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Sample records for methylenetetrahydrofolate reductase polymorphisms

  1. Serum homocysteine, folate level and methylenetetrahydrofolate reductase 677, 1298 gene polymorphism in Korean schizophrenic patients.

    PubMed

    Lee, Young Sik; Han, Doug Hyun; Jeon, Chang Moo; Lyoo, In Kyoon; Na, Chul; Chae, Seok Lae; Cho, Soo Churl

    2006-05-15

    High homocysteine serum level has been regarded as one of the important factors that influence the development of schizophrenia. Genetic variations of methylenetetrahydrofolate reductase, which is a main enzyme reducing homocysteine level, are reported in schizophrenic patients. We measured the serum level of homocysteine/folate and methylenetetrahydrofolate reductase C677T/A1298C gene polymorphism in 235 patients with schizophrenia. Plasma homocysteine levels were higher and folate levels were lower in patients than in comparison subjects. Variations of C677T were more frequent in patients than in comparison subjects. Patients with the 677TT genotype showed higher homocysteine levels than patients with the CC and CT genotypes. These findings suggest that folate supplement may be beneficial to some schizophrenic patients with homocysteinemia due to the genetic defect of methylenetetrahydrofolate reductase. PMID:16641680

  2. The association between methylenetetrahydrofolate reductase gene C677T polymorphisms and breast cancer risk in Chinese population.

    PubMed

    Wang, Yadong; Yang, Haiyan; Gao, Huiyan; Wang, Haiyu

    2015-12-01

    With great interest, we read the recent article entitled "Methylenetetrahydrofolate reductase polymorphisms and breast cancer risk in Chinese population: a meta-analysis of 22 case-control studies" published online in Tumor Biology, 2014, 35: 1695-1701. This article suggests that methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism was significantly associated with breast cancer risk in Chinese population. The result is encouraging. Nevertheless, three key issues in this meta-analysis are worth noticing. PMID:26537580

  3. [Alzheimer's disease and methylenetetrahydrofolate reductase gene polymorphisms: a potential nutrigenomic approach for Mexico].

    PubMed

    Castillo-Quan, Jorge I; Pérez-Osorio, Julia M

    2009-01-01

    The establishment of medical genomics in Mexico offers the possibility to study in a more comprehensive manner the etiological factors of different diseases, providing a global view of the interaction between the genome and the environment. Nutrition is recognized as a significant determinant in several diseases, yet its interaction with polymorphisms, and in general with the genome, has not been properly addressed Mexico has a high prevalence of polymorphisms of the methylenetetrahydrofolate reductase gene, and in both clinical and basic studies this has been associated with an increased susceptibility of developing Alzheimer's disease. We propose a potential nutrigenomic approach for the study of Alzheimer disease in Mexico. PMID:19518022

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

    PubMed

    Liew, Siaw-Cheok; Gupta, Esha Das

    2015-01-01

    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

  5. Meta-analysis of methylenetetrahydrofolate reductase polymorphism and lung cancer risk in Chinese

    PubMed Central

    Wang, Xin; Yue, Kai; Hao, Liran

    2015-01-01

    Numerous studies have investigated association of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism with lung cancer (LC) susceptibility in Chinese; however, the findings are inconsistent. Therefore, we performed a meta-analysis. PubMed, ISI Web of Knowledge, Chinese National Knowledge Infrastructure, and Wanfang were searched. Pooled ORs and 95% CIs were used to assess the strength of the associations. Overall, 10 studies with 2487 cases and 3228 controls investigating the MTHFR C677T polymorphism and LC risk were included. We did not find a significant association between MTHFR C677T polymorphism and LC risk. However, significantly increased LC risk was found in the population from North China, which was not found in the population from South China. In conclusion, our meta-analysis suggested that MTHFR C677T polymorphism might influence the risk of LC. PMID:25785167

  6. Methylenetetrahydrofolate Reductase Gene Polymorphisms in Children with Attention Deficit Hyperactivity Disorder

    PubMed Central

    Gokcen, Cem; Kocak, Nadir; Pekgor, Ahmet

    2011-01-01

    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

  7. Controversial roles of methylenetetrahydrofolate reductase polymorphisms and folate in breast cancer disease.

    PubMed

    Bravatà, Valentina

    2015-02-01

    Breast cancer (BC) represents a highly heterogeneous tumour at both the clinical and molecular levels. Single-nucleotide polymorphisms (SNPs) of the folate-metabolising enzyme methylenetetrahydrofolate-reductase (MTHFR) may modify the association between folate intake and BC and influence plasma folate concentration. The role of folate in BC is equivocal, association studies between the common MTHFR SNPs C677T and A1298C and BC risk are controversial. In this study, I have reviewed observed associations between folate intake, as well as its blood levels, and BC. The purpose of this review is to analyse the role of folate and the two SNPs associated with reduced enzyme activity in BC. I explored the most relevant and updated work that emphasises positive and negative associations among these variables. My findings indicate that no definitive conclusions can be drawn from the studies on this topic. However, this manuscript highlights variables that could be useful to explore in further association analyses. PMID:25318348

  8. Prevalence of methylenetetrahydrofolate reductase 677 C-T polymorphism among mothers of Down syndrome children

    PubMed Central

    Kaur, Anupam; Kaur, Amandeep

    2013-01-01

    INTRODUCTION: The relationship between chromosomal non-disjunction leading to aneuploidy and folate metabolism has drawn attention in the recent years. In this study, we examined the polymorphism in the gene encoding the folate metabolizing enzyme methylenetetrahydrofolate reductase (MTHFR), namely, 677 C-T in women having Down syndrome (DS) children. MATERIALS AND METHODS: The prevalence of these variant genotypes (MTHFR 677 C-T polymorphism) in women having DS children (case mothers) (n = 110) was compared with controls (n = 111) from Punjab. Genotyping was done using the polymerase chain reaction method followed by restriction fragment length polymorphism. RESULTS: In the present study, 1.8% of case mothers had TT genotype while none of the control mothers showed this genotype. T allele frequency among cases was 0.13 and 0.11 in controls. The Chi-square value showed a non-significant difference between cases and controls. CONCLUSION: No association has been observed between 677 C-T polymorphism and risk of non-disjunction in case mothers. Detection of polymorphisms in more genes of folate pathway is required to find out the exact cause of non-disjunction. PMID:24497705

  9. Association between methylenetetrahydrofolate reductase C677T polymorphism and psoriasis: A meta-analysis.

    PubMed

    Wu, Dongze; Shi, Deshun; Yang, Li; Zhu, Xiaoliang

    2016-02-01

    Several studies have evaluated the associations between methylenetetrahydrofolate reductase (MTHFR) C677T and psoriasis. However, the results remain inconclusive. The objective of the present study was to conduct a qualitative and quantitative meta-analysis investigating the associations between MTHFR C677T and psoriasis. A published work search of PubMed, Embase, Web of Science and Chinese National Knowledge Infrastructure database were conducted to identify all publications concerning MTHFR C677T polymorphism and psoriasis on 1 October 2014. The principal outcome measure for evaluating the strength of the association was crude odds ratios along with their corresponding 95% confidence intervals. Data were extracted and statistical analyses were implemented using STATA version 12.0 software. A total of 1179 psoriatic cases and 937 controls from five case-control studies concentrating on the association between MTHFR C677T polymorphism and psoriasis were included in this qualitative meta-analysis. Pooled analysis revealed that there is no association between this polymorphism and susceptibility to psoriasis in dominant, recessive, allele and additive models under a random-effect model. However, a marginal significant association was found in the overdominant model under fixed-effect model. Subgroup analysis of ethnicity demonstrated that there is no association between MTHFR C677T polymorphism and either Asian or European psoriatic patients. In conclusion, MTHFR C677T polymorphism, qualitatively, is not a genetic factor for the pathogenesis of psoriasis but could quantitatively reflect the severity of psoriasis to some extent. PMID:26212228

  10. Association between 5, 10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms and congenital heart disease: A meta-analysis☆

    PubMed Central

    Wang, Wenju; Hou, Zongliu; Wang, Chunhui; Wei, Chuanyu; Li, Yaxiong; Jiang, Lihong

    2013-01-01

    Background Inconsistent results were reported in recent literature regarding the association between methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C polymorphisms and the susceptibility of congenital heart disease (CHD). In this study, we performed a meta-analysis to investigate the associations by employing multiple analytical methods. Methods Literature search was performed and published articles were obtained from PubMed, Embase and CNKI databases based on the exclusion and inclusion criteria. Data were extracted from eligible studies and the crude odds ratios and their corresponding 95% confidence intervals (CIs) were calculated using random or fix effects model to evaluate the associations between the MTHFR C677T/A1298C polymorphisms and CHD development. Subgroup based analysis was performed by Hardy–Weinberg equilibrium, ethnicity, types of CHD, source of control and sample size. Results Twenty-four eligible studies were included in this meta-analysis. Significant association was found between fetal MTHFR C677T polymorphism and CHD development in all genetic models. The pooled ORs and 95% CIs in all genetic models indicated that MTHFR C677T polymorphism was significantly associated with CHD in Asian, but not Caucasian in subgroup analysis. The maternal MTHFR C677T polymorphism was not associated with CHD except for recessive model. Moreover, neither maternal nor fetal MTHFR A1298C polymorphism was associated with CHD. Conclusion The fetal MTHFR C677T polymorphism may increase the susceptibility to CHD. Fetal MTHFR C677T polymorphism was more likely to affect Asian fetus than Caucasian. The MTHFR A1298C polymorphism may not be a risk of congenital heart disease. PMID:25606381

  11. Folate Pathway Gene Methylenetetrahydrofolate Reductase C677T Polymorphism and Alzheimer Disease Risk in Asian Population.

    PubMed

    Rai, Vandana

    2016-07-01

    The association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and susceptibility to Alzheimers disease (AD) was controversial in previous studies. The present meta-analysis was designed to investigate the association of MTHFR C677T polymorphism with AD. Nine studies were identified by search of PubMed, Google Scholar, Elsevier, Springer Link databases, up to January 2013. Odds ratios (ORs) with corresponding 95 % confidence interval (CI) were calculated using fixed effects model or random effects model. All statistical analysis was done by Mix version 1.7. MTHFR C677T polymorphism had a significant association with susceptibility to AD in all genetic models (for T vs C: OR 1.29, 95 % CI 1.15-1.44, p < 0.0001; for TT + CT vs CC: OR 1.38, 95 % CI 1.16-1.364, p = 0.0002; for TT vs CC: OR 1.60, 95 % CI 1.25-2.04, p = 0.0001; for CT vs CC: OR 1.28, 95 % CI 1.1-1.53, p < 0.008; for TT vs CT + CC: OR 1.37, 95 % CI 1.12-1.67, p = 0.002). Results from present meta-analysis supported that the MTHFR C677T polymorphism was associated with an increased risk of AD in Asian population. PMID:27382194

  12. Interactions of Methylenetetrahydrofolate Reductase C677T Polymorphism with Environmental Factors on Hypertension Susceptibility.

    PubMed

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

    2016-01-01

    Hypertension is considered to be the result of genes, environment, and their interactions. Among them age, sex, tobacco use, alcohol consumption, and being overweight/obesity are well documented environmental determinants, and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is nominated as a potential genetic candidate. However, the synergistic effect of the MTHFR C677T polymorphism with these environmental factors on the risk of hypertension has received little attention. The aim of this study was to explore the associations of the MTHFR C677T polymorphism, environmental factors, and their interactions with hypertension predisposition in a Northern Chinese Han population. A total of 708 participants were enrolled in the study. The genotypes of the MTHFR C677T were determined by a TaqMan assay. We found that participants of an older age, being overweight/obesity, with a smoking habit, drinking habit, or carrying the 677T allele were at an increased risk of hypertension. Additionally, there existed marginally significant interactions of the polymorphism with age and overweight/obesity. However, future large, well-designed studies in Chinese and other populations, as well as mechanistic studies, are still needed to validate our findings, especially considering that the interactions observed in our study were only marginally significant. PMID:27322299

  13. Interactions of Methylenetetrahydrofolate Reductase C677T Polymorphism with Environmental Factors on Hypertension Susceptibility

    PubMed Central

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

    2016-01-01

    Hypertension is considered to be the result of genes, environment, and their interactions. Among them age, sex, tobacco use, alcohol consumption, and being overweight/obesity are well documented environmental determinants, and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is nominated as a potential genetic candidate. However, the synergistic effect of the MTHFR C677T polymorphism with these environmental factors on the risk of hypertension has received little attention. The aim of this study was to explore the associations of the MTHFR C677T polymorphism, environmental factors, and their interactions with hypertension predisposition in a Northern Chinese Han population. A total of 708 participants were enrolled in the study. The genotypes of the MTHFR C677T were determined by a TaqMan assay. We found that participants of an older age, being overweight/obesity, with a smoking habit, drinking habit, or carrying the 677T allele were at an increased risk of hypertension. Additionally, there existed marginally significant interactions of the polymorphism with age and overweight/obesity. However, future large, well-designed studies in Chinese and other populations, as well as mechanistic studies, are still needed to validate our findings, especially considering that the interactions observed in our study were only marginally significant. PMID:27322299

  14. Polymorphism in methylenetetrahydrofolate reductase, plasminogen activator inhibitor-1, and apolipoprotein E in hemodialysis patients.

    PubMed

    Al-Muhanna, Fahad; Al-Mueilo, Samir; Al-Ali, Amein; Larbi, Emmanuel; Rubaish, Abdullah; Abdulmohsen, Mohammed Fakhry; Al-Zahrani, Alhussain; Al-Ateeq, Suad

    2008-11-01

    The methylenetetrahydrofolate reductase (MTHFR) gene polymorphism, apolipoprotein E (apo epsilon4) gene polymorphism and polymorphism of plasminogen activator inhibitor-1 (PAI-1) have been shown to be associated with end-stage renal disease (ESRD). To determine the prevalence of these mutations in Saudi patients with ESRD on hemodialysis, we studied the allelic frequency and genotype distribution in patients receiving hemodialysis and in a control group, all residing in the Eastern Province of Saudi Arabia. The genotypes were determined using allele specific hybridization procedures and were confirmed by restriction fragment length polymorphism. The T allele frequency and homozygous genotype of MTHFR in ESRD patients were 14% and 2.4%, respectively compared to 13.4% and 0%, respectively in the control group. The allele frequency and homozygous genotype of 4G/4G PAI-1 gene polymorphism were 46.4% and 4.8% respectively in ESRD patients compared to 57.1% and 32% respectively in the control group. The apo s4 allele frequency and homozygous genotype distribution in hemodialysis patients were 7% and 2.4%, respectively compared to 13% and 2% in the control group. Although allele frequency of C677T of MTHFR was statistically similar in the hemodialysis patients and in the control group, the homozygotes T allele genotype was over represented in the hemodialysis group compared to normal. The prevalence of PAI-1 4G/4G polymorphism in ESRD patients was lower when compared to the control group. The prevalence of apo s4 allele did not differ significantly between the two groups. The present results demonstrate that all three studied polymorphic mutations are present in our population and that they may contribute to the etiology of the disease in our area. PMID:18974580

  15. Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia.

    PubMed

    Wiemels, J L; Smith, R N; Taylor, G M; Eden, O B; Alexander, F E; Greaves, M F

    2001-03-27

    Low folate intake as well as alterations in folate metabolism as a result of polymorphisms in the enzyme methylenetetrahydrofolate reductase (MTHFR) have been associated with an increased incidence of neural tube defects, vascular disease, and some cancers. Polymorphic variants of MTHFR lead to enhanced thymidine pools and better quality DNA synthesis that could afford some protection from the development of leukemias, particularly those with translocations. We now report associations of MTHFR polymorphisms in three subgroups of pediatric leukemias: infant lymphoblastic or myeloblastic leukemias with MLL rearrangements and childhood lymphoblastic leukemias with either TEL-AML1 fusions or hyperdiploid karyotypes. Pediatric leukemia patients (n = 253 total) and healthy newborn controls (n = 200) were genotyped for MTHFR polymorphisms at nucleotides 677 (C-->T) and 1,298 (A-->C). A significant association for carriers of C677T was demonstrated for leukemias with MLL translocations (MLL+, n = 37) when compared with controls [adjusted odd ratios (OR) = 0.36 with a 95% confidence interval (CI) of 0.15-0.85; P = 0.017]. This protective effect was not evident for A1298C alleles (OR = 1.14). In contrast, associations for A1298C homozygotes (CC; OR = 0.26 with a 95% CI of 0.07--0.81) and C677T homozygotes (TT; OR = 0.49 with a 95% CI of 0.20--1.17) were observed for hyperdiploid leukemias (n = 138). No significant associations were evident for either polymorphism with TEL-AML1+ leukemias (n = 78). These differences in allelic associations may point to discrete attributes of the two alleles in their ability to alter folate and one-carbon metabolite pools and impact after DNA synthesis and methylation pathways, but should be viewed cautiously pending larger follow-up studies. The data provide evidence that molecularly defined subgroups of pediatric leukemias have different etiologies and also suggest a role of folate in the development of childhood leukemia. PMID:11274424

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

    PubMed

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

    2015-02-01

    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

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

    PubMed

    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

    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

  18. Methylenetetrahydrofolate reductase polymorphisms increase risk of esophageal squamous cell carcinoma in a Chinese population.

    PubMed

    Song, C; Xing, D; Tan, W; Wei, Q; Lin, D

    2001-04-15

    Methylenetetrahydrofolate reductase (MTHFR) plays a central role in folate metabolism that affects DNA methylation and synthesis. Because germ-line mutations at nucleotides 677 (C-->T) and 1298 (A-->C) in the MTHFR gene cause diminished enzyme activity, and aberrant DNA methylation is oncogenic, we examined the relationship between these two MTHFR polymorphisms and susceptibility to esophageal squamous cell carcinoma (ESCC) in 240 ESCC cases and 360 age- and sex-matched controls in northern CHINA: We found that the allele frequency of MTHFR 677T was significantly higher among cases than among controls (63% versus 41%, P < 0.001). Subjects with the 677TT genotype had a more than 6-fold increased risk of developing ESCC [adjusted odds ratio (OR), 6.18; 95% confidence interval (CI), 3.32-11.51] compared with those who had the 677CC genotype. Furthermore, the elevated ESCC risk associated with the 677 polymorphism was in an allele-dose relationship (trend test, P = 0.0001) with ORs of 1.00, 3.14 (95% CI, 1.94-5.08), and 6.18 (95% CI, 3.32-11.51) for the CC, CT, and TT genotype, respectively, after adjustment for age, sex, smoking status, and the MTHFR 1298 polymorphism. The allele frequency for the MTHFR 1298C was 14% among cases and 17% among controls. The 1298CC genotype was extremely rare in both controls (1.4%) and cases (2.9%) and was also associated with an elevated risk of ESCC (adjusted OR, 4.43; 95% CI, 1.23-16.02) compared with the 1298AA genotype, whereas the 1298AC genotype had no effect on the risk of ESCC. Thus, our findings support the hypothesis that genetic polymorphisms in the MTHFR gene may contribute to susceptibility to carcinogenesis of the esophagus in the at-risk Chinese population. PMID:11309278

  19. Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and promoter methylation in cervical oncogenic lesions and cancer

    PubMed Central

    Botezatu, Anca; Socolov, Demetra; Iancu, Iulia V; Huica, Irina; Plesa, Adriana; Ungureanu, Carmen; Anton, Gabriela

    2013-01-01

    The aim of this study was to investigate the role of methylenetetrahydrofolate reductase (MTHFR) polymorphisms and MTHFR methylation pattern in cervical lesions development among women from Romania, a country with high prevalence of human papillomavirus (HPV) cervical infections. To achieve this goal, blood samples and cervical cytology specimens (n = 77)/tumour tissue specimens (n = 23) were investigated. As control, blood and negative cytological smears (n = 50) were used. A statistically significant association was found between T allele of C677T polymorphism and cervical lesions, heterozygote women presenting a threefold increased risk (normal/cervical lesions and tumours: wild homozygote 34/41 (0.68/0.41), heterozygote 14/51 (0.28/0.51), mutant homozygote 2/8 (0.04/0.08); OR = 3.081, P = 0.0035). Using χ square test for the control group, the HPV-negative and HPV-positive patients with cervix lesions, a significant correlation between viral infection and T allele of C677T polymorphism (P = 0.0287) was found. The MTHFR promoter was methylated in all HGSIL and tumour samples, significant differences being noted between HPV-positive samples, control group and cases of cervical dysplastic lesions without HPV DNA (P < 0. 0001) and between samples from patients with high-risk (hr)HPV versus low-risk (lr)HPV (P = 0.0026). No correlations between polymorphisms and methylation were observed. In Romania, individuals carrying T allele are susceptible for cervical lesions. MTHFR promoter methylation is associated with cervical severity lesions and with hrHPV. PMID:23444906

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

    PubMed Central

    Liu, Xiaojiao; Yang, Pei

    2012-01-01

    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

  1. 5,10 Methylenetetrahydrofolate reductase genetic polymorphism as a risk factor for neural tube defects

    SciTech Connect

    Ou, C.Y.; Brown, V.K.; Khoury, M.J.

    1996-06-28

    Persons with a thermolabile form of the enzyme 5,10 methylenetetrahydrofolate reductase (MTHFR) have reduced enzyme activity and increased plasma homocysteine which can be lowered by supplemental folic acid. Thermolability of the enzyme has recently been shown to be caused by a common mutation (677C{sup {r_arrow}}T) in the MTHFR gene. We studied 41 fibroblast cultures from NTD-affected fetuses and compared their genotypes with those of 109 blood specimens from individuals in the general population. 677C{sup {r_arrow}}T homozygosity was associated with a 7.2 fold increased risk for NTDs (95% confidence interval: 1.8-30.3; p value: 0.001). These preliminary data suggest that the 677C{sup {r_arrow}}T polymorphism of the MTHFR gene is a risk factor for spina bifida and anencephaly that may provide a partial biologic explanation for why folic acid prevents these types of NTD. 13 refs., 1 fig., 1 tab.

  2. Methylenetetrahydrofolate reductase and methionine synthase reductase gene polymorphisms and protection from microvascular complications in adolescents with type 1 diabetes.

    PubMed

    Wiltshire, Esko J; Mohsin, Fauzia; Chan, Albert; Donaghue, Kim C

    2008-08-01

    Folate status has been associated with endothelial dysfunction in adolescents with type 1 diabetes, and elevated total plasma homoocyst(e)ine (tHcy) is a risk for vascular disease in the non-diabetic population. Polymorphisms in genes involved in folate and homocysteine metabolism are implicated in vascular disease. We aimed to determine whether polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) genes are risk factors for early microvascular disease in a large group of adolescents with type 1 diabetes. Four hundred and eighty adolescents were screened annually for retinopathy and microalbuminuria for a median of 4 yr. Molecular analysis for the polymorphisms 677C-->T, 1298A-->C in MTHFR, and 66A-->G in MTRR was performed. The MTRR 66GG genotype reduced the risk for elevated albumin excretion rate (AER) (OR 0.47, CI 0.25, 0.88, p = 0.018) and showed a trend to reduced risk for microalbuminuria (OR 0.27, CI 0.06-1.21, p = 0.09). Survival without elevated AER was increased with the MTRR 66GG genotype (12.4 vs. 9.7 yr, p = 0.04) and with the MTHFR 1298CC genotype (15.2 vs. 10.2 yr, p = 0.007). Conversely, survival without retinopathy was reduced with the MTHFR 677TT and MTRR 66GG combined genotype (6.2 vs. 10.2 yr, p = 0.015). The MTRR 66GG and MTHFR 1298 CC genotypes may confer protection against early nephropathy, possibly because they are associated with lower tHcy. The MTHFR 677 TT was only related to earlier onset retinopathy in combination with MTRR 66GG. PMID:18774994

  3. Association of methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism with autism: evidence of genetic susceptibility.

    PubMed

    Rai, Vandana

    2016-08-01

    Autism (MIM 209850) is a heterogeneous neurodevelopmental disease that manifests within the first 3 years of life. Numerous articles reported that dysfunctional folate-methionine pathway enzymes may play an important role in the pathophysiology of autism. Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme of this pathway and MTHFR C677T polymorphism reported as risk factor for autism in several case control studies. However, controversial reports were also published. Hence the present meta-analysis was designed to investigate the relationship of the MTHFR C677T polymorphism with the risk of autism. Electronic databases were searched for case control studies with following search terms - 'MTHFR', 'C677T', in combination with 'Autism'. Pooled OR with its corresponding 95 % CI was calculated and used as association measure to investigate the association between MTHFR C677T polymorphism and risk of autism. Total of thirteen studies were found suitable for the inclusion in the present meta-analysis, which comprises 1978 cases and 7257 controls. Meta-analysis using all four genetic models showed significant association between C677T polymorphism and autism (ORTvs.C = 1.48; 95 % CI: 1.18-1.86; P = 0.0007; ORTT + CT vs. CC = 1.70, 95 % CI = 0.96-2.9, p = 0.05; ORTT vs. CC = 1.84, 95 % CI = 1.12-3.02, p = 0.02; ORCT vs.CC = 1.60, 95 % CI = 1.2-2.1, p = 0.003; ORTT vs.CT+CC = 1.5, 95 % CI = 1.02-2.2, p = 0.03). In total 13 studies, 9 studies were from Caucasian population and 4 studies were from Asian population. The association between C677T polymorphism and autism was significant in Caucasian (ORTvs.C = 1.43; 95 % CI = 1.1-1.87; p = 0.009) and Asian population (ORTvs.C = 1.68; 95 % CI = 1.02-2.77; p = 0.04) using allele contrast model. In conclusion, present meta-analysis strongly suggested a significant association of the MTHFR C677T polymorphism with autism. PMID:26956130

  4. Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review.

    PubMed

    Gilbody, Simon; Lewis, Sarah; Lightfoot, Tracy

    2007-01-01

    The authors performed a meta-analysis of studies examining the association between polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, including MTHFR C677T and A1298C, and common psychiatric disorders, including unipolar depression, anxiety disorders, bipolar disorder, and schizophrenia. The primary comparison was between homozygote variants and the wild type for MTHFR C677T and A1298C. For unipolar depression and the MTHFR C677T polymorphism, the fixed-effects odds ratio for homozygote variants (TT) versus the wild type (CC) was 1.36 (95% confidence interval (CI): 1.11, 1.67), with no residual between-study heterogeneity (I(2) = 0%)--based on 1,280 cases and 10,429 controls. For schizophrenia and MTHFR C677T, the fixed-effects odds ratio for TT versus CC was 1.44 (95% CI: 1.21, 1.70), with low heterogeneity (I(2) = 42%)--based on 2,762 cases and 3,363 controls. For bipolar disorder and MTHFR C677T, the fixed-effects odds ratio for TT versus CC was 1.82 (95% CI: 1.22, 2.70), with low heterogeneity (I(2) = 42%)-based on 550 cases and 1,098 controls. These results were robust to various sensitively analyses. This meta-analysis demonstrates an association between the MTHFR C677T variant and depression, schizophrenia, and bipolar disorder, raising the possibility of the use of folate in treatment and prevention. PMID:17074966

  5. Association of Blood Lead Levels with Methylenetetrahydrofolate Reductase Polymorphisms among Chinese Pregnant Women in Wuhan City

    PubMed Central

    Shen, Wei; Zhang, Bin; Liu, Shuyun; Wu, Hongling; Gu, Xue; Qin, Lingzhi; Tian, Ping; Zeng, Yun; Ye, Linxiang; Ni, Zemin; Wang, Qi

    2015-01-01

    Background Pregnancy is an important stimulus of bone lead release. Elevated blood lead levels (BLLs) may cause adverse pregnancy outcomes for mothers and harmful lead effects on fetuses. However, the reports about maternal BLL changes during pregnancy are conflicting to some extent. This article is to explore the variations in BLLs among pregnant women. The relationships of BLLs with methylenetetrahydrofolate reductase (MTHFR) gene C677T, A1298C, and G1793A polymorphisms, which are associated with bone resorption, were also studied. A total of 973 women, including 234, 249, and 248 women in their first, second, and third trimesters, respectively, and 242 non-pregnant women, were recruited at the Wuhan Women and Children Medical Health Center. Methods BLLs were determined using a graphite furnace atomic absorption spectrometer. Single-nucleotide polymorphisms of MTHFR were identified with the TaqMan probe method. Results The geometric mean (geometric standard deviation) of BLLs was 16.2 (1.78) μg/L for all participants. All the studied MTHFR alleles were in Hardy-Weinberg equilibrium. Multiple-linear regression analysis revealed the following results. Among the pregnant women, those that carried MTHFR 677CC (i.e. wild-genotype homozygote) and 1298CC (i.e. mutant-genotype homozygote) exhibited higher BLLs than those that carried 677CT/TT (standardized β = 0.074, P = 0.042) and 1298AC/AA (standardized β = 0.077, P = 0.035) when other covariates (e.g., age, no. of children, education and income, etc.) were adjusted. The BLLs of pregnant women consistently decreased during the pregnancy and these levels positively correlated with BMI (standard β = 0.086–0.096, P<0.05). Conclusions The 1298CC mutant-type homozygote in the MTHFR gene is a risk factor for high BLLs among low-level environmental lead-exposed Chinese pregnant women, whose BLLs consistently decreased during gestation. PMID:25723397

  6. Methylenetetrahydrofolate reductase gene C677T polymorphism and breast cancer risk: Evidence for genetic susceptibility

    PubMed Central

    Kumar, Pradeep; Yadav, Upendra; Rai, Vandana

    2015-01-01

    There are several evidences supporting the role of 5–10 methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms in breast cancer (BC). Case control association studies on breast cancer have been repeatedly performed over the last two decades, but results are inconsistent. We performed a meta-analysis to confirm the association between MTHFR C677T polymorphism and BC risk. The articles were retrieved by searching the PubMed, Google Scholar, and Springer Link databases. Crude odds ratios (OR) with 95% confidence intervals (CIs) was used to assess the strength of association between C677T polymorphism and BC. Publication bias was assessed by Egger's and Begg-Mazumdar tests. Meta-analysis was performed with Open Meta Analyst. Total 75 studies with 31,315 cases and 35, 608 controls were found suitable for the inclusion in the present meta-analysis. The results of meta-analysis suggested that there were moderate significant association between C677T polymorphism and BC risk using overall comparisons in five genetic models (T vs. C: OR = 1.08, 95% CI = 1.03–1.13, p = < 0.001; TT + CT vs. CC: OR = 1.06, 95% CI = 1.02–1.09, p = < 0.001; TT vs. CC: OR = 1.17, 95% CI = 1.06–1.28, p = 0.001; CT vs. CC OR = 1.05, 95% CI = 1.01–1.08, p = 0.005; TT vs. CT + CC: OR = 1.12, 95% CI = 1.03–1.22, p = 0.005). In conclusion, results of present meta-analysis showed modest association between MTHFR C677T polymorphism with breast cancer in total studies. However, sub-group analysis results based on ethnicity showed strong significant association between TT genotype and breast cancer (TT vs. CC; OR°=°1.26; 95% CI: 1.06–1.51; p = 0.009) in Asian population but in Caucasian population such association was not observed (TT vs. CC; OR°=°1.08; 95% CI: 0.99–1.14; p = 0.05). PMID:26629412

  7. Methylenetetrahydrofolate reductase gene A1298C polymorphism in pediatric stroke--case-control and family-based study.

    PubMed

    Balcerzyk, Anna; Niemiec, Paweł; Kopyta, Ilona; Emich-Widera, Ewa; Pilarska, Ewa; Pienczk-Ręcławowicz, Karolina; Kaciński, Marek; Wendorff, Janusz; Żak, Iwona

    2015-01-01

    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

  8. Thymidylate synthase and methylenetetrahy-drofolate reductase gene polymorphisms and gastric cancer susceptibility in a population of Northern Brazil.

    PubMed

    Araújo, M D; Borges, B N; Rodrigues-Antunes, S; Burbano, R M R; Harada, M L

    2015-01-01

    The folate metabolic pathway, which is involved in DNA synthesis and methylation, is associated with individual susceptibility to several diseases, including gastric tumors. In this study, we investigated four polymorphisms [thymidylate synthase enhancer region, single nucleotide polymorphism thymidylate synthase 5' (TS5'), TS3' untranslated region, and methylenetetrahydrofolate reductase (MTHFR) 677C> T] in 2 genes related to the folate pathway, TS and MTHFR, and their possible association with the risk gastric cancer development in a population from Pará state, Brazil. For the TS enhancer region, TS3' untranslated region, and single nucleotide polymorphism TS5' polymorphisms, no significant results were obtained. For the MTHFR 677C>T polymorphism, TT genotype carriers had a higher risk of developing tumors in the antrum (P = 0.19 vs CC and P = 0.02 vs CT) and intestine (odds ratio = 4.18, 95% confidence interval = 0.66-26.41; P = 0.252 vs CC and odds ratio = 2.25, 95% confidence interval = 0.32-15.75; P = 0.725 vs CT). Those carrying at least 1 T allele had an increased risk of lymph node metastasis (odds ratio = 3.00, 95% confidence interval = 0.88-10.12; P = 0.133). Our results suggest that polymorphisms in MTHFR affect the susceptibility to gastric tumors in the Brazilian population and may be a factor causing poor prognosis in such patients. PMID:26345936

  9. Bladder exstrophy-epispadias complex and the role of methylenetetrahydrofolate reductase C677T polymorphism: A case control study

    PubMed Central

    Raman, Venkat Shankar; Bajpai, Minu; Ali, Abid

    2016-01-01

    Purpose: The Bladder Exstrophy-Epispadias Complex (BEEC) is the most serious form of midline abdominal malformation. The etiology of BEEC is unknown and is thought to be multifactorial. Methylenetetrahydrofolate reductase (MTHFR) polymorphism C677T is strongly associated with other midline abnormalities such as neural tube defects. No proper case-control study existed comparing MTHFR polymorphism with BEEC. We sought to find an association with MTHFR polymorphism and patients with bladder exstrophy (BE). Materials and Methods: The design of the study was a case-control study, involving 50 children with BEEC and 50 normal healthy school children. Genetic analysis for MTHFR 677 polymorphism was carried out after DNA extraction and polymerase chain reaction amplification. Epidemiological analysis was done by using the birth defect questionnaire on parents of BEEC. Results: Forty-two classical BE, two cloacal exstrophies (CE), four epispadias, and two exstrophy variant patients were a part of this study. Severe variety of BE had a significant association with C667T MTHFR polymorphism as compared to the normal control population (P = 0.01). Conclusion: C677T MTHFR polymorphism has a strong association with severe variety (CE) of BEEC occurrence. PMID:26862292

  10. Functional Inference of Methylenetetrahydrofolate Reductase Gene Polymorphisms on Enzyme Stability as a Potential Risk Factor for Down Syndrome in Croatia

    PubMed Central

    Vraneković, Jadranka; Babić Božović, Ivana; Starčević Čizmarević, Nada; Buretić-Tomljanović, Alena; Ristić, Smiljana; Petrović, Oleg; Kapović, Miljenko; Brajenović-Milić, Bojana

    2010-01-01

    Understanding the biochemical structure and function of the methylenetetrahydrofolate reductase gene (MTHFR) provides new evidence in elucidating the risk of having a child with Down syndrome (DS) in association with two common MTHFR polymorphisms, C677T and A1298C. The aim of this study was to evaluate the risk for DS according to the presence of MTHFR C677T and A1298C polymorphisms as well as the stability of the enzyme configuration. This study included mothers from Croatia with a liveborn DS child (n = 102) or DS pregnancy (n = 9) and mothers with a healthy child (n = 141). MTHFR C677T and A1298C polymorphisms were assessed by PCR-RFLP. Allele/genotype frequencies differences were determined using χ2 test. Odds ratio and the 95% confidence intervals were calculated to evaluate the effects of different alleles/genotypes. No statistically significant differences were found between the frequencies of allele/genotype or genotype combinations of the MTHFR C677T and A1298C polymorphisms in the case and the control groups. Additionally, the observed frequencies of the stable (677CC/1298AA, 677CC/1298AC, 677CC/1298CC) and unstable (677CT/1298AA, 677CT/1298AC, 677TT/1298AA) enzyme configurations were not significantly different. We found no evidence to support the possibility that MTHFR polymorphisms and the stability of the enzyme configurations were associated with risk of having a child with DS in Croatian population. PMID:20592453

  11. Risk of colorectal cancer associated with the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in the Kashmiri population.

