using a 32-item food-frequency questionnaire. A dietary pattern specific to the Greek-Cypriot population, which closely resembles the Mediterranean diet, was derived using principal component analysis (PCA) and used as our dietary variable. Genotyping was performed on subjects from the MASTOS study, a case-control study of BC in Cyprus, using TaqMan assays. Adjusted odds ratios (ORs) were estimated using logistic regression analyses. High adherence to the PCA-derived Mediterranean dietary pattern further reduced BC risk with increasing number of variant MTHFR 677T alleles (ORQ4vs.Q1 for 677TT = 0.37, 95 % CI 0.20-0.69, for 677 CT = 0.60, 95 % CI 0.42-0.86). Additionally, high adherence to the Mediterranean dietary pattern decreased BC risk in subjects with at least one MTR 2756A allele (ORQ4vs.Q1 for 2756AA = 0.59, 95 % CI 0.43-0.81, for 2756AG = 0.59, 95 % CI 0.39-0.91) and in subjects with the MTHFR 1298CC genotype (ORQ4vs.Q1 0.44, 95 % CI 0.30-0.65). Overall P-interaction values, however, were not statistically significant. Our study suggests that these MTHFR and MTR SNPs may act as effect modifiers, highlighting their biological significance in the association between Mediterranean diet, the one-carbon metabolism pathway and BC. PMID:25604861

Kakkoura, Maria G; Demetriou, Christiana A; Loizidou, Maria A; Loucaides, Giorgos; Neophytou, Ioanna; Marcou, Yiola; Hadjisavvas, Andreas; Kyriacou, Kyriacos

2015-03-01

354

Detailed Analysis of Gene Polymorphisms Associated with Ischemic Stroke in South Asians  

PubMed Central

The burden of stroke is disproportionately high in the South Asian subcontinent with South Asian ethnicity conferring a greater risk of ischemic stroke than European ancestry regardless of country inhabited. While genes associated with stroke in European populations have been investigated, they remain largely unknown in South Asians. We conducted a comprehensive meta-analysis of known genetic polymorphisms associated with South Asian ischemic stroke, and compared effect size of the MTHFR C677T-stroke association with effect sizes predicted from homocysteine-stroke association. Electronic databases were searched up to August 2012 for published case control studies investigating genetic polymorphisms associated with ischemic stroke in South Asians. Pooled odds ratios (OR) for each gene-disease association were calculated using a random-effects model. We identified 26 studies (approximately 2529 stroke cases and 2881 controls) interrogating 33 independent genetic polymorphisms in 22 genes. Ten studies described MTHFR C677T (108 with TT genotype and 2018 with CC genotype) -homocysteine relationship and six studies (735 stroke cases and 713 controls) described homocysteine-ischemic stroke relationship. Risk association ORs were calculated for ACE I/D (OR 5.00; 95% CI, 1.17–21.37; p?=?0.03), PDE4D SNP 83 (OR 2.20; 95% CI 1.21–3.99; p?=?0.01), PDE4D SNP 32 (OR 1.57; 95% CI 1.01–2.45, p?=?0.045) and IL10 G1082A (OR 1.44; 95% CI, 1.09–1.91, p?=?0.01). Significant association was observed between elevated plasma homocysteine levels and MTHFR/677 TT genotypes in healthy South Asians (Mean difference (?X) 5.18 µmol/L; 95% CI 2.03–8.34: p?=?0.001). Our results demonstrate that the genetic etiology of ischemic stroke in South Asians is broadly similar to the risk conferred in Europeans, although the dataset is considerably smaller and warrants the same clinical considerations for risk profiling. PMID:23505425

Yadav, Sunaina; Hasan, Nazeeha; Marjot, Thomas; Khan, Muhammad S.; Prasad, Kameshwar; Bentley, Paul; Sharma, Pankaj

2013-01-01

355

[Analysis of the effect of N5, N10-methylenetetrahydrofolate reductase gene C(677)-->T polymorphism on the ischemic stroke development in persons with various risk factors].  