    PubMed

    Sameer, A S; Shah, Z A; Nissar, S; Mudassar, S; Siddiqi, M A

    2011-01-01

    Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in folate metabolism and is involved in DNA synthesis, DNA repair and DNA methylation. The two common functional polymorphisms of MTHFR, 677 C→T and 1298 A→C, have been shown to impact various diseases, including cancer. The 677 C→T polymorphism has been widely investigated in different cancers and has been implicated as a risk factor for the development of various cancers. We investigated MTHFR C677T genotype frequency in colorectal cancer cases in the Kashmiri population and correlated this information with the known clinicopathological characters of colorectal cancer, in a case-control study. Eighty-six colorectal cancer cases were studied for MTHFR C677T polymorphism, compared to 160 controls taken from the general population, employing the PCR-RFLP technique. We found the frequency of the three different genotypes of MTHFR in our ethnic Kashmir population, i.e., CC, CT and TT, to be 68.6, 20.9 and 10.4% among colorectal cancer cases and 75.6, 16.9 and 7.5% among the general control population, respectively. There was a significant association between the MTHFR TT genotype and colorectal cancer in the higher age group. We conclude that the MTHFR C677T polymorphism slightly increases the risk for colorectal cancer development in our ethnic Kashmir population. PMID:21732284

  12. The methylenetetrahydrofolate reductase C677T gene polymorphism decreases the risk of childhood acute lymphocytic leukaemia.

    PubMed

    Franco, R F; Simões, B P; Tone, L G; Gabellini, S M; Zago, M A; Falcão, R P

    2001-12-01

    We have determined the prevalence of methylenetetrahydrofolate reductase (MTHFR) mutations C677T and A1298C in 71 children (< or = 15 years) with acute lymphoblastic leukaemia (ALL) and in 71 control subjects. Odds ratio (OR) for ALL linked to MTHFR C677T was 0.4 (95% CI 0.2-0.8); for heterozygotes it was 0.5 (95% CI 0.2-0.9) and for homozygotes it was 0.3 (95%CI 0.09-0.8). MTHFR A1298C yielded an overall OR for ALL of 1.3 (95% CI: 0.7-2.6); for heterozygotes it was 1.3 (95% CI: 0.7-7.6) and for homozygotes it was 2.8 (95% CI 0.5-15.6). In conclusion, MTHFR C677T was linked to a significant 2.4-fold decreased risk of developing childhood ALL, whereas MTHFR A1298C did not significantly affect the risk of ALL in our population. PMID:11736945

  13. Polymorphisms of glutathione S-transferase and methylenetetrahydrofolate reductase genes in Moldavian patients with ulcerative colitis: Genotype-phenotype correlation

    PubMed Central

    Varzari, Alexander; Deyneko, Igor V.; Tudor, Elena; Turcan, Svetlana

    2015-01-01

    Background Glutathione S-transferases (GSTM1, GSTT1, and GSTP1) and methylenetetrahydrofolate reductase (MTHFR) are important enzymes for protection against oxidative stress. In addition, MTHFR has an essential role in DNA synthesis, repair, and methylation. Their polymorphisms have been implicated in the pathogenesis of ulcerative colitis (UC). The aim of the present study was to investigate the role of selected polymorphisms in these genes in the development of UC in the Moldavian population. Methods In a case-control study including 128 UC patients and 136 healthy individuals, GSTM1 and GSTT1 genotypes (polymorphic deletions) were determined using multiplex polymerase chain reaction (PCR). The GSTP1 rs1695 (Ile105Val), MTHFR rs1801133 (C677T), and MTHFR rs1801131 (A1298C) polymorphisms were studied with restriction fragment length polymorphism (RFLP) analysis. Genotype–phenotype correlations were examined using logistic regression analysis. Results None of the genotypes, either alone or in combination, showed a strong association with UC. The case-only sub-phenotypic association analysis showed an association of the MTHFR rs1801133 polymorphism with the extent of UC under co-dominant (p corrected = 0.040) and recessive (p corrected = 0.020; OR = 0.15; CI = 0.04–0.63) genetic models. Also, an association between the MTHFR rs1801131 polymorphism and the severity of UC was reported for the over-dominant model (p corrected = 0.023; coefficient = 0.32; 95% CI = 0.10–0.54). Conclusion The GST and MTHFR genotypes do not seem to be a relevant risk factor for UC in our sample. There was, however, evidence that variants in MTHFR may influence the clinical features in UC patients. Additional larger studies investigating the relationship between GST and MTHFR polymorphisms and UC are required. PMID:26862484

  14. Methylenetetrahydrofolate Reductase C677T and A1298C Polymorphisms in Male Partners of Recurrent Miscarriage Couples

    PubMed Central

    Tara, Somayeh-Sadat; Ghaemimanesh, Fatemeh; Zarei, Saeed; Reihani-Sabet, Fakhreddin; Pahlevanzadeh, Zhamak; Modarresi, Mohammad Hosein; Jeddi-Tehrani, Mahmood

    2015-01-01

    Background: Methylenetetrahydrofolate reductase (MTHFR) single-nucleotide polymorphisms (SNPs) C677T and A1298C have been described as strong risk factors for idiopathic recurrent miscarriage (RM). However, very few studies have investigated the association of paternal MTHFR SNPs with RM. The aim of the present study was to evaluate the prevalence of paternal C677T and A1298C SNPs among Iranian RM couples. Methods: The study subjects comprised 225 couples with more than three consecutive pregnancy losses, and 100 control couples with no history of pregnancy complications. All females in the case group had MTHFR polymorphisms; and genotype SNPs were analyzed by PCR-RFLP. Groups were statistically compared using Mann Whitney U-test and Chi-square statistical tests. The p<0.05 were considered significant. Results: Statistically significant difference was detected in the frequency of MTHFR SNPs in male partners of the two groups (p=0.019). Combined heterozygosity of MTHFR polymorphisms was a common phenomenon in the males; 52 (23.1%) and 14 (14%) of males in RM and control groups, respectively. Absence of combined homozygosity for both SNPs in all studied groups/genders was observed. Conclusion: The MTHFR gene composition of male partners of RM couples may contribute to increased risk of miscarriage. PMID:27110516

  15. Methylenetetrahydrofolate Reductase A1298C Polymorphism and Breast Cancer Risk: A Meta-analysis of 33 Studies

    PubMed Central

    Rai, V

    2014-01-01

    Methylenetetrahydrofolate reductase (MTHFR) enzyme is essential for DNA synthesis and DNA methylation, and its gene polymorphisms have been implicated as risk factors for birth defects, neurological disorders, and different types of cancers. Several studies have investigated the association between the MTHFR A1298C polymorphism and breast cancer (BC) risk, but the results were inconclusive. To assess the risk associated with MTHFR A1298C polymorphism, a comprehensive meta-analysis was performed. PubMed, Google Scholar, Elsevier and Springer Link databases were searched for case-control studies relating the association between MTHFR A1298C polymorphism and BC risk and estimated summary odds ratios (ORs) with confidence intervals (CIs) for assessment. Up to January 2014, 33 case-control studies involving 15,919 BC patients and 19,700 controls were included in the present meta-analysis. The results showed that the A1298C polymorphism was not associated with BC risk in all the five genetic models (C vs. A allele (allele contrast): OR = 0.99, 95% confidence interval (CI): 0.93–1.05; AC versus AA (heterozygote/codominant): OR = 0.97, 95% CI: 0.89–1.04; CC versus AA (homozygote): OR = 0.99, 95% CI: 0.91–1.06; CC + AC versus AA (dominant model): OR = 0.97, 95% CI: 0.90–1.05; and CC versus AC + AA (recessive model): OR = 0.99, 95% CI: 0.91–1.07). The present meta-analysis did not support any association between the MTHFR A1298C polymorphism and BC risk. PMID:25506474

  16. Methylenetetrahydrofolate reductase (MTHFR) 677C>T gene polymorphism as a possible factor for reducing clinical severity of psoriasis

    PubMed Central

    Karabacak, Ercan; Aydin, Ersin; Ozcan, Omer; Dogan, Bilal; Gultepe, Mustafa; Cosar, Alpaslan; Muftuoglu, Tuba

    2014-01-01

    Methylenetetrahydrofolate reductase (MTHFR) is a crucial enzyme in homocysteine/methionine metabolism. It catalysis the formation of 5-methyltetrahydrofolate (5-methyl-THF), which is the methyl donor for synthesis of methionine from homocysteine (Hcy). Decreases in folate consumption due to MTHFR polymorphism may affect production rate of keratinocytes of which had faster reproduction rates with a continuous DNA turnover and this may affect the clinical picture of psoriasis. This study aimed to investigate correlation of C677T polymorphisms in the MTHFR gene with severity of psoriasis and to evaluate the status of plasma Hcy, folate and vitamin B12 levels in patient with chronic plaque psoriasis. The study included 60 patients with chronic plaque psoriasis. The C677T polymorphisms were genotyped using PCR (Qiagen). Psoriasis Area and Severity Index (PASI) score below 7 was defined as mild, between 7 and 12 as moderate, and above 12 as severe disease. There was a significant difference between the severity of disease classification (p<0.05) with respect to the C677T polymorphism in the MTHFR gene. Severe involvement (PASI score >12) was observed in 38.46% of wild type (CC), but only 12.50% of homozygote (TT) and 7.69% of heterozygote (CT) patients. Significant differences between gene polymorphism and Hcy levels were noted in TT and CT genotypes respectively (p=0.025 and p=0.040). Plasma Hcy, folate and vitamin B12 levels were not correlated with the PASI score. Our data indicate a possible correlation of MTHFR polymorphism with severity of psoriasis. PMID:24753765

  17. Methylenetetrahydrofolate Reductase C677T Polymorphism and Recurrent Pregnancy Loss Risk in Asian Population: A Meta-analysis.

    PubMed

    Rai, Vandana

    2016-10-01

    The C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene was implicated to be associated with thrombophilia due to its role in catalyzing the formation of 5-methylenetetrahydrofolate, a co-substrate for the conversion of homocysteine to methionine. Several case-control studies were investigated MTHFR C677T polymorphism as risk for recurrent pregnancy loss (RPL). These studies rendered contradictory results, some indicating that the polymorphism is associated with the risk of RPL whereas others concluded there is no association. To shed light on these inconclusive findings, a meta-analysis of all available studies published from Asian population relating the C677T polymorphism to the risk of RPL was conducted. The following electronic databases were searched without language restrictions: PubMed, Google Scholars, Elsevier and Springer Link up to December, 2015. Meta-analysis was performed using MetaAnalyst and Mix version 1.7. Meta-analysis results suggested that MTHFR C677T polymorphism contributed to the increased RPL risk in Asian population using all five genetic models (for T vs. C: OR 1.35, 95 % CI 1.09-1.68, p = 0.009; for TT + CT vs. CC: OR 1.44, 95 % CI 1.14-1.82, p = 0.006; for CT vs. CC: OR 1.39, 95 % CI 1.07-1.8, p = 0.01; for TT vs. CC: OR 1.79, 95 % CI 1.23.2.6, p = 0.007; for TT vs. CT + CC: OR 1.61, 95 % CI 1.02-2.56, p = 0.04). In conclusion, this meta-analysis demonstrates a strong association between the MTHFR C677T variant and RPL in Asian population and raising the importance of the use of folate in its treatment and prevention. PMID:27605737

  18. Association of Methylenetetrahydrofolate Reductase C677T Polymorphism with Hyperhomocysteinemia and Deep Vein Thrombosis in the Iranian Population

    PubMed Central

    Ghaznavi, Habib; Soheili, Zahra; Samiei, Shahram; Soltanpour, Mohammad Soleiman

    2015-01-01

    Purpose: Deep venous thrombosis (DVT) is a common but elusive condition characterized by a high morbidity and mortality rate. The aim of the present study was to investigate the correlation between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism with plasma total homocysteine (tHcy) levels and DVT risk in an Iranian population. Materials and Methods: Our study population consisted of 67 patients with a diagnosis of DVT and 67 healthy subjects as controls. Genotyping of MTHFR C677T polymorphism was performed by the polymerase chain reaction technique combined with restriction enzyme fragment length polymorphism (PCR-RFLP) and measurement of tHcy levels was done by enzyme immunoassay method. Results: Plasma tHcy levels were significantly higher in DVT patients than controls (18.09±7.6 vs. 10.5±4.3, P=0.001). Also, plasma tHcy levels were significantly higher in MTHFR 677TT genotypes compared to 677CC genotypes in both DVT patients (P=0.016) and controls (P=0.03). Neither heterozygote nor homozygote genotypes of MTHFR C677T polymorphism was significantly correlated with DVT (P>0.05). The distribution of MTHFR C677T genotypes was similar between men and women in both DVT patients and controls (P>0.05). Moreover, the frequency of mutant 677T allele did not differ significantly between the two groups (28.3% vs. 21.6%, P=0.15). Conclusion: Based on this study, we propose that hyperhomocysteinemia but not homozygosity for MTHFR C677T polymorphism is a significant risk factor for DVT in the Iranian population. Also, MTHFR 677TT genotype is a determinant of elevated plasma tHcy levels. PMID:26719836

  19. Polymorphisms of 5,10-methylenetetrahydrofolate reductase and thymidylate synthase, dietary folate intake, and the risk of leukemia in adults.

    PubMed

    Liu, Ping; Zhang, Min; Xie, Xing; Jin, Jie; Holman, C D'Arcy J

    2016-03-01

    The 5,10-methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TS) are critical enzymes in folate metabolism. Previous studies have reported conflicting results on the associations between MTHFR/TS polymorphisms and adult leukemia risk, which may due to the lack of information on folate intake. We investigated the risks of adult leukemia with genetic polymorphisms of folate metabolic enzymes (MTHFR C677T, A1298C, and TS) and evaluated if the associations varied by dietary folate intake from a multicenter case-control study conducted in Chinese. This study comprised 442 incident adult leukemia cases and 442 outpatient controls, individually matched to cases by gender, birth quinquennium, and study site. Genotypes were determined by a polymerase chain reaction (PCR) or PCR-based restriction fragment length polymorphism assay. Dietary folate intake was assessed by face-to-face interviews using a validated food-frequency questionnaire. The MTHFR 677TT genotype conferred a significant higher risk of leukemia in males than in females and exhibited an increased risk of acute myeloid leukemia (AML) but a decreased risk of acute lymphoblastic leukemia (ALL). The MTHFR 1298AC genotype appeared to decrease the risks of leukemia in both genders, in AML and ALL. Stratified analysis by dietary folate intake showed the increased risks of leukemia with the MTHFR 677TT and TS 2R3R/2R2R genotypes were only significant in individuals with low folate intake. A significant interaction between TS polymorphism and dietary folate intake was observed (P = 0.03). This study suggests that dietary folate intake and gender may modify the associations between MTHFR/TS polymorphisms and adult leukemia risk. PMID:26438060

  20. Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and nonsyndromic orofacial clefts susceptibility in a southern Chinese population.

    PubMed

    Han, Yue; Pan, Yongchu; Du, Yifei; Tong, Na; Wang, Meilin; Zhang, Zhengdong; Wan, Linzhong; Wang, Lin

    2011-12-01

    Nonsyndromic orofacial clefts (NSOC) are one of the most common congenital anomalies in humans. Great efforts have been taken to unravel its genetic background. Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme in folate metabolism and two of its functional polymorphisms, MTHFR C677T and MTHFR A1298C, might be associated with NSOC susceptibility. The aim of the present study was to investigate their associations with risks of NSOC in a southern Chinese population. We found that MTHFR 677 TT and 677 CT/TT were associated with increased risk of cleft lip with or without cleft palate; meanwhile, MTHFR 1298 AC and 1298 AC/CC had protective effects against cleft lip with or without cleft palate. In further stratified analysis, we found that MTHFR 677 CT contributed to elevated risk of cleft lip only, as did MTHFR 677 CT/TT. On the contrary, MTHFR 1298 AC and 1298 AC/CC appeared to be protective against cleft lip with cleft palate. These results suggested that these two polymorphisms were involved in the development of NSOC in a southern Han Chinese population. PMID:21612398

  1. Methylenetetrahydrofolate reductase gene polymorphisms in Burkina Faso: impact on plasma fasting homocysteine and after methionine loading test.

    PubMed

    Angius, Andrea; Simpore, Jacques; Persico, Ivana; Sassu, Alessandro; Prodi, Dionigio Antonio; Musumeci, Salvatore

    2007-01-01

    In Burkina Faso the levels of plasma homocysteine (Hcy) are lower and the methionine loading tests suggest a more effective Hcy metabolism. The polymorphisms of methylenetetrahydrofolate reductase (MTHFR) showed a relevant difference in the allele frequencies of T MTHFR-677 in young and in old subjects, while the allele frequency of C MTHFR-1298 was comparable in young and old subjects. The aim of this paper was to study the impact of the MTHFR polymorphisms on plasma fasting Hcy and after methionine loading in Burkina Faso. The young subjects with CC MTHFR-677 genotype had levels of Hcy significantly lower than CT and TT subjects. The level of Hcy in subjects who had AA, AC and CC MTHFR-1298 genotypes were comparable. The levels of Hcy after the methionine loading test were significantly higher in CT and TT MTHFR-677 genotype. These results suggest that the genetic situation in Burkina Faso is different from that of other Western countries and this guarantees the maintenance of lower plasma levels of Hcy in young and old Africans. The elevated levels of plasma Hcy in old subjects compared to young subjects, against the low prevalence of the T allele in elderly subjects, is discussed. PMID:17323822

  2. Maternal Methylenetetrahydrofolate Reductase C677T Polymorphism and Down Syndrome Risk: A Meta-Analysis from 34 Studies

    PubMed Central

    Rai, Vandana; Yadav, Upendra; Kumar, Pradeep; Yadav, Sushil Kumar; Mishra, Om Prakesh

    2014-01-01

    Background Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme of folate metabolic pathway which catalyzes the irreversible conversion of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. 5-methyltetrahydrofolate donates methyl group for the methylation of homocysteine to methionine. Several studies have investigated maternal MTHFR C677T polymorphism as a risk factor for DS, but the results were controversial and inconclusive. To come into a conclusive estimate, authors performed a meta-analysis. Aim A meta-analysis of published case control studies was performed to investigate the association between maternal MTHFR C677T polymorphism and Down syndrome. Methods PubMed, Google Scholar, Elsevier, Springer Link databases were searched to select the eligible case control studies using appropriate keywords. The pooled odds ratio (OR) with 95%confidence interval were calculated for risk assessment. Results Thirty four studies with 3,098 DS case mothers and 4,852 control mothers were included in the present meta-analysis. The pooled OR was estimated under five genetic models and significant association was found between maternal MTHFR 677C>T polymorphism and Down syndrome under four genetic models except recessive model (for T vs. C, OR = 1.26, 95% CI = 1.09–1.46, p = 0.001; for TT vs. CC, OR = 1.49, 95% CI = 1.13–1.97, p = 0.008; for CT vs. CC, OR = 1.29, 95% CI = 1.10–1.51, p = 0.001; for TT+CT vs. CC, OR = 1.35, 95% CI = 1.13–1.60, p = 0.0008; for TT vs. CT+CC, OR = 0.76, 95% CI = 0.60–0.94, p = 0.01). Conclusion The results of the present meta-analysis support that maternal MTHFR C677T polymorphism is a risk factor for DS- affected pregnancy. PMID:25265565

  3. Association of the methylenetetrahydrofolate reductase gene C677T polymorphism with the risk of male infertility: a meta-analysis.

    PubMed

    Zhu, Xudong; Liu, Zhiguo; Zhang, Maochen; Gong, Ruihong; Xu, Yajun; Wang, Baoming

    2016-03-01

    Several molecular epidemiological studies have been conducted to examine the association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and male infertility susceptibility, but the results remain inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. In this meta-analysis, a total of 26 case-control studies including 5659 infertility cases and 5528 controls were selected to evaluate the possible association. The pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were used to assess the strength of association of C677T polymorphism with male infertility in the additive model, dominant model, recessive model and allele-frequency genetic model. In the overall analysis, the frequency of the 677T allele was significantly associated with male infertility susceptibility (OR = 2.32, 95%CI = 2.04-2.65 for TT vs. CC genotype; OR = 1.09, 95%CI = 1.00-1.19 for CT vs. CC genotype; OR = 1.19, 95%CI = 1.10-1.29 for CT/TT vs. CC genotype; OR = 1.54, 95%CI = 1.36-1.74 for TT vs. CC/TT genotype; OR = 1.22, 95%CI = 1.15-1.30 for T vs. C allele). A subgroup analysis of the subjects showed that significantly strong association between MTHFR C677T polymorphism and male infertility was present only in Asians, but not in Caucasians. Additionally, MTHFR C677T was associated with a significant increase in the risk of azoospermia in all genetic models. Meanwhile, no significantly increased risks of oligoasthenotertozoospermia (OAT) were found in most of the genetic models. In conclusion, this meta-analysis is in favor that the MTHFR C677T polymorphism is capable of causing male infertility susceptibility, especially in Asians and the subgroup of azoospermia. PMID:26584688

  4. A Meta-Analysis of Association between Methylenetetrahydrofolate Reductase Gene (MTHFR) 677C/T Polymorphism and Diabetic Retinopathy

    PubMed Central

    Luo, Shasha; Wang, Furu; Shi, Chao; Wu, Zhifeng

    2016-01-01

    Aims: To shed light on the conflicting findings of the association between the methylenetetrahydrofolate reductase gene (MTHFR) 677C/T polymorphism and the risk of diabetic retinopathy (DR), a meta-analysis was conducted. Methods: A predefined search was performed on 1747 DR cases and 3146 controls from 18 published studies by searching electronic databases and reference lists of relevant articles. A random-effects or fixed-effects model was used to estimate the sizes of overall and stratification effects of the MTHFR 677C/T polymorphism on the risk of DR, as appropriate. Results: Risks were evaluated by odds ratios (OR) with 95% confidence intervals (95% CI). We found a significant association between the MTHFR 677C/T polymorphism and the risk of DR for each genetic model (recessive model: OR = 1.67; 95% CI: 1.19–2.40 and dominant model: OR = 1.71; 95% CI: 1.28–2.28; respectively). In stratified analysis; we further found that the Asian group with both types of diabetes mellitus (DM) showed a significant association with genetic models (recessive model: OR = 2.16; 95% CI: 1.75–2.60 and dominant model: OR = 1.98; 95% CI: 1.42–2.76; respectively). Conclusions: Our study suggested that the MTHFR 677C/T polymorphism may contribute to DR development, especially in Asian populations. Prospective and additional genome-wide association studies (GWAS) are needed to clarify the real role of the MTHFR gene in determining susceptibility to DR. PMID:27517946

  5. Haplotype analysis of the 5,10-methylenetetrahydrofolate reductase (MTHFR) c.1298A>C (E429A) polymorphism

    PubMed Central

    2011-01-01

    Background The polymorphism 5,10-methylenetetrahydrofolate reductase (MTHFR) c.1298A>C is associated with various diseases. 45 DNA samples homozygous for the A allele and 40 DNA probes homozygous for the C allele were taken from healthy German subjects of white Caucasian origin to analyze the haplotype of the two MTHFR c.1298A>C alleles. Samples were genotyped for the polymorphism MTHFR c.677C>T and for the silent polymorphisms MTHFR c.129C>T, IVS2 533 G>A, c.1068C>T and IVS10 262C>G. Findings Haplotype construction revealed that the C-allele of MTHFR c.1298A>C was more frequently observed in cis with c.129T, IVS2 533A, c.677C, c.1068T, and IVS10 262 G than expected from normal distribution. Estimation of the most recent common ancestor with the DMLE + 2.3 program resulted in an estimated age of approximately 36,660 years of the MTHFR c.1298C allele. Conclusion Given that the era from 30,000 to 40,000 years ago is characterised by the spread of modern humans in Europe and that the prevalence of the MTHFR c.1298C allele is significantly higher in Central Europe in comparison to African populations, a selective advantage of MTHFR c.1298C could be assumed, e. g. by adaption to changes in the nutritional environment. The known founder ancestry of the T allele of MTHFR c.677C>T allele, together with the present data suggests that the MTHFR mutant alleles c.677T and 1298C arose from two independent ancestral alleles, that both confer a selective advantage. PMID:22023786

  6. Association between a microRNA-214 binding site polymorphism in the methylenetetrahydrofolate reductase gene and esophageal squamous cell carcinoma.

    PubMed

    Shen, G R; Li, W Z; Liu, Y C; Li, X P; Yuan, H Y

    2016-01-01

    MicroRNAs (miRNAs) are key regulators of gene expression and play an important role in the development and progression of various diseases including esophageal squamous cell carcinoma (ESCC). In this study, we determined whether a polymorphism at the miR-214 binding site in the 3'-untranslated region (3'-UTR) of the methylenetetrahydrofolate reductase gene (MTHFR) is associated with susceptibility to ESCC. A total of 448 ESCC cases and 460 gender- and age-matched subjects were recruited for the study. The genotypes of the rs114673809 single nucleotide polymorphism (SNP) were determined by polymerase chain reaction sequencing. Associations between genotypes of MTHFR rs114673809 and ESCC risk were determined using logistic regression analyses. In the recessive model, when the MTHFR rs114673809 GG homozygote genotype was used as the reference group, the GA genotype was not associated with the risk of ESCC (GA vs GG: OR = 1.261, 95%CI = 0.960-1.657, P = 0.110), but the AA genotype was associated with increased risk of ECSS (AA vs GG: OR = 1.752, 95%CI = 1.076-2.853, P = 0.027). Additionally, the rs114673809 A allele carriers also showed a 1.286-fold increased ESCC risk compared with those carrying the rs114673809 G allele genotype. Furthermore, we observed a significant increase in plasma homocysteine levels in ESCC cases carrying the AA genotype relative to ESCC cases carrying the GG genotype. Our data demonstrate that a polymorphism at the miR-214 binding site in the 3'-UTR of MTHFR is an ESCC susceptibility SNP in the Chinese population. PMID:27323028

  7. Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and fluorouracil-based treatment in Taiwan colorectal cancer.

    PubMed

    Wu, Nai-Chun; Su, Shih-Ming; Lin, Tai-Jung; Chin, Jen; Hou, Chun-Fang; Yang, Jhong-Ying; Liu, Wen-Sheng; Chang, Li-Ching

    2015-09-01

    This study aimed to investigate the association between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and the prognosis of colorectal cancer (CRC) patients undergoing 5-fluorouracil (5-FU)-based chemotherapy in Taiwan. We investigated 126 CRC cases. The most common polymorphisms C677T (rs1801133) and A1298C (rs1801131) in MTHFR were genotyped using PCR-restriction fragment length polymorphism. The frequencies of C677T and A1298C were further compared with those in the HapMap database for Whites and Asians. In this study, we found that TT-homozygosity at MTHFR C677T was significantly associated with survival in CRC patients [P<0.001; 95% confidence interval (CI)=0.068-0.212]. In CRC patients receiving 5-FU-based chemotherapy, the TT genotype at C677T was also significantly associated with survival (P=0.001; 95% CI=0.113-0.400) and recurrence after surgery (P<0.001; 95% CI=0.295-0.609). The A1298C genotypes had a significant impact on survival (χ=7.103; P=0.029). The MTHFR A1298C CC genotype may increase the risk of death in Taiwanese CRC patients. The MTHFR C677T TT genotype was present at a lower frequency in our CRC patients than in the HapMap Asian population, but the frequency was similar to that in Whites in the HapMap database. The distribution of MTHFR A1298C genotypes was similar in our CRC and in the HapMap Asian population, but was different from that in the White population. This study suggested that MTHFR C677T and A1298C are associated with prognosis in CRC patients undergoing 5-FU-based chemotherapy. PMID:26111049

  8. Methylenetetrahydrofolate reductase C677T polymorphism is associated with increased risk of coronary artery disease in young South African Indians.

    PubMed

    Ramkaran, Prithiksha; Phulukdaree, Alisa; Khan, Sajidah; Moodley, Devapregasan; Chuturgoon, Anil A

    2015-10-15

    Methylenetetrahydrofolate reductase (MTHFR) reduces 5',10'-methylenetetrahydrofolate to 5'-methyltetrahydrofolate, and is involved in remethylation of homocysteine to methionine, two important reactions involved in folate metabolism and methylation pathways. The common MTHFR C677T single nucleotide polymorphism (SNP) (rs1801133) has been associated with raised levels of homocysteine, a well known risk factor for coronary artery disease (CAD). CAD is a major cause of mortality worldwide. The age of onset of this chronic disorder is on the decline, particularly in the Indian population. Indians in South Africa (SA) have a higher prevalence of premature CAD compared to Black South Africans. The MTHFR C677T SNP has not been investigated in the SA Indian population. The present study therefore investigated the MTHFR C677T SNP in young SA Indian males with CAD compared to young Indian and Black male controls. A total of 290 subjects were recruited into this study which included 106 CAD patients (diagnosed on angiography, mean age 37.5, range 24-45 years), 100 Indian male controls (mean age 37.5, range 28-45 years), and 84 Black male controls (mean age 36.4, range 25-45). Polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP) was used to genotype CAD patients and healthy controls. Data for clinical markers were obtained from pathology reports. There was a significant association between the 677 MTHFR variant (T) allele and CAD patients compared to the healthy Indian controls (p=0.0353, OR=2.105 95% CI 1.077-4.114). Indian controls presented with a higher frequency of the variant allele compared to Black controls (7% vs. 2% respectively, p=0.0515 OR=3.086 95% CI 0.9958-9.564). The MTHFR C677T SNP did not influence levels of total cholesterol, LDL, HDL, triglycerides, fasting glucose, fasting insulin, HbA1c or hsCRP. The higher frequency of the MTHFR 677 variant allele in South African Indians may be a contributing factor to the higher

  9. [Polymorphism of genes coding for angiotensin I converting enzyme and methylenetetrahydrofolate reductase in patients with ischemic heart disease].

    PubMed

    Goracy, I

    2000-01-01

    Due to its multifarious biological activity the renin-angiotensin system occupies a special position among risk factors of ischemic heart disease. The discovery of I/D polymorphism of the ACE gene led to a better understanding of genetic control of this enzyme. Hyperhomocysteinemia is an independent risk factor of ischemic heart disease. Elevated plasma levels of homocysteine may be due to improper diet (e.g. shortage of folic acid) and/or genetic influence. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the metabolism of homocysteine. The present study was performed in 100 patients (14 women and 86 men, mean age 54.2 +/- 9.2 years) with a history of myocardial infarction. The control group included 100 patients (10 women and 90 men, mean age 52.3 +/- 10 years) without such history. PCR was used to detect I/D ACE and C677T MTHFR polymorphisms. Genomic DNA was isolated from peripheral blood nuclear cells and amplified by PCR with two pairs of primers flanking the polymorphic regions. The restriction enzyme Hinf I was used to identify genotypes of the MTHFR polymorphism. No difference between both groups was found concerning the distribution of I/D ACE genotypes (31% II, 51% ID, 18% DD in the study group; 30% II, 57% ID, 13% DD in the control group; Tab. 1) or the distribution of C677T MTHFR genotypes (46% CC, 45% CT, 9% TT in the study group; 39% CC, 50% CT, 11% TT in the control group; Tab. 2). There was a significant effect of I/D genotype on ACE activity (IU/L) in the study (II = 18.2 +/- 17.9; ID = 33.5 +/- 19.9; DD = 68.9 +/- 21.9) and in the control group (II = 24.2 +/- 18.1; ID = 31.5 +/- 20.9; DD = 51.4 +/- 19.5; Tab. 3). No correlation was confirmed between ACE or MTHFR genotypes and age at infarction or left ventricular mass (Tabs. 4, 5, 6). The results indicate that neither the I/D ACE nor the C677T MTHFR polymorphisms are associated with risk of myocardial infarction in the Polish population. PMID:11712321

  10. 5,10-Methylenetetrahydrofolate reductase codon 677 and 1298 polymorphisms and colon cancer in African Americans and whites.

    PubMed

    Keku, Temitope; Millikan, Robert; Worley, Kendra; Winkel, Scott; Eaton, Allison; Biscocho, Lorna; Martin, Christopher; Sandler, Robert

    2002-12-01

    We evaluated polymorphisms in methylenetetrahydrofolate reductase (MTHFR), folate intake and alcohol consumption in relation to risk of colon cancer in a population-based case-control study in North Carolina. The study included 555 cases (244 African Americans and 311 whites) and 875 controls (331 African Americans and 544 whites). Total folate intake of <400 versus > or =400 microg/day showed a weak positive association with colon cancer among both African Americans [adjusted odds ratio (OR) = 1.4, 95% confidence interval (CI) = 1.0-2.0] and whites (OR = 1.6, 95% CI = 1.2-2.2). No association was observed with use of alcohol. Compared with wild-type genotypes, there was no association between the low activity MTHFR codon 677 TT genotype and colon cancer, but the low activity codon 1298 CC genotype was inversely associated with colon cancer in whites (OR = 0.5, 95% CI = 0.3-0.9). Unlike previous studies, we did not observe a strong protective effect of the codon 677 TT low-activity genotype when folate intake was high. Instead, we observed an increased risk of colon cancer when folate intake was low for participants with wild- type genotypes. Adjusted ORs for the combined effects of codon 677 CC and codon 1298 AA genotypes and folate intake <400 microg/day were 1.9 (95% CI = 1.1-3.4) in African Americans and 2.5 (95% CI = 1.2-5.2) in whites. Our results suggest that variation at MTHFR codon 1298 (within the COOH-terminal region) may be more important for colon cancer than variation at codon 677 (NH(2)-terminal region), and in populations where folate intake is low, wild-type MTHFR activity may increase risk for colon cancer. PMID:12496052

  11. Methionine synthase reductase 66A->G polymorphism is associated with increased plasma homocysteine concentration when combined with the homozygous methylenetetrahydrofolate reductase 677C->T variant.