PubMed

The results ofMTHFR gene C(677)-->T (rs1801133) polymorphism determined in 170 patients with ischemic atherothrombotic stroke (IATS) and 124 healthy subjects (control group) are presented in the paper. It has been shown that in patients with IATS, the frequencies of main homozygotes (CC), heterozygotes (CT) and minor homozygotes (TT) are 52.4, 35.9, 11.8% (in control--46.0, 48.4, 5.6%, P = 0.044 by chi2-test). TT homozygotes have a greater chance of developing IATS than carriers of main C-allele (CT + CC) (OR = 2.3, CI = 0.911-5.449, P = 0.049). In the representatives of the Ukrainian population there is a relationship between the frequency of MTHFR gene C(677)-->T polymorphism genotypes and the risk of IATS. This connection is manifested in male patients, in persons with normal blood pressure, and in people who do not have the habit of smoking. The sex of the patients, body mass index, blood pressure and smoking affect the level of the studied polymorphism association with stroke. PMID:25007516

Harbuzova, V Iu; Polonikov, O V; Stro?, D O; Matla?, O I; Ataman, Iu O; Sukharieva, V A; Ataman, O V

2014-01-01

356

Imprinting of the Gene Encoding a Human Cyclin-Dependent Kinase Inhibitor, p57KIP2, on Chromosome 11p15  

Microsoft Academic Search

Parental origin-specific alterations of chromosome 11p15 in human cancer suggest the involvement of one or more maternally expressed imprinted genes involved in embryonal tumor suppression and the cancer-predisposing Beckwith-Wiedemann syndrome (BWS). The gene encoding cyclin-dependent kinase inhibitor p57KIP2, whose overexpression causes G1 phase arrest, was recently cloned and mapped to this band. We find that the p57KIP2 gene is imprinted,

Shuhei Matsuoka; Jeffrey S. Thompson; Michael C. Edwards; Janet M. Barletta; Paul Grundy; Linda M. Kalikin; J. Wade Harper; Stephen J. Elledge; Andrew P. Feinberg

1996-01-01

357

Adult Patients with Eosinophilic Esophagitis Do Not Show an Increased Frequency of the HLA-DQ2\\/DQ8 Genotypes Predisposing to Celiac Disease  

Microsoft Academic Search

Background  Recent articles have described patients that share eosinophilic esophagitis (EoE) and celiac disease (CD) suggesting a true\\u000a relationship between both diseases.\\u000a \\u000a \\u000a \\u000a \\u000a Aims  The purpose of this study was to investigate whether HLA DQ2 and DQ8 predisposing to CD are increased in adult patients with\\u000a EoE.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  HLA alleles conferring risk for CD was assessed in 75 adult EoE patients attended at two

Alfredo J. Lucendo; Ángel Arias; Isabel Pérez-Martínez; Antonio López-Vázquez; Jesús Ontañón-Rodríguez; Sonia González-Castillo; Livia C. De Rezende; Luis Rodrigo

2011-01-01

358

The anti-aging gene KLOTHO is a novel target for epigenetic silencing in human cervical carcinoma  

Microsoft Academic Search

BACKGROUND: Klotho was originally characterized as an anti-aging gene that predisposed Klotho-deficient mice to a premature aging-like syndrome. Recently, KLOTHO was reported to function as a secreted Wnt antagonist and as a tumor suppressor. Epigenetic gene silencing of secreted Wnt antagonists is considered a common event in a wide range of human malignancies. Abnormal activation of the canonical Wnt pathway

Jaehyouk Lee; Dong-Jun Jeong; Jinsun Kim; Soonduck Lee; Jin-Hwa Park; Boogi Chang; Sam-Il Jung; Lisha Yi; Youngsoo Han; Young Yang; Keun Il Kim; Jong-Seok Lim; Inchul Yang; Seob Jeon; Dong Han Bae; Chang-Jin Kim; Myeong-Sok Lee

2010-01-01

359

Immunoprinting: various genes are associated with increased risk to develop rheumatoid arthritis in different groups of adult patients  

Microsoft Academic Search

To identify genes that contribute to the manifestation of rheumatoid arthritis we performed association studies via microsatellite analyses of immunorelevant loci (HLA-DRB, 5 T cell receptor loci, TNFa, IL1, 112, IL5R and CD40L). A total of 183 patients and 275 healthy controls were typed in terms of HLA and grouped according to the known predisposing HLADRB1 genes (DRB1*04; relative risk

M. Gomolka; H. Menninger; J. E. Saal; E.-M. Lemmel; E. D. Albert; O. Niwa; J. T. Epplen; C. Epplen

1995-01-01

360

MTHFR POLYMORPHISMS AND COLORECTAL NEOPLASIA  

Technology Transfer Automated Retrieval System (TEKTRAN)

Folate is essential for the synthesis, repair and methylation of DNA. Aberrations in folate metabolism can modify our risk for cancer. Folate depletion alters DNA methylation patterns and increases DNA uracil-content and the frequency of DNA breaks. These DNA aberrations are involved in the etiology...

361

T27863C Mutation in the 5*-Flanking Region of the Endothelial Nitric Oxide Synthase Gene Is Associated With Coronary Spasm  

Microsoft Academic Search

Conclusions—Taken together, these findings strongly suggest that the T 27863 C mutation in the eNOS gene reduces the endothelial NO synthesis and predisposes the patients with the mutation to coronary spasm. (Circulation. 1999;99:2864-2870.)

Masafumi Nakayama; Hirofumi Yasue; Michihiro Yoshimura; Yukio Shimasaki; Kiyotaka Kugiyama; Hisao Ogawa; Takeshi Motoyama; Yoshihiko Saito; Yoshihiro Ogawa; Yoshihiro Miyamoto; Kazuwa Nakao

362

Long-Term Expression of Human Coagulation Factor VIII and Correction of Hemophilia A after in vivo Retroviral Gene Transfer in Factor VIII-Deficient Mice  

Microsoft Academic Search

Hemophilia A is caused by a deficiency in coagulation factor VIII (FVIII) and predisposes to spontaneous bleeding that can be life-threatening or lead to chronic disabilities. It is well suited for gene therapy because a moderate increase in plasma FVIII concentration has therapeutic effects. Improved retroviral vectors expressing high levels of human FVIII were pseudotyped with the vesicular stomatitis virus

Thierry Vandendriessche; Veerle Vanslembrouck; Inge Goovaerts; Hans Zwinnen; Marie-Line Vanderhaeghen; Desire Collen; Marinee K. L. Chuah

1999-01-01

363

Association of Factor V Leiden Gene Polymorphism With Arteriovenous Graft Failure  

PubMed Central

Background Dialysis grafts fail due to recurrent stenosis and thrombosis. Vasoactive and pro-thrombotic substances affecting intimal hyperplasia or thrombosis may modify graft outcomes. Study design Genetic polymorphisms association study of patients enrolled in a multi-center, randomized clinical trial. Setting and participants 354 Dialysis Access Consortium (DAC) Study patients receiving a new graft with DNA samples obtained. Subjects were randomized to treatment with aspirin+dipyridamole vs placebo. Predictor DNA sequence polymorphisms for the following candidate genes and their interaction with the study intervention: methylenetetrahydrofolate reductase (MTHFR), heme oxygenase 1 (HO-1), Factor V (F5), transforming growth factor ?1 (TGF-?1), Klotho, nitric oxide synthase (NOS), and angiotensin converting enzyme (ACE). Outcome Graft failure (>50% stenosis, angioplasty, thrombosis, surgical intervention or permanent loss of function). Results During a median patient follow-up of 34.3 months, 304 grafts failed. After adjusting for clinical factors (patient age, gender, access location, diabetes, cardiovascular disease, baseline aspirin use, body mass index, timing of graft placement, and study treatment) and genetic ancestral background, SNP rs6019 of the Factor V gene was significantly associated with graft failure in a dominant model (HR of 1.70 [95% CI, 1.32–2.19; p<0.001] for G/C and G/G genotypes vs C/C genotypes). There was no significant association between graft failure and polymorphisms of MTHFR, HO-1, TGF-?1, Klotho, NOS, or ACE. Limitations Small sample size Conclusion Factor V Leiden is associated with an increased risk of graft failure. Anticoagulation may reduce graft failure in patients with the G/C or G/G genotypes. PMID:22281051

Allon, Michael; Zhang, Li; Maya, Ivan D.; Bray, Molly S.; Fernandez, Jose R.

2011-01-01

364

NIAM-deficient mice are predisposed to the development of proliferative lesions including B-cell lymphomas.  