    PubMed

    Vaughn, Jaimie D; Bailey, Lynn B; Shelnutt, Karla P; Dunwoody, Kristina M von-Castel; Maneval, David R; Davis, Steven R; Quinlivan, Eoin P; Gregory, Jesse F; Theriaque, Douglas W; Kauwell, Gail P A

    2004-11-01

    Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) are important for homocysteine remethylation. This study was designed to determine the influence of genetic variants (MTHFR 677C-->T, MTHFR 1298A-->C, and MTRR 66A-->G), folate, and vitamin B-12 status on plasma homocysteine in women (20-30 y; n = 362). Plasma homocysteine was inversely (P < 0.0001) associated with serum folate and plasma vitamin B-12 regardless of genotype. Plasma homocysteine was higher (P < 0.05) for women with the MTHFR 677 TT/1298 AA genotype combination compared with the CC/AA, CC/AC, and CT/AA genotypes. Women with the MTHFR 677 TT/MTRR 66 AG genotype had higher (P < 0.05) plasma homocysteine than all other genotype combinations except the TT/AA and TT/GG genotypes. There were 5.4-, 4.3-, and 3.8-fold increases (P < 0.001) in risk for plasma homocysteine in the top 5, 10, and 20%, respectively, of the homocysteine distribution for subjects with the MTHFR 677 TT compared with the CC and CT genotypes. Predicted plasma homocysteine was inversely associated with serum folate (P = 0.003) and plasma vitamin B-12 (P = 0.002), with the degree of correlation dependent on MTHFR 677C-->T genotype. These data suggest that coexistence of the MTHFR 677 TT genotype with the MTRR 66A-->G polymorphism may exacerbate the effect of the MTHFR variant alone. The potential negative effect of combined polymorphisms of the MTHFR and MTRR genes on plasma homocysteine in at-risk population groups with low folate and/or vitamin B-12 status, such as women of reproductive potential, deserves further investigation. PMID:15514263

  12. Association between the methylenetetrahydrofolate reductase c.677C>T polymorphism and bone mineral density: an updated meta-analysis.

    PubMed

    Li, Hong-Zhuo; Wang, Wei; Liu, Yi-Ling; He, Xiao-Feng

    2016-02-01

    Many studies have reported an association between the methylenetetrahydrofolate reductase (MTHFR) c.677C>T polymorphism and reduced bone mineral density (BMD), but results have been inconsistent. We, therefore, performed a meta-analysis to further explore this association. Twenty-one studies, comprising 33,045 subjects, analyzed the association of MTHFR c.677C>T with femoral neck BMD. Significant association with reduced BMD was observed in Caucasians (recessive model: WMD = -0.004 g/cm(2), 95 % CI -0.008 to -0.006), post-menopausal women (recessive model: WMD = -0.005 g/cm(2), 95 % CI -0.007 to -0.003), men (dominant model: WMD = -0.004 g/cm(2), 95 % CI -0.005 to -0.004; recessive model: WMD = -0.004 g/cm(2), 95 % CI -0.005 to -0.004; TT vs. CC: WMD = -0.006 g/cm(2), 95 % CI -0.006 to -0.006; CT vs. CC: WMD = -0.003 g/cm(2), 95 % CI -0.003 to -0.003), and cohort studies (recessive model: WMD = -0.003 g/cm(2), 95 % CI -0.006 to -0.001). Twenty-two studies, which included 32,271 subjects, analyzed the MTHFR c.677C>T association with lumbar spine BMD. Significant association with reduced BMD was observed in Caucasians, women, post-menopausal women, men, and cohort studies. Seven studies, comprising 6806 subjects, analyzed the MTHFR c.677C>T association with total hip BMD, but no significant association was observed in any population. Nine studies involving 5591 subjects analyzed the association with total body BMD. Significant association with reduced BMD was observed in overall and women subgroup analyses. In summary, this meta-analysis indicates that the MTHFR c.677C>T polymorphism is associated with reduced BMD in lumbar spine and femoral neck in Caucasians, post-menopausal women, and men, and with total body BMD in women. In addition, our results suggest that new studies examining the association between MTHFR c.677C>T polymorphism and BMD of lumbar spine and femoral neck in Asians is warranted, because I (2) > 75.0 % was observed

  13. Associations between Methylenetetrahydrofolate Reductase (MTHFR) Polymorphisms and Non-Alcoholic Fatty Liver Disease (NAFLD) Risk: A Meta-Analysis

    PubMed Central

    Sun, Man-Yi; Zhang, Li; Shi, Song-Li; Lin, Jing-Na

    2016-01-01

    Background C677T and A1298C are the most common allelic variants of Methylenetetrahydrofolate Reductase (MTHFR) gene. The association between MTHFR polymorphisms and the occurrence of non-alcoholic fatty liver disease (NAFLD) remains controversial. This study was thus performed to examine whether MTHFR mutations are associated with the susceptibility to NAFLD. Methods A first meta-analysis on the association between the MTHFR polymorphisms and NAFLD risks was carried out via Review Manager 5.0 and Stata/SE 12.0 software. The on-line databases, such as PubMed, EMBASE, CENTRAL, WOS, Scopus and EBSCOhost (updated to April 1st, 2016), were searched for eligible case-control studies. The odd radio (OR), 95% confidence interval (CI) and P value were calculated through Mantel-Haenszel statistics under random- or fixed-effect model. Results Eight articles (785 cases and 1188 controls) contributed data to the current meta-analysis. For C677T, increased NAFLD risks were observed in case group under homozygote model (T/T vs C/C, OR = 1.49, 95% CI = 1.03~2.15, P = 0.04) and recessive model (T/T vs C/C+C/T, OR = 1.42, 95% CI = 1.07~1.88, P = 0.02), but not the other genetics models, compared with control group. For A1298C, significantly increased NAFLD risks were detected in allele model (C vs A, OR = 1.53, 95% CI = 1.13~2.07, P = 0.006), homozygote model (C/C vs A/A, OR = 2.81, 95% CI = 1.63~4.85, P = 0.0002), dominant model (A/C+C/C vs A/A, OR = 1.60, 95% CI = 1.06~2.41, P = 0.03) and recessive model (C/C vs A/A+A/C, OR = 2.08, 95% CI = 1.45~3.00, P<0.0001), but not heterozygote model. Conclusion T/T genotype of MTHFR C677T polymorphism and C/C genotype of MTHFR A1298C are more likely to be associated with the susceptibility to NAFLD. PMID:27128842

  14. Polymorphisms and haplotypes in methylenetetrahydrofolate reductase gene and head and neck squamous cell carcinoma risk.

    PubMed

    Galbiatti, Ana Lívia Silva; Ruiz, Mariangela Torreglosa; Rodrigues, Juliana Olsen; Raposo, Luiz Sérgio; Maníglia, José Victor; Pavarino, Érika Cristina; Goloni-Bertollo, Eny Maria

    2012-01-01

    Functional polymorphisms in genes encoding enzymes involved in folate metabolism might modulate head and neck carcinoma risk because folate participates in DNA methylation and synthesis. We therefore conducted a case-control study of 853 individuals (322 head and neck cancer cases and 531 non-cancer controls) to investigate associations among MTHFR C677T and MTHFR A1298C polymorphisms and head and neck squamous cell carcinoma risk. Interactions between these two polymorphisms and risk factors and clinical histopathological parameters were also evaluated. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was used to genotype the polymorphisms and Chi-square test and multiple logistic regression were used for statistical analyses. The variables age≥49 years, male gender, tobacco habits and alcohol consumption, MTHFR 1298 AC or CC genotypes, combined genotypes with two or more polymorphic alleles and 677T and 1298C polymorphic alleles were associated with increased risk for this disease (P<0.05). Furthermore, we found that 1298 AC or CC genotypes were associated with age≥49 years, tobacco and alcohol habits (P<0.05). Regarding clinical histopathological parameters, the A1298C polymorphism was more frequent in patients with oral cavity as primary site (P<0.05). MTHFR polymorphisms may contribute for increase risk for head and neck carcinoma and the variables age≥49 years, male gender, tobacco and alcohol habits were associated with MTHFR 1298AC or CC genotypes, confirming that individuals with these variables and MTHFR A1298C polymorphism has higher risk for this disease. PMID:21556759

  15. Serum homocysteine, vitamin B12, folic acid levels and methylenetetrahydrofolate reductase (MTHFR) gene polymorphism in vitiligo.

    PubMed

    Yasar, Ali; Gunduz, Kamer; Onur, Ece; Calkan, Mehmet

    2012-01-01

    The aim of this study was to determine serum vitamin B12, folic acid and homocysteine (Hcy) levels as well as MTHFR (C677, A1298C) gene polymorphisms in patients with vitiligo, and to compare the results with healthy controls. Forty patients with vitiligo and 40 age and sex matched healthy subjects were studied. Serum vitamin B12 and folate levels were determined by enzyme-linked immunosorbent assay. Plasma Hcy levels and MTHFR polymorphisms were determined by chemiluminescence and real time PCR methods, respectively. Mean serum vitamin B12 and Hcy levels were not significantly different while folic acid levels were significantly lower in the control group. There was no significant relationship between disease activity and vitamin B12, folic acid and homocystein levels. No significant difference in C677T gene polymorphism was detected. Heterozygote A1298C gene polymorphism in the patient group was statistically higher than the control group. There was no significant relationship between MTHFR gene polymorphisms and vitamin B12, folic acid and homocysteine levels. In conclusion, vitamin B12, folate and Hcy levels are not altered in vitiligo and MTHFR gene mutations (C677T and A1298C) do not seem to create susceptibility for vitiligo. PMID:22846211

  16. Association of methylenetetrahydrofolate reductase (MTHFR) gene polymorphism with ischemic stroke in the Eastern Chinese Han population.

    PubMed

    Lv, Q-Q; Lu, J; Sun, H; Zhang, J-S

    2015-01-01

    The association between the MTHFR genetic polymorphism and ischemic stroke has been reported by a number of investigators. However, the results have been controversial and conflicting. The aim of this study was to explore the association between the MTHFR variants C677T and A1298C and the risk of ischemic stroke in an Eastern Chinese Han population. A total of 199 patients with ischemic stroke and 241 controls were recruited. Genotyping of the MTHFR C677T and A1298C polymorphisms was carried out using the Taqman 7900HT Sequence Detection System. The overall estimates (odds ratio: OR) for the allele (C) and genotype (AC+CC) of the A1298C polymorphism were 1.57 [95% confidence interval (CI) = 1.16-2.10], and 2.36 (95%CI = 1.39-4.00), respectively, establishing significant association of the MTHFR A1298C polymorphism with ischemic stroke. In contrast, there were no statistically significant differences compared to controls between MTHFR C677T polymorphic variants in the association ischemic stroke risk. Furthermore, haplotype-based analysis demonstrated that compared with the C-677-A-1298 haplotype, the C-677-C-1298 and T-677-C-1298 haplotypes showed significant increased risk of ischemic stroke (OR = 1.56; 95%CI = 1.07- 2.2; P = 0.02; OR = 1.76; 95%CI = 1.17-2.65; P < 0.01, respectively). We concluded that the A1298C polymorphism and the haplotypes C-677-C-1298 and T-677-C-1298 in MTHFR might modulate the risk of ischemic stroke in the Eastern Chinese Han population. PMID:25966188

  17. Methylenetetrahydrofolate reductase C677T gene polymorphism in Turkish patients with polycystic ovary syndrome.

    PubMed

    Karadeniz, Muammer; Erdogan, Mehmet; Zengi, Ayhan; Eroglu, Zuhal; Tamsel, Sadik; Olukman, Murat; Saygili, Fusun; Yilmaz, Candeger

    2010-08-01

    Higher Levels of Hcy are associated with several clinical conditions, among them non-insulin-dependent diabetes mellitus, endometrial dysplasia and hypertension with insulin resistance, and polycystic ovary syndrome. The purpose of this study was to investigate the serum homocystein levels and other metabolic parameters in relationship with the MTHFR C677T gene polymorphism in patients with PCOS. Our study included 86 young women with PCOS constituting the study group and 70 healthy women constituting the control group. Homocystein levels, metabolic, and hormonal parameters were measured, and genetic analysis of the MTHFR C677T gene polymorphism was performed in all the subjects. A statistically significant difference was observed in mean homocystein levels between patients with PCOS when compared to the control group. The MTHFR 677 CC genotypes had significantly higher proportions in the control group compared to the PCOS patients (χ(2) = 21.381, P < 0.001). Our data show that homocystein levels were higher than normal subjects in patients with PCOS and that the MTHFR C677T gene polymorphism does not influence homocystein levels of patients with PCOS. PMID:20960113

  18. Methylenetetrahydrofolate reductase gene polymorphisms and the risk of colorectal carcinoma in a sample of Egyptian individuals.

    PubMed

    El Awady, Mostafa K; Karim, Amr M; Hanna, Laila S; El Husseiny, Lamia A; El Sahar, Medhat; Menem, Hanan A Abdel; Meguid, Nagwa A

    2009-01-01

    The study was planned as a pilot study to investigate two common polymorphisms in the MTHFR gene c.677C > T and c.1298A > C and their association with enhanced risk of colorectal cancer (CRC) in a sample of Egyptian individuals. Venous blood samples were withdrawn from 35 cases of CRC and 68 healthy controls. Specimens from colonic and rectal carcinoma tissues in addition to cancer free tissues were obtained from all cases. Frequencies of MTHFR677T and 1298C alleles were significantly higher among cases of CRC tumor tissues (50% and 56%, respectively) than germ line alleles in CRC patients (33% and 41%, respectively) and healthy controls (21% and 35%, respectively). Frequencies of heterozygous and homoyzgous polymorphisms of MTHFR at positions 677 and 1298 in carcinoma tissues were always the highest. At position 677, TT and CT genotype frequencies were 17% and 66% with an odds ratio {OR} of 11 [95% confidence interval {CI} 2.39-50.59] and OR 8.34 [95%CI 2.97-23.92], respectively, in carcinoma tissues. While in the germ line of patients the genotype frequencies of 677TT and CT were 6% and 54% with OR 1.57 [95%CI 0.26-9.51] and 2.99 [95%CI 1.25-7.12], respectively, compared to controls (6% and 29%, respectively). The combined genotype MTHFR 1298CC + AC frequencies were 86% with OR 3.71 [95%CI 1.28-10.78] in carcinoma tissues, 69% with OR 1.35 [95%CI 0.57-3.21] in germ line of patients and 62% in controls. The combined genotype 677CT plus any of the following genotypes 1298AA, AC or CC enhanced risk of CRC, when comparing germ line DNA polymorphism of patients versus peripheral blood DNA of control subjects with OR 4.5 [95%CI 0.94-21.56], OR 3.12 [95%CI 0.79-12.36] and OR 18 [95%CI 1.56-207.5], respectively, suggesting strong genetic predisposition of certain Egyptian population to CRC. These results suggested that at least one C to T polymorphism at 677MTHFR gene is required to significantly increase the risk for CRC development. Further large scale studies are

  19. Methylenetetrahydrofolate reductase gene polymorphisms and the risk of anencephaly in Mexico.

    PubMed

    Muñoz, Julia Blanco; Lacasaña, Marina; Cavazos, Ricardo García; Borja-Aburto, Victor Hugo; Galavíz-Hernández, Carlos; Garduño, Clemente Aguilar

    2007-06-01

    The precise etiology of neural tube defects (NTDs) is not known. There is some evidence that mutations in MTHFR gene provide susceptibility to NTDs in some populations; however, other studies have not found this association. One of the problems with previous studies is that they treat NTDs as a homogeneous group, when specific defects could have different etiologies. We conducted a case-control study specifically for anencephaly, based on the Mexican Epidemiological Surveillance System of Neural Tube Defects to evaluate its association with maternal MTHFR 677C > T and 1298A > C polymorphisms, in three states with high frequencies of NTDs: Puebla, Estado de México and Guerrero. We interviewed and collected blood samples from 118 case mothers and 112 control mothers. The questionnaire included information on their reproductive history, socioeconomic characteristics, prenatal care, tobacco and alcohol use, presence of chronic diseases, acute illnesses and fever, consumption of multivitamins and drugs during the periconceptional period. After adjusting for potential confounders, the risk from the mutated homozygous mothers (677TT genotype) was significantly higher than that from mothers with 677CC genotype (OR 3.16, 95% CI 1.29-7.73); in the case of the heterozygous mothers, an increased risk of anencephaly was observed, even though this was not statistically significant (OR 1.81 95% CI 0.78-4.25). The association found between maternal 677TT genotype and anencephaly and the elevated presence of the 677T allele among Mexican women of fertile age urges intensifying folic acid supplementation which has proved to modify this genetic risk in other populations. PMID:17439956

  20. Association between methylenetetrahydrofolate reductase (MTHFR) polymorphisms and susceptibility to Graves' ophthalmopathy.

    PubMed

    Lee, Jae Yeun; Kim, Nam Keun; Cho, Yong Wook; Lew, Helen

    2016-09-01

    The pathogenesis of Graves' ophthalmopathy (GO) remains to be entirely elucidated. The present study aimed to determine the association between phenotypic expression of the MTHFR gene and susceptibility to GO in patients with Graves' disease (GD). A prospective case‑controlled study was conducted with 122 patients with GD and GO (n=72) or without GO (n=50) and 100 healthy controls in South Korea. Patient history, including smoking, nutritional status, thyroid function and antithyroid antibodies were investigated and clinical activity score, VISA classification (which includes vision, inflammation, strabismus and appearance/exposure) and orbit computed tomography were evaluated. Fasting plasma total homocysteine (tHcy) concentration was measured, and genotype analysis of the MTHFR gene was conducted. The TT homozygous genotype was associated with a two‑fold increased risk of GO [adjusted odds ratio (AOR), 2.19; 95% confidence interval (CI), 0.78‑6.14]. However, this result was not significant. The TT genotype significantly increased the risk of GO compared with that in healthy controls (AOR, 2.92; 95% CI, 1.11‑7.65). The MTHFR 677CT/1298AA genotype decreased the risk of GO in patients with GD (AOR, 0.26; 95% CI, 0.08‑0.91). tHcy levels in patients with GD without GO were significantly higher than in patients with GO, however, they were within the normal limit. The current study identified an association between MTHFR polymorphisms and GO. These results will aid understanding of the pathogenesis of GO and facilitate development of genetic therapeutic strategies. PMID:27430300

  1. 5,10-methylenetetrahydrofolate reductase 677 and 1298 polymorphisms, folate intake, and microsatellite instability in colon cancer.

    PubMed

    Eaton, Allison M; Sandler, Robert; Carethers, John M; Millikan, Robert C; Galanko, Joseph; Keku, Temitope O

    2005-08-01

    The 5,10-methylenetetrahydrofolate reductase (MTHFR) gene plays a critical role in folate metabolism. Studies on the association between MTHFR polymorphisms and length changes in short tandem repeat DNA sequences [microsatellite instability (MSI)] are inconsistent. Using data from colon cancer cases (n=503) enrolled as part of an existing population-based case-control study, we investigated the association between MTHFR 677 and MTHFR 1298 polymorphisms and MSI. We also examined whether the association was modified by folate intake. Participants were case subjects enrolled as part of the North Carolina Colon Cancer Study. Consenting cases provided information about lifestyle and diet during in-home interviews as well as blood specimens and permission to obtain tumor blocks. DNA from normal and tumor tissue sections was used to determine microsatellite status (MSI). Tumors were classified as MSI if two or more microsatellite markers (BAT25, BAT26, D5S346, D2S123, and D17S250) had changes in the number of DNA sequence repeats compared with matched nontumor tissue. Tumors with one positive marker (MSI-low) or no positive markers (microsatellite stable) were grouped together as non-MSI tumors (microsatellite stable). MTHFR 677 and MTHFR 1298 genotypes were determined by real-time PCR using the 5' exonuclease (Taqman) assay. Logistic regression was used to calculate odds ratio (OR) and 95% confidence intervals (95% CI). MSI was more common in proximal tumors (OR, 3.8; 95% CI, 1.7-8.4) and in current smokers (OR, 4.0; 95% CI, 1.6-9.7). Compared with MTHFR 677 CC referent, MTHFR 677 CT/TT genotype was inversely associated with MSI among White cases (OR, 0.36; 95% CI, 0.16-0.81) but not significant among African Americans. Although not statistically significant, a similar inverse association was observed between MTHFR 677 CT/TT genotype and MSI among the entire case subjects (OR, 0.54; 95% CI, 0.26-1.10). Among those with adequate folate intake (>400 microg total folate

  2. Methylenetetrahydrofolate reductase deficiency: importance of early diagnosis.

    PubMed

    Fattal-Valevski, A; Bassan, H; Korman, S H; Lerman-Sagie, T; Gutman, A; Harel, S

    2000-08-01

    Methylenetetrahydrofolate reductase deficiency is the most common inborn error of folate metabolism and should be suspected when homocystinuria is combined with hypomethioninemia. The main clinical findings are neurologic signs such as severe developmental delay, marked hypotonia, seizures, microcephaly, apnea, and coma. Most patients present in early life. The infantile form is severe, with rapid deterioration leading to death usually within 1 year. Treatment with betaine has been shown to be efficient in lowering homocysteine concentrations and returning methionine to normal, but the clinical response is variable. We report two brothers with methylenetetrahydrofolate reductase deficiency: the first was undiagnosed and died at 8 months of age from neurologic deterioration and apnea, while his brother, who was treated with betaine from the age of 4 months, is now 3 years old and has developmental delay. PMID:10961793

  3. C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase gene: effect on methotrexate-related toxicity in adult acute lymphoblastic leukaemia.

    PubMed

    Eissa, Deena Samir; Ahmed, Tamer Mohamed

    2013-03-01

    Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme involved in folate metabolism. Two polymorphisms, C677T and A1298C, were described leading to reduced enzyme activity. Methotrexate (MTX) is an antifolate agent of consolidation and maintenance therapy of acute lymphoblastic leukaemia (ALL). Despite its clinical success, MTX can be associated with serious toxicities resulting in treatment interruption or discontinuation, impacting disease outcome. There is evidence that MTX toxicity can be affected by polymorphisms in genes encoding for drug-metabolizing enzymes such as MTHFR. Therefore, we aimed to investigate the influence of MTHFR C677T and A1298C polymorphisms on the frequency of MTX-related toxicity, disease outcome and patients' survival. MTHFR polymorphisms were assessed in 50 adult patients with de novo ALL using real-time PCR. Patients were followed-up for the development of haematologic and/or nonhaematologic toxicity and assessment of clinical outcome. Frequency of C677T polymorphisms was 42% for TT, 24% for CT and 34% for CC; A1298C polymorphisms were 28, 6 and 66% for CC, AC and AA, respectively. MTX therapy was significantly associated with neutropaenia, hepatic and gastrointestinal toxicities, unfavourable response at day 14 of induction therapy, increased relapse and mortality rates and shorter survival in patients with 677 TT genotype than in those with CC and CT, whereas 1298 CC genotype patients had lower frequency of neutropaenia, hepatic toxicity and relapse than in those with AA and AC. Our study suggests MTHFR polymorphism as an attractive predictor of MTX-related toxicity in adult ALL, considering it a potential prognostic factor influencing disease outcome. PMID:23183238

  4. Association of methylenetetrahydrofolate reductase C677T-A1298C polymorphisms with risk for esophageal adenocarcinoma, Barrett's esophagus, and reflux esophagitis.

    PubMed

    Ekiz, F; Ormeci, N; Coban, S; Karabulut, H G; Aktas, B; Tukun, A; Tuncali, T; Yüksel, O; Alkış, N

    2012-07-01

    Incidence of the esophagus adenocarcinoma has been dramatically increasing in Western countries since the last decade. Gastroesophageal reflux disease and Barrett's esophagus are risk factors for adenocarcinoma. Methylenetetrahydrofolate reductase (MTHFR) genes play a key role not only in folate metabolism but also in esophagus, stomach, pancreatic carcinoma, and acute leukemias. Studies have suggested that genetic polymorphisms of MTHFR (C677T) may clarify the causes and events involved in esophageal carcinogenesis. In this study, we evaluated MTHFR C677T and A1298C polymorphisms, and vitamin B12, folate, and plasma homocystein levels in patients with esophageal adenocarcinoma (EAC), Barrett's esophagus (BE), chronic esophagitis, and healthy controls (n = 26, n = 14, n = 30, and n = 30, respectively). The mean age of patients in the EAC and BE groups was significantly higher compared with the control group (P < 0.001, P = 0.003, respectively). In all patient groups, serum folate levels were significantly lower than that of the control group (P < 0.01, P < 0.05, and P < 0.01, respectively). There was no statistically significant association between folate levels and MTHFR gene polymorphisms. No differences were found in terms of MTHFR gene polymorphisms, homocystein, and B12 levels among the groups. MTHFR gene polymorphisms and folate deficiency are not predictors of early esophageal carcinoma. However, further studies using larger series of patients are needed to evaluate the effect of genetic polymorphisms in the folate metabolic pathway and to clarify the role of folate deficiency and folate metabolism in the development of esophagus adenocarcinoma. PMID:21951971

  5. Association between Methylenetetrahydrofolate Reductase (MTHFR) Gene Polymorphisms and Susceptibility to Childhood Acute Lymphoblastic Leukemia in an Iranian Population

    PubMed Central

    Bahari, Gholamreza; Hashemi, Mohammad; Naderi, Majid; Taheri, Mohsen

    2016-01-01

    Background: The present study was aimed to examine the possible association between methylene tetrahydrofolate reductase (MTHFR) gene polymorphisms and childhood acute lymphoblastic leukemia (ALL) in a sample of Iranian population. Subjects and Methods: A total of 220 subjects including 100 children diagnosed with ALL and 120 healthy children participated in the case-control study. The single nucleotide polymorphisms (SNPs) of MTHFR were determined by ARMS-PCR or PCR-RFLP method. Results: Our investigation revealed that rs13306561 both TC and TC + CC genotypes decreased the risk of ALL compared to TT genotype (OR=0.32, 95%CI=0.15-0.68, p=0.002 and OR=0.35, 95%CI=0.17-0.70, p=0.003, respectively). In addition, the rs13306561 C allele decreased the risk of ALL in comparison with T allele (OR=0.42, 95% CI=0.22-0.78, P=0.005). MTHFR rs1801131 (A1298C) polymorphism showed that the AC heterozygous genotype decreased the risk of ALL in comparison with AA homozygous genotype (OR=0.43, 95%CI=0.21-0.90, p=0.037). Neither the overall Chi-square comparison of cases and control subjects (𝜒2=5.54, p=0.063) nor the logistic regression analysis showed significant association between C677T polymorphism and ALL (OR=1.25, 95% CI=0.69-2.23, p=0.552; CT vs. CC). Conclusion: The current investigation findings showed that MTHFR rs1801131 and rs13306561 polymorphisms decreased the risk of ALL in the population which has been studied. Further studies with larger sample sizes and different ethnicities are required to validate our findings. PMID:27489588

  6. The association of gastric cancer risk with plasma folate, cobalamin, and methylenetetrahydrofolate reductase polymorphisms in the European Prospective Investigation into Cancer and Nutrition.

    PubMed

    Vollset, Stein Emil; Igland, Jannicke; Jenab, Mazda; Fredriksen, Ase; Meyer, Klaus; Eussen, Simone; Gjessing, Håkon K; Ueland, Per Magne; Pera, Guillem; Sala, Núria; Agudo, Antonio; Capella, Gabriel; Del Giudice, Giuseppe; Palli, Domenico; Boeing, Heiner; Weikert, Cornelia; Bueno-de-Mesquita, H Bas; Carneiro, Fátima; Pala, Valeria; Vineis, Paolo; Tumino, Rosario; Panico, Salvatore; Berglund, Göran; Manjer, Jonas; Stenling, Roger; Hallmans, Göran; Martínez, Carmen; Dorronsoro, Miren; Barricarte, Aurelio; Navarro, Carmen; Quirós, José R; Allen, Naomi; Key, Timothy J; Bingham, Sheila; Linseisen, Jakob; Kaaks, Rudolf; Overvad, Kim; Tjønneland, Anne; Büchner, Frederike L; Peeters, Petra H M; Numans, Mattijs E; Clavel-Chapelon, Françoise; Boutron-Ruault, Marie-Christine; Trichopoulou, Antonia; Lund, Eiliv; Slimani, Nadia; Ferrari, Pietro; Riboli, Elio; González, Carlos A

    2007-11-01

    Previous studies have shown inconsistent associations of folate intake and polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene with gastric cancer risk. Our nested case-control study within the European Prospective Investigation into Cancer and Nutrition cohort is the first prospective study of blood folate levels and gastric cancer. Gastric cancer cases (n=247) and controls (n=631) were matched for study center, age, sex, and time of blood donation. Two common single nucleotide polymorphisms of the MTHFR gene were determined, as were plasma concentrations of folate, cobalamin (vitamin B12), total homocysteine, and methylmalonic acid (cobalamin deficiency marker) in prediagnostic plasma. Risk measures were calculated with conditional logistic regression. Although no relations were observed between plasma folate or total homocysteine concentrations and gastric cancer, we observed a trend toward lower risk of gastric cancer with increasing cobalamin concentrations (odds ratio, 0.79 per SD increase in cobalamin; P=0.01). Further analyses showed that the inverse association between cobalamin and gastric cancer was confined to cancer cases with low pepsinogen A levels (marker of severe chronic atrophic gastritis) at the time of blood sampling. The 677 C-->T MTHFR polymorphism was not associated with gastric cancer, but we observed an increased risk with the variant genotype of the 1298 A-->C polymorphism (odds ratio, 1.47 for CC versus AA; P=0.04). In conclusion, we found no evidence of a role of folate in gastric cancer etiology. However, we observed increased gastric cancer risk at low cobalamin levels that was most likely due to compromised cobalamin status in atrophic gastritis preceding gastric cancer. PMID:18006931

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

    PubMed

    Geçene, Muharrem; Tuncay, Figen; Borman, Pınar; Yücel, Dogan; Senes, Mehmet; Yılmaz, Behice Kaniye

    2013-06-01

    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 μmol/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

  8. Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms resulting in suboptimal oocyte maturation: a discussion of folate status, neural tube defects, schizophrenia, and vasculopathy

    PubMed Central

    Jongbloet, Piet Hein; Verbeek, André LM; den Heijer, Martin; Roeleveld, Nel

    2008-01-01

    Several conditions apparent at birth, e.g., neural tube defects (NTDs) and cardiac anomalies, are associated with polymorphisms in folate-related genes, such as the 677C → T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene. Similar associations have been established for several constitutional chronic diseases in adulthood, such as schizophrenia, cardiovascular diseases, dementia, and even neoplasias in different organ systems. This spectrum of developmental anomalies and constitutional diseases may be linked to high-risk conceptions related to preovulatory overripeness ovopathy (PrOO). Some developmental anomalies, such as NTDs, are to a large extent prevented by supplementation of folic acid before conception, but supplementation does not seem to prevent cardiovascular disease or cognitive decline. These diverging results can be elucidated by introduction of the PrOO concept, as MTHFR polymorphisms and inherent low folate levels induce both non-optimal maturation of the oocyte and unsuccessful DNA methylation and demethylation, i.e. epigenetic mutations. The PrOO concept is testable and predicts in a random population the following: (1) female carriers of specific genetic MTHFR variants exhibit more ovulatory disturbances and inherent subfecundity traits, (2) descendents from a carrier mother, when compared with those from a wild-type mother, are more frequently conceived in PrOO high-risk conditions and, thus, (3) disadvantaged in life expectancy. If so, some MTHFR polymorphisms represent a novel, genetically determined, PrOO high-risk conception category comparable to those which are environmentally and behaviorly influenced. These high-risk conditions may cause developmental anomalies and defective epigenetic reprogramming in progeny. The interaction between genetic and environmental factors is a plausible mechanism of multifactorial inheritance. PMID:18616826

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

    PubMed

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

    2014-04-01

    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

  10. Methylenetetrahydrofolate Reductase C677T Polymorphism and Type 2 Diabetes Mellitus in Chinese Population: A Meta-Analysis of 29 Case-Control Studies

    PubMed Central

    Zhu, Bo; Wu, Xiaomei; Zhi, Xueyuan; Liu, Lei; Zheng, Quanmei; Sun, Guifan

    2014-01-01

    Background Methylenetetrahydrofolate reductase (MTHFR), a key enzyme in folate metabolism, had significant effects on the homocysteine levels. The common functional MTHFR C677T polymorphism had been extensively researched. Several studies had evaluated the relationship between MTHFR C677T polymorphism and type 2 diabetes mellitus (T2DM), but the results were still controversial in the Chinese Han population. This meta-analysis was conducted to evaluate the relationship between MTHFR C677T polymorphism and T2DM in the Chinese Han population. Methods We searched the relevant studies in multiple electronic databases, which published up to December 2013. We reviewed and extracted data from all the included studies on the relationship between MTHFR C677T polymorphism and T2DM in the Chinese Han population. The odds ratios (ORs) and their 95% confidence intervals (95%CIs) were used to evaluate the relationship. Fixed-effects and random-effects meta-analysis were used to pool ORs by the heterogeneity. Publication bias and sensitivity analysis were also examined. Results 29 studies were finally included in our meta-analysis, which contained 4656 individuals with T2DM and 2127 healthy controls. There was a significant relationship between MTHFR C677T polymorphism and T2DM under dominant (OR: 1.70, 95% CI: 1.42–2.02), recessive (OR: 1.48, 95% CI: 1.21–1.80), homozygous (OR: 1.89, 95% CI: 1.47–2.42), heterozygous (OR: 1.58, 95% CI: 1.33–1.87), and additive (OR: 1.46, 95% CI: 1.28–1.68) genetic model in a random-effects model. Subgroup analysis also reached similar results. Sensitivity analysis indicated that the overall result were dependable. Conclusions There was a significant relationship between MTHFR C677T polymorphism and T2DM in the Chinese Han population. The results of our meta-analysis suggested that MTHFR 677T allele might be a risk genetic factor of T2DM in the Chinese Han population. PMID:25047451

  11. Meta-analyses of the methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and risk of head and neck and lung cancer.

    PubMed

    Boccia, Stefania; Boffetta, Paolo; Brennan, Paul; Ricciardi, Gualtiero; Gianfagna, Francesco; Matsuo, Keitaro; van Duijn, Cornelia M; Hung, Rayjean J

    2009-01-01

    Authors report the results of four meta-analyses of studies that examined the association between methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and head and neck cancer (nine studies, 2076 cases and 4834 controls for C677T; four studies, 1439 cases and 3941 controls for A1298C), and lung cancer (ten studies, 5274 cases and 7435 controls for C677T; seven studies, 5098 cases and 6243 controls for A1298C). The summary odds ratio (OR) of head and neck cancer was 0.92 (95% CI: 0.76-1.11) for MTHFR 677 TT and 0.68 (95% CI: 0.37-1.26) for MTHFR 1298 CC. The OR of lung cancer was 1.22 [95% confidence interval (CI): 0.95-1.55] for MTHFR 677 TT and 1.07 (95% CI: 0.83-1.38) for MTHFR 1298 CC. Results from the meta-analysis of three studies on C677T stratified according to dietary folate intake showed an increased risk for individuals with low folate intake (OR = 1.37, 95% CI: 0.92-2.06 for head and neck and OR = 1.28, 95% CI: 0.97-1.68 for lung) versus high folate intake (OR = 0.85, 95% CI: 0.63-1.16 for head and neck, and OR = 0.94, 95% CI: 0.79-1.12 for lung). Despite the lack of formal statistical significance, these findings are consistent with the hypothesis that folate play a role in lung and head/neck carcinogenesis, and show the need to incorporate data on folate intake when interpreting results of MTHFR polymorphisms in relation to cancer risk. PMID:18789576

  12. Meta- and pooled analyses of the methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and gastric cancer risk: a huge-GSEC review.