PubMed

Nuclear Interactor of ARF and Mdm2 (NIAM, gene designation Tbrg1) is a largely unstudied inhibitor of cell proliferation that helps maintain chromosomal stability. It is a novel activator of the ARF-Mdm2-Tip60-p53 tumor suppressor pathway as well as other undefined pathways important for genome maintenance. To examine its predicted role as a tumor suppressor, we generated NIAM mutant (NIAM(m/m)) mice homozygous for a ?-galactosidase expressing gene-trap cassette in the endogenous gene. The mutant mice expressed significantly lower levels of NIAM protein in tissues compared to wild-type animals. Fifty percent of aged NIAM deficient mice (14 to 21 months) developed proliferative lesions, including a uterine hemangioma, pulmonary papillary adenoma, and a Harderian gland adenoma. No age-matched wild-type or NIAM(+/m) heterozygous animals developed lesions. In the spleen, NIAM(m/m) mice had prominent white pulp expansion which correlated with enhanced increased reactive lymphoid hyperplasia and evidence of systemic inflammation. Notably, 17% of NIAM mutant mice had splenic white pulp features indicating early B-cell lymphoma. This correlated with selective expansion of marginal zone B cells in the spleens of younger, tumor-free NIAM-deficient mice. Unexpectedly, basal p53 expression and activity was largely unaffected by NIAM loss in isolated splenic B cells. In sum, NIAM down-regulation in vivo results in a significant predisposition to developing benign tumors or early stage cancers. These mice represent an outstanding platform for dissecting NIAM's role in tumorigenesis and various anti-cancer pathways, including p53 signaling. PMID:25393878

Reed, Sara M; Hagen, Jussara; Muniz, Viviane P; Rosean, Timothy R; Borcherding, Nick; Sciegienka, Sebastian; Goeken, J Adam; Naumann, Paul W; Zhang, Weizhou; Tompkins, Van S; Janz, Siegfried; Meyerholz, David K; Quelle, Dawn E

2014-01-01

365

c-Myc over-expression in Ramos Burkitt's lymphoma cell line predisposes to iron homeostasis disruption in vitro  

SciTech Connect

Burkitt's lymphoma is an aggressive B-cell neoplasm resulting from deregulated c-myc expression. We have previously shown that proliferation of Burkitt's lymphoma cell lines such as Ramos is markedly reduced by iron treatment. It has been shown that iron induces expression of c-myc which, owing to its transcriptional regulatory functions, regulates genes involved in iron metabolism. Transient enhancement of c-myc expression by iron could increase the expression of genes involved in iron incorporation, which could lead to an accumulation of intracellular free iron. Here, we have investigated whether cells with a high basal level of c-Myc were more likely to accumulate free iron. Our results suggest that the basal level of c-Myc in Ramos cells is twofold higher than what is seen in HL-60 cells. Moreover, in Ramos cells, where c-Myc is expressed at a high level, H-ferritin expression is down-regulated, transferrin receptor (CD71) expression is increased, and ferritin translation is inhibited. These modifications in iron metabolism, resulting from the strong basal expression of c-Myc, and amplified by iron addition, could lead to a disruption in homeostasis and consequently to growth arrest.

Habel, Marie-Eve [Hema-Quebec, Recherche et Developpement, 1009, route du Vallon, Sainte-Foy, Que., G1V 5C3 (Canada); Departement de biochimie et microbiologie, Universite Laval, Quebec, Que., G1K 7P4 (Canada); Jung, Daniel [Hema-Quebec, Recherche et Developpement, 1009, route du Vallon, Sainte-Foy, Que., G1V 5C3 (Canada) and Departement de biochimie et microbiologie, Universite Laval, Quebec, Que., G1K 7P4 (Canada)]. E-mail: djung@hema-quebec.qc.ca

2006-03-24

366

A nuclear defect in the 4p16 region predisposes to multiple mitochondrial DNA deletions in families with Wolfram syndrome.  

PubMed Central

Wolfram syndrome is a progressive neurodegenerative disorder transmitted in an autosomal recessive mode. We report two Wolfram syndrome families harboring multiple deletions of mitochondrial DNA. The deletions reached percentages as high as 85-90% in affected tissues such as the central nervous system of one patient, while in other tissues from the same patient and from other members of the family, the percentages of deleted mitochondrial DNA genomes were only 1-10%. Recently, a Wolfram syndrome gene has been linked to markers on 4p16. In both families linkage between the disease locus and 4p16 markers gave a maximum multipoint lod score of 3.79 at theta = 0 (P<0.03) with respect to D4S431. In these families, the syndrome was caused by mutations in this nucleus-encoded gene which deleteriously interacts with the mitochondrial genome. This is the first evidence of the implication of both genomes in a recessive disease. PMID:8601620

Barrientos, A; Volpini, V; Casademont, J; Genís, D; Manzanares, J M; Ferrer, I; Corral, J; Cardellach, F; Urbano-Márquez, A; Estivill, X; Nunes, V

1996-01-01

367

Genetic variation of fifteen folate metabolic pathway associated gene loci and the risk of incident head and neck carcinoma: The Women’s Genome Health Study  

PubMed Central

Objective Recent studies have demonstrated the importance of folate metabolic pathway (FMP) in the pathogenesis of head and neck cancinoma (HNC). Whether the genetic variation within the FMP associated genes modulates HNC remains elusive. To date, prospective, epidemiological data on the relationship of FMP gene variation with the risk of HNC are sparse. Methods The association between 203 tag-SNPs (tSNPs) of 15 FMP associated genes (CBS, BHMT, DHFR, FOLR1, FOLR2, FOLR3, MTHFR, MTR, MTRR, MTHFD1, RFC1, SHMT1, SLC19A1, TCN2, and TYMS) and incident HNC was investigated in 23,294 Caucasian female participants of the prospective Women’s Genome Health Study. All were free of known cancer at baseline. During a 15-year follow-up period, 55 participants developed a first ever HNC. Multivariable Cox regression analysis was performed to investigate the relationship between genotypes and HNC risk assuming an additive genetic model. Haplotype-block analysis was also performed. Results A total of 11 tSNPs within DHFR, MTHFR, RFC1, and TYMS were associated with HNC risk (all p-uncorrected <0.050). Further investigation using the haplotype-block analysis revealed an association of several prespecified haplotypes of RFC1 with HNC risk (all p-uncorrected <0.050). Conclusion If corroborated in other large prospective studies, the present findings suggest that genetic variation within the folate metabolic pathway gene loci examined, in particular, the replication factor C-1 (RFC1) gene variation may influence HNC risk. PMID:23276522

Zee, Robert Y.L.; Rose, Lynda; Chasman, Daniel I.; Ridker, Paul M

2013-01-01

368

Bayesian variable selection for hierarchical gene-environment and gene-gene interactions.  

PubMed

We propose a Bayesian hierarchical mixture model framework that allows us to investigate the genetic and environmental effects, gene by gene interactions and gene by environment interactions in the same model. Our approach incorporates the natural hierarchical structure between the main effects and interaction effects into a mixture model, such that our methods tend to remove the irrelevant interaction effects more effectively, resulting in more robust and parsimonious models. We consider both strong and weak hierarchical models. For a strong hierarchical model, both the main effects between interacting factors must be present for the interactions to be considered in the model development, while for a weak hierarchical model, only one of the two main effects is required to be present for the interaction to be evaluated. Our simulation results show that the proposed strong and weak hierarchical mixture models work well in controlling false-positive rates and provide a powerful approach for identifying the predisposing effects and interactions in gene-environment interaction studies, in comparison with the naive model that does not impose this hierarchical constraint in most of the scenarios simulated. We illustrate our approach using data for lung cancer and cutaneous melanoma. PMID:25154630

Liu, Changlu; Ma, Jianzhong; Amos, Christopher I

2015-01-01

369

[The effect of polymorphism of genes of xenobiotics detoxication on the frequencies of spontaneous and induced chromosome aberrations in human lymphocytes].  

PubMed

Here presented the data on the frequencies of chromosome aberrations in lymphocytes of peripheral blood of 97 volunteers depending on genotypes by genes of xenobiotics detoxication before and after gamma-irradiation with dose of 1 Gy in vitro. The frequencies of aberrations were estimated by analyzing not less than 500-1000 metaphases per person. The data of cytogenetic analysis were compared with the results of PCR-genotyping of loci GSTM1, GSTT1, GSTP1, CYP1A1, CYP2D6, NAT2, and MTHFR. The significant differences by the frequencies of aberrations between "single-locus" genotypes were not found except for GSTM1 locus, for which the enhanced frequency of spontaneous aberrations of chromosome type in "positive" genotypes compared to "zero" ones, i.e., homozygotes by deletion (p = 0.04) was observed. The minimum frequency of spontaneous aberrations of chromosome type was recorded for carriers of double homozygotes by deletion of GSTM1-GSTT1: 0.0006 +/- 0.0003 against 0.0027 +/- 0.0003 for the rest of genotypes (p = 0.016 by the Mann-Witney test). The frequency of gamma-induced chromosome aberrations was correlated with the total amount of minor alleles in loci GSTP1, NAT2, and MTHFR (r = 0.25 at p = 0.0065). PMID:19947517