    PubMed

    Boccia, Stefania; Hung, Rayjean; Ricciardi, Gualtiero; Gianfagna, Francesco; Ebert, Matthias P A; Fang, Jing-Yuan; Gao, Chang-Ming; Götze, Tobias; Graziano, Francesco; Lacasaña-Navarro, Marina; Lin, Dongxin; López-Carrillo, Lizbeth; Qiao, You-Lin; Shen, Hongbing; Stolzenberg-Solomon, Rachael; Takezaki, Toshiro; Weng, Yu-Rong; Zhang, Fang Fang; van Duijn, Cornelia M; Boffetta, Paolo; Taioli, Emanuela

    2008-03-01

    Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the metabolism of folate, whose role in gastric carcinogenesis is controversial. The authors performed a meta-analysis and individual data pooled analysis of case-control studies that examined the association between C677T and A1298C polymorphisms (the former being associated with low folate serum levels) and gastric cancer (meta-analyses: 16 studies, 2,727 cases and 4,640 controls for C677T and seven studies, 1,223 cases and 2,015 controls for A1298C; pooled analyses: nine studies, 1,540 cases and 2,577 controls for C677T and five studies, 1,146 cases and 1,549 controls for A1298C). An increased risk was found for MTHFR 677 TT in the meta-analysis (odds ratio (OR) = 1.52, 95% confidence interval (CI): 1.31, 1.77) and pooled analysis (OR = 1.49, 95% CI: 1.14, 1.95). No association resulted for MTHFR 1298 CC (meta-OR = 0.94, 95% CI: 0.65, 1.35; pooled OR = 0.90, 95% CI: 0.69, 1.34). Results from the pooled analysis of four studies on C677T stratified according to folate levels showed an increased risk for individuals with low (OR = 2.05, 95% CI: 1.13, 3.72) versus high (OR = 0.95, 95% CI: 0.54, 1.67) folate levels. Overall, these findings support the hypothesis that folate plays a role in gastric carcinogenesis. PMID:18162478

  13. Genetic susceptibility of methylenetetrahydrofolate reductase (MTHFR) gene C677T, A1298C, and G1793A polymorphisms with risk for bladder transitional cell carcinoma in men.

    PubMed

    Safarinejad, Mohammad Reza; Shafiei, Nayyer; Safarinejad, Shiva

    2011-12-01

    We performed a case-control study of 158 bladder transitional cell carcinoma (TCC) cases and 316 controls to investigate the association between methylenetetrahydrofolate reductase (MTHFR) C677T, A1298G, and G1793A polymorphisms and bladder cancer susceptibility by polymerase chain reaction restriction fragment length polymorphism (PCR-RLFP) technique. The controls were frequency-matched to the cases by age (± 5 years), ethnicity, and smoking status. We also measured serum levels of total homocysteine (tHcy), folate, and vitamin B12. It was found that the 1298AC (odds ratio, OR = 3.74; 95% confidence interval, CI = 2.34-5.47; P = 0.001) and 1298CC (OR = 3.46, 95% CI = 2.37-5.52; P = 0.001) genotypes of MTHFR A1298C were significantly associated with increased risk of bladder TCC. The MTHFR C677T and G1793A polymorphisms were not associated with bladder TCC. After stratification for grade and stage, we observed that the 677TT (OR = 4.47, 95% CI = 2.74-6.72; P = 0.001) and MTHFR 1298CC (OR = 4.78, 95% CI = 2.82-6.89; P = 0.001) genotypes of MTHFR were associated with increased risk of muscle-invasive bladder TCC. We also found that the MTHFR 677CT+1298AA genotypes were associated with an approximately 70% reduction in risk of bladder cancer (OR = 0.31; 95% CI = 0.15-0.68) compared to the combined referent genotype. There were 8 haplotypes and 16 haplotype genotypes based on these three variants. When we used the haplotypes and assumed that the 677T, 1298C, and 1793G alleles were risk alleles, the adjusted odds ratios increased as the number of risk alleles increased: 1.00 for 0-1 variant, 1.88 (1.4-2.7) for any two risk alleles and 2.07 (1.6-2.8) for any three risk alleles. Serum tHcy levels were significantly higher in carriers of the 677T, 1298C, and 1793G alleles compared to noncarriers (all P < 0.01). There was no significant correlation between serum levels of tHcy and folate and bladder cancer risk. Further studies in larger samples size and different

  14. Association of methylenetetrahydrofolate reductase C677T polymorphism and serum lipid levels in the Guangxi Bai Ku Yao and Han populations

    PubMed Central

    2010-01-01

    Background The association of methylenetetrahydrofolate reductase (MTHFR) gene polymorphism and serum lipid profiles is still controversial in diverse ethnics. Bai Ku Yao is an isolated subgroup of the Yao minority in China. The aim of the present study was to eveluate the association of MTHFR C677T polymorphism and several environmental factors with serum lipid levels in the Guangxi Bai Ku Yao and Han populations. Methods A total of 780 subjects of Bai Ku Yao and 686 participants of Han Chinese were randomly selected from our previous stratified randomized cluster samples. Genotyping of the MTHFR C677T was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. Results The levels of serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein (Apo) AI and ApoB were lower in Bai Ku Yao than in Han (P < 0.05-0.001). The frequency of C and T alleles was 77.4% and 22.6% in Bai Ku Yao, and 60.9% and 39.1% in Han (P < 0.001); respectively. The frequency of CC, CT and TT genotypes was 58.7%, 37.3% and 4.0% in Bai Ku Yao, and 32.6%, 56.4% and 11.0% in Han (P < 0.001); respectively. The levels of TC and LDL-C in both ethnic groups were significant differences among the three genotypes (P < 0.05-0.01). The T allele carriers had higher serum TC and LDL-C levels than the T allele noncarriers. The levels of ApoB in Han were significant differences among the three genotypes (P < 0.05). The T allele carriers had higher serum ApoB levels as compared with the T allele noncarriers. The levels of TC, TG and LDL-C in Bai Ku Yao were correlated with genotypes (P < 0.05-0.001), whereas the levels of LDL-C in Han were associated with genotypes (P < 0.001). Serum lipid parameters were also correlated with sex, age, body mass index, alcohol consumption, cigarette smoking, and blood pressure in the both ethnic

  15. Relationship of the 1793G-A and 677C-T polymorphisms of the 5,10-methylenetetrahydrofolate reductase gene to coronary artery disease.

    PubMed

    Kebert, Cory B; Eichner, June E; Moore, William E; Schechter, Eliot; Yaoi, Takuro; Vogel, Steve; Allen, Richard A; Dunn, S Terence

    2006-01-01

    Numerous studies have investigated the relationship between polymorphisms, in particular 677C-T and 1298A-C, of the methylene-tetrahydrofolate reductase (MTHFR) gene and coronary artery disease (CAD) with conflicting results. This study investigates the potential association of two point mutations in MTHFR, 677C-T and 1793G-A, along with other risk factors, with CAD. This is the first hospital-based study to investigate 1793G-A in this context. Genotype analysis was performed on 729 Caucasians and 66 African Americans undergoing coronary angiography using a novel PCR-based assay involving formation of Holliday junctions. Allelic frequencies for 677C-T were 66.2% C and 33.8% T for Caucasians and 90.9% C and 9.1% T for African Americans. With respect to the 1793G-A polymorphism, allelic frequencies were 94.7% G and 5.3% A for Caucasians and 99.2% G and 0.8% A for African Americans. Disease associations were examined in the Caucasian patients due to their greater genotype variability and larger number in the patient cohort. Results suggest that neither 677CT heterozygotes (OR-1.36; 95% CI 0.95 to 1.96) nor mutant homozygotes (OR-0.73; 95% CI 0.44 to 1.20) have either an increased or decreased risk for CAD compared to the 677CC genotype. Likewise, the 1793GA genotype did not demonstrate a statistically significant association with CAD compared to 1793GG patients (OR-0.79; 95% CI 0.47 to 1.33). Mean homocysteine levels (mumol/L) increased from normal to mutant for 677C-T (677CC: 10.2; 677CT: 11.0; 677TT: 11.6) and normal to heterozygous in 1793G-A (1793GG: 10.7; 1793GA: 11.5). These MTHFR polymorphisms did not contribute to the prediction of clinically defined CAD in Caucasians. PMID:17264399

  16. Relationship of the 1793G-A and 677C-T Polymorphisms of the 5,10-Methylenetetrahydrofolate Reductase Gene to Coronary Artery Disease

    PubMed Central

    Kebert, Cory B.; Eichner, June E.; Moore, William E.; Schechter, Eliot; Yaoi, Takuro; Vogel, Steve; Allen, Richard A.; Dunn, S. Terence

    2006-01-01

    Numerous studies have investigated the relationship between polymorphisms, in particular 677C-T and 1298A-C, of the methylene-tetrahydrofolate reductase (MTHFR) gene and coronary artery disease (CAD) with conflicting results. This study investigates the potential association of two point mutations in MTHFR, 677C-T and 1793G-A, along with other risk factors, with CAD. This is the first hospital-based study to investigate 1793G-A in this context. Genotype analysis was performed on 729 Caucasians and 66 African Americans undergoing coronary angiography using a novel PCR-based assay involving formation of Holliday junctions. Allelic frequencies for 677C-T were 66.2% C and 33.8% T for Caucasians and 90.9% C and 9.1% T for African Americans. With respect to the 1793G-A polymorphism, allelic frequencies were 94.7% G and 5.3% A for Caucasians and 99.2% G and 0.8% A for African Americans. Disease associations were examined in the Caucasian patients due to their greater genotype variability and larger number in the patient cohort. Results suggest that neither 677CT heterozygotes (OR-1.36; 95% CI 0.95 to 1.96) nor mutant homozygotes (OR-0.73; 95% CI 0.44 to 1.20) have either an increased or decreased risk for CAD compared to the 677CC genotype. Likewise, the 1793GA genotype did not demonstrate a statistically significant association with CAD compared to 1793GG patients (OR-0.79; 95% CI 0.47 to 1.33). Mean homocysteine levels (μmol/L) increased from normal to mutant for 677C-T (677CC: 10.2; 677CT: 11.0; 677TT: 11.6) and normal to heterozygous in 1793G-A (1793GG: 10.7; 1793GA: 11.5). These MTHFR polymorphisms did not contribute to the prediction of clinically defined CAD in Caucasians. PMID:17264399

  17. 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...

  18. Uracil misincorporation into DNA of leukocytes of young women with positive folate balance depends on plasma vitamin B12 concentrations and methylenetetrahydrofolate reductase polymorphisms. A pilot study.

    PubMed

    Kapiszewska, Maria; Kalemba, Malgorzata; Wojciech, Urszula; Milewicz, Tomasz

    2005-08-01

    Changes in the folate and vitamin B12 status in the body influence the extent of uracil misincorporation (UrMis) into DNA, which is one of the biomarkers of genomic stability and, thus, portends a risk of cancer. In our study, the level of UrMis into DNA was evaluated by the comet assay (using the specific DNA repair enzyme, uracil DNA glycosylase) in leukocytes from blood donated by healthy young women with positive folate balance achieved by 4 weeks of folic acid supplementation (400 microg/day). The nutritional status was evaluated on the basis of nine food diaries recorded by the subjects during two winter months. The data were computerized, and the intake of nutrients and micronutrients was estimated using the DIETA 2 program (Food and Nutrition Institute, Warsaw, Poland) linked to recently updated Polish food tables. The plasma folate and vitamin B12 concentration, as well as methylenetetrahydrofolate reductase (MTHFR) polymorphisms, were evaluated to determine their influence on the level of UrMis into DNA. The mean value of B12 intake for all subjects reached 100% of the Polish recommended dietary allowances (RDA), whereas the mean value of folate intake, before folate supplementation, was 50%, suggesting moderate deficiency. Folic acid supplementation brought the folate intake way above the RDA, and plasma folate concentration in each individual was above the deficient range (mean value 14.67 ng/ml). The UrMis did not correlate with the plasma folate concentration, but the level of UrMis was significantly lower in subjects with plasma vitamin B12 concentration above 400 pg/ml (P=.02) only after folic acid supplementation. The concentration of folate in plasma correlated (Ppolymorphism, which was accompanied by a

  19. Impact of Genetic Polymorphism of methylenetetrahydrofolate reductase C677T on Development of Hyperhomocysteinemia and Related Oxidative Changes in Egyptian β-Thalassemia Major Patients

    PubMed Central

    Abd-Elmawla, Mai A.; Rizk, Sherine M.; Youssry, Ilham; Shaheen, Amira A.

    2016-01-01

    Background β-thalasemia major (β-TM) patients often suffer from various vascular complications together with increased oxidative stress. Hyperhomocysteinemia (Hhcy) has been defined as a risk factor for these complications. Genetic polymorphism of methylenetetrahydrofolate reductase (MTHFR) C677T has been shown to cause Hhcy particularly in individuals with low B-vitamins. However, the status of homocysteine (hcy) in β-TM has not yet been adequately defined. Aim To evaluate the genetic polymorphism of MTHFR C677T among β-TM patients and its prospective contribution to Hhcy and related oxidative changes. Subjects and Methods Genotyping for MTHFR C677T was done by PCR-RFLP technique. Plasma hcy, vitamin B12, folate, malondialdehyde (MDA), total antioxidant capacity (TAC), oxidized low density lipoprotein (oxLDL), total nitric oxide (NOx) and lipid profile were determined in 66 β-TM patients and 66 control subjects of matched age and sex. Results The prevalence of MTHFR 677TT genotype was significant among β-TM patients (12%) compared to (3%) controls (OR = 4.9, 95%CI:1.2–24.2,P = 0.03). A strong association between Hhcy and MTHFR TT genotype was observed (OR = 7.7, 95%CI:2.8–20.9) where all β-TM patients with TT genotype were hyperhomocystienemic (≥ 15 μmol/l) and having sub-optimal folate level than those with CT or CC genotypes. Hyperhomocystienemic patients have suffered from increased oxidative stress characterized by significant increase in plasma MDA and oxLDL, and a significant reduction of plasma TAC and total NOx. Lipid profile of those patients was severely affected indicated by reduction in HDL and HDL/LDL and elevation in atherogenic index as compared with CC genotype. Other measured parameters were not significantly different among β-TM patients with different MTHFR genotypes. Conclusion This study suggests that Egyptian β-TM patients with MTHFR 677TT genotype could be at increasing risk of developing Hhcy particularly with folate

  20. Anxiety and Methylenetetrahydrofolate Reductase Mutation Treated With S-Adenosyl Methionine and Methylated B Vitamins.

    PubMed

    Anderson, Shanna; Panka, Jacob; Rakobitsch, Robin; Tyre, Kaitlin; Pulliam, Kerry

    2016-04-01

    This case report highlights challenges faced in the clinical management of patients with methylenetetrahydrofolate reductase (MTHFR) gene mutations and the importance of precise dosage when recommending methylated B vitamins to compensate for deficiencies caused by the polymorphism or symptoms related to the polymorphism. It also underscores the importance of obtaining ongoing objective assessments of anxiety (eg, Patient Reported Outcomes Measurement Information System, or PROMIS) to help gauge patient response. PMID:27330489

  1. Comparison of the frequency of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in depressed versus nondepressed patients.

    PubMed

    Lizer, Mitsi H; Bogdan, Renee L; Kidd, Robert S

    2011-11-01

    Numerous studies have found an association between low serum folate levels and incidence of depression. Folic acid supplementation has been successfully used as an adjunct to treat depression in these patients. However, some individuals have a genetic deficiency in the methylene tetrahydrofolate reductase (MTHFR) gene that limits conversion of folic acid to its biologically active form, L-methylfolate. Several studies have identified a higher frequency of genetic variations in the MTHFR gene in depressed patients than in nondepressed controls. This study evaluated the frequency of the most common genetic variation MTHFR C667T in a group of depressed U.S. Caucasians and compared results with those of a control group of nondepressed U.S. Caucasians. Subjects were recruited from a psychiatric practice, an ambulatory care clinic, and the community. Informed consent and a cheek swab sample were obtained from each subject for analysis using real-time polymerase chain reaction (PCR). Allele and genotype frequencies were compared using Pearson X2 analysis. Complete data were obtained for 156 subjects. No significant differences were found in frequency of the MTHFR C667T T allele (0.415 vs 0.365; p=0.408) or the MTHFR C667T TT genotype (20.7% vs 17.6%; p=0.619) between the depressed and non-depressed controls, respectively. Therefore, use of L-methylfolate without an additional indication of need does not appear to be warranted in this group of U.S. Caucasians. Some patients may benefit from L-methylfolate, but an evidence-based approach, such as MTHFR genotyping, should be used to identify these specific patients. Additional research is also needed to confirm the benefit of L-methylfolate in specific patient populations (e.g., MTHFR TT genotype). PMID:22108397

  2. Pulmonary Embolism in a Sarcoidosis Patient Double Heterozygous for Methylenetetrahydrofolate Reductase Gene Polymorphisms and Factor V Leiden and Homozygous for the D-Allele of Angiotensin Converting Enzyme Gene

    PubMed Central

    El-Majzoub, Nadim; Mahfouz, Rami; Kanj, Nadim

    2015-01-01

    Sarcoidosis is a multisystem granulomatous disease of unknown etiology and pathogenesis. It presents in patients younger than 40 years of age. The lungs are the most commonly affected organ. Till the present day, there is no single specific test that will accurately diagnose sarcoidosis; as a result, the diagnosis of sarcoidosis relies on a combination of clinical, radiologic, and histologic findings. Patients with sarcoidosis have been found to have an increased risk of pulmonary embolism compared to the normal population. MTHFR and factor V Leiden mutations have been reported to increase the risk of thrombosis in patients. We hereby present a case of a middle aged man with sarcoidosis who developed a right main pulmonary embolism and was found to be double heterozygous for methylenetetrahydrofolate reductase gene polymorphisms and factor V Leiden and homozygous for the D-allele of the angiotensin converting enzyme gene. PMID:26347783

  3. 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...

  4. Methyltetrahydrofolate vs Folic Acid Supplementation in Idiopathic Recurrent Miscarriage with Respect to Methylenetetrahydrofolate Reductase C677T and A1298C Polymorphisms: A Randomized Controlled Trial

    PubMed Central

    Hekmatdoost, Azita; Vahid, Farhad; Yari, Zahra; Sadeghi, Mohammadreza; Eini-Zinab, Hassan; Lakpour, Niknam; Arefi, Soheila

    2015-01-01

    Purpose To determine whether 5-methylenetetrahydrofolate (MTHF) is more effective than folic acid supplementation in treatment of recurrent abortion in different MTHFR gene C677T and A1298C polymorphisms. Methods A randomized, double blind, placebo-controlled trial conducted April 2011-September 2014 in recurrent abortion clinics in Tehran, Iran. The participants were women with three or more idiopathic recurrent abortion, aged 20 to 45 years. Two hundred and twenty eligible women who consented to participate were randomly assigned to receive either folic acid or 5-MTHF according to the stratified blocked randomization by age and the number of previous abortions. Participants took daily 1 mg 5-methylentetrahydrofolate or 1 mg folic acid from at least 8 weeks before conception to the 20th week of the pregnancy. The primary outcome was ongoing pregnancy rate at 20th week of pregnancy, and the secondary outcomes were serum folate and homocysteine at the baseline, after 8 weeks, and at the gestational age of 4, 8, 12, and 20 weeks, MTHFR gene C677T and A1298C polymorphisms. Results There was no significant difference in abortion rate between two groups. Serum folate increased significantly in both groups over time; these changes were significantly higher in the group receiving 5-MTHF than the group receiving folic acid (value = 2.39, p<00.1) and the result was the same by considering the time (value = 1.24, p<0.01). Plasma tHcys decreased significantly in both groups over time; however these changes were not significantly different between the groups (value = 0.01, p = 0.47). Conclusion The results do not support any beneficial effect of 5-MTHF vs. folate supplementation in women with recurrent abortion with any MTHFR C677T and/or A1298C polymorphism. Trial Registration ClinicalTrials.gov NCT01976676 PMID:26630680

  5. Evidence for a Hexaheteromeric Methylenetetrahydrofolate Reductase in Moorella thermoacetica

    PubMed Central

    Mock, Johanna; Wang, Shuning; Huang, Haiyan; Kahnt, Jörg

    2014-01-01

    Moorella thermoacetica can grow with H2 and CO2, forming acetic acid from 2 CO2 via the Wood-Ljungdahl pathway. All enzymes involved in this pathway have been characterized to date, except for methylenetetrahydrofolate reductase (MetF). We report here that the M. thermoacetica gene that putatively encodes this enzyme, metF, is part of a transcription unit also containing the genes hdrCBA, mvhD, and metV. MetF copurified with the other five proteins encoded in the unit in a hexaheteromeric complex with an apparent molecular mass in the 320-kDa range. The 40-fold-enriched preparation contained per mg protein 3.1 nmol flavin adenine dinucleotide (FAD), 3.4 nmol flavin mononucleotide (FMN), and 110 nmol iron, almost as predicted from the primary structure of the six subunits. It catalyzed the reduction of methylenetetrahydrofolate with reduced benzyl viologen but not with NAD(P)H in either the absence or presence of oxidized ferredoxin. It also catalyzed the reversible reduction of benzyl viologen with NADH (diaphorase activity). Heterologous expression of the metF gene in Escherichia coli revealed that the subunit MetF contains one FMN rather than FAD. MetF exhibited 70-fold-higher methylenetetrahydrofolate reductase activity with benzyl viologen when produced together with MetV, which in part shows sequence similarity to MetF. Heterologously produced HdrA contained 2 FADs and had NAD-specific diaphorase activity. Our results suggested that the physiological electron donor for methylenetetrahydrofolate reduction in M. thermoacetica is NADH and that the exergonic reduction of methylenetetrahydrofolate with NADH is coupled via flavin-based electron bifurcation with the endergonic reduction of an electron acceptor, whose identity remains unknown. PMID:25002540

  6. Evidence for a hexaheteromeric methylenetetrahydrofolate reductase in Moorella thermoacetica.

    PubMed

    Mock, Johanna; Wang, Shuning; Huang, Haiyan; Kahnt, Jörg; Thauer, Rudolf K

    2014-09-01

    Moorella thermoacetica can grow with H₂ and CO₂, forming acetic acid from 2 CO₂ via the Wood-Ljungdahl pathway. All enzymes involved in this pathway have been characterized to date, except for methylenetetrahydrofolate reductase (MetF). We report here that the M. thermoacetica gene that putatively encodes this enzyme, metF, is part of a transcription unit also containing the genes hdrCBA, mvhD, and metV. MetF copurified with the other five proteins encoded in the unit in a hexaheteromeric complex with an apparent molecular mass in the 320-kDa range. The 40-fold-enriched preparation contained per mg protein 3.1 nmol flavin adenine dinucleotide (FAD), 3.4 nmol flavin mononucleotide (FMN), and 110 nmol iron, almost as predicted from the primary structure of the six subunits. It catalyzed the reduction of methylenetetrahydrofolate with reduced benzyl viologen but not with NAD(P)H in either the absence or presence of oxidized ferredoxin. It also catalyzed the reversible reduction of benzyl viologen with NADH (diaphorase activity). Heterologous expression of the metF gene in Escherichia coli revealed that the subunit MetF contains one FMN rather than FAD. MetF exhibited 70-fold-higher methylenetetrahydrofolate reductase activity with benzyl viologen when produced together with MetV, which in part shows sequence similarity to MetF. Heterologously produced HdrA contained 2 FADs and had NAD-specific diaphorase activity. Our results suggested that the physiological electron donor for methylenetetrahydrofolate reduction in M. thermoacetica is NADH and that the exergonic reduction of methylenetetrahydrofolate with NADH is coupled via flavin-based electron bifurcation with the endergonic reduction of an electron acceptor, whose identity remains unknown. PMID:25002540

  7. Influence of 5,10-methylenetetrahydrofolate reductase gene polymorphism on plasma homocysteine concentration in patients with end-stage renal disease.

    PubMed

    Lee, H A; Choi, J S; Ha, K S; Yang, D H; Chang, S K; Hong, S Y

    1999-08-01

    The purpose of this study is to observe the influence of the methylenetetrahydrofolate reductase (MTHFR) gene (677C-->T substitution) on plasma homocysteine levels in end-stage renal disease (ESRD) patients who received a relatively large amount of folate (2 mg/d) and are undergoing hemodialysis. A cross-sectional study of plasma homocysteine, vitamin B(12), and folate was performed in patients with ESRD. The study population for the MTHFR gene study included 312 healthy subjects and 106 patients with ESRD undergoing hemodialysis. The C677T transition in the MTHFR gene was detected by HinF 1 restriction enzyme analysis and subsequent electrophoresis in a 3% agarose gel. The genotype of the MTHFR gene in 106 patients with ESRD was homozygous C677T mutation (VV) in 17 patients (16.1%) and heterozygous (AV) in 63 patients (58.4%); 26 patients (24.5%) did not carry this mutation (AA). The mean levels of homocysteine, vitamin B(12), and folate in the patients with ESRD were 23.3 +/- 14.0 mmol/L, 620.2 +/- 98.5 pmol/L, and 138.6 +/- 55.6 nmol/L, respectively. There was no significant difference in homocysteine levels among the three genotypes: 28.2 +/- 19.4 mmol/L for VV, 22.7 +/- 14.9 mmol/L for AV, and 23.4 +/- 11.1 mmol/L for AA genotype (P > 0.05). There was no difference in genotype distribution between the patient groups of less than 25th and greater than 75th percentiles, classified according to plasma homocysteine levels (P = 0.47). In conclusion, with high-dose folate supplementation, the hyperhomocysteinemia in patients with ESRD does not seem to be caused by the 677C-->T mutation in the MTHFR gene. PMID:10430972

  8. Retrospective approach to methylenetetrahydrofolate reductase mutations in children.

    PubMed

    Özer, Işıl; Özçetin, Mustafa; Karaer, Hatice; Kurt, Semiha G; Şahin, Şemsettin

    2011-07-01

    Methylenetetrahydrofolate reductase reduces methyltetrahydrofolate, a cosubstrate in the remethylation of homocysteine, from methylenetetrahydrofolate. Congenital defects, hematologic tumors, and intrauterine growth retardation can occur during childhood. This study evaluated clinical and laboratory treatment approaches in children diagnosed with methylenetetrahydrofolate reductase mutations. Our group included 23 boys and 14 girls, aged 103.4 ± 70.8 months S.D. Clinical findings of patients and homocysteine, vitamin B12, folate, hemogram, electroencephalography, cranial magnetic resonance imaging, and echocardiography data were evaluated in terms of treatment approach. Our patients' findings included vitamin B12 at 400.4 ± 224.6 pg/mL S.D. (normal range, 300-700 pg/mL), folate at 10.1 ± 4.5 ng/mL S.D. (normal range, 1.8-9 ng/mL), and homocysteine at 8.4 ± 4.7 μmol/L S.D. (normal range, 5.5-17 μmol/L). Eighty-eight percent of patients demonstrated clinical findings. In comparisons involving categorical variables between groups, χ(2) tests were used. No relationship was evident between mutation type, laboratory data, and clinical severity. All mothers who had MTHFR mutations and had babies with sacral dimples had taken folate supplements during pregnancy. To avoid the risk of neural tube defects, pregnant women with a MTHFR mutation may require higher than normally recommended doses of folic acid supplementation for optimum health. PMID:21723457

  9. Methylenetetrahydrofolate Reductase C677T: Hypoplastic Left Heart and Thrombosis.

    PubMed

    Spronk, Kimberly J; Olivero, Anthony D; Haw, Marcus P; Vettukattil, Joseph J

    2015-10-01

    The incidence of congenital heart defects is higher in infants with mutation of methylenetetrahydrofolate reductase (MTHFR) gene. The MTHFR C677T gene decreases the bioavailability of folate and increases plasma homocysteine, a risk factor for thrombosis. There have been no reported cases in the literature on the clinical implications of this procoagulable state in the setting of cyanotic heart disease, which itself has prothrombotic predisposition. Two patients with hypoplastic left heart syndrome developed postoperative thrombotic complications, both were homozygous for MTHFR C677T. We present these cases and highlight the implications of MTHFR mutation in the management of complex congenital heart disease. PMID:26467879

  10. 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

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

    2015-01-01

    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. PMID:25859445

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

    SciTech Connect

    Goyette, P.; Frosst, P.; Rosenblatt, D.S.; Rozen. R.

    1995-05-01

    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.

  12. Subacute methotrexate neurotoxicity and cerebral venous sinus thrombosis in a 12-year-old with acute lymphoblastic leukemia and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: homocysteine-mediated methotrexate neurotoxicity via direct endothelial injury.

    PubMed

    Mahadeo, Kris M; Dhall, Girish; Panigrahy, Ashok; Lastra, Carlos; Ettinger, Lawrence J

    2010-02-01

    From as early as the 1970s methotrexate has been associated with disseminated necrotizing leukoencephalopathy and other neurotoxic sequelae. Yet, a clear mechanism for methotrexate-induced neurotoxicity has not been established. The authors describe the case of a 12-year-old male with acute lymphoblastic leukemia and a homozygous methylenetetrahydrofolate reductase C677T mutation, who developed subacute methotrexate-induced toxicity and cerebral venous thrombosis after receiving intrathecal methotrexate. The role of homocysteine as a possible mediator in methotrexate-induced neurotoxicity via direct endothelial injury is discussed. PMID:20121554

  13. C667T and A1298C polymorphisms of methylenetetrahydrofolate reductase gene and susceptibility to myocardial infarction: A systematic review and meta-analysis.

    PubMed

    Alizadeh, Shahab; Djafarian, Kurosh; Moradi, Sajjad; Shab-Bidar, Sakineh

    2016-08-15

    MTHFR C677T and A1298C polymorphisms have been reported to be associated with the risk of myocardial infarction (MI), although the results of previous studies have been inconsistent. The aim of this study was to explore whether these polymorphisms play a role in the genetic susceptibility to MI. A comprehensive search of MEDLINE and EMBASE databases was conducted for studies evaluating the association between the C667T and A1298C polymorphisms and MI risk. Odds ratios (OR) with 95% confidence intervals (CIs) were calculated to assess the strength of association in the dominant model, recessive model, allelic model, and genotypes contrast. A total of 47 studies were finally included in this meta-analysis. Overall, the results showed no statistically significant association between C667T and A1298C polymorphisms and MI risk. However, in subgroup analysis by ethnicity, the T allele of C677T polymorphism was associated with a 63% increased risk of MI compared with the C allele (T vs. C, OR=1. 63, 95%CI=1.15-2.10, fixed effects) in African populations, while compared to wild homozygote genotype, CT genotype was associated with a decreased risk of MI in North American populations (CT vs. CC, OR=0.81, 95%CI=0.64-0.98, fixed effects). Moreover, C677T polymorphism had a protective effect against MI risk under the dominant model (OR=0.93, 945%CI=0.87-0.99, fixed effects) in elderly (≥50) population. The A1298C polymorphism was not significantly associated with MI risk. Unlike A1298C polymorphism, C677T polymorphism was associated with risk of MI in African, North American, and elderly populations. PMID:27179899

  14. Cancer-testis gene expression is associated with the methylenetetrahydrofolate reductase 677 C>T polymorphism in non-small cell lung carcinoma

    PubMed Central

    2013-01-01

    Background Tumor-specific, coordinate expression of cancer-testis (CT) genes, mapping to the X chromosome, is observed in more than 60% of non-small cell lung cancer (NSCLC) patients. Although CT gene expression has been unequivocally related to DNA demethylation of promoter regions, the underlying mechanism leading to loss of promoter methylation remains elusive. Polymorphisms of enzymes within the 1-carbon pathway have been shown to affect S-adenosyl methionine (SAM) production, which is the sole methyl donor in the cell. Allelic variants of several enzymes within this pathway have been associated with altered SAM levels either directly, or indirectly as reflected by altered levels of SAH and Homocysteine levels, and altered levels of DNA methylation. We, therefore, asked whether the five most commonly occurring polymorphisms in four of the enzymes in the 1-carbon pathway associated with CT gene expression status in patients with NSCLC. Methods Fifty patients among a cohort of 763 with NSCLC were selected based on CT gene expression status and typed for five polymorphisms in four genes known to affect SAM generation by allele specific q-PCR and RFLP. Results We identified a significant association between CT gene expression and the MTHFR 677 CC genotype, as well as the C allele of the SNP, in this cohort of patients. Multivariate analysis revealed that the genotype and allele strongly associate with CT gene expression, independent of potential confounders. Conclusions Although CT gene expression is associated with DNA demethylation, in NSCLC, our data suggests this is unlikely to be the result of decreased MTHFR function. PMID:24063603

  15. [Methylenetetrahydrofolate reductase polymorphism C677T in patients with consolidated fractures and pseudarthrosis of long bones: relationship with homocystein and inflammatory mediators].

    PubMed

    Bezsmertnyĭ, Iu O

    2013-01-01

    In article described research the results of the prevalence of the genetic polymorphism of the gene Methylentetrahydrofolatereductase C677T (MTHFR) in 130 patients with pseudarthrosis of long bones and in those with consolidated fractures. The incidence of allele-T among patients with pseudarthrosis was 1.4 times higher than among those with consolidated fractures. Pathological genotype MTHFR 677-TT was associated with the development avital types of pseudarthrosis and increase the proportion of people with hyperhomocysteinemia, high content of inflammatory mediators and development refracture. PMID:24605633

  16. Severe scoliosis in a patient with severe methylenetetrahydrofolate reductase deficiency.

    PubMed

    Munoz, Tatiana; Patel, Jinesh; Badilla-Porras, Ramses; Kronick, Jonathan; Mercimek-Mahmutoglu, Saadet

    2015-01-01

    Severe methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessively inherited inborn error of folate metabolism. We report a new patient with severe MTHFR deficiency who presented at age 4 months with early onset severe scoliosis associated with severe hypotonia. Markedly decreased MTHFR enzyme activity (0.3 nmoles CHO/mg protein/h; reference range>9) and compound heterozygous mutations (c. 1304T>C; p.Phe435Ser and c.1539dup; p.Glu514Argfs∗24) in the MTHFR gene confirmed the diagnosis. She was treated with vitamin B12, folic acid and betaine supplementation and showed improvements in her developmental milestones and hypotonia. To the best of our knowledge, this is the first patient with MTHFR deficiency reported with severe early onset scoliosis. Despite the late diagnosis and treatment initiation, she showed favorable short-term neurodevelopmental outcome. This case suggests that homocysteine measurement should be included in the investigations of patients with developmental delay, hypotonia and scoliosis within first year of life prior to organizing genetic investigations. PMID:24726568

  17. Mutation Update and Review of Severe Methylenetetrahydrofolate Reductase Deficiency.

    PubMed

    Froese, D Sean; Huemer, Martina; Suormala, Terttu; Burda, Patricie; Coelho, David; Guéant, Jean-Louis; Landolt, Markus A; Kožich, Viktor; Fowler, Brian; Baumgartner, Matthias R

    2016-05-01

    Severe 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency is caused by mutations in the MTHFR gene and results in hyperhomocysteinemia and varying severity of disease, ranging from neonatal lethal to adult onset. Including those described here, 109 MTHFR mutations have been reported in 171 families, consisting of 70 missense mutations, 17 that primarily affect splicing, 11 nonsense mutations, seven small deletions, two no-stop mutations, one small duplication, and one large duplication. Only 36% of mutations recur in unrelated families, indicating that most are "private." The most common mutation is c.1530A>G (numbered from NM_005957.4, p.Lys510 = ) causing a splicing defect, found in 13 families; the most common missense mutation is c.1129C>T (p.Arg377Cys) identified in 10 families. To increase disease understanding, we report enzymatic activity, detected mutations, and clinical onset information (early, <1 year; or late, >1 year) for all published patients available, demonstrating that patients with early onset have less residual enzyme activity than those presenting later. We also review animal models, diagnostic approaches, clinical presentations, and treatment options. This is the first large review of mutations in MTHFR, highlighting the wide spectrum of disease-causing mutations. PMID:26872964

  18. Maternal Supplementary Folate Intake, Methylenetetrahydrofolate Reductase (MTHFR) C677T and A1298C Polymorphisms and the Risk of Orofacial Cleft in Iranian Children

    PubMed Central

    Ebadifar, Asghar; KhorramKhorshid, Hamid Reza; Kamali, Koorosh; Salehi Zeinabadi, Mehdi; Khoshbakht, Tayyebeh; Ameli, Nazila

    2015-01-01

    Background: The purpose of this study was to describe the association of MTHFR gene single nucleotide polymorphisms (C677T and A1298C) and maternal supplementary folate intake with orofacial clefts in the Iranian population. Methods: In this case-control study, peripheral venous blood was taken from 65 patients with orofacial clefts and 215 unaffected controls for DNA extraction and kept in EDTA for further analysis. The genotyping was carried out using Polymerase Chain Reaction (PCR) followed by Restriction Fragment Length Polymorphism (RFLP) and gel electrophoresis. Data were analyzed using Chi square test and logistic regression tests. Results: Genotype frequencies of 677TT were reported to be 13.5 and 36.1% in controls and CL/P patients, respectively, which showed a significant difference compared to CC as reference (OR=4.118; 95% CI=1.997–8.492; p=0.001). Conversely, 1298CC with frequencies of 10.8 and 12.7% in controls and patients, respectively, showed no significant difference compared to AA (OR=2.359; 95% CI=0.792–7.023; p=0.123). Comparing patients whose mothers did not report the folate supplement intake during pregnancy, to controls, it was observed that lack of folate intake was a predisposing factor for having a child with oral clefts (OR=5/718, p=0.000). Conclusion: Children carrying the 677TT variant of the MTHFR gene may have an increased risk of CL/P. In addition, the finding that the risk associated with this allele was obviously higher when the mothers didn’t use folic acid, supports the hypothesis that folic acid may play a role in the etiology of CL/P. PMID:26140186

  19. Status of vitamin B-12 and B-6 but not of folate, homocysteine and the methylenetetrahydrofolate reductase C677T polymorphism are associated with impaired cognition and depression in adults

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene differs in frequency in different ethnic groups which have differing prevalence of age-related cognitive impairments. We used a battery of neuropsychological tests to examine association of the MTHFR C677T polymorphism w...

  20. Allelic variations in 5, 10-methylenetetrahydrofolate reductase gene and susceptibility to cervical cancer in Indian women.

    PubMed

    Nandan, Naveen Kumar; Wajid, Saima; Biswas, Shilpie; Juneja, Sominder Singh; Rizvi, Moshahid; Prakash, Raminder; Naqvi, Samar Husain

    2008-01-01

    Methylenetetrahydrofolate reductase (MTHFR) gene located on chromosome 1p36.3 catalyses the conversion of 5,10-methylenetetrahydrofolate to 5,methyltetrahydrofolate, the major methyl donor for the conversion of homocysteine to methionine. Two common polymorphisms in the MTHFR gene have been identified, 677C>T in exon 4, leading to substitution of alanine by valine and 1298A>C in exon 7 which leads to the replacement of glutamic acid by alanine resulting into reduced enzyme activity. The potential influence of MTHFR activity on DNA methylation and on the availability of uridylates and thymidylates for DNA synthesis and repair makes MTHFR an attractive candidate for cancer predisposing gene. In order to elucidate the role of MTHFR polymorphism in cervical cancer, both the exons for 677C>T and 1298A>C mutations were analyzed among 219 females, including 77 females with normal cervical cytology, 80 with cervical dysplasia and 62 with squamous cell carcinoma of uterine cervix. Females with mutant allele at 677 position (CT/TT genotypes) were found to be almost three times the risk of cervical dysplasia than females with CC genotype [OR, 2.9; (CI, 1.5-5.7)], but were less likely to develop squamous cell carcinoma [OR, 1.5 (CI, 0.7-3.2)]. Similar findings were observed for mutation at 1298 position, females with AC/CC genotypes were almost four times the risk of cervical dysplasia [OR, 4.3 (CI, 2.1-9.0)], as compared to AA genotype. Our study lends further support to the hypothesis that the MTHFR polymorphism (677C>T or 1298A>C) is involved in susceptibility to cervical dysplasia. PMID:19356065

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

    PubMed

    Karimian, Mohammad; Colagar, Abasalt Hosseinzadeh

    2016-04-01

    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

  2. Mesenteric venous thrombosis with bowel infarction and hyperhomocysteinemia due to homozygous methylenetetrahydrofolate reductase C677T genotype.

    PubMed

    Hotoleanu, Cristina; Andercou, Octavian; Andercou, Aurel

    2008-01-01

    The case of a 30-year-old man with bowel infarction due to mesenteric venous thrombosis and multiple risk factors, including mild hyperhomocysteinemia due to methylenetetrahydrofolate reductase C677T polymorphism and recent abdominal surgery, is reported. His clinical manifestation consisted of persistent abdominal pain; complementary examinations showed nonspecific findings such as leukocytosis and dilated loops of the bowel. The diagnosis of mesenteric venous thrombosis with bowel infarction was made during laparotomy and confirmed by anatomopathologic examination. He underwent segmental resection associated with lifelong anticoagulant therapy and vitamin B supplementation with a favorable course. PMID:19000982

  3. Coronary reactivity, homocysteine and methylenetetrahydrofolate reductase gene variation in young men during pravastatin therapy.

    PubMed

    Nieminen, Tuomo; Knuuti, Juhani; Hämelahti, Päivi; Kähönen, Mika; Laaksonen, Reijo; Janatuinen, Tuula; Vesalainen, Risto; Nuutila, Pirjo; Jokela, Hannu; Lehtimäki, Terho

    2007-01-01

    High plasma homocysteine (Hcy) has been linked to impaired endothelial function. We investigated whether treatment with pravastatin affects the Hcy levels. Moreover, we studied whether the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism affects coronary vasomotion at baseline and during the treatment with pravastatin. Fifty-one healthy, mildly hypercholesterolemic men (mean age 35+/-4 years) attended this randomised, double-blind, placebo-controlled study. The volunteers were randomised into groups with 6-month treatment with pravastatin (40 mg/day, n=25) or placebo (n=26). Coronary blood flow measurements with positron emission tomography at rest and during adenosine infusion as well as biochemical analyses were done at baseline and at the end of the treatment period. The Hcy concentration decreased significantly during the pravastatin therapy (-0.81+/-1.46 micromol/l, p=0.01), but not during placebo (0.02+/-2.39 micromol/l, p=0.97). The MTHFR polymorphism did not affect the Hcy concentration or coronary flow indices. Neither did the MTHFR polymorphism modulate the effects of pravastatin on coronary vasomotion. In conclusion, a 6-month therapy with pravastatin decreases Hcy concentration in Finnish healthy young men. The MTHFR genotype is neither a determinant of baseline coronary flow indices nor does it modulate the effect of pravastatin on coronary reactivity. PMID:17574929

  4. Methylenetetrahydrofolate reductase, diet, and risk of colon cancer.

    PubMed

    Slattery, M L; Potter, J D; Samowitz, W; Schaffer, D; Leppert, M

    1999-06-01

    Individuals with different forms of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, carriers of the C677T mutation versus wild type, show differences in enzyme levels; these differences have been hypothesized to be related to DNA methylation and, perhaps, to the nucleotide pool size. Using data from an incident case-control study, we evaluated the combined effect of dietary intake of folate, methionine, vitamin B6, vitamin B12, and alcohol and various forms of the MTHFR gene on risk of colon cancer. Individuals homozygous for the variant form of the MTHFR gene (TT) had a slightly lower risk of colon cancer than did individuals who were wild type [CC, odds ratio (OR) = 0.8, 95% confidence interval (CI) = 0.6-1.1 for men; and OR = 0.9, 95% CI = 0.6-1.2 for women]. High levels of intake of folate, vitamin B6, and vitamin B12 were associated with a 30-40% reduction in risk of colon cancer among those with the TT relative to those with low levels of intake who were CC genotype. Associations were stronger for proximal tumors, in which high levels of intake of these nutrients were associated with a halving of risk among those with the TT genotype. The inverse association with high levels of these nutrients in those with the TT genotype was stronger among those diagnosed at an older age. Although imprecise, the inverse association with the low-risk diet that was high in folate and methionine and without alcohol was observed for both the TT genotype (OR = 0.4 95% CI = 0.1-0.9) and the CC/CT genotype (OR = 0.6, 95% CI = 0.4-1.0), but this association was not seen with the high-risk diet for either the TT or CC/CT genotype. Although associations were generally weak, these findings suggest that those with differing MTHFR genotypes may have different susceptibilities to colon cancer, based on dietary consumption of folate, vitamin B6, and vitamin B12. PMID:10385141

  5. Impact of new mutations in the methylenetetrahydrofolate reductase gene assessed on biochemical phenotypes: a familial study.

    PubMed

    Tonetti, C; Amiel, J; Munnich, A; Zittoun, J

    2001-12-01

    Methylenetetrahydrofolate reductase (MTHFR) deficiency was identified in two out of four children born from nonconsanguineous parents. One of the affected children exhibited some clinical findings suggesting cystathionine beta-synthase deficiency; MTHFR activity was extremely reduced. In addition, hyperhomocysteinaemia, hypomethioninaemia, low total folate, especially methylfolate in red blood cells, and a reduced methylfolate/total folate ratio were found. Two mutations not yet reported, one on exon 1 of the gene changing an arginine to stop codon and one other on exon 9 changing an arginine to tryptophan were identified in both children in the compound heterozygous state associated with a common polymorphism, 1298A>C, also in the heterozygous state. The mother, homozygous for the mutation on exon 9 and for the polymorphism 1298A>C on exon 7, was clinically and biochemically normal, with normal folate status, mainly methylfolate levels in red blood cells, although MTHFR activity was moderately decreased. The father, heterozygous for the transition arginine to stop codon and for the common polymorphism 677C>T on exon 4, exhibited major biochemical abnormalities, hyperhomocysteinaemia and low methylfolate levels in red blood cells, but was clinically normal. The unaffected children had a biochemical pattern close to that of their mother and were heterozygous for the mutation on exon 9 and also for the two common polymorphisms, 677C>T and 1298A>C. In the affected children, some biochemical abnormalities, including folate status, especially methylfolate levels, were improved with treatment combining methyltetrahydrofolic acid, hydroxocobalamin, pyridoxine and betaine; however, homocysteine concentrations remained high and methionine concentrations were lowered. The father was treated with folic acid, which partially improved biochemical abnormalities. The impact of these mutations is discussed. PMID:11916316

  6. The Association of Methylenetetrahydrofolate Reductase Genotypes with the Risk of Childhood Leukemia in Taiwan

    PubMed Central

    Chang, Wen-Shin; Ji, Hong-Xue; Hsiao, Chieh-Lun; Miao, Chia-En; Hsu, Yuan-Nian; Bau, Da-Tian

    2015-01-01

    Background Acute lymphoblastic leukemia (ALL) is the most prevalent type of pediatric cancer, the causes of which are likely to involve an interaction between genetic and environmental factors. To evaluate the effects of the genotypic polymorphisms in methylenetetrahydrofolate reductase (MTHFR) on childhood ALL risk in Taiwan, two well-known polymorphic genotypes of MTHFR, C677T (rs1801133) and A1298C (rs1801131), were analyzed to examine the extent of their associations with childhood ALL susceptibility and to discuss the MTHFR genotypic contribution to childhood ALL risk among different populations. Methodology/Principal Findings In total, 266 patients with childhood ALL and an equal number of non-cancer controls recruited were genotyped utilizing PCR-RFLP methodology. The MTHFR C677T genotype, but not the A1298C, was differently distributed between childhood ALL and control groups. The CT and TT of MTHFR C677T genotypes were significantly more frequently found in controls than in childhood ALL patients (odds ratios=0.60 and 0.48, 95% confidence intervals=0.42–0.87 and 0.24–0.97, respectively). As for gender, the boys carrying the MTHFR C677T CT or TT genotype conferred a lower odds ratio of 0.51 (95% confidence interval=0.32–0.81, P=0.0113) for childhood ALL. As for age, those equal to or greater than 3.5 years of age at onset of disease carrying the MTHFR C677T CT or TT genotype were of lower risk (odds ratio= 0.43 and 95% confidence interval=0.26–0.71, P=0.0016). Conclusions Our results indicated that the MTHFR C677T T allele was a protective biomarker for childhood ALL in Taiwan, and the association was more significant in male patients and in patients 3.5 years of age or older at onset of disease. PMID:25793509

  7. Genetic variants in 3′-UTRs of methylenetetrahydrofolate reductase (MTHFR) predict colorectal cancer susceptibility in Koreans

    PubMed Central

    Joo Jeon, Young; Woo Kim, Jong; Mi Park, Hye; Kim, Jung O; Geun Jang, Hyo; Oh, Jisu; Gyu Hwang, Seong; Won Kwon, Sung; Oh, Doyeun; Keun Kim, Nam

    2015-01-01

    Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) play important roles in tumor development, progression, and metastasis. Moreover, recent studies have reported that a number of 3′-UTR polymorphisms potentially bind to specific microRNAs in a variety of cancers. The aim of this study was to investigate the association of four MTHFR polymorphisms, 2572C>A [rs4846049], 4869C>G [rs1537514], 5488C>T [rs3737967], and 6685T>C [rs4846048] with colorectal cancer (CRC) in Koreans. A total of 850 participants (450 CRC patients and 400 controls) were enrolled in the study. The genotyping of MTHFR 3′-UTR polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism analysis or TaqMan allelic discrimination assay. We found that MTHFR 2572C>A, 4869C>G, and 5488C>T genotypes were substantially associated with CRC susceptibility. Of the potentially susceptible polymorphisms, MTHFR 2572C>A was associated with increased homocysteine and decreased folate levels in the plasma based on MTHFR 677CC. Our study provides the evidences for 3′-UTR variants in MTHFR gene as potential biomarkers for use in CRC prevention. PMID:26046315

  8. Free-floating thrombus of the carotid artery with a homozygous methylenetetrahydrofolate reductase gene mutation: a case report.

    PubMed

    Colak, Necmettin; Nazli, Yunus; Kosehan, Dilek; Alpay, Mehmet Fatih; Cakir, Omer

    2013-02-01

    Free-floating thrombus (FFT) of the carotid artery is a rare condition of currently unknown etiology. We describe a symptomatic patient with an FFT in the left common carotid artery. A duplex ultrasonography scan showed the presence of a mobile floating thrombus moving in cyclical motion with the cardiac cycles in the left common carotid artery. During emergency surgery, an FFT was seen at this location and removed. No underlying wall defect was seen at the time of surgery. In a genetic screening test, TT homozygous for the methylenetetrahydrofolate reductase (MTHFR) C677T genetic polymorphisms was detected. The patient recovered uneventfully, with no neurogical events. Lifelong anticoagulant therapy was recommended. An aggressive surgical approach is recommended in the patient to prevent embolic episodes. PMID:22101856

  9. A case of vascular parkinsonism associated with hyperhomocysteinemia and methylenetetrahydrofolate reductase gene variant (C677T).

    PubMed

    Hara, Kenju; Onda, Keigo; Ouchi, Haruka; Shibano, Ken; Ishiguro, Hideaki

    2016-03-01

    A 56-year-old man, who presented with 6 years history of difficulty in walking, was diagnosed as having vascular parkinsonism on the basis of the clinical findings of parkinsonism, pyramidal sign and the brain MRI findings of multiple lacunar infarction. Although he did not have hypertension, he had hyperhomocysteinemia and homozygous methylenetetrahydrofolate reductase (MTHFR) gene variant (C677T) as risk factors for ischemic stroke. Recent studies have shown that hyperhomocysteinemia and MTHFR gene variant are associated with small-vessel disease, suggesting that these risk factors may underlie vascular parkinsonism, particularly in patients lacking hypertension and in those with a relatively younger age at onset of this disease. PMID:26797478

  10. Methylenetetrahydrofolate reductase homozygous mutation in a young boy with cerebellar infarction.

    PubMed

    Spalice, Alberto; Del Balzo, Francesca; Perla, Francesco Massimo; Properzi, Enrico; Carducci, Carla; Antonozzi, Italo; Iannetti, Paola

    2009-01-01

    Posterior circulation vascular occlusive disease in children is a rare and uncommonly reported event. Among the numerous risk factors, the methylenetetrahydrofolate reductase (MTHFR) mutation is considered to be a common genetic cause of thrombosis in adults and children. Recently, a link between the MTHFR mutation and cerebrovascular disorders was reported in children. Diffusion tensor imaging (DTI) is a great improvement on magnetic resonance imaging (MRI), making the in vivo anatomical and pathological study of the brain and its fibers possible. In our patient cerebellar infarction was associated with MTHFR mutation and, in a standard neurological examination, DTI revealed normal white matter tracts. PMID:21589820

  11. Methylenetetrahydrofolate reductase homozygous mutation in a young boy with cerebellar infarction

    PubMed Central

    Spalice, Alberto; Del Balzo, Francesca; Perla, Francesco Massimo; Properzi, Enrico; Carducci, Carla; Antonozzi, Italo; Iannetti, Paola

    2009-01-01

    Posterior circulation vascular occlusive disease in children is a rare and uncommonly reported event. Among the numerous risk factors, the methylenetetrahydrofolate reductase (MTHFR) mutation is considered to be a common genetic cause of thrombosis in adults and children. Recently, a link between the MTHFR mutation and cerebrovascular disorders was reported in children. Diffusion tensor imaging (DTI) is a great improvement on magnetic resonance imaging (MRI), making the in vivo anatomical and pathological study of the brain and its fibers possible. In our patient cerebellar infarction was associated with MTHFR mutation and, in a standard neurological examination, DTI revealed normal white matter tracts. PMID:21589820

  12. Severe methylenetetrahydrofolate reductase deficiency revealed by a pulmonary embolism in a young adult.

    PubMed

    Tonetti, Carole; Ruivard, Marc; Rieu, Virginie; Zittoun, Jacqueline; Giraudier, Stephane

    2002-11-01

    Deficiency in methylenetetrahydrofolate reductase (MTHFR), the enzyme involved in the remethylation of homocysteine to methionine using methyltetrahydrofolate as cofactor, induces hyperhomocysteinaemia, homocysteinuria, hypomethioninaemia and low methylfolate levels. Diagnosis usually occurs during infancy because of various neurological abnormalities. We report MTHFR deficiency diagnosed in an adult woman after a pulmonary embolism. Her adult sister, intellectually retarded, suffered from the same disease. Molecular analysis of the MTHFR gene exhibited four different mutations (two missense mutations, one exon skipping and C677T). The impact of these mutations was analysed through the biological abnormalities in the parents and children. PMID:12406076

  13. Alteration of the alkaloid profile in genetically modified tobacco reveals a role of methylenetetrahydrofolate reductase in nicotine N-demethylation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme of the tetrahydrofolate (THF)-mediated one-carbon (C1) metabolic network. This enzyme catalyzes reduction of 5,10-methylene-THF to 5-methyl-THF. The latter donates its methyl group to homocysteine forming Met, which is then used for the syn...

  14. [Posterior-predominant leukoencephalopathy which was caused by methylenetetrahydrofolate reductase deficiency and successfully treated with folic acid].

    PubMed

    Tamura, Asako; Sasaki, Ryogen; Kagawa, Ken; Nakatani, Kaname; Osaka, Hitoshi; Tomimoto, Hidekazu

    2014-01-01

    A 35-year-old woman was admitted with subacute intellectual deterioration. Laboratory studies showed elevated total homocysteine and decreased folic acid. MRI revealed leukoencephalopathy with a posterior predominance, and hyperintensity in the pyramidal tracts on T2-weighted and FLAIR images. The enzyme assay showed a deficiency of methylenetetrahydrofolate reductase (MTHFR) activity with low residual activity of 4.2% of the mean control value in cultured fibroblasts. Sequence analysis of the MTHFR gene demonstrated two homozygous missense mutations, c.677C>T (p.Ala222Val) and c.685A>C (p.Ile225Leu). c.677C>T (p.Ala222Val) is known as a common polymorphism and c.685A>C (p.Ile225Leu) is considered to be a novel polymorphism. A diagnosis of MTHFR deficiency was made. Treatment with folic acid, vitamin B12 and B6 made significant improvement of intellectual deterioration and reduction in the total homocysteine level. They also made marked resolution of leukoencephalopathy. Posterior-predominant leukoencephalopathy was found to be an excellent marker of MTHFR deficiency, and may help to establish the diagnosis. PMID:24705833

  15. Heterotrimeric NADH-Oxidizing Methylenetetrahydrofolate Reductase from the Acetogenic Bacterium Acetobacterium woodii

    PubMed Central

    Bertsch, Johannes; Öppinger, Christian; Hess, Verena; Langer, Julian D.

    2015-01-01

    ABSTRACT The methylenetetrahydrofolate reductase (MTHFR) of acetogenic bacteria catalyzes the reduction of methylene-THF, which is highly exergonic with NADH as the reductant. Therefore, the enzyme was suggested to be involved in energy conservation by reducing ferredoxin via electron bifurcation, followed by Na+ translocation by the Rnf complex. The enzyme was purified from Acetobacterium woodii and shown to have an unprecedented subunit composition containing the three subunits RnfC2, MetF, and MetV. The stable complex contained 2 flavin mononucleotides (FMN), 23.5 ± 1.2 Fe and 24.5 ± 1.5 S, which fits well to the predicted six [4Fe4S] clusters in MetV and RnfC2. The enzyme catalyzed NADH:methylviologen and NADH:ferricyanide oxidoreductase activity but also methylene-tetrahydrofolate (THF) reduction with NADH as the reductant. The NADH:methylene-THF reductase activity was high (248 U/mg) and not stimulated by ferredoxin. Furthermore, reduction of ferredoxin, alone or in the presence of methylene-THF and NADH, was never observed. MetF or MetVF was not able to catalyze the methylene-THF-dependent oxidation of NADH, but MetVF could reduce methylene-THF using methyl viologen as the electron donor. The purified MTHFR complex did not catalyze the reverse reaction, the endergonic oxidation of methyl-THF with NAD+ as the acceptor, and this reaction could not be driven by reduced ferredoxin. However, addition of protein fractions made the oxidation of methyl-THF to methylene-THF coupled to NAD+ reduction possible. Our data demonstrate that the MTHFR of A. woodii catalyzes methylene-THF reduction according to the following reaction: NADH + methylene-THF → methyl-THF + NAD+. The differences in the subunit compositions of MTHFRs of bacteria are discussed in the light of their different functions. IMPORTANCE Energy conservation in the acetogenic bacterium Acetobacterium woodii involves ferredoxin reduction followed by a chemiosmotic mechanism involving Na

  16. Methylenetetrahydrofolate reductase: evidence for spatially distinct subunit domains obtained by scanning transmission electron microscopy and limited proteolysis

    SciTech Connect

    Matthews, R.G.; Vanoni, M.A.; Hainfeld, J.F.; Wall, J.

    1984-10-10

    Scanning transmission electron microscopy of individual unfixed molecules of methylenetetrahydrofolate reductase has been used to determine the molecular mass distribution of the protein. Methylenetetrahydrofolate reductase, which has a subunit molecular mass of 77 kilodaltons, was found to exist predominantly as a dimer with an apparent molecular mass of 136 +/- 29 kilodaltons. The mass distribution of the enzyme molecules was unchanged in the presence of the allosteric inhibitor S-adenosylmethionine. Examination of negatively stained protein molecules suggested that each subunit of the dimer consists of two globular domains of approximately equal size. Limited proteolysis of the enzyme by trypsin gave results which were entirely consistent with that view. In the presence of 1% trypsin, the enzyme was cleaved into two fragments. The masses of these fragments were 39 and 36 kilodaltons as assessed by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. Tryptic cleavage did not lead to loss of NADPH-menadione or NADPH-methylenetetrahydrofolate oxidoreductase activity, and the flavin prosthetic group remained bound to the protein. However, the cleaved protein was completely desensitized with respect to inhibition by S-adenosylmethionine. These results suggest that each subunit of methylenetetrahydrofolate reductase contains two domains and that allosteric inhibition requires specific interactions between these domains. The region between these two domains appears to be very sensitive to proteolysis, while the domains themselves are relatively resistant to further degradation. 14 references, 3 figures.

  17. Methylenetetrahydrofolate reductase mutations, a genetic cause for familial recurrent neural tube defects

    PubMed Central

    Yaliwal, Laxmi V.; Desai, Rathnamala M.

    2012-01-01

    Methylenetetrahydrofolate reductase (MTHFR) gene mutations have been implicated as risk factors for neural tube defects (NTDs). The best-characterized MTHFR genetic mutation 677C→T is associated with a 2–4 fold increased risk of NTD if patient is homozygous for this mutation. This risk factor is modulated by folate levels in the body. A second mutation in the MTHFR gene is an A→C transition at position 1298. The 1298A→C mutation is also a risk factor for NTD, but with a smaller relative risk than 677C→T mutation. Under conditions of low folate intake or high folate requirements, such as pregnancy, this mutation could become of clinical importance. We present a case report with MTHFR genetic mutation, who presented with recurrent familial pregnancy losses due to anencephaly/NTDs. PMID:22754237

  18. Methylenetetrahydrofolate reductase deficiency alters levels of glutamate and γ-aminobutyric acid in brain tissue

    PubMed Central

    Jadavji, N.M.; Wieske, F.; Dirnagl, U.; Winter, C.

    2015-01-01

    Methylenetetrahydrofolate reductase (MTHFR) is an enzyme key regulator in folate metabolism. Deficiencies in MTHFR result in increased levels of homocysteine, which leads to reduced levels of S-adenosylmethionine (SAM). In the brain, SAM donates methyl groups to catechol-O-methyltransferase (COMT), which is involved in neurotransmitter analysis. Using the MTHFR-deficient mouse model the purpose of this study was to investigate levels of monoamine neurotransmitters and amino acid levels in brain tissue. MTHFR deficiency affected levels of both glutamate and γ-aminobutyric acid in within the cerebellum and hippocampus. Mthfr−/− mice had reduced levels of glutamate in the amygdala and γ-aminobutyric acid in the thalamus. The excitatory mechanisms of homocysteine through activation of the N-methyl-d-aspartate receptor in brain tissue might alter levels of glutamate and γ-aminobutyric acid. PMID:26937386

  19. Effect of multivitamins on plasma homocysteine in patients with the 5,10 methylenetetrahydrofolate reductase C677T homozygous state.

    PubMed

    Dell'edera, Domenico; Tinelli, Andrea; Milazzo, Giusi Natalia; Malvasi, Antonio; Domenico, Carone; Pacella, Elena; Pierluigi, Compagnoni; Giuseppe, Tarantino; Marcello, Guido; Francesco, Lomurno; Epifania, Annunziata Anna

    2013-08-01

    The role of hyperhomocysteinemia (HHcy) as a cardiovascular risk factor remains a matter of debate, while it correlates with folates, it demonstrates inverse correlation with plasma homocysteine (Hcy) levels and vitamin B12 levels and reduces plasma Hcy levels following supplementation with multivitamins. The purpose of this study was to demonstrate that administering multivitamins at specific doses for 90 days restores normal plasma Hcy levels in women who are homozygous for the thermolabile variant of 5,10 methylenetetrahydrofolate reductase (MTHFR C677T). We enrolled 106 healthy females aged between 30 and 42 years, who were non-smokers, non-vegetarian, normotensive and who had no history of food abuse in the previous months. Only females were enrolled in order to rule out any bias due to the variation in Hcy plasma concentrations between males and females. Patient blood sampling was performed in order to determine plasma Hcy, serum folic acid and vitamin B12 levels. Furthermore, molecular characterization of the C677T polymorphism present in the MTHFR gene, was also performed. The results of this study demonstrated that supplementation with specific multivitamins restores normal plasma Hcy levels, regardless of the MTHFR genotype. Furthermore, it is unnecessary to adminster high doses of folate to reduce plasma Hcy levels, and administering high doses of folate may cause pro-inflammatory and pro-proliferative effects. PMID:23818036

  20. Association study of methylenetetrahydrofolate reductase A1298C mutation with cerebral venous thrombosis risk in an Iranian population

    PubMed Central

    Habib, Ghaznavi; Zahra, Soheili; Shahram, Samiei; Soltanpour, Mohammad Soleiman

    2015-01-01

    Background: Cerebral venous thrombosis (CVT) is an uncommon condition characterized by severe clinical manifestations and high mortality rate. There is limited data on the role of methylenetetrahydrofolate reductase (MTHFR) A1298C mutation as a risk factor for CVT development in Iranians. Aim: The aim was to investigate a possible association between fasting plasma homocysteine (Hcy) levels, MTHFR A1298C mutation, and CVT in Iranian population. Materials and Methods: The study population consisted of 50 patients with a diagnosis of CVT (20–63 years old) and 75 healthy subjects (18–65 years old) as control. Genotyping of the MTHFR A1298C mutation and Hcy measurement was carried out by polymerase chain reaction-restriction fragment length polymorphism technique and enzyme immunoassay method, respectively. Results: Fasting plasma total Hcy levels were significantly higher in CVT patients than controls (P = 0.015). No significant differences were observed in the MTHFR A1298C genotypes frequency between CVT patients and controls (P > 0.05). The frequency of the 1298C allele was 36% and 37.5% in CVT patients and controls, respectively and did not differ significantly between the two groups (P = 0.16). Conclusions: Our study demonstrated that MTHFR A1298Cmutation is not a significant risk factor for CVT. PMID:26539365

  1. Seven novel mutations at the 5,10-methylenetetrahydrofolate reductase locus

    SciTech Connect

    Goyette, P.; Frosst, P.; Rosenblatt, D.S.; Rozen, R.

    1994-09-01

    5,10-methylenetetrahydrofolate reductase (MTHFR), a flavoprotein, catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cofactor for methionine synthase in the methylation of homocysteine to methionine. Severe MTHFR deficiency, which causes homocysteinemia, is an autosomal recessive disorder with variable clinical features; developmental delay, perinatal death, mental retardation and asymptomatic individuals have been observed. A milder deficiency has been reported in patients with cardiovascular disease. We have recently described the isolation of a cDNA for MTHFR and the identification of 2 mutations in patients with severe MTHFR deficiency. We report here the characterization of 7 additional mutations at this locus: 5 missense mutations and 2 splicing mutations. Mutation analysis was performed by SSCP on PCR products generated either from reverse transcription-PCR of patients` total fibroblast RNA or from PCR of patients` genomic DNA. The 5 missense mutations are as follows: 1 Arg to Cys substitution in a hydrophilic segment proposed to be the hinge region that connects the catalytic and regulatory domains, 2 different Arg to Cys substitutions in 2 patients whose enzymatic thermolability is responsive to FAD, 1 Thr to Met substitution affecting an evolutionarily-conserved residue and a Pro to Leu substitution. The 2 splicing mutations affect the 5{prime} splice site and the 3{prime} splice site of 2 introns, respectively. The 5{prime} splice site mutation generates a 57 bp in-frame deletion of the RNA through the utilization of a cryptic 5{prime} splice site within the coding sequence. The identification of 9 mutations at this locus has allowed us to make preliminary correlations between genotype and phenotype and to contribute to a structure:function analysis of the enzyme.

  2. [Methylenetetrahydrofolate reductase deficiency-induced schizophrenia in a school-age boy].

    PubMed

    Wang, Qiao; Liu, Jing; Liu, Yu-Peng; Li, Xi-Yuan; Ma, Yan-Yan; Wu, Tong-Fei; Ding, Yuan; Song, Jin-Qing; Wang, Yu-Jie; Yang, Yan-Ling

    2014-01-01

    Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive disorder. It is known that MTHFR deficiency may result in hyperhomocysteinemia, but MTHFR deficiency-induced schizophrenia has been rarely reported. Here we present the clinical course, biochemical and genetic characteristics of schizophrenia resulted from MTHFR deficiency in a school-age boy. He was 13 years old. He was admitted with a two-year history of fear, auditory hallucination, learning difficulty, sleeping problems, irascibility, drowsing and giggling. At admission, he had significantly elevated plasma and urine levels of total homocysteine, significantly decreased levels of folate in serum and cerebrospinal fluid, and a normal blood concentration of methionine. Further DNA sequencing analysis showed 665C>T homozygous mutations in the MTHFR gene. The patient was diagnosed with MTHFR deficiency-associated schizophrenia and treatment with calcium folinate, vitamin B12, vitamin B6, and betaine was initiated. After the treatment for 1 week, his plasma and urine levels of homocysteine were decreased to a normal range and the clinical symptoms were significantly improved. After 3 months of treatment, the patient returned to school. He is now living with normal school life. In summary, children with late-onset MTHFR deficiency and secondary cerebral folate deficiency may lead to schizophrenia. This rare condition can be early diagnosed through analyses of blood and urine total homocysteine, amino acids in blood and folate in blood and cerebral fluid and successfully treated with folinic acid, vitamin B6, vitamin B12 and betaine. PMID:24461181

  3. Might erectile dysfunction be due to the thermolabile variant of methylenetetrahydrofolate reductase?

    PubMed

    Lombardo, F; Sgrò, P; Gandini, L; Dondero, F; Jannini, E A; Lenzi, A

    2004-10-01

    Hyperhomocysteinemia is considered one of the most important cardiovascular risk factors increasing considerably the risk of stroke and myocardial infarction. With respect to endothelial function, direct effects of hyperhomocysteinemia on vascular endothelial cells have been demonstrated through the reduction of endothelial nitric oxide production. In this paper, we report the case of a young man with homozygote genotype mutated with 5-methylenetetrahydrofolate reductase (MTHFR) thermolabile variant who, in the absence of relational stress, developed an erectile dysfunction (ED) refractory to the vasoactive type-V phosphodiesterase (PDE5) inhibitor therapy. After one month of treatment with 5 mg/day folic acid and 1000 microg/day cyanocobalamin, the patient restarted the assumption of 50 mg sildenafil, obtaining satisfying erections during sexual intercourse. We suggest that hyperhomocysteinemia may interfere with penile blood supply and, thus, be responsible for ED. If this relationship is confirmed, plasma levels and urinary homocysteine (HCy) should be evaluated in selected young patients with vascular ED. Furthermore, careful attention should be given to the risk of ED when dealing with this metabolic disturbance. PMID:15648556

  4. Purification and Properties of NADH-Dependent 5,10-Methylenetetrahydrofolate Reductase (MetF) from Escherichia coli

    PubMed Central

    Sheppard, Christal A.; Trimmer, Elizabeth E.; Matthews, Rowena G.