Sal'nikova, L E; Akaeva, E A; Elisova, T V; Kuznetsova, G I; Kuz'mina, N S; Vesnina, I N; Lapteva, N Sh; Chumachenko, A G; Romanchuk, V A; Rubanovich, A V

2009-01-01

370

27-Hydroxycholesterol up-regulates CD14 and predisposes monocytic cells to superproduction of CCL2 in response to lipopolysaccharide.  

PubMed

We investigated the possibility that a cholesterol-rich milieu can accelerate response to pathogen-associated molecular patterns in order to elucidate mechanisms underlying aggravation of atherosclerosis after bacterial infection. The consumption of a high-cholesterol diet resulted in enhanced the expression of CD14 in arteries of ApoE(-/-) mice. 27-Hydroxycholesterol (27OHChol), the most abundant cholesterol oxide in atherosclerotic lesions, induced the significant expression of CD14 by THP-1 monocytic cells, but not by vascular smooth muscle cells or Jurkat T cells. Additions of lipopolysaccharide (LPS) to 27OHChol-treated THP-1 monocytic cells resulted in superinduction in terms of the gene transcription of CCL2 and the secretion of its gene product. In contrast, cholesterol did not cause increased the expression of CD14 in the aforementioned cells, and the addition of LPS to cholesterol-treated monocytic cells did not result in enhanced the expression of CCL2. The conditioned medium isolated from THP-1 cells exposed to 27OHChol plus LPS further induced the migration of monocytic cells in comparison with conditioned media obtained from THP-1 cells treated with 27OHChol or LPS alone. Treatment with 27OHChol also resulted in the enhanced secretion of MMP-9 and soluble CD14 (sCD14), and the secretion of sCD14 was blocked by a selective MMP-9 inhibitor. The inhibition of the ERK pathway resulted in significantly attenuated the secretion of sCD14 via mechanisms that were distinct from those by PI3K inhibition. We propose that 27OHChol can prime monocytes/macrophages by up-regulation of CD14 such that LPS-mediated inflammatory reaction is accelerated, thereby contributing to aggravated development of atherosclerotic lesions by enhancing recruitment of monocytic cells after infection with Gram-negative bacteria. PMID:25497142

Kim, Sun-Mi; Kim, Bo-Young; Eo, Seong-Kug; Kim, Chi-Dae; Kim, Koanhoi

2015-03-01

371

A novel NKX2-5 loss-of-function mutation predisposes to familial dilated cardiomyopathy and arrhythmias.  

PubMed

Dilated cardiomyopathy (DCM) is the most prevalent type of primary myocardial disease, which is the third most common cause of heart failure and the most frequent reason for heart transplantation. Aggregating evidence demonstrates that genetic risk factors are involved in the pathogenesis of idiopathic DCM. Nevertheless, DCM is of remarkable genetic heterogeneity and the genetic defects underpinning DCM in an overwhelming majority of patients remain unknown. In the present study, the whole coding exons and splice junction sites of the NKX2-5 gene, which encodes a homeodomain transcription factor crucial for cardiac development and structural remodeling, were sequenced in 130 unrelated patients with idiopathic DCM. The available relatives of the index patient harboring an identified mutation and 200 unrelated ethnically matched healthy individuals used as controls were genotyped for the NKX2-5 gene. The functional effect of the mutant NKX2-5 was characterized in contrast to its wild-type counterpart using a dual-luciferase reporter assay system. As a result, a novel heterozygous NKX2-5 mutation, p.S146W, was identified in a family with DCM inherited as an autosomal dominant trait, which co-segregated with DCM in the family with complete penetrance. Notably, the mutation carriers also had arrhythmias, such as paroxysmal atrial fibrillation and atrioventricular block. The missense mutation was absent in 400 reference chromosomes and the altered amino acid was completely conserved evolutionarily among species. Functional analysis revealed that the NKX2-5 mutant was associated with a significantly reduced transcriptional activity. The findings expand the mutational spectrum of NKX2-5 linked to DCM and provide novel insight into the molecular mechanisms underlying DCM, contributing to the antenatal prophylaxis and allele-specific management of DCM. PMID:25503402