    1999-01-01

    A K-12 strain of Escherichia coli that overproduces methylenetetrahydrofolate reductase (MetF) has been constructed, and the enzyme has been purified to apparent homogeneity. A plasmid specifying MetF with six histidine residues added to the C terminus has been used to purify histidine-tagged MetF to homogeneity in a single step by affinity chromatography on nickel-agarose, yielding a preparation with specific activity comparable to that of the unmodified enzyme. The native protein comprises four identical 33-kDa subunits, each of which contains a molecule of noncovalently bound flavin adenine dinucleotide (FAD). No additional cofactors or metals have been detected. The purified enzyme catalyzes the reduction of methylenetetrahydrofolate to methyltetrahydrofolate, using NADH as the reductant. Kinetic parameters have been determined at 15°C and pH 7.2 in a stopped-flow spectrophotometer; the Km for NADH is 13 μM, the Km for CH2-H4folate is 0.8 μM, and the turnover number under Vmax conditions estimated for the reaction is 1,800 mol of NADH oxidized min−1 (mol of enzyme-bound FAD)−1. NADPH also serves as a reductant, but exhibits a much higher Km. MetF also catalyzes the oxidation of methyltetrahydrofolate to methylenetetrahydrofolate in the presence of menadione, which serves as an electron acceptor. The properties of MetF from E. coli differ from those of the ferredoxin-dependent methylenetetrahydrofolate reductase isolated from the homoacetogen Clostridium formicoaceticum and more closely resemble those of the NADH-dependent enzyme from Peptostreptococcus productus and the NADPH-dependent enzymes from eukaryotes. PMID:9922232

  5. Polymorphism in methylentetra-hydrofolate reductase gene: important role in diseases.

    PubMed

    Kiseljaković, Emina; Jadrić, Radivoj; Hasić, Sabaheta; Skenderi, Faruk; Resić, Halima; Winterhalter-Jadrić, Mira

    2008-05-01

    It has been recognized that some people have a genetic variant which leads to elevated levels of homocysteine and impairs ability to process folate. This condition was recognized as independent risk factor of coronary heart disease. Recently, connection between this termolabile mutation of the methylenetetrahydrofolate reductase and numerous conditions and diseases has been established. Aim of this review is to draw attention to this interesting area in medicine. Additionally, well defined study about presence and frequency of gene polymorphism in our region will provide proper diagnosis and achieve possible delay of development of diseases with vitamin supplementation. PMID:18498269

  6. C677T methylenetetrahydrofolate reductase and plasma homocysteine levels among Thai vegans and omnivores.

    PubMed

    Kajanachumpol, Saowanee; Atamasirikul, Kalayanee; Tantibhedhyangkul, Phieuvit

    2013-01-01

    Hyperhomocysteinemia among vegetarians and vegans is caused mostly by vitamin B12 deficiency. A C-to-T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene results in a thermolabile MTHFR, which may affect homocysteine (Hcy) levels. The importance of this gene mutation among populations depends on the T allele frequency. Blood Hcy, vitamin B12, folate, vitamin B6, and MTHFR C677T mutation status were determined in 109 vegans and 86 omnivores aged 30 - 50 years. The vegans had significantly higher Hcy levels than the omnivores, geometric means (95 % CI) 19.2 (17.0 - 21.7) µmol/L vs. 8.53 (8.12 - 8.95) µmol/L, p < 0.001. A C-to-T mutation in the vegans increased plasma Hcy, albeit insignificantly; geometric means 18.2 µmol/L, 20.4 µmol/L, and 30.0 µmol/L respectively in CC, CT, and TT MTHFR genotypes. There was also a significant decrease in serum folate; geometric means 12.1 ng/mL, 9.33 ng/mL, and 7.20 ng/mL respectively, in the CC, CT, and TT mutants, p = 0.006, and particularly, in the TT mutant compared with the CC wild type, 7.20 ng/mL vs. 12.1 ng/mL, p = 0.023. These findings were not seen in the omnivores. It was concluded that hyperhomocysteinemia is prevalent among Thai vegans due to vitamin B12 deficiency. C-to-T MTHFR mutation contributes only modestly to the hyperhomocysteinemia. PMID:24491881

  7. Nonarteritic anterior ischemic optic neuropathy: associations with homozygosity for the C677T methylenetetrahydrofolate reductase mutation.

    PubMed

    Glueck, Charles J; Wang, Ping; Bell, Howard; Rangaraj, Venkat; Goldenberg, Naila

    2004-03-01

    The association between nonarteritic anterior ischemic optic neuropathy (NAION) and coagulation disorders was prospectively assessed at least 3 months after the occurrence of ocular vascular events in 12 white patients in an outpatient clinical research center. Two community-based ophthalmologists evaluated the 12 NAION patients in the consecutive order of their referral. Polymerase chain reaction-complementary DNA assays of gene mutations associated with coagulation disorders and serologic coagulation measurements in study patients were compared with those in 36 healthy, normal race-, sex-, and age-matched controls, with 3 controls matched for each case. Of the 12 patients, 4 men and 8 women (mean age 62 +/- 15 years, 3 of them 55 years or older), 8 had unilateral NAION (bilateral in 4). The 12 patients with NAION were more likely than controls to demonstrate homozygosity for the methylenetetrahydrofolate reductase (MTHFR) C677T mutation (50% vs 11 %; Fisher's P =.009, with the likelihood of a type I error quite small, 0.9%). Our sample size had a power of 80% to detect this case-control difference in C677T MTHFR homozygosity at an alpha value of.05. Of the 12 NAION patients, 7 (58%) had at least 1 gene mutation in the C677T MTHFR, G1691A V Leiden, or G20210A prothrombin gene, compared with 5 of 36 controls (14%) (chi(2) = 9.48, P =. 002, with the likelihood of a type I error quite small, 0.2%). Our sample size had a power of 85% to detect this case-control difference at alpha =. 05. Of the 8 women with NAION, 5 (63%) first experienced the condition while taking hormone replacement therapy (n = 4) or during pregnancy (n = 1), with superposition of estrogen-induced thrombophilia on heritable thrombophilia and hypofibrinolysis. Confirmation of a causal relationship between coagulation disorders and NAION should facilitate its prevention and treatment and help protect against thrombi in other vascular beds. PMID:15007309

  8. Methylenetetrahydrofolate reductase genotypes and haplotypes associated with susceptibility to colorectal cancer in an eastern Chinese Han population.

    PubMed

    Li, H; Xu, W L; Shen, H L; Chen, Q Y; Hui, L L; Long, L L; Zhu, X L

    2011-01-01

    Methylenetetrahydrofolate reductase (MTHFR) plays an important role in folate metabolism and is involved in DNA synthesis, DNA repair and DNA methylation. The two common functional polymorphisms of MTHFR, C677T and A1298C have been associated with several diseases, including cancer. We made a case-control study to analyze a possible association of MTHFR gene polymorphisms C677T and A1298C with risk for colorectal cancer in an eastern Chinese Han population of 137 patients with a confirmed histopathological diagnosis of CRC and 145 age- and gender-matched controls with no history of cancer. DNA was isolated from peripheral blood samples and the genotypes were determined by PCR-RFLP. The concentrations of folate in plasma were measured by chemiluminescence immunoassay. The MTHFR 677TT genotype had a protective effect against colorectal cancer, with an odds ratio (OR) = 0.467 (95% confidence interval (CI) = 0.225-0.966). The 1298CC genotype was significantly correlated with a reduced risk of colorectal cancer (OR = 0.192; 95%CI = 0.040-0.916). Compared with the MTHFR 677CC and MTHFR 1298 AA genotypes, for individuals who carried both MTHFR 677CC and 1298CC genotypes, the OR of colorectal cancer was 0.103 (95%CI = 0.012-0.900); among individuals who carried both MTHFR 677TT and 1298AC genotypes, the OR for risk of colorectal cancer was 0.169 (95%CI = 0.044-0.654). MTHFR 677TT+CT genotypes had a significantly lower plasma folate concentration than those with the MTHFR 677CC genotype. MTHFR 1298AC+CC genotypes had a lower plasma folate concentration than those with the MTHFR 1298AA genotype (P < 0.05). In conclusion, subjects with the MTHFR 677TT and MTHFR 1298CC genotypes appeared to have a significantly lower risk for colorectal cancer. MTHFR haplotypes 677CC/1298CC and 677TT/1298AC were less common in cases than in controls. These haplotypes, when compared to the most common haplotype 677CC/1298AA, were associated with a decreased risk for colorectal cancer. We

  9. Methylenetetrahydrofolate reductase homozygosis and low-density lipoproteins in patients with genotype 1 chronic hepatitis C.

    PubMed

    Petta, S; Bellia, C; Mazzola, A; Cabibi, D; Cammà, C; Caruso, A; Di Marco, V; Craxì, A; Ciaccio, M

    2012-07-01

    Methylenetetrahydrofolate reductase status, homocysteine and lipoproteins levels have been associated with severity of disease and both rapid and sustained virological response (SVR) in patients with genotype 1 chronic hepatitis C (CHC). We aimed to assess the association of homocysteine and MTHFR status with serum cholesterol levels and their potential links to both histological findings and virological response, in patients with genotype 1 hepatitis C virus (HCV). A total of 119 consecutive patients were evaluated by biopsy and metabolic measurements. A total of 103 healthy blood donors were used as controls. Serum homocysteine and MTHFR C677T mutation were also evaluated. All patients underwent antiviral therapy with PEG-IFN alfa-2a plus ribavirin. HCV-RNA was assessed at baseline, week 4, week 12, at the end of therapy and after 6 months of follow-up. Mean serum values of homocysteine were higher in patients than in controls (15.8 ± 5.8 μg/L vs 12.5 ± 5.8 μg/L; P < 0.001), with a similar CC, CT and TT MTHFR distribution (23.6%, 48.7% and 27.7% in G1-CHC vs 34%, 48.5% and 17.5% in controls; P = 0.14). In genotype 1, HCV MTHFR TT homozygosis was independently linked to higher LDL (OR 1.016; CI 1.002-1.031; P = 0.03), but not to homocysteine. No association were found between homocysteine, MTHFR and histological features or both rapid virological response (RVR) and SVR. Low cholesterol (OR 0.988, 95%CI 0.975-0.999, P = 0.04) was independently linked to severe fibrosis, and high LDL was the only independent positive predictors of both RVR and SVR (OR 1.036; 95%CI 1.017-1.055; P < 0.001; and OR 1.016; 95%CI 1.001-1.031; P = 0.04 respectively). In patients with genotype 1 hepatitis C, showing higher homocysteine serum levels than controls, MTHFR C677T homozygosis, via modulating cholesterol levels, could interfere with liver fibrosis and response to antiviral therapy. PMID:22676358

  10. Thermolabile methylenetetrahydrofolate reductase: an inherited risk factor for coronary artery disease.

    PubMed Central

    Kang, S S; Wong, P W; Susmano, A; Sora, J; Norusis, M; Ruggie, N

    1991-01-01

    Severe methylenetetrahydrofolate reductase (MTHFR) deficiency with less than 2% of normal enzyme activity is characterized by neurological abnormalities, atherosclerotic changes, and thromboembolism. We have discovered a "new" variant of MTHFR deficiency which is characterized by the absence of neurological abnormalities, an enzyme activity of about 50% of the normal value, and distinctive thermolability under specific conditions of heat inactivation. In this study, lymphocyte MTHFR specific activities in the thermolabile variant and control groups were 5.58 +/- 0.91 and 10.33 +/- 2.89 nmol formaldehyde formed/mg protein/h, respectively. The difference was significant (P less than .01). However, there was overlap among the individual values from the two groups. On the other hand, residual MTHFR activity after heat inactivation was 11.2 +/- 1.43% in the thermolabile variant and 36.3 +/- 5.18% in the controls. There was no overlap. Enzyme studies in 10 subjects with thermolabile MTHFR and their family members support the hypothesis that thermolabile MTHFR is inherited as an autosomal recessive trait. To elucidate the association of thermolabile MTHFR with the development of coronary artery disease, we determined the thermostability of lymphocyte MTHFR in 212 patients with proven coronary artery disease and in 202 controls without clinical evidence of atherosclerotic vascular disease. Thermolabile MTHFR was found in 36 (17.0%) cardiac patients and 10 (5.0%) controls. The difference in incidence between the two groups was statistically significant (P less than .01). The average age at onset of clinical coronary artery disease in 36 patients with thermolabile MTHFR was 57.3 +/- 7.6 years (35-72 years). The mean total plasma homocysteine concentration in patients with thermolabile MTHFR was 13.19 +/- 5.32 nmol/ml and was significantly different from the normal mean of 8.50 +/- 2.80 nmol/ml (P less than .05). There was no association between thermolabile MTHFR and other

  11. The C677T mutation in the methylenetetrahydrofolate reductase gene predisposes to hyperhomocysteinemia in children with familial hypercholesterolemia treated with cholestyramine.

    PubMed

    Tonstad, S; Refsum, H; Ose, L; Ueland, P M

    1998-02-01

    In children with familial hypercholesterolemia, heterozygosity and homozygosity for the C677T mutation in the methylenetetrahydrofolate reductase gene was associated with low serum folate and increased susceptibility to elevation of plasma total homocysteine during cholestyramine treatment. Because of the independent relationship between elevated plasma total homocysteine and cardiovascular disease, folate supplementation may be prudent in these children. PMID:9506661

  12. Insights into severe 5,10-methylenetetrahydrofolate reductase deficiency: molecular genetic and enzymatic characterization of 76 patients.

    PubMed

    Burda, Patricie; Schäfer, Alexandra; Suormala, Terttu; Rummel, Till; Bürer, Céline; Heuberger, Dorothea; Frapolli, Michele; Giunta, Cecilia; Sokolová, Jitka; Vlášková, Hana; Kožich, Viktor; Koch, Hans Georg; Fowler, Brian; Froese, D Sean; Baumgartner, Matthias R

    2015-06-01

    5,10-Methylenetetrahydrofolate reductase (MTHFR) deficiency is the most common inherited disorder of folate metabolism and causes severe hyperhomocysteinaemia. To better understand the relationship between mutation and function, we performed molecular genetic analysis of 76 MTHFR deficient patients, followed by extensive enzymatic characterization of fibroblasts from 72 of these. A deleterious mutation was detected on each of the 152 patient alleles, with one allele harboring two mutations. Sixty five different mutations (42 novel) were detected, including a common splicing mutation (c.1542G>A) found in 21 alleles. Using an enzyme assay in the physiological direction, we found residual activity (1.7%-42% of control) in 42 cell lines, of which 28 showed reduced affinity for nicotinamide adenine dinucleotide phosphate (NADPH), one reduced affinity for methylenetetrahydrofolate, five flavin adenine dinucleotide-responsiveness, and 24 abnormal kinetics of S-adenosylmethionine inhibition. Missense mutations causing virtually absent activity were found exclusively in the N-terminal catalytic domain, whereas missense mutations in the C-terminal regulatory domain caused decreased NADPH binding and disturbed inhibition by S-adenosylmethionine. Characterization of patients in this way provides a basis for improved diagnosis using expanded enzymatic criteria, increases understanding of the molecular basis of MTHFR dysfunction, and points to the possible role of cofactor or substrate in the treatment of patients with specific mutations. PMID:25736335

  13. Hyperbaric Oxygen Therapy in Branch Retinal Artery Occlusion in a 15-Year-Old Boy with Methylenetetrahydrofolate Reductase Mutation

    PubMed Central

    Kadayifcilar, Sibel; Eldem, Bora

    2015-01-01

    Purpose. To report the efficacy of hyperbaric oxygen (HBO) therapy in a case of branch retinal artery occlusion (BRAO) in a 15-year-old boy. Methods. We report a 15-year-old boy with sudden loss of vision due to BRAO. Examination included laboratory evaluation for systemic risk factors. Follow-up exams included visual acuity, fundus examination, fundus fluorescein angiography, and visual field testing. HBO therapy was employed for treatment. Results. Medical history was positive for isolated glucocorticoid deficiency. Laboratory evaluation disclosed hyperhomocysteinemia and methylenetetrahydrofolate reductase (MTHFR) mutation. The visual acuity 0.05 at presentation improved to 0.8 after 20 days of HBO therapy. There was no change on visual fields. Conclusion. In this pediatric case, HBO therapy was useful in the treatment of BRAO. PMID:25722905

  14. Significance of 5,10-methylenetetrahydrofolate reductase gene variants in acute lymphoblastic leukemia in Indian population: an experimental, computational and meta-analysis.

    PubMed

    Bellampalli, Ravishankara; Phani, Nagaraja M; Bhat, Kamalakshi G; Prasad, Krishna; Bhaskaranand, Nalini; Guruprasad, Kanive P; Rai, Padmalatha S; Satyamoorthy, Kapaettu

    2015-05-01

    Acute lymphoblastic leukemia (ALL) arises due to several genetic alterations in progenitor cells, and methotrexate is frequently used as part of the treatment regimen. Although there is evidence for an effect of 5,10-methylenetetrahydrofolate reductase gene (MTHFR) C677T and A1298C variations on drug response in ALL, its risk association for ALL is still unresolved. In a case-control study of 203 patients with ALL and 246 controls and meta-analysis in the Indian population, we showed an insignificant association of MTHFR C677T and A1298C genotypes with childhood and adult ALL. Comprehensive in silico characterization of non-synonymous single nucleotide polymorphisms (nsSNPs) and SNPs of the 3' untranslated region (UTR) revealed nine nsSNPs as deleterious, and three SNPs in the 3'UTR could possibly alter the binding of miRNAs. The study revealed that several overlooked SNPs may contribute to the risk of ALL susceptibility and further studies of these SNPs with functional characterization in a large sample size are required to understand the significant role of MTHFR in ALL development. PMID:25115513

  15. Association between methionine synthase reductase A66G polymorphism and primary infertility in Chinese males.

    PubMed

    Li, X Y; Ye, J Z; Ding, X P; Zhang, X H; Ma, T J; Zhong, R; Ren, H Y

    2015-01-01

    We examined the association between the methionine synthase reductase (MTRR A66G), methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), and methionine synthase (MS A2756G) genotypes and non-obstructive male infertility in a Chinese population. This case-control study included 162 infertile Chinese patients with azoospermia (N = 100) or oligoasthenozoospermia (N = 62) and 120 fertile men as controls. The polymorphisms MTRR A66G, MTHFR C677T, A1298C, and MS A2756G were identified by direct DNA sequencing and the results were statistically analyzed. We found no association between the incidence of any of these variants in azoospermia patients and control populations. The frequency of the MTRR66 polymorphic genotypes (AG, AG+GG) was significantly higher in the oligoasthenozoospermia group compared to the controls (P = 0.013, 0.012). Our findings revealed an association between the single-nucleotide polymorphism A66G in the MTRR gene and male infertility, particularly in oligoasthenozoospermia males, suggesting that this polymorphism is a genetic risk factor for male infertility in Chinese men. PMID:25966116

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

    PubMed Central

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

    2014-01-01

    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

  17. Altered protein phosphatase 2A methylation and Tau phosphorylation in the young and aged brain of methylenetetrahydrofolate reductase (MTHFR) deficient mice

    PubMed Central

    Sontag, Jean-Marie; Wasek, Brandi; Taleski, Goce; Smith, Josephine; Arning, Erland; Sontag, Estelle; Bottiglieri, Teodoro

    2014-01-01

    Common functional polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, a key enzyme in folate and homocysteine metabolism, influence risk for a variety of complex disorders, including developmental, vascular, and neurological diseases. MTHFR deficiency is associated with elevation of homocysteine levels and alterations in the methylation cycle. Here, using young and aged Mthfr knockout mouse models, we show that mild MTHFR deficiency can lead to brain-region specific impairment of the methylation of Ser/Thr protein phosphatase 2A (PP2A). Relative to wild-type controls, decreased expression levels of PP2A and leucine carboxyl methyltransferase (LCMT1) were primarily observed in the hippocampus and cerebellum, and to a lesser extent in the cortex of young null Mthfr−/− and aged heterozygous Mthfr+/− mice. A marked down regulation of LCMT1 correlated with the loss of PP2A/Bα holoenzymes. Dietary folate deficiency significantly decreased LCMT1, methylated PP2A and PP2A/Bα levels in all brain regions examined from aged Mthfr+/+ mice, and further exacerbated the regional effects of MTHFR deficiency in aged Mthfr+/− mice. In turn, the down regulation of PP2A/Bα was associated with enhanced phosphorylation of Tau, a neuropathological hallmark of Alzheimer’s disease (AD). Our findings identify hypomethylation of PP2A enzymes, which are major CNS phosphatases, as a novel mechanism by which MTHFR deficiency and Mthfr gene-diet interactions could lead to disruption of neuronal homeostasis, and increase the risk for a variety of neuropsychiatric disorders, including age-related diseases like sporadic AD. PMID:25202269

  18. Altered protein phosphatase 2A methylation and Tau phosphorylation in the young and aged brain of methylenetetrahydrofolate reductase (MTHFR) deficient mice.

    PubMed

    Sontag, Jean-Marie; Wasek, Brandi; Taleski, Goce; Smith, Josephine; Arning, Erland; Sontag, Estelle; Bottiglieri, Teodoro

    2014-01-01

    Common functional polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, a key enzyme in folate and homocysteine metabolism, influence risk for a variety of complex disorders, including developmental, vascular, and neurological diseases. MTHFR deficiency is associated with elevation of homocysteine levels and alterations in the methylation cycle. Here, using young and aged Mthfr knockout mouse models, we show that mild MTHFR deficiency can lead to brain-region specific impairment of the methylation of Ser/Thr protein phosphatase 2A (PP2A). Relative to wild-type controls, decreased expression levels of PP2A and leucine carboxyl methyltransferase (LCMT1) were primarily observed in the hippocampus and cerebellum, and to a lesser extent in the cortex of young null Mthfr (-/-) and aged heterozygous Mthfr (+/-) mice. A marked down regulation of LCMT1 correlated with the loss of PP2A/Bα holoenzymes. Dietary folate deficiency significantly decreased LCMT1, methylated PP2A and PP2A/Bα levels in all brain regions examined from aged Mthfr (+/+) mice, and further exacerbated the regional effects of MTHFR deficiency in aged Mthfr (+/-) mice. In turn, the down regulation of PP2A/Bα was associated with enhanced phosphorylation of Tau, a neuropathological hallmark of Alzheimer's disease (AD). Our findings identify hypomethylation of PP2A enzymes, which are major CNS phosphatases, as a novel mechanism by which MTHFR deficiency and Mthfr gene-diet interactions could lead to disruption of neuronal homeostasis, and increase the risk for a variety of neuropsychiatric disorders, including age-related diseases like sporadic AD. PMID:25202269

  19. Severe methylenetetrahydrofolate reductase deficiency in mice results in behavioral anomalies with morphological and biochemical changes in hippocampus.

    PubMed

    Jadavji, Nafisa M; Deng, Liyuan; Leclerc, Daniel; Malysheva, Olga; Bedell, Barry J; Caudill, Marie A; Rozen, Rima

    2012-06-01

    The brain is particularly sensitive to folate metabolic disturbances, since methyl groups are critical for its functions. Methylenetetrahydrofolate reductase (MTHFR) generates the primary circulatory form of folate required for homocysteine remethylation to methionine. Neurological disturbances have been described in homocystinuria caused by severe MTHFR deficiency. The goal of this study was to determine if behavioral anomalies are present in severe Mthfr-deficient (Mthfr(-/-)) mice and to identify neurobiological changes that could contribute to these anomalies. Adult male mice of 3 Mthfr genotypes (+/+, +/-, -/-) were tested on motor, anxiety, exploratory and cognitive tasks. Volumes (whole brain and hippocampus) and morphology, global DNA methylation, apoptosis, expression of choline acetyltransferase (ChAT) and glucocorticoid receptor (GR), and concentrations of choline metabolites were assessed in hippocampus. Mthfr(-/-) mice had impairments in motor function and in short- and long-term memory, increased exploratory behavior and decreased anxiety. They showed decreased whole brain and hippocampal volumes, reduced thickness of the pyramidal cell layer of CA1 and CA3, and increased apoptosis in hippocampus. There was a disturbance in choline metabolism as manifested by differences in acetylcholine, betaine or glycerophosphocholine concentrations, and by increased ChAT levels. Mthfr(-/-) mice also had increased GR mRNA and protein. Our study has revealed significant anomalies in affective behavior and impairments in memory of Mthfr(-/-) mice. We identified structural changes, increased apoptosis, altered choline metabolism and GR dysregulation in hippocampus. These findings, as well as some similar observations in cerebellum, could contribute to the behavioral changes and suggest that choline is a critical metabolite in homocystinuria. PMID:22521626

  20. Plasma homocysteine levels related to interactions between folate status and methylenetetrahydrofolate reductase: a study in 52 healthy subjects.

    PubMed

    Zittoun, J; Tonetti, C; Bories, D; Pignon, J M; Tulliez, M

    1998-11-01

    Hyperhomocysteinemia, a risk factor for vascular disease, is related to vitamin B12, vitamin B6, and especially folate deficiency, or to genetic factors such as mutations in methylenetetrahydrofolate reductase (MTHFR), an enzyme involved in the remethylation pathway of homocysteine to methionine. Recently, a C677 --> T mutation identified in the MTHFR gene was found to be frequently associated with decreased MTHFR activity and an elevated plasma homocysteine concentration. Since hyperhomocysteinemia seems to be determined by both genetic and environmental factors, we studied the interactions between MTHFR (phenotype and genotype) and folate status, including methyltetrahydrofolate (methylTHF), the product of MTHFR, on the homocysteine concentration in 52 healthy subjects, (28 women and 24 men; mean age, 32.7 years). MTHFR activity seems to be dependent on folate status, as shown by a lower activity in folate-deficient subjects and a return to normal values after supplementation with folic acid, and also by a decreased enzymatic activity on phytohemagglutinin (PHA)-stimulated lymphocytes grown in a folic acid-deficient medium. Conversely, the C677 --> T mutation seems to influence folate metabolism. Subjects who were homozygous for this mutation (+/+) had significantly higher plasma homocysteine and lower plasma folate and total and methylfolate levels in red blood cells (RBCs) than heterozygous (+/-) and normal (-/-) subjects. The ratio of RBC methylfolate to RBC total folate was, respectively, 0.27 in +/+, 0.66 in +/-, and 0.71 in -/-. This mutation seems to have an impact on methylTHF generation. These data illustrate the interactions between nutritional and genetic factors. PMID:9826223

  1. Folate Intake at RDA Levels Is Inadequate for Mexican American Men with the Methylenetetrahydrofolate Reductase 677TT Genotype123

    PubMed Central

    Solis, Claudia; Veenema, Kristin; Ivanov, Alexandre A.; Tran, Sally; Li, Rui; Wang, Wei; Moriarty, David J.; Maletz, Charles V.; Caudill, Marie A.

    2009-01-01

    Since the establishment of the 1998 folate recommended dietary allowance (RDA), the methylenetetrahydrofolate reductase (MTHFR) 677C→T variant has emerged as a strong modifier of folate status. This controlled feeding study investigated the adequacy of the RDA, 400 μg/d as dietary folate equivalents (DFE), for Mexican American men with the MTHFR 677CC or TT genotype. Because of the interdependency between folate and choline, the influence of choline intake on folate status was also assessed. Mexican American men (n = 60; 18–55 y) with the MTHFR 677CC (n = 31) or TT (n = 29) genotype consumed 438 μg DFE/d and total choline intakes of 300, 550 (choline adequate intake), 1100, or 2200 mg/d for 12 wk. Folate status response was assessed via serum folate (SF), RBC folate, plasma total homocysteine (tHcy), and urinary folate. SF decreased (P < 0.001) 66% to 7.9 ± 0.7 nmol/L (means ± SEM) in men with the 677TT genotype and 62% to 11.3 ± 0.9 nmol/L in the 677CC genotype. Plasma tHcy increased (P < 0.0001) 170% to 31 ± 3 μmol/L in men with the 677TT genotype and 18% to 11.6 ± 0.3 μmol/L in the 677CC genotype. At the end of the study, 34% (677TT) and 16% (677CC) had SF concentrations <6.8 nmol/L and 79% (677TT) and 7% (677CC) had tHcy concentrations >14 μmol/L. Choline intake did not influence the response of the measured variables. These data showed that the folate RDA is not adequate for men of Mexican descent, particularly for those with the MTHFR 677TT genotype, and demonstrated a lack of influence of choline intake on the folate status variables measured in this study. PMID:18156406

  2. Opposite effects of plasma homocysteine and the methylenetetrahydrofolate reductase C677T mutation on carotid artery geometry in asymptomatic adults.

    PubMed

    Demuth, K; Moatti, N; Hanon, O; Benoit, M O; Safar, M; Girerd, X

    1998-12-01

    Studies of symptomatic patients have identified hyperhomocysteinemia as an independent risk factor for vascular disease. In case-control studies, a point mutation (C677T) in the gene encoding 5,10-methylenetetrahydrofolate reductase (MTHFR) has also been linked to an increased risk of vascular disease through its effect on homocysteinemia. Our aim was to extend these observations to asymptomatic subjects by studying the influence of both homocysteinemia and its mutation on carotid artery geometry. We examined 144 subjects free of atherosclerotic lesions. Fasting homocysteinemia was measured by high-performance liquid chromatography with fluorometric detection. MTHFR genotype was analyzed by polymerase chain reaction followed by HinfI digestion. Carotid artery geometry was characterized by internal diameter and intima-media thickness, as assessed by a high-resolution echo-tracking system. Subjects in the upper homocysteine tertile had a greater carotid internal diameter than did subjects in the middle and lower tertiles (6516+/-770 versus 6206+/-641 and 5985+/-558 microm, respectively; P<0.001). Subjects homozygous for the mutation had a smaller carotid artery internal diameter than did subjects heterozygous or homozygous for the wild-type allele (5846+/-785 versus 6345+/-673 and 6199+/-671 microm, respectively; P<0.05). Homocysteinemia was not significantly increased in subjects homozygous for the mutation. In multivariate regression analysis, homocysteinemia was independently and positively associated with lumen diameter (P=0.0008) and wall thickness (P=0.020). Conversely, homozygosity for the mutation was negatively associated with internal diameter (P=0.009). These preliminary data suggest that mildly elevated homocysteinemia and homozygosity for the MTHFR C677T mutation are associated with opposite preclinical modifications of carotid artery geometry. If confirmed, these results may have important implications for new treatment strategies for vascular disease

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

    PubMed Central

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

    2015-01-01

    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

  4. Role of Hyperhomocysteinemia and Methylene Tetrahydrofolate Reductase C677T Polymorphism in Idiopathic Portal Vein Thrombosis

    PubMed Central

    Ghaznavi, Habib; Soheili, Zahra; Samiei, Shahram; Soltanpour, Mohammad Soleiman

    2016-01-01

    Purpose: Portal vein thrombosis (PVT) is a rare and life-threatening vascular disorder characterized by obstruction or narrowing of the portal vein. Hyperhomocysteinemia and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism has been studied in PVT patients with conflicting results. In the present study the association of hyperhomocysteinemia and MTHFR C677T polymorphism with PVT risk was investigated in Iranians. Materials and Methods: Our study population consisted of 10 idiopathic PVT patients and 80 healthy control subjects matched for age and sex. MTHFR C677T polymorphism was genotyped by the polymerase chain reaction technique combined with restriction enzyme fragment length polymorphism (PCR-RFLP) technique and plasma total homocysteine (tHcy) levels were determined by enzyme immunoassay method. Results: Mean plasma tHcy levels were significantly higher in PVT patients (20.2±6.8) than control subjects (10.9±4.7) (P=0.001). Moreover, plasma tHcy levels were significantly higher in 677T allele carriers relative to 677C allele carriers in both PVT patients (P=0.01) and control subjects (P=0.03). Neither homozygote nor heterozygote genotypes of MTHFR C677T polymorphism correlated significantly with PVT risk (P>0.05). Moreover, MTHFR C677T polymorphism didn’t increase the risk of PVT under dominant (CT+TT vs. CC) or recessive (TT vs. CC+CT) genetic models analyzed (P>0.05). The difference in frequency of minor 677T allele between PVT patients and control subjects was not statistically significant (P>0.05). Conclusion: Based on the current study, we suggest that hyperhomocysteinemia constitutes a significant and common risk factor for PVT. Also, MTHFR C677T polymorphism is not a risk factor for PVT but is a contributing factor for elevated plasma tHcy levels. PMID:27051654

  5. Analysis of the apo E/apo C-I, angiotensin converting enzyme and methylenetetrahydrofolate reductase genes as candidates affecting human longevity.

    PubMed

    Galinsky, D; Tysoe, C; Brayne, C E; Easton, D F; Huppert, F A; Dening, T R; Paykel, E S; Rubinsztein, D C

    1997-03-21

    Genetic factors are likely to affect human survival, since twin studies have shown greater concordance for age of death in monozygotic compared to dizygotic twins. Coronary artery disease is an important contributor to premature mortality in the UK. Accordingly, we have chosen genes associated with cardiovascular risk, apo E/apo C-I, angiotensin converting enzyme (ACE) and methylenetetrahydrofolate reductase (MTHFR), as candidates which may affect longevity/survival into old age. An association study was performed by comparing allele and genotype frequencies at polymorphic loci associated with these genes in 182 women and 100 men aged 84 years and older with 100 boys and 100 girls younger than 17 years. MTHFR allele and genotype frequencies were similar in the elderly and young populations. Apo C-I allele and genotype frequencies were significantly different in the elderly women compared to the younger sample (P < 0.05). No difference was observed in the elderly men. At the neighbouring apo E gene, we only observed a difference between genotypes in the elderly women and the young sample; however, this did not retain significance when the genotype frequencies of the young sample were adjusted to values expected from the allele frequencies on the basis of Hardy-Weinberg equilibrium and compared to observed genotypes in elderly men and women. In contrast to previous studies, apo E2 was not overrepresented in the elderly men or women. Thus, the proposition that apo E2, E3 and E4 protein isoforms are themselves functionally associated with increasing risks for early death, may be too simplistic. The I/I ACE was depleted in the elderly males but not the elderly females. Furthermore, significant differences were observed between ACE genotypes in elderly men and elderly women. These data suggest that the penetrance of loci which influence survival may vary according to sex. The depletion of the ACE I/I genotype in elderly men is generally consistent with a previous study

  6. Plasma homocysteine in adolescents depends on the interaction between methylenetetrahydrofolate reductase genotype, lipids and folate: a seroepidemiological study

    PubMed Central

    Gil-Prieto, Ruth; Hernández, Valentín; Cano, Beatriz; Oya, Manuel; Gil, Ángel

    2009-01-01

    Background Many publications link high homocysteine levels to cardiovascular disease. In Spain there is little information on the prevalence of hyperhomocysteinaemia and associated vitamin factors among the general population, and less still among children. Cardiovascular risk factors in the childhood population may be related to the appearance of cardiovascular disease at adult age. The aim of this study is to establish a definition of hyperhomocysteinaemia in adolescents and to analyze the influence of vitamin and metabolic factors in homocysteine levels in this population group. Methods Descriptive, cross-sectional epidemiological study to estimate serum homocysteine, vitamin B12 and folate levels, as well as plasma total, HDL- and LDL- cholesterol in a schoolgoing population aged 13 to 17 years in Madrid, Spain. Spearman correlation analysis was performed to ascertain quantitative comparison, Pearson's χ2 test (frequency < 5, Fisher) was used for comparison of prevalences, Mann-Whitney U and Kruskal-Wallis test were used for comparison of means and Bonferroni correction was used for post-hoc tests. A multivariate logistic regression model was performed in the multivariate analysis. Results Based on the classic values for definition of hyperhomocysteinaemia in adults, prevalence of hyperhomocysteinaemia in the study population was: 1.26% for 15 μmol/L; and 2.52% for 12 μmol/L. Deficits in HDL cholesterol and serum folate levels yielded adjusted Odds Ratios (OR) for hyperhomocysteinemia of 2.786, 95% CI (1.089-7.126), and 5.140, 95% CI (2.347-11.256) respectively. Mutation of the methylenetetrahydrofolate reductase (MTHFR) C677T genotype also raises the risk of hyperhomocysteinaemia (CC→CT: OR = 2.362; 95% CI (1.107-5.042) CC→TT: OR = 6.124, 95% CI (2.301-16.303)) Conclusion A good definition of hyperhomocysteinaemia in adolescents is the 90th percentile, equivalent to 8.23 μmol/L. Risk factors for hyperhomocysteinaemia are cHDL and folate deficiency, and

  7. Homocysteinemia is inversely correlated with platelet count and directly correlated with sE- and sP-selectin levels in females homozygous for C677T methylenetetrahydrofolate reductase.

    PubMed

    Rongioletti, Mauro; Baldassini, Mauro; Papa, Fabrizio; Capoluongo, Ettore; Rocca, Bianca; Cristofaro, Raimondo De; Salvati, Giuseppina; Larciprete, Giovanni; Stroppolo, Annalisa; Angelucci, Piero Antonio; Cirese, Elio; Ameglio, Franco

    2005-01-01

    Plasma homocysteine levels depend in part on the molecular nature of the methylenetetrahydrofolate reductase (MTHFR) and on blood folate intake. Little has been reported on platelet counts in the presence of hyperhomocysteinemia and MTHFR polymorphisms, with the exception of delayed platelet recovery in homozygous MTHFR C677T subjects after treatment with methotrexate for ovarian cancer. The aim of this investigation was to evaluate the possibility of a link between the platelet count and plasma homocysteine levels in different MTHFR variants in 165 female patients. Determinations of plasma homocysteine levels were by ELISA and of MTHFR polymorphisms (A1298C and C677T) were by inverse hybridization. Serum P- and E-selectin concentrations were obtained by ELISA. An inverse correlation (R=-0.88, P<0.001) was observed between blood platelet counts and plasma homocysteine levels in the women homozygous for MTHFR C677T. This correlation did not depend on pregnancy or other variables reported. Serum concentrations of sE- and sP-selectin, markers of endothelial and platelet activation, were significantly and positively correlated with homocysteine levels. These findings suggest that homocysteine affects platelet numbers in women with MTHFR C677T possibly consequent to endothelial and platelet activation. PMID:16011963

  8. Molecular analysis of factor V Leiden, factor V Hong Kong, factor II G20210A, methylenetetrahydrofolate reductase C677T, and A1298C mutations related to Turkish thrombosis patients.

    PubMed

    Dölek, Bilgen; Eraslan, Serpil; Eroğlu, Sevim; Kesim, Belgin Eroglu; Ulutin, Turgut; Yalçiner, Altan; Laleli, Yahya R; Gözükirmizi, Nermin

    2007-10-01

    Inherited gene disorders related to the hemostatic system have been documented as risk factors for thrombosis. The roles of factor V Hong Kong (FV Hong Kong), factor V Leiden (FV Leiden), factor II G20210A (FII G20210A), methylenetetrahydrofolate reductase (MTHFR) C677T, and MTHFR A1298C mutations in Turkish patients with thrombosis (270 patients) compared with healthy controls (114 subjects) were evaluated. Polymerase chain reaction-based restriction enzyme analysis was carried out to screen these mutations, and single-strand conformation analysis was established to identify variations using the primers selected for restriction enzyme analysis studies. As a result, a significant relationship was determined among FV Leiden, FII G20210A, and thrombosis. The FV Hong Kong mutation was observed in only 2 patients with pulmonary vein thrombosis who are FV Leiden/FV Hong Kong compound heterozygous for FV gene. MTHFR C677T and A1298C were equally distributed in the patient group compared with the control group. All named mutations were also identified with single-strand conformation analysis, but a new variant/polymorphism during studies was not found. Because some inherited abnormalities are associated with thromboembolic disorders, determining the mutations and gene-to-gene interactions in patients with thrombosis history has a great impact on diagnosis and treatment of these diseases. PMID:17911197

  9. Methyltetrahydrofolate reductase polymorphism influences onset of Huntington's disease.

    PubMed

    Brune, N; Andrich, J; Gencik, M; Saft, C; Müller, Th; Valentin, S; Przuntek, H; Epplen, J T

    2004-01-01

    Onset of Huntington's disease (HD) negatively correlates with CAG repeat length of the HD gene, which encodes the protein huntingtin. This protein interacts with the homocysteine metabolizing enzyme cystathionine betasynthase (CBS). Objective of this study was to analyze the impact of CAG repeats, polymorphisms of various homocysteine metabolizing enzymes, like CBS, Methyltetrahydrofolate Reductase (MTHTR), Methionine Synthase Reductase (MSR) and methionine synthase (MS) on HD onset in 171 patients. The significant impact of CAG repeats on HD onset (chi2= 25.54, FG = 4, p<0.0001) with a significant correlation between both (R= -0.521, p=0.01) was obvious. HD patients with the homozygous MTHFR-1298-CC significantly (p = 0.024) earlier experienced HD symptoms. There was no influence demonstrable of CBS, MSR and MS. Determination of MTHFR polymorphisms and CAG repeats enables screening for subjects with putative early HD onset in order to study neuroprotective compounds in their efficacy to delay HD symptoms. PMID:15354395

  10. No Association of Functional Polymorphisms in Methlylenetetrahydrofolate Reductase and the Risk and Minor Physical Anomalies of Schizophrenia in Korean Population

    PubMed Central

    Kim, Su-Gyeong; Song, Joo Yun; Joo, Eun-Jeong; Jeong, Seong Hoon; Kim, Se Hyun; Lee, Kyu Young; Lee, Nam Young; Ahn, Yong Min; Kim, Yong Sik

    2011-01-01

    Methylenetetrahydrofolate reductase (MTHFR), a critical enzyme in folate metabolism, plays an important role in DNA methylation. It has been suggested that abnormal DNA methylation contributes to the pathogenesis of schizophrenia and congenital anomalies. The previous findings regarding the genetic relationship between MTHFR and schizophrenia are controversial. This study investigated the association of the two functional polymorphisms of MTHFR, C677T and A1298C, with the risk for schizophrenia. Furthermore, we conducted an updated meta-analysis on the two polymorphisms. In addition, we investigated the relationship between the polymorphisms and minor physical anomaly (MPA), which may represent neurodevelopmental aberrations in 201 schizophrenia patients and 350 normal control subjects. There was no significant association between either of the two polymorphisms and the risk of schizophrenia (chi-square = 0.001, df = 1, P = 0.971 for C677T; chi-square = 1.319, df = 1, P = 0.251 for A1298C). However, in meta-analysis, the C677T polymorphism showed a significant association in the combined and Asian populations (OR = 1.13, P = 0.005; OR = 1.21, P = 0.011, respectively) but not in the Korean and Caucasian populations alone. Neither polymorphism was associated with MPAs measured by the Waldrop scale (chi-square = 2.513, df = 2, P = 0.285). In conclusion, the present findings suggest that in the Korean population, the MTHFR polymorphisms are unlikely to be associated with the risk for schizophrenia and neurodevelopmental abnormalities related to schizophrenia. PMID:22022190

  11. Elevated total plasma homocysteine and 667C{r_arrow}T mutation of the 5,10-methylenetetrahydrofolate reductase gene in thrombotic vascular disease

    SciTech Connect

    De Franchis, R.; Sebastio, G.; Andria, G.

    1996-07-01

    Moderate elevation of total plasma homocysteine (tHcy) has been reported as an independent risk factor for thrombotic vascular disease, a well-known multifactorial disorder. Possible genetic causes of elevated tHcy include defects of the sulfur-containing amino acids metabolism due to deficiencies of cystathionine {Beta}-synthase, of 5,10-methylenetetrahydrofolate reductase (MTHFR), and of the enzymes of cobalamin metabolism. An impaired activity of MTHFR due to a thermolabile form of the enzyme has been observed in {le}28% of hyperhomocysteinemic patients with premature vascular disease. More recently, the molecular basis of such enzymatic thermolability has been related to a common mutation of the MTHFR gene, causing a C-to-T substitution at nt 677 (677C{r_arrow}T). This mutation was found in 38% of unselected chromosomes from 57 French Canadian individuals. The homozygous state for the mutation was present in 12% of these subjects and correlated with significantly elevated tHcy. Preliminary evidence indicates that the frequency of homozygotes for the 677C{r_arrow}T mutation may vary significantly in populations from different geographic areas. 5 refs., 2 tabs.

  12. Massive pulmonary embolism associated with Factor V Leiden, prothrombin, and methylenetetrahydrofolate reductase gene mutations in a young patient on oral contraceptive pills: a case report.

    PubMed

    Charafeddine, Khalil M; Mahfouz, Rami A; Ibrahim, Georges Y; Taher, Ali T; Hoballah, Jamal J; Taha, Assad M

    2010-10-01

    Factor V Leiden (Factor V G1691A), prothrombin gene mutation G20210A, and homozygous C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene are known to predispose venous thromboembolism (VTE). We present herein a rare case of a young woman heterozygous for these mutations and taking oral contraceptive pills for less than 2 months, diagnosed to have massive deep venous thrombosis and bilateral pulmonary embolism. The patient was managed for 10 days in the hospital and discharged home on oral anticoagulants. This case suggests that screening for these factors in people with family history of thrombosis and in relatives of patients with these mutations is highly recommended to prevent fatal consequences. In addition, a new guideline for treatment and prophylaxis with anticoagulant for these patients and others who are at risk of developing VTE (American College of Chest Physicians [ACCP] guidelines-Chest 2008) has been published recently. Our recommendation is to promote for the internationally published algorithms through their application, where necessary, to prevent any future thrombotic morbidity or mortality incidents. PMID:19520679

  13. Alteration of the Alkaloid Profile in Genetically Modified Tobacco Reveals a Role of Methylenetetrahydrofolate Reductase in Nicotine N-Demethylation1[C][W][OA

    PubMed Central

    Hung, Chiu-Yueh; Fan, Longjiang; Kittur, Farooqahmed S.; Sun, Kehan; Qiu, Jie; Tang, She; Holliday, Bronwyn M.; Xiao, Bingguang; Burkey, Kent O.; Bush, Lowell P.; Conkling, Mark A.; Roje, Sanja; Xie, Jiahua

    2013-01-01

    Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme of the tetrahydrofolate (THF)-mediated one-carbon (C1) metabolic network. This enzyme catalyzes the reduction of 5,10-methylene-THF to 5-methyl-THF. The latter donates its methyl group to homocysteine, forming methionine, which is then used for the synthesis of S-adenosyl-methionine, a universal methyl donor for numerous methylation reactions, to produce primary and secondary metabolites. Here, we demonstrate that manipulating tobacco (Nicotiana tabacum) MTHFR gene (NtMTHFR1) expression dramatically alters the alkaloid profile in transgenic tobacco plants by negatively regulating the expression of a secondary metabolic pathway nicotine N-demethylase gene, CYP82E4. Quantitative real-time polymerase chain reaction and alkaloid analyses revealed that reducing NtMTHFR expression by RNA interference dramatically induced CYP82E4 expression, resulting in higher nicotine-to-nornicotine conversion rates. Conversely, overexpressing NtMTHFR1 suppressed CYP82E4 expression, leading to lower nicotine-to-nornicotine conversion rates. However, the reduced expression of NtMTHFR did not affect the methionine and S-adenosyl-methionine levels in the knockdown lines. Our finding reveals a new regulatory role of NtMTHFR1 in nicotine N-demethylation and suggests that the negative regulation of CYP82E4 expression may serve to recruit methyl groups from nicotine into the C1 pool under C1-deficient conditions. PMID:23221678

  14. Factor V Leiden, factor V Cambridge, factor II GA20210, and methylenetetrahydrofolate reductase in cerebral venous and sinus thrombosis: A case-control study

    PubMed Central

    Saadatnia, Mohammad; Salehi, Mansour; Movahedian, Ahmad; Shariat, Seyed Ziaeddin Samsam; Salari, Mehri; Tajmirriahi, Marzieh; Asadimobarakeh, Elham; Salehi, Rasoul; Amini, Gilda; Ebrahimi, Homa; Kheradmand, Ehsan

    2015-01-01

    Background: Factor V G1691A (FV Leiden), FII GA20210, and methylenetetrahydrofolate reductase (MTHFR) C677T mutations are the most common genetic risk factors for thromboembolism in the Western countries. However, there is rare data in Iran about cerebral venous and sinus thrombosis (CVST) patients. The aim of this study was to evaluate the frequency of common genetic thrombophilic factors in CVST patients. Materials and Methods: Forty consequently CVST patients from two University Hospital in Isfahan University of Medical Sciences aged more than 15 years from January 2009 to January 2011 were recruited. In parallel, 51 healthy subjects with the same age and race from similar population selected as controls. FV Leiden, FII GA20210, MTHFR C677T, and FV Cambridge gene mutations by polymerase chain reaction technique were evaluated in case and control groups. Results: FV Leiden, FII GA20210, and FV Cambridge gene mutations had very low prevalence in both case (5%, 2%, 0%) and control (2.5%, 0%, 0%) and were not found any significant difference between groups. MTHFR C677T mutations was in 22 (55%) of patients in case group and 18 (35.5%) of control group (P = 0.09). Conclusion: This study showed that the prevalence of FV Leiden, FII GA20210, and FV Cambridge were low. Laboratory investigations of these mutations as a routine test for all patients with CVST may not be cost benefit. PMID:26600830

  15. POLYMORPHISMS IN CYTOPLASMIC SERINE HYDROXYMETHYLTRANSFERASE AND METHYLENETETRAHYDROFOLATE REDUCTASE AFFECT THE RISK OF CARDIOVASCULAR DISEASE IN MEN

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genetic variation in folate-regulating enzymes contributes to the risk of cardiovascular disease (CVD). The cytoplasmic serine hydroxymethyltransferase (cSHMT) enzyme is proposed to regulate a key metabolic intersection in folate metabolism. We hypothesized that a variant in cSHMT (cSHMT 1420CT) aff...

  16. Methylenetetrahydrofolate reductase variants associated with hypertension and cardiovascular disease interact with dietary polyunsaturated fatty acids to modulate plasma homocysteine in puerto rican adults.

    PubMed

    Huang, Tao; Tucker, Katherine L; Lee, Yu-Chi; Crott, Jimmy W; Parnell, Laurence D; Shen, Jian; Smith, Caren E; Ordovas, Jose M; Li, Duo; Lai, Chao-Qiang

    2011-04-01

    Although methylenetetrahydrofolate reductase (MTHFR) genetic variants are associated with plasma homocysteine (Hcy) and cardiovascular disease (CVD), little is known whether dietary fatty acid intake modulates these associations. The goal was to examine the interaction of MTHFR variants with dietary fatty acids influencing plasma Hcy in 995 Boston Puerto Rican adults. We found that plasma Hcy concentration was negatively correlated with (n-3) PUFA intake (r = -0.117; P = 0.022), and the ratio of (n-3):(n-6) PUFA in the diet (r = -0.122; P = 0.009). Further, 2 functional MTHFR variants, 1298A>C and 677C>T, which are not in linkage disequilibrium in this population, were significantly associated with hypertension (OR = 1.72, P = 0.024, and OR = 1.60, P = 0.002, respectively). In addition, the 1298A>C variant was significantly associated with CVD (OR = 3.32; P = 0.030). Importantly, this variant exhibited significant interactions with intakes of total and (n-6) PUFA and the (n-3):(n-6) PUFA ratio of the diet. The plasma Hcy concentration of carriers of risk allele 1298C was greater than that of noncarriers only when participants had consumed a high-PUFA diet (>7.8% energy) but was not greater when they had low intake of PUFA (≤7.8% energy). In addition, participants with combined genotypes of both SNP (677 TT with 1298 AC or CC) who consumed high levels of (n-3) PUFA (>0.66% energy) had lower plasma Hcy compared with those who had the same genotype and consumed low levels of (n-3) PUFA (≤0.66% energy). Our study suggests that dietary PUFA intake modulates the effect of 2 MTHFR variants on plasma Hcy in Boston Puerto Rican adults. PMID:21270364

  17. Methylenetetrahydrofolate reductase (MTHFR-677 and MTHFR-1298) genotypes and haplotypes and plasma homocysteine levels in patients with occlusive artery disease and deep venous thrombosis.

    PubMed

    Spiroski, Igor; Kedev, Sashko; Antov, Slobodan; Arsov, Todor; Krstevska, Marija; Dzhekova-Stojkova, Sloboda; Bosilkova, Gordana; Kostovska, Stojanka; Trajkov, Dejan; Petlichkovski, Aleksandar; Strezova, Ana; Efinska-Mladenovska, Olivija; Spiroski, Mirko

    2008-01-01

    The aim was to investigate different genotypes and haplotypes of methylenetetrahydrofolate reductase (MTHFR-677, -1298) and plasma concentration of total homocysteine (tHcy) in Macedonian patients with occlusive artery disease (OAD) and deep venous thrombosis (DVT). Investigated groups consists of 80 healthy, 74 patients with OAD, and 63 patients with DVT. Plasma tHcy was measured with Microplate Enzyme Immunoassay. Identification of MTHFR genotypes and haplotypes was done with CVD StripAssay. The probability level (P-value) was evaluated by the Student's t-test. Plasma concentration of tHcy in CC and CT genotypes of MTHFR C677T was significantly increased in patients with OAD and in patients with DVT. Plasma concentration of tHcy in AC genotype of MTHFR A1298C was increased in patients with OAD and in patients with DVT. Plasma concentration of tHcy was significantly increased in AA genotype of patients with OAD, but not in patients with DVT. We found a significant increase of plasma tHcy in patients with OAD in comparison with healthy respondents for normal:heterozygote (CC:AC), heterozygote:normal (CT:AA), and heterozygote:heterozygote (CT:AC) haplotypes. Plasma concentration of tHcy in patients with DVT in comparison with healthy respondents was significantly increased for normal:normal (CC:AA), normal heterozygote (CC:AC), and heterozygote:heterozygote (CT:AC) haplotypes. We conclude that MTHFR C677T and MTHFR A1289C genotypes and haplotypes are connected with tHcy plasma levels in Macedonian patients with OAD and DVT. PMID:18800176

  18. Molecular genetic analysis in mild hyperhomocysteinemia: A common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease

    SciTech Connect

    Kluijtmans, L.A.J.; Heuvel, L.P.W.J. van den; Stevens, E.M.B.

    1996-01-01

    Mild hyperhomocysteinemia is an established risk factor for cardiovascular disease. Genetic aberrations in the cystathionine P-synthase (CBS) and methylenetetrahydrofolate reductase (MTHFR) genes may account for reduced enzyme activities and elevated plasma homocysteine levels. In 15 unrelated Dutch patients with homozygous CBS deficiency, we observed the 833T{yields}C (1278T) mutation in 50% of the alleles. Very recently, we identified a common mutation (677C{yields}T; A{yields}V) in the MTHFR gene, which, in homozygous state, is responsible for the thermolabile phenotype and which is associated with decreased specific MTHFR activity and elevated homocysteine levels. We screened 60 cardiovascular patients and 111 controls for these two mutations, to determine whether these mutations are risk factors for premature cardiovascular disease. Heterozygosity for the 833T{yields}C mutation in the CBS gene was observed in one individual of the control group but was absent in patients with premature cardiovascular disease. Homozygosity for the 677C-{yields}T mutation in the MTHFR gene was found in 9 (15%) of 60 cardiovascular patients and in only 6 ({approximately}5%) of 111 control individuals (odds ratio 3.1 [95% confidence interval 1.0-9.21]). Because of both the high prevalence of the 833T-{yields}C mutation among homozygotes for CBS deficiency and its absence in 60 cardiovascular patients, we may conclude that heterozygosity for CBS deficiency does not appear to be involved in premature cardiovascular disease. However, a frequent homozygous mutation in the MTHFR gene is associated with a threefold increase in risk for premature cardiovascular disease. 35 refs., 3 figs., 1 tab.

  19. Evaluation of the relationship between C677T variants of methylenetetrahydrofolate reductase gene and hyperhomocysteinemia in children receiving antiepileptic drug therapy.

    PubMed

    Vurucu, Sebahattin; Demirkaya, Erkan; Kul, Mustafa; Unay, Bulent; Gul, Davut; Akin, Ridvan; Gokçay, Erdal

    2008-04-01

    Homocysteine (Hcy) is a sulfur-containing amino acid involved in methionine metabolism. Elevated plasma Hcy concentration is a possible risk factor for vascular disease. Folate and vitamin B-12 are vitamins that are necessary for remethylization of Hcy to methionine. The methylenetetrahydrofolate reductase (MTHFR) is the key enzyme in remethylation of Hcy to methionine and supplies the required 5-methyltetrahydrofolate as the methyl donor for this reaction. It is well known that some antiepileptic drugs (AED) can lead to hyperhomocysteinemia by affecting the levels of folate and vitamin B-12. The C677T variant of MTHFR gene can also lead to hyperhomocysteinemia particularly when serum folate level is decreased. In this study, we investigated the levels of serum folate, vitamin B-12 and Hcy in epileptic patients receiving carbamazepine (CBZ) or valproic acid (VPA) as monotherapy, and we also evaluated the probable contribution of the C677T variant of MTHFR gene in hyperhomocysteinemia. A total of 93 patients with idiopathic epilepsy receiving CBZ or VPA as monotherapy were included in this study. CBZ and VPA groups consisted of 29 and 64 patients, respectively. The control group comprised 62 healthy children. We measured serum folate, vitamin B-12 and Hcy levels in each group. We found that mean serum folate level was statistically lower and mean Hcy level was higher in epileptic patients receiving CBZ or VPA when compared with those of controls'. We also determined the C677T variants of MTHFR gene (as normal, heterozygote or homozygote) in epileptic patients. We compared the variant groups for serum folate, vitamin B-12 and Hcy levels and found no significant differences among them. In conclusion, C677T variants of MTHFR gene have no contribution in hyperhomocysteinemia in epileptic patients receiving CBZ or VPA. PMID:18234410

  20. Conversion of 5-formyltetrahydrofolic acid to 5-methyltetrahydrofolic acid is unimpaired in folate-adequate persons homozygous for the C677T mutation in the methylenetetrahydrofolate reductase gene.

    PubMed

    Stern, L L; Bagley, P J; Rosenberg, I H; Selhub, J

    2000-09-01

    Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolic acid (5-CH(3)-H(4) folic acid), the methyl donor for the formation of methionine from homocysteine. A common C677T transition in the MTHFR gene results in a variant with a lower specific activity and a greater sensitivity to heat than the normal enzyme, as measured in vitro. This study was undertaken to determine the capacity of homozygotes for the MTHFR C677T transition to convert 5-formyltetrahydrofolic acid (5-HCO-H(4) folic acid) to 5-CH(3)-H(4) folic acid, a process that requires the action of MTHFR. Six subjects homozygous for the C677T transition (T/T) and 6 subjects with wild-type MTHFR (C/C) were given a 5-mg oral dose of (6R:,S:)-5-HCO-H(4) folic acid. Plasma and urine were analyzed for 5-CH(3)-H(4) folic acid concentrations using affinity/HPLC coupled with fluorescence or UV detection. The mean areas under the curves created by the rise and fall of plasma 5-CH(3)-H(4) folic acid after the oral dose did not differ between the two genotypes, 424.5 +/- 140.3 (T/T) vs. 424.1+/- 202.4 h.nmol/L (C/C). There also was no significant difference in the mean cumulative 7-h urinary excretion of 5-CH(3)-H(4) folic acid between the T/T (2.5 +/- 1.4 micromol) and C/C (1.9 +/- 1.0 micromol) genotypes. Under the conditions employed, the conversion of oral 5-HCO-H(4) folic acid to 5-CH(3)-H(4) folic acid is not impaired in persons with the T/T MTHFR genotype. Possible reasons for these findings are discussed. PMID:10958818

  1. Genetic Variation of Methylenetetrahydrofolate Reductase (MTHFR) and Thymidylate Synthase (TS) Genes Is Associated with Idiopathic Recurrent Implantation Failure.

    PubMed

    Choi, Youngsok; Kim, Jung Oh; Shim, Sung Han; Lee, Yubin; Kim, Ji Hyang; Jeon, Young Joo; Ko, Jung Jae; Lee, Woo Sik; Kim, Nam Keun

    2016-01-01

    The one-carbon metabolism pathway disorder was important role in successful pregnancy. The MTHFR and TS protein were crucial factor in one-carbon metabolism. To investigate the association between recurrent implantation failure (RIF) and enzymes in the one-carbon metabolism pathway. A total of 120 women diagnosed with RIF and 125 control subjects were genotyped for MTHFR 677C>T, 1298A>C, TSER 2R/3R and TS 1494del/ins by a polymerase chain reaction-restriction fragment length polymorphism assay. According to the gene-gene combination analysis, the MTHFR 677/MTHFR 1298 (TT/AA) and MTHFR 677/TS 1494 (TT/6bp6bp) genetic combinations were associated with relatively higher risks [adjusted odds ratio (AOR), 2.764; 95% CI, 1.065-7.174; P = 0.037 and AOR, 3.186; 95% CI, 1.241-8.178; P = 0.016] in RIF patients compared to the CC/AA (MTHFR 677/MTHFR 1298) and TT/6bp6bp (MTHFR 677/TS 1494) combinations, respectively. The results suggested that the combined MTHFR 677/MTHFR 1298 genotype might be associated with increased risk of RIF. To the best of our knowledge, this study is the first to elucidate the potential association of MTHFR, TS and TSER polymorphisms with RIF risk in Korean patients. PMID:27560137

  2. Genetic Variation of Methylenetetrahydrofolate Reductase (MTHFR) and Thymidylate Synthase (TS) Genes Is Associated with Idiopathic Recurrent Implantation Failure

    PubMed Central

    Shim, Sung Han; Lee, Yubin; Kim, Ji Hyang; Jeon, Young Joo; Ko, Jung Jae; Lee, Woo Sik; Kim, Nam Keun

    2016-01-01

    The one-carbon metabolism pathway disorder was important role in successful pregnancy. The MTHFR and TS protein were crucial factor in one-carbon metabolism. To investigate the association between recurrent implantation failure (RIF) and enzymes in the one-carbon metabolism pathway. A total of 120 women diagnosed with RIF and 125 control subjects were genotyped for MTHFR 677C>T, 1298A>C, TSER 2R/3R and TS 1494del/ins by a polymerase chain reaction-restriction fragment length polymorphism assay. According to the gene-gene combination analysis, the MTHFR 677/MTHFR 1298 (TT/AA) and MTHFR 677/TS 1494 (TT/6bp6bp) genetic combinations were associated with relatively higher risks [adjusted odds ratio (AOR), 2.764; 95% CI, 1.065–7.174; P = 0.037 and AOR, 3.186; 95% CI, 1.241–8.178; P = 0.016] in RIF patients compared to the CC/AA (MTHFR 677/MTHFR 1298) and TT/6bp6bp (MTHFR 677/TS 1494) combinations, respectively. The results suggested that the combined MTHFR 677/MTHFR 1298 genotype might be associated with increased risk of RIF. To the best of our knowledge, this study is the first to elucidate the potential association of MTHFR, TS and TSER polymorphisms with RIF risk in Korean patients. PMID:27560137

  3. Regulation of Folate-Mediated One-Carbon Metabolism by Glycine N-Methyltransferase (GNMT) and Methylenetetrahydrofolate Reductase (MTHFR).

    PubMed

    Wang, Yi-Cheng; Wu, Ming-Tsung; Lin, Yan-Jun; Tang, Feng-Yao; Ko, Hsin-An; Chiang, En-Pei

    2015-01-01

    Folate-mediated one-carbon metabolism is an important therapeutic target of human diseases. We extensively investigated how gene-nutrient interactions may modulate human cancer risk in 2 major folate metabolic genes, MTHFR and GNMT. The biochemical impacts of MTHFR and GNMT on methyl group supply, global DNA methylation, nucleotide biosynthesis, DNA damage, and partitioning of the folate dependent 1-carbon group were carefully studied. The distinct model systems used included: EB virus-transformed lymphoblasts expressing human MTHFR polymorphic genotypes; liver-derived GNMT-null cell-lines with and without GNMT overexpression; and HepG2 cells with stabilized inhibition of MTHFR using shRNA, GNMT wildtype, heterozygotous (GNMT(het)) and knockout (GNMT(nul)) mice. We discovered that the MTHFR TT genotype significantly reduces folate-dependent remethylation under folate restriction, but it assists purine synthesis when folate is adequate. The advantage of de novo purine synthesis found in the MTHFR TT genotype may account for the protective effect of MTHFR in human hematological malignancies. GNMT affects transmethylation kinetics and S-adenosylmethionine (adoMet) synthesis, and facilitates the conservation of methyl groups by limiting homocysteine remethylation fluxes. Restoring GNMT assists methylfolate-dependent reactions and ameliorates the consequences of folate depletion. GNMT expression in vivo improves folate retention and bioavailability in the liver. Loss of GNMT impairs nucleotide biosynthesis. Over-expression of GNMT enhances nucleotide biosynthesis and improves DNA integrity by reducing uracil misincorporation in DNA both in vitro and in vivo. The systematic series of studies gives new insights into the underlying mechanisms by which MTHFR and GNMT may participate in human tumor prevention. PMID:26598833

  4. [Features of allele polymorphism of genes involved in homocysteine and folate metabolism in patients with atherosclerosis of the lower extremity arteries].

    PubMed

    Klenkova, N A; Kapustin, S I; Saltykova, N B; Shmeleva, V M; Blinov, M N

    2009-01-01

    Under study were features of allele polymorphism of genes of methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), methionine synthase (MS A 2756G), methionine synthase reductase (MTRR A66G) and methylenetetrahydrofolate dehydrogenase (MTHFD G1958A) in patients with atherosclerosis of the lower extremity arteries (ALEA). Patients with hyperhomocysteinemia (HHcy) had statistically significant increase of allele MTHFR 677T and MTRR 66GG as compared both with the control group and with the group of patients without HHcy. It suggests that polymorphism of genes involved in homocystein and folate metabolism might affect the risk of HHcy in patients with ALEA. PMID:20209990

  5. Polymorphisms in the methylene tetrahydrofolate reductase and methionine synthase reductase genes and their correlation with unexplained recurrent spontaneous abortion susceptibility.

    PubMed

    Zhu, L

    2015-01-01

    We aimed to explore the correlation between unexplained recurrent spontaneous abortion and polymorphisms in the methylene tetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) genes. A case control study was conducted in 118 patients with unexplained recurrent spontaneous abortion (abortion group) and 174 healthy women (control group). The genetic material was extracted from the oral mucosal epithelial cells obtained from all subjects. The samples were subjected to fluorescence quantitative PCR to detect the single nucleotide polymorphisms (SNPs) in the MTHFR (C677T and A1298C) and MTRR (A66G) gene loci. The distribution frequency (18/118, 15.3%) of the MTHFR 677TT genotype was significantly higher in the abortion group (χ2 = 11.006, P = 0.004) than in the control group (2/174, 1.1%); on the other hand, the distribution frequency of the MTHFR A1298C genotype did not significantly differ between the abortion and control groups (χ(2) = 0.441, P = 0.507). The distribution frequency of the MTRR A66G genotype was also significantly higher in the abortion group (14/118, 11.9%; χ(2) = 10.503, P = 0.005) than in the control group (8/174, 4.6%). The MTHFR C677T and MTRR A66G polymorphisms are significantly correlated with the occurrence of spontaneous abortion. PMID:26345779

  6. The role of vitamin B12 in fasting hyperhomocysteinemia and its interaction with the homozygous C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene. A case-control study of patients with early-onset thrombotic events.

    PubMed

    D'Angelo, A; Coppola, A; Madonna, P; Fermo, I; Pagano, A; Mazzola, G; Galli, L; Cerbone, A M

    2000-04-01

    Total fasting plasma homocysteine (tHcy), homozygosity for the C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene and for the A2756G mutation of the methionine synthase (MS) gene, vitamin B12 and folate plasma levels were evaluated in 170 consecutive patients (89 M, 81 F; mean age 41 +/- 12 yrs) with documented early-onset thrombosis (89 venous, 69 arterial, 12 both; mean age at first episode 36 +/- 11 yrs), and in 182 age- and sex-matched healthy control subjects. Moderate hyperhomocysteinemia (HHcy, tHcy >19.5 microM in men and >15 microM in women) was detected in 45 patients (26.5%) and in 18 controls (9.9%, Mantel-Haenszel OR and 95% C.I. after stratification for arterial or venous thrombosis: 3.25, 1.78-5.91). The 677TT MTHFR genotype was not significantly more prevalent in patients (27.6%) than in controls (21.4%, RR = 1.42: 0.84-2.41), and markedly contributed to HHcy (Mantel-Haenszel RR after stratification for case/control status: 8.29, 4.61-14.9). The 2756GG MS genotype, observed in 4 patients (2.4%) and 8 controls (4.4%), was not associated to HHcy. tHcy was negatively correlated to folate and vitamin B12 levels, with better correlation found in subjects with the 677TT mutation (r = -0.42 and -0.25) than with the 677CC or CT MTHFR genotype (r = 0).37 and -0.11). However, folate was similar in patients and controls and vitamin B12 was higher in patients (460 +/- 206 vs. 408 +/-185 pg/ml, p = 0.011). In a generalized linear model, 44% of the variation in tHcy levels was explained by folate and vitamin B12 levels, the MTHFR genotype, gender, and by the interaction of the MTHFR genotype with folate (p < or =0.028); the interactions of vitamin B12 with the MTHFR genotype, gender and patient/control status also significantly contributed to the variation in tHcy levels (p < or =0.028). A 4-week administration of 5-methyltetrahydrofolate (15 mg/day) markedly lowered plasma tHcy in 24 patients with MTHFR 677TT genotype, but the response to

  7. Aldose reductase C-106T polymorphism is associated with the risk of essential hypertension.

    PubMed

    Wang, Yaqin; Yu, Min; Mo, Long; Li, Zhenyu; Wang, Junjie; Zhou, Hong-Hao; Ouyang, Dong-Sheng

    2016-10-10

    Aldose Reductase (AR), encoded by AKR1B1, is a member of NADPH-dependent aldo-keto reductase superfamily. The C-106T polymorphism of AKR1B1 is closely related to the diabetic complications. Our previous studies have indicated that the expression of AR was increased in spontaneously hypertensive rats, suggesting the effect of AR in hypertension. Here we investigated whether AKR1B1 C-106T polymorphism was associated with essential hypertension (EH). AKR1B1 C-106T polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and the direct sequencing methods. 383 healthy subjects and 383 essential hypertensive patients were recruited in this study. The polymorphism of AKR1B1 C-106T in EH and normal tensive (NT) groups was in agreement with Hardy-Weinberg equilibrium. -106T allele of AKR1B1 C-106T variants was more frequent in EH patients compared with normal tensive subjects, indicating that -106T allele was a risk factor of EH (OR=1.841, 95%CI=1.366-2.481). In male patients, C-106T polymorphism was associated significantly with decreased serum high density lipoprotein cholesterol and higher systolic blood pressure levels. Our results suggest that -106T allele of AKR1B1 C-106T polymorphism may be associated with increased risk for EH in Chinese Han population. PMID:27343777

  8. 5,10-methylene tetrahydrofolate reductase C677T gene polymorphism, homocysteine concentration and the extent of premature coronary artery disease in southern Iran.

    PubMed

    Senemar, Sara; Saffari, Babak; Sharifkazemi, Mohammad Bagher; Bahari, Marzieh; Jooyan, Najmeh; Dehaghani, Elham Davoudi; Yavarian, Majid

    2013-01-01

    Elevated level of plasma homocysteine (Hcy) has been identified as an independent risk factor for coronary artery disease (CAD). Furthermore, numerous studies have documented the influences of a common polymorphism (C677T) of methylenetetrahydrofolate reductase (MTHFR) on homocysteine levels. However the relationship between this mutation and cardiovascular diseases (CVD) has remained as a controversial issue. The present study was undertaken to investigate the relationship between C677T polymorphism of MTHFR gene, plasma total Hcy levels and the number of affected vessels as a criterion for the extent of CAD. MTHFR genotypes and plasma homocysteine (HCY) concentrations were examined in 231 patients and 300 healthy subjects who underwent diagnostic coronary angiography. A multiple linear regression analysis was performed to identify the predictors of Hcy levels whereas logistic regression model was built to determine the association of Hcy quartiles with the risk of CAD adjusted for risk factors. The prevalence of MTHFR genotypes was similar between CAD patients and non-CAD individuals while the geometric mean of Hcy values was significantly higher in patient group (14.13 ± 4.11 μmol/l) than in control group (10.19 ± 3.52 μmol/l) (P < 0.001). Moreover, unlike the MTHFR polymorphism, Hcy concentration increased with increasing number of stenosed vessels and the CAD risk increased about 2 folds in the top two Hcy quartiles (≥ 17.03 and 13.20-17.02 μmol/l) compared with the lowest quartile (≤ 9.92 μmol/l) after controlling for conventional risk factors (P<0.001 for both). Our data suggest that hyperhomocysteinaemia (HHcy) is significantly associated to CAD risk increase as well as to the extent of coronary atherosclerosis. PMID:26417236

  9. [Relationship of MTHFR gene polymorphisms with infertility].