Yuan, Fang; Qiu, Xing-Biao; Li, Ruo-Gu; Qu, Xin-Kai; Wang, Juan; Xu, Ying-Jia; Liu, Xu; Fang, Wei-Yi; Yang, Yi-Qing; Liao, De-Ning

2015-02-01

372

Ionizing radiation predisposes non-malignant human mammaryepithelial cells to undergo TGF beta-induced epithelial to mesenchymaltransition  

SciTech Connect

Transforming growth factor {beta}1 (TGF{beta}) is a tumor suppressor during the initial stage of tumorigenesis, but it can switch to a tumor promoter during neoplastic progression. Ionizing radiation (IR), both a carcinogen and a therapeutic agent, induces TGF{beta}, activation in vivo. We now show that IR sensitizes human mammary epithelial cells (HMEC) to undergo TGF{beta}-mediated epithelial to mesenchymal transition (EMT). Non-malignant HMEC (MCF10A, HMT3522 S1 and 184v) were irradiated with 2 Gy shortly after attachment in monolayer culture, or treated with a low concentration of TGF{beta} (0.4 ng/ml), or double-treated. All double-treated (IR+TGF{beta}) HMEC underwent a morphological shift from cuboidal to spindle-shaped. This phenotype was accompanied by decreased expression of epithelial markers E-cadherin, {beta}-catenin and ZO-1, remodeling of the actin cytoskeleton, and increased expression of mesenchymal markers N-cadherin, fibronectin and vimentin. Furthermore, double-treatment increased cell motility, promoted invasion and disrupted acinar morphogenesis of cells subsequently plated in Matrigel{trademark}. Neither radiation nor TGF{beta} alone elicited EMT, even though IR increased chronic TGF{beta} signaling and activity. Gene expression profiling revealed that double treated cells exhibit a specific 10-gene signature associated with Erk/MAPK signaling. We hypothesized that IR-induced MAPK activation primes non-malignant HMEC to undergo TGF{beta}-mediated EMT. Consistent with this, Erk phosphorylation were transiently induced by irradiation, persisted in irradiated cells treated with TGF{beta}, and treatment with U0126, a Mek inhibitor, blocked the EMT phenotype. Together, these data demonstrate that the interactions between radiation-induced signaling pathways elicit heritable phenotypes that could contribute to neoplastic progression.

Andarawewa, Kumari L.; Erickson, Anna C.; Chou, William S.; Costes, Sylvain; Gascard, Philippe; Mott, Joni D.; Bissell, Mina J.; Barcellos-Hoff, Mary Helen

2007-04-06

373

Binding of specific ligand by D2- and NMDA-receptors of striatum cells in two rat strains predisposed and resistant to audiogenic seizures.  

PubMed

We studied parameters of specific receptor binding of D2-dopamine receptor ligand [(3)H]-sulpiride and NMDA-receptor ligand [(3)H]-MK-801 on the membranes of striatum cells in Krushinsky-Molodkina rats (predisposed to audiogenic seizures) and strain "0" selected for the absence of audiogenic seizures. No interstrain differences were observed in affinity (K(d)) of both D2- and NMDA-receptors to ligands. At the same time, significant interstrain differences in receptor density (B(max)) were found for both D2-receptors and NMDA-receptors. The reduced number of dopamine and glutamate receptors in the striatum can be associated with neurological peculiarities of Krushinsky-Molodkina rat strain (audiogenic seizures and postictal catalepsy). PMID:23330123

Firstova, Ju Ju; Abaimov, D A; Surina, N M; Poletaeva, I I; Fedotova, I B; Kovalev, G I

2012-12-01

374

A Strong Candidate for the Breast and Ovarian Cancer Susceptibility Gene BRCA1  

Microsoft Academic Search

A strong candidate for the 17q-linked BRCA1 gene, which influences susceptibility to breast and ovarian cancer, has been identified by positional cloning methods. Probable predisposing mutations have been detected in five of eight kindreds presumed to segregate BRCA1 susceptibility alleles. The mutations include an 11-base pair deletion, a 1-base pair insertion, a stop codon, a missense substitution, and an inferred

Yoshio Miki; Jeff Swensen; Donna Shattuck-Eidens; P. Andrew Futreal; Keith Harshman; Sean Tavtigian; Qingyun Liu; Charles Cochran; L. Michelle Bennett; Wei Ding; Russell Bell; Judith Rosenthal; Charles Hussey; Thanh Tran; Melody McClure; Cheryl Frye; Tom Hattier; Robert Phelps; Astrid Haugen-Strano; Harold Katcher; Kazuko Yakumo; Zahra Gholami; Daniel Shaffer; Steven Stone; Steven Bayer; Christian Wray; Robert Bogden; Priya Dayananth; John Ward; Patricia Tonin; Steven Narod; Pam K. Bristow; Frank H. Norris; Leah Helvering; Paul Morrison; Paul Rosteck; Mei Lai; J. Carl Barrett; Cathryn Lewis; Susan Neuhausen; Lisa Cannon-Albright; David Goldgar; Roger Wiseman; Alexander Kamb; Mark H. Skolnick

1994-01-01

375

TP53 p.R337H is a conditional cancer-predisposing mutation: further evidence from a homozygous patient  

PubMed Central

Background Adrenocortical carcinomas (ACCs) are among the most common childhood cancers occurring in infants affected with the Li-Fraumeni and Li- Fraumeni-like (LFS/LFL) syndromes, which are caused by dominant germline mutations in the TP53 gene. In Brazil, a particular mutation, occurring in the tetramerisation domain of the gene, p.R337H, is exceedingly common due to a founder effect and is strongly associated with ACC. In this report, we describe the phenotype and long-term clinical follow-up of a female child diagnosed with ACC and homozygous for the TP53 p.R337H founder mutation. Case presentation At age 11 months, the patient was diagnosed with a virilising anaplastic adrenal cortical tumour, which was completely excised without disturbing the adrenal capsule. Family history was consistent with an LFL tumour pattern, and genotyping identified the TP53 p.R337H mutation in both alleles in genomic DNA from lymphocytes and fibroblasts. Haplotype analysis confirmed the occurrence of the mutation in the same founder haplotype previously described in other Brazilian patients. No other germline or somatic TP53 mutations or rearrangements were identified. At age 9 years, the child was asymptomatic and had no evidence of endocrine derangements. Full body and brain magnetic resonance imaging (MRI) failed to detect any suspicious proliferative lesions, and cardiopulmonary exercise testing results were within the normal reference for the child’s age, ruling out a major exercise capacity deficiency. Conclusion This is the first clinical and aerobic functional capacity documentation of a patient who carries two mutant TP53 alleles and no wild-type allele. Our results support the hypothesis that TP53 p.R337H, the most common TP53 mutation ever described in any population, is a conditional mutant. Furthermore, our observations over a long period of clinical follow-up suggest that TP53 p.R337H homozygotes do not have a more severe disease phenotype than do heterozygote carriers of the same mutation. Patients with the homozygous TP53 p.R337H genotype will require careful surveillance for lifetime cancer risk and for effects on metabolic capacity later in life. PMID:23570263

2013-01-01

376

Role of MTHFR (677, 1298) haplotype in the risk of developing secondary leukemia after treatment of breast cancer and hematological malignancies  

Microsoft Academic Search

Therapy-related myelodysplasia and acute myeloid leukemia (t-MDS\\/AML) is a malignancy occurring after exposure to chemotherapy and\\/or radiotherapy. Polymorphisms involved in chemotherapy\\/radiotherapy response genes could be related to an increased risk of developing this neoplasia. We have studied 11 polymorphisms in genes of drug detoxification pathways (NQO1, glutathione S-transferase pi) and DNA repair xeroderma pigmentosum, complementation group (3) (XPC(3), X-ray repair

V M Guillem; M Collado; M J Terol; M J Calasanz; J Esteve; M Gonzalez; C Sanzo; J Nomdedeu; P Bolufer; A Lluch; M Tormo; M Tormo Díaz

2007-01-01

377

Mesenchymal Phenotype Predisposes Lung Cancer Cells to Impaired Proliferation and Redox Stress in Response to Glutaminase Inhibition  

PubMed Central

Recent work has highlighted glutaminase (GLS) as a key player in cancer cell metabolism, providing glutamine-derived carbon and nitrogen to pathways that support proliferation. There is significant interest in targeting GLS for cancer therapy, although the gene is not kno