    PubMed

    Guo, Kai-min; Tian, Run-hui; Wang, Hong-liang

    2016-02-01

    The folate metabolic pathway plays important roles in cellular physiology by participating in nucleotide synthesis, DNA repair and methylation, and maintenance and stability of the genome. Methylenetetrahydrofolate reductase (MTHFR) is a key regulatory enzyme involved in folate metabolism. Polymorphisms of MTHFR may change the level of homocysteine and affect DNA synthesis and methylation, leading to an increased oxidative stress and disturbed methylation reactions and consequently affecting reproductive function. This article presents an overview on MTHFR gene polymorphisms, proposing that multicentered, large-sample and long-term prospective studies are needed to reveal the relationship between MTHFR gene polymorphisms and infertility. PMID:26939404

  10. Structures of NADH and CH[subscript 3]-H[subscript 4] Folate Complexes of Escherichia coli Methylenetetrahydrofolate Reductase Reveal a Spartan Strategy for a Ping-Pong Reaction

    SciTech Connect

    Pejchal, Robert; Sargeant, Ryan; Ludwig, Martha L.

    2010-03-08

    Methylenetetrahydrofolate reductases (MTHFRs; EC 1.7.99.5) catalyze the NAD(P)H-dependent reduction of 5,10-methylenetetrahydrofolate (CH{sub 2}-H{sub 4}folate) to 5-methyltetrahydrofolate (CH{sub 3}-H{sub 4}folate) using flavin adenine dinucleotide (FAD) as a cofactor. The initial X-ray structure of Escherichia coli MTHFR revealed that this 33-kDa polypeptide is a ({beta}{alpha}){sub 8} barrel that aggregates to form an unusual tetramer with only 2-fold symmetry. Structures of reduced enzyme complexed with NADH and of oxidized Glu28Gln enzyme complexed with CH{sub 3}-H{sub 4}folate have now been determined at resolutions of 1.95 and 1.85 {angstrom}, respectively. The NADH complex reveals a rare mode of dinucleotide binding; NADH adopts a hairpin conformation and is sandwiched between a conserved phenylalanine, Phe223, and the isoalloxazine ring of FAD. The nicotinamide of the bound pyridine nucleotide is stacked against the si face of the flavin ring with C4 adjoining the N5 of FAD, implying that this structure models a complex that is competent for hydride transfer. In the complex with CH{sub 3}-H{sub 4}folate, the pterin ring is also stacked against FAD in an orientation that is favorable for hydride transfer. Thus, the binding sites for the two substrates overlap, as expected for many enzymes that catalyze ping-pong reactions, and several invariant residues interact with both folate and pyridine nucleotide substrates. Comparisons of liganded and substrate-free structures reveal multiple conformations for the loops {beta}2-{alpha}2 (L2), {beta}3-{alpha}3 (L3), and {beta}4-{alpha}4 (L4) and suggest that motions of these loops facilitate the ping-pong reaction. In particular, the L4 loop adopts a 'closed' conformation that allows Asp120 to hydrogen bond to the pterin ring in the folate complex but must move to an 'open' conformation to allow NADH to bind.

  11. Genetic variation in Glutathione S-Transferase Omega-1, Arsenic Methyltransferase and Methylene-tetrahydrofolate Reductase, arsenic exposure and bladder cancer: a case–control study

    PubMed Central

    2012-01-01

    Background Ingestion of groundwater with high concentrations of inorganic arsenic has been linked to adverse health outcomes, including bladder cancer, however studies have not consistently observed any elevation in risk at lower concentrations. Genetic variability in the metabolism and clearance of arsenic is an important consideration in any investigation of its potential health risks. Therefore, we examined the association between genes thought to play a role in the metabolism of arsenic and bladder cancer. Methods Single nucleotide polymorphisms (SNPs) in GSTO-1, As3MT and MTHFR were genotyped using DNA from 219 bladder cancer cases and 273 controls participating in a case–control study in Southeastern Michigan and exposed to low to moderate (<50 μg/L) levels of arsenic in their drinking water. A time-weighted measure of arsenic exposure was constructed using measures from household water samples combined with past residential history, geocoded and merged with archived arsenic data predicted from multiple resources. Results While no single SNP in As3MT was significantly associated with bladder cancer overall, several SNPs were associated with bladder cancer among those exposed to higher arsenic levels. Individuals with one or more copies of the C allele in rs11191439 (the Met287Thr polymorphism) had an elevated risk of bladder cancer (OR = 1.17; 95% CI = 1.04-1.32 per 1 μg/L increase in average exposure). However, no association was observed between average arsenic exposure and bladder cancer among TT homozygotes in the same SNP. Bladder cancer cases were also 60% less likely to be homozygotes for the A allele in rs1476413 in MTHFR compared to controls (OR = 0.40; 95% CI = 0.18-0.88). Conclusions Variation in As3MT and MTHFR is associated with bladder cancer among those exposed to relatively low concentrations of inorganic arsenic. Further investigation is warranted to confirm these findings. PMID:22747749

  12. Malaria antifolate resistance with contrasting Plasmodium falciparum dihydrofolate reductase (DHFR) polymorphisms in humans and Anopheles mosquitoes

    PubMed Central

    Mharakurwa, Sungano; Kumwenda, Taida; Mkulama, Mtawa A. P.; Musapa, Mulenga; Chishimba, Sandra; Shiff, Clive J.; Sullivan, David J.; Thuma, Philip E.; Liu, Kun; Agre, Peter

    2011-01-01

    Surveillance for drug-resistant parasites in human blood is a major effort in malaria control. Here we report contrasting antifolate resistance polymorphisms in Plasmodium falciparum when parasites in human blood were compared with parasites in Anopheles vector mosquitoes from sleeping huts in rural Zambia. DNA encoding P. falciparum dihydrofolate reductase (EC 1.5.1.3) was amplified by PCR with allele-specific restriction enzyme digestions. Markedly prevalent pyrimethamine-resistant mutants were evident in human P. falciparum infections—S108N (>90%), with N51I, C59R, and 108N+51I+59R triple mutants (30–80%). This resistance level may be from selection pressure due to decades of sulfadoxine/pyrimethamine use in the region. In contrast, cycloguanil-resistant mutants were detected in very low frequency in parasites from human blood samples—S108T (13%), with A16V and 108T+16V double mutants (∼4%). Surprisingly, pyrimethamine-resistant mutants were of very low prevalence (2–12%) in the midguts of Anopheles arabiensis vector mosquitoes, but cycloguanil-resistant mutants were highly prevalent—S108T (90%), with A16V and the 108T+16V double mutant (49–57%). Structural analysis of the dihydrofolate reductase by in silico modeling revealed a key difference in the enzyme within the NADPH binding pocket, predicting the S108N enzyme to have reduced stability but the S108T enzyme to have increased stability. We conclude that P. falciparum can bear highly host-specific drug-resistant polymorphisms, most likely reflecting different selective pressures found in humans and mosquitoes. Thus, it may be useful to sample both human and mosquito vector infections to accurately ascertain the epidemiological status of drug-resistant alleles. PMID:22065788

  13. Malaria antifolate resistance with contrasting Plasmodium falciparum dihydrofolate reductase (DHFR) polymorphisms in humans and Anopheles mosquitoes.

    PubMed

    Mharakurwa, Sungano; Kumwenda, Taida; Mkulama, Mtawa A P; Musapa, Mulenga; Chishimba, Sandra; Shiff, Clive J; Sullivan, David J; Thuma, Philip E; Liu, Kun; Agre, Peter

    2011-11-15

    Surveillance for drug-resistant parasites in human blood is a major effort in malaria control. Here we report contrasting antifolate resistance polymorphisms in Plasmodium falciparum when parasites in human blood were compared with parasites in Anopheles vector mosquitoes from sleeping huts in rural Zambia. DNA encoding P. falciparum dihydrofolate reductase (EC 1.5.1.3) was amplified by PCR with allele-specific restriction enzyme digestions. Markedly prevalent pyrimethamine-resistant mutants were evident in human P. falciparum infections--S108N (>90%), with N51I, C59R, and 108N+51I+59R triple mutants (30-80%). This resistance level may be from selection pressure due to decades of sulfadoxine/pyrimethamine use in the region. In contrast, cycloguanil-resistant mutants were detected in very low frequency in parasites from human blood samples-S108T (13%), with A16V and 108T+16V double mutants (∼4%). Surprisingly, pyrimethamine-resistant mutants were of very low prevalence (2-12%) in the midguts of Anopheles arabiensis vector mosquitoes, but cycloguanil-resistant mutants were highly prevalent-S108T (90%), with A16V and the 108T+16V double mutant (49-57%). Structural analysis of the dihydrofolate reductase by in silico modeling revealed a key difference in the enzyme within the NADPH binding pocket, predicting the S108N enzyme to have reduced stability but the S108T enzyme to have increased stability. We conclude that P. falciparum can bear highly host-specific drug-resistant polymorphisms, most likely reflecting different selective pressures found in humans and mosquitoes. Thus, it may be useful to sample both human and mosquito vector infections to accurately ascertain the epidemiological status of drug-resistant alleles. PMID:22065788

  14. Human Aldo-Keto Reductases: Function, Gene Regulation, and Single Nucleotide Polymorphisms

    PubMed Central

    Penning, Trevor M.; Drury, Jason E.

    2007-01-01

    Aldo-Keto Reductases (AKRs) are a superfamily of NAD(P)H linked oxidoreductases that are generally monomeric 34- 37 kDa proteins present in all phyla. The superfamily consists of 15 families, which contains 151 members (www.med.upenn.edu/akr). Thirteen human AKRs exist that use endogenous substrates (sugar and lipid aldehydes, prostaglandins, retinals and steroid hormones), and in many instances they regulate nuclear receptor signaling. Exogenous substrates include metabolites implicated in chemical carcinogenesis: NNK (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone), polycyclic aromatic hydrocarbon trans-dihydrodiols, and aflatoxin dialdehyde. Promoter analysis of the human genes identifies common elements involved in their regulation which include osmotic response elements, antioxidant response elements, xenobiotic response elements, AP-1 sites and steroid response elements. The human AKRs are highly polymorphic, and in some instances single nucleotide polymorphisms (SNPs) of high penetrance exist. This suggests that there will be inter-individual variation in endogenous and xenobiotic metabolism which in turn affect susceptibility to nuclear receptor signaling and chemical carcinogenesis. PMID:17537398

  15. The Drop That Spilled the Cup: Acute Myocardial Infarction in a Young Woman with Underlying Thrombophilic Polymorphisms and Oral Contraceptive Use

    PubMed Central

    Capilli, Gianfranco; Patané, Anella Antonietta

    2014-01-01

    We present the case of a 28-year-old woman who was admitted to our cardiology unit for acute coronary syndrome. Her history was notable for cardiovascular disease familiarity, active smoking, and oral contraceptive use. On further analysis, she was noted to have thrombophilic polymorphisms involving the plasminogen activator inhibitor (PAI), angiotensin-converting enzyme (ACE), and methylenetetrahydrofolate reductase (MTHFR) genes. We discuss the implications that these cofactors may have had in the genesis of the disease. PMID:25587456

  16. The drop that spilled the cup: acute myocardial infarction in a young woman with underlying thrombophilic polymorphisms and oral contraceptive use.

    PubMed

    Russo, Nunzio; Franzì, Enrico; Capilli, Gianfranco; Patané, Anella Antonietta; Russo, Silvia Paola; Evola, Rosario

    2014-01-01

    We present the case of a 28-year-old woman who was admitted to our cardiology unit for acute coronary syndrome. Her history was notable for cardiovascular disease familiarity, active smoking, and oral contraceptive use. On further analysis, she was noted to have thrombophilic polymorphisms involving the plasminogen activator inhibitor (PAI), angiotensin-converting enzyme (ACE), and methylenetetrahydrofolate reductase (MTHFR) genes. We discuss the implications that these cofactors may have had in the genesis of the disease. PMID:25587456

  17. Survival and risk of relapse of acute lymphoblastic leukemia in a Mexican population is affected by dihydrofolate reductase gene polymorphisms

    PubMed Central

    GÓMEZ-GÓMEZ, YAZMÍN; ORGANISTA-NAVA, JORGE; SAAVEDRA-HERRERA, MÓNICA VIRGINIA; RIVERA-RAMÍREZ, ANA BERTHA; TERÁN-PORCAYO, MARCO ANTONIO; DEL CARMEN ALARCÓN-ROMERO, LUZ; ILLADES-AGUIAR, BERENICE; LEYVA-VÁZQUEZ, MARCO ANTONIO

    2012-01-01

    Dihydrofolate reductase (DHFR) is the major target of methotrexate, a key component in childhood acute lymphoblastic leukemia (ALL) treatment. Polymorphisms in the gene coding for DHFR have been associated with adverse event treatment. This study evaluated the effect of the -A317G and C829T polymorphisms in the DHFR gene on survival and risk of relapse of ALL. Seventy patients with ALL and 100 healthy individuals were genotyped by the polymerase chain reaction-restriction fragment length polymorphism method. An association between the polymorphisms and the risk of relapse was found (p<0.05); patients with the -317G/G genotype were found to have an 8.55 (95% CI 1.84–39.70) higher chance of relapse and carriers of the 829T/T genotype had a 14.0 (95% CI 1.13–172.63) higher chance of relapse. Other variables, such as age and leukocyte count, were associated (p<0.05) with the risk of relapse of the disease. Individuals with the G/G and T/T genotype of the -A317G and C829T polymorphisms had poorer survival compared to other genotype groups (log-rank test; p<0.05). Although preliminary, these data seem to suggest a role for the DHFR polymorphisms in the risk of relapse of ALL and the mortality risk in these patients. PMID:22969948

  18. Molecular genetic analysis of the gene encoding the trifunctional enzyme MTHFD (methylenetetrahydrofolate-dehydrogenase, methenyltetrahydrofolate-cyclohydrolase, formyltetrahydrofolate synthetase) in patients with neural tube defects.

    PubMed

    Hol, F A; van der Put, N M; Geurds, M P; Heil, S G; Trijbels, F J; Hamel, B C; Mariman, E C; Blom, H J

    1998-02-01

    It is now well recognized that periconceptional folic acid or folic acid containing multivitamin supplementation reduces the risk of neural tube defects (NTDs). Recently we were able to show that homozygosity for a thermolabile variant of the enzyme methylenetetrahydrofolate reductase is associated with an increased risk for spina bifida in patients recruited from the Dutch population. However, this genetic risk factor could not account for all folic acid preventable NTDs. In an attempt to identify additional folate related enzymes that contribute to NTD etiology we now studied the methylenetetrahydrofolate dehydrogenase gene on chromosome 14q24 which encodes a single protein with three catalytic properties important in the folate metabolism. The cDNA sequence of 38 familial and 79 sporadic patients was screened for the presence of mutations by single strand conformation polymorphism (SSCP) analysis followed by sequencing. Two amino acid substitutions were identified. The first one (R293H) was detected in a patient with familial spina bifida and not in 300 control individuals. The mutation was inherited from the unaffected maternal grandmother and was also present in two younger brothers of the index patient, one of them displaying spina bifida occulta and the other being unaffected. The second change turned out to be an amino acid polymorphism (R653Q) that was present in both patients and controls with similar frequencies. Our results so far provide no evidence for a major role of the methylenetetrahydrofolate-dehydrogenase (MTHFD) gene in NTD etiology. However, the identification of a mutation in one family suggests that this gene can act as a risk factor for human NTD. PMID:9611072

  19. Color polymorphs of aldose reductase inhibitor epalrestat: configurational, conformational and synthon differences.

    PubMed

    Swapna, Battini; Suresh, Kuthuru; Nangia, Ashwini

    2016-03-01

    We report five crystalline polymorphs and an amorphous phase of epalrestat together with configurational isomerism and color behavior: form I (deep red), form II (deep orange), form III (bright yellow), form IV (yellow), and form V (orange) are in the E,Z configuration of the drug, and a Z,Z isomer (bright yellow). Two pathways are identified for polymorph conversion: direct transformation of the E,Z isomer and another pathway via the Z,Z isomer to the E,Z polymorphs. From a pharmaceutical perspective, the stability of polymorphs was established under grinding, solvent slurry and thermal conditions: form I (thermodynamic) > form II > form V > form III > form IV (least stable). PMID:26889760

  20. [Relationship between hyperhomocysteinemia and C677T polymorphism of methylene tetrahydrofolate reductase gene in a healthy Algerian population].

    PubMed

    Hambaba, L; Abdessemed, S; Yahia, M; Laroui, S; Rouabah, F

    2008-01-01

    Plasmatic homocysteine concentration depends mostly on 5,10 methylene tetrahydrofolate reductase (MTHFR) polymorphisms, a key enzyme in folate metabolism. The most common point mutation C677T is associated to cardiovascular and neurological pathologies; its ethnic repartition is quite heterogenic. In the present study, we proposed to describe the genotypic and allelic frequencies of C677T polymorphism and its influence on plasmatic homocysteine level in a healthy Algerian population. The investigation was turned on 100 apparently healthy voluntary subjects. Homocysteine concentration was determined using an immunoassay by fluorescence polarisation on IMx. Genotypes were determined by RT-PCR (Light cycle 480). Mean homocysteine concentration value was 14,69 +/- 7,30 micromol/L. 41% of people sample show a moderate hyperhomocysteinemia (>15 micromol/L). For the MTHFR C677T, estimated frequency of the allele T in the 100 people sample was about 35,5% with genotypic frequency of 6%. Plasmatic homocysteine is significantly higher in people carrying allele T: (CC vs CT: 11,8 +/- 2,97 micromol/L vs 15,47 +/- 6,74 micromol/L, p = 0,0004); (CC vs TT: 11,8 +/- 2,97 micromol/L vs 30,05 +/- 13,35 micromol/L, p = 0,01) and (CT vs TT: 15,47 +/- 6,74 micromol/L vs 30,05 +/- 13,35 micromol/L, p = 0,021). Our study shows an intermediate allelic frequency that joins the North-South world gradient and a high hyperhomocysteinemia prevalence. C677T polymorphism of MTHFR seems playing a predominant role in the moderate hyperhomocyteinemia. These two observations should be taken into consideration in the evaluation of morbid and/or lethal pathologies predisposition in the Algerian population. PMID:19091662

  1. Association of Methylene Tetrahydrofolate Reductase Polymorphism with BMD and Homocysteine in Premenopausal North Indian Women

    PubMed Central

    Pandey, Sanjeev Kumar; Singh, Ankur; Polipalli, Sunil Kumar; Gupta, Sangeeta; Kapoor, Seema

    2013-01-01

    Background and Aim: Osteoporosis (OP) is a common nutrigenomic disease associated with various genetic components. Observational studies have indicated that mildly elevated homocysteine was a strong risk factor for osteoporotic fractures. Yet there is no clear biologic mechanism for an effect of homocysteine on bone.The aim of this study was to investigate the association of MTHFR C677T and A1298C polymorphisms, and to verify the association of these polymorphisms with bone mineral density and homocysteine in premenopausal women of northern India. Material and Methods: We included 402 north Indian patients with altered BMD, both Osteopenic (OPN) and Osteoporosis, and normal controls. Genotype identification for MTHFR C677T and A1298C polymorphisms were analyzed by PCR-RFLP method, correlated with Bone Mineral Density (BMD), Homocysteine (Hcy), Folate and Vitamin B12. Results: The study groups did not differ in terms of age, weight and body mass indices. Prevalence of Genotype frequencies (GFs) for MTHFRC677T OP were (n: 402): CC 361 (89.8%), CT 25 (6.22%), TT 16 (3.98%) and that for MTHFR A1298C were (n: 402) AA 353(87.81%), AC 29(7.21%), CC 20(4.98%). Folate was significantly lower in the OP group than those in both the other groups, while there was no significant difference in Hcy in the OP group relative to OPN, as compared to controls. Conclusion: The GFs for MTHFR C677T and A1298C polymorphisms were not different between both groups. In conclusion, polymorphism of the MTHFR 677T is associated with small differences in BMD with folate levels. Further, more investigations should be done in larger studies for other epigenetic pathways, that may increase the risk of Osteoporosis. PMID:24551672

  2. Folate metabolism-related gene polymorphisms and susceptibility to primary liver cancer in North China.

    PubMed

    Cui, Lian-Hua; Song, Yang; Si, Hongzong; Shen, Fangzhen; Shin, Min-Ho; Kim, Hee Nam; Choi, Jin-Su

    2012-09-01

    Genetic factors may contribute to individual differences in cancer susceptibility. This study was designed to investigate the effects of the polymorphisms of methylenetetrahydrofolate reductase 677 C → T (MTHFR 677 C → T), methylenetetrahydrofolate reductase 1298 A → C (MTHFR 1298A → C), thymidylate synthase (TYMS 3R → 2R), and methionine synthase 2756 A → G (MTR 2756 A → G) on the risk of primary liver cancer (PLC). We conducted a case-control study involving 356 PLC cases and 641 healthy controls in North China. Compared with the MTHFR 677CC genotype, the MTHFR 677TT genotype showed an increased risk for PLC (TT vs. CC: adjusted odds ratio (OR) = 1.56; 95% confidence interval (CI): 1.02-2.40; P = 0.043) after adjusting for gender and age, whereas the MTHFR 1298CC genotype showed a significantly decreased risk for PLC (CC vs. AA: adjusted OR = 0.23; 95% CI: 0.08-0.70; P = 0.010). However, no significant association was found between the TYMS 3R → 2R or the MTR 2756 A → G polymorphism and the risk of PLC. Our results suggest that the MTHFR 677 C → T and the MTHFR 1298A → C genetic polymorphisms might play important role in hepatic carcinogenesis. Further studies with larger sample sizes are required to validate this association. PMID:21956592

  3. Plasma homocysteine levels, methylene tetrahydrofolate reductase A1298C gene polymorphism and risk of retinal vein thrombosis.

    PubMed

    Ghaznavi, Habib; Soheili, Zahra; Samiei, Shahram; Soltanpour, Mohammad Soleiman

    2016-09-01

    There are limited data regarding the role of methylene tetrahydrofolate reductase (MTHFR) A1298C polymorphism and hyperhomocysteinemia as risk factors for retinal vein thrombosis (RVT) in Iranians. This study aimed to examine a possible association between fasting plasma total homocysteine (tHcy) levels, MTHFR A1298C polymorphism and RVT development in Iranian patients. Our study population consisted of 73 patients with a diagnosis of RVT (52.7 ± 16.2 years) and 73 age and sex-matched healthy controls (49.1 ± 14.6 years). Genotyping for the MTHFR A1298Cpolymorphism was conducted by PCR-RFLP technique and plasma tHcy levels were measured by an enzyme immunoassay method. Fasting plasma tHcy levels were 20.29 ± 8.5 μmol/l in RVT patients and 10.9 ± 3.1 μmol/l in control subjects. The number of cases with abnormal tHcy values (hyperhomocysteinemia) was significantly higher in the RVT patients than control subjects (P = 0.0001). The prevalence of MTHFR 1298CC homozygote genotype was similar in RVT patients and controls (17.8 vs.15.1%, P = 0.45). There were no significant differences in genotype distribution of MTHFR A1298C polymorphism between males and females in both RVT patients and controls (P > 0.05). The frequency of the 1298C allele was 39.1 and 35.6% in patients and controls, respectively, and did not differ significantly between them (P = 0.23). Moreover, heterozygote and homozygote genotypes in the RVT patients had significantly higher abnormal tHcy values than corresponding genotypes in control subjects (P < 0.001). Our study demonstrated that hyperhomocysteinemia but not homozygosity for MTHFR A1298C polymorphism is a significant risk factor for RVT in the Iranian population. PMID:26650461

  4. Mutant dihydrofolate reductase-thymidylate synthase genes in pyrimethamine-resistant Plasmodium falciparum with polymorphic chromosome duplications.

    PubMed

    Tanaka, M; Gu, H M; Bzik, D J; Li, W B; Inselburg, J

    1990-08-01

    We have identified dihydrofolate reductase (DHFR) gene point mutations and chromosomal changes in pyrimethamine-resistant mutants selected in vitro of Plasmodium falciparum strain FCR3. A pyrimethamine-resistant derivative of the pyrimethamine-sensitive strain FCR3, FCR3-D8, that had been grown in the absence of pyrimethamine for an extended time, was grown in two concentrations of pyrimethamine, and surviving drug-resistant parasites were subcloned. One selected mutant, FCR3-D81, that grew at 1 X 10(-6) M pyrimethamine, contained a single point mutation in the DHFR domain which caused an amino acid change (Phe to Ser) at amino acid 223, whereas another mutant, FCR3-D85, that grew at 5 X 10(-6) M pyrimethamine had that same mutation and an additional point mutation that changed amino acid 54 (Asp to Asn). The selection of FCR3-D85, whose nucleotide sequence was identical to that previously reported for FCR3-D8, confirmed that the original FCR3-D8 parasite population had changed during extended growth in vitro in the absence of drug pressure. FCR3-D81 and FCR3-D85 cells contained different pairs of polymorphic chromosomes that hybridized to a DHFR-TS probe as well as to three other chromosome 4 specific DNAs, indicating that at least part of chromosome 4 had been duplicated and that these parasites were aneuploid with 15 rather than 14 chromosomes. The mutant DHFR-TS genes were diploid. We consider the roles of the polymorphic chromosome duplications and DHFR point mutation(s) as causes of pyrimethamine resistance. PMID:2233901

  5. Associations of the A66G Methionine Synthase Reductase Polymorphism in Colorectal Cancer: A Systematic Review and Meta-Analysis.

    PubMed

    Pabalan, Noel; Singian, Eloisa; Tabangay, Lani; Jarjanazi, Hamdi; Singh, Neetu

    2015-01-01

    Inconsistency in the reported associations between the A66G polymorphism in the methionine synthase reductase (MTRR) gene and colorectal cancer (CRC) prompted a meta-analysis, so that we could obtain a more precise estimate. Databases searches of the published literature yielded 20 case-control studies from 17 articles (8,371 cases and 12,574 controls). We calculated pooled odds ratios (ORs) and 95% confidence intervals in three genetic comparisons (A allele, G allele, and A/G genotype). We found no evidence of overall associations between MTRR A66G and CRC risk (OR 0.96-1.05, P = 0.12-0.44). This was materially unchanged when reanalyzed without the Hardy-Weinberg equilibrium (HWE)-deviating studies (OR 0.97-1.06, P = 0.11-0.65). In the A allele comparison, however, outlier treatment generated significant protection (OR 0.91, P = 0.01). Combined removal of the outliers and HWE-deviating studies reflected this summary effect (OR 0.90, P = 0.01) as did the pooled OR from high-quality studies (OR 0.90, P = 0.01). Only the Asian subgroup showed significant (both at P = 0.05) A allele (OR 1.13) and A/G genotype (OR 0.88) associations. In conclusion, post-outlier A allele effects were protective. Our study also suggests ethnic-specific associations with Asian susceptibility and protection in the A allele and A/G genotype comparisons, respectively. Folate status showed no association of this polymorphism with CRC. PMID:26549973

  6. Associations of the A66G Methionine Synthase Reductase Polymorphism in Colorectal Cancer: A Systematic Review and Meta-Analysis

    PubMed Central

    Pabalan, Noel; Singian, Eloisa; Tabangay, Lani; Jarjanazi, Hamdi; Singh, Neetu

    2015-01-01

    Inconsistency in the reported associations between the A66G polymorphism in the methionine synthase reductase (MTRR) gene and colorectal cancer (CRC) prompted a meta-analysis, so that we could obtain a more precise estimate. Databases searches of the published literature yielded 20 case–control studies from 17 articles (8,371 cases and 12,574 controls). We calculated pooled odds ratios (ORs) and 95% confidence intervals in three genetic comparisons (A allele, G allele, and A/G genotype). We found no evidence of overall associations between MTRR A66G and CRC risk (OR 0.96–1.05, P = 0.12–0.44). This was materially unchanged when reanalyzed without the Hardy–Weinberg equilibrium (HWE)-deviating studies (OR 0.97–1.06, P = 0.11–0.65). In the A allele comparison, however, outlier treatment generated significant protection (OR 0.91, P = 0.01). Combined removal of the outliers and HWE-deviating studies reflected this summary effect (OR 0.90, P = 0.01) as did the pooled OR from high-quality studies (OR 0.90, P = 0.01). Only the Asian subgroup showed significant (both at P = 0.05) A allele (OR 1.13) and A/G genotype (OR 0.88) associations. In conclusion, post-outlier A allele effects were protective. Our study also suggests ethnic-specific associations with Asian susceptibility and protection in the A allele and A/G genotype comparisons, respectively. Folate status showed no association of this polymorphism with CRC. PMID:26549973

  7. MTHFR polymorphisms' influence on outcome and toxicity in acute lymphoblastic leukemia patients.

    PubMed

    Chiusolo, Patrizia; Reddiconto, Giovanni; Farina, Giuliana; Mannocci, Alice; Fiorini, Alessia; Palladino, Mariangela; La Torre, Giuseppe; Fianchi, Luana; Sorà, Federica; Laurenti, Luca; Leone, Giuseppe; Sica, Simona

    2007-12-01

    Recently the influence of polymorphisms of different genes involved in metabolism of chemoterapic agents have been studied especially in childhood acute lymphoblastic leukemia (ALL). We evaluated the influence of C677T and A1298C methylenetetrahydrofolate reductase (MTHFR) polymorphisms on time to relapse and survival and on methotrexate (MTX) toxicity in 82 ALL adult patients. Relapse free survival and event free survival between homozygous wild-type and variant patients in both polymorphisms were not significantly different. However, we observed an association between 677TT variant and survival in a subset of ALL patients homogenously treated with MTX-based maintenance (p=0.02). In the same subgroup we confirmed the role of 677TT variant on toxicity during MTX treatment (p=0.003). PMID:17512587

  8. Effectiveness of add-on l-methylfolate therapy in a complex psychiatric illness with MTHFR C677 T genetic polymorphism.

    PubMed

    Jha, Shailesh; Kumar, Pankaj; Kumar, Rajesh; Das, Aparna

    2016-08-01

    The 5,10-methylenetetrahydrofolate reductase (MTHFR) gene plays a central role in folate metabolism. Many studies have demonstrated an association between MTHFR C677 T variant with depression, schizophrenia and bipolar disorder as one of them being comorbid to other. This has justified the use of folate supplement in psychiatric disorders mainly depression but still not in various other comorbid complex psychiatric disorders. Here we have tried to show how the l-methylfolate in conjunction with the conventional psychotropic drugs can be useful in a state of such complex psychiatric phenomenon and comorbid diagnosis with genetic polymorphism of MTHFR C677 T mutation. PMID:27520898

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

    PubMed Central

    2014-01-01

    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

  10. Quinone Reductase 2 Is a Catechol Quinone Reductase

    SciTech Connect

    Fu, Yue; Buryanovskyy, Leonid; Zhang, Zhongtao

    2008-09-05

    The functions of quinone reductase 2 have eluded researchers for decades even though a genetic polymorphism is associated with various neurological disorders. Employing enzymatic studies using adrenochrome as a substrate, we show that quinone reductase 2 is specific for the reduction of adrenochrome, whereas quinone reductase 1 shows no activity. We also solved the crystal structure of quinone reductase 2 in complexes with dopamine and adrenochrome, two compounds that are structurally related to catecholamine quinones. Detailed structural analyses delineate the mechanism of quinone reductase 2 specificity toward catechol quinones in comparison with quinone reductase 1; a side-chain rotational difference between quinone reductase 1 and quinone reductase 2 of a single residue, phenylalanine 106, determines the specificity of enzymatic activities. These results infer functional differences between two homologous enzymes and indicate that quinone reductase 2 could play important roles in the regulation of catecholamine oxidation processes that may be involved in the etiology of Parkinson disease.

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

    PubMed

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

    2014-01-01

    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

  12. A Polymorphism in Hepatocyte Nuclear Factor 1 Alpha, rs7310409, Is Associated with Left Main Coronary Artery Disease

    PubMed Central

    Liu, Rui; Liu, Hanning; Gu, Haiyong; Teng, Xiao; Nie, Yu; Zhou, Zhou; Zhao, Yan; Hu, Shengshou; Zheng, Zhe

    2014-01-01

    Coronary artery disease is the leading cause of mortality and morbidity in the world. Left main coronary artery disease (LMCAD) is a particularly severe phenotypic form of CAD and has a genetic basis. We hypothesized that some inflammation- and hyperhomocysteinemia-related gene polymorphisms may contribute to LMCAD susceptibility in a Chinese population. We studied the association between polymorphisms in the genes hepatocyte nuclear factor 1 alpha (HNF1A; rs7310409, G/A), C-reactive protein (rs1800947 and rs3093059 T/C), methylenetetrahydrofolate reductase (rs1801133, C/T), and methylenetetrahydrofolate dehydrogenase (rs1076991, A/G) in 402 LMCAD and 804 more peripheral CAD patients in a Chinese population. Genotyping was performed using the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry method. When the HNF1A rs7310409 GG homozygote genotype was used as the reference group, both the individual, GA and AA, and combined GA/AA genotypes were associated with an increased risk of LMCAD. This single nucleotide polymorphism (rs7310409) is strongly associated with plasma CRP levels. In conclusion, the present study provides evidence that the HNF1A rs7310409 G/A functional polymorphism may contribute to the risk of LMCAD. PMID:25202455

  13. A variety of gene polymorphisms associated with idiopathic granulomatous mastitis

    PubMed Central

    Destek, Sebahattin; Gul, Vahit Onur; Ahioglu, Serkan

    2016-01-01

    Idiopathic granulomatous mastitis (IGM) is a rare and chronic inflammatory disorder. IGM mimics breast cancer regarding its clinical and radiological features. Etiology of IGM remains unclarified. Our patient was 37-year-old and 14 weeks pregnant. There was pain, redness and swelling in the right breast. The mass suggestive of malignancy was detected in sonography. Serum CA 125 and CA 15-3 levels were high. Genetic analysis was performed for the etiology. methylenetetrahydrofolate reductase (MTHFR) C 677 TT, β-fibrinogen-455 G>A, plasminogen activator inhibitor (PAI)-1 5 G/5 G, angiotensin-converting enzyme (ACE) I/D mutation was found. IGM was diagnosed by cor biopsy. An association was also reported between breast cancer and mutations in MTHFR-C 677 T, PAI-1, ACE genes. Genetic polymorphisms may involve in the development of IGM as it was seen in our case. Further studies should be conducted to better clarify this plausible association. PMID:27619324

  14. A variety of gene polymorphisms associated with idiopathic granulomatous mastitis.

    PubMed

    Destek, Sebahattin; Gul, Vahit Onur; Ahioglu, Serkan

    2016-01-01

    Idiopathic granulomatous mastitis (IGM) is a rare and chronic inflammatory disorder. IGM mimics breast cancer regarding its clinical and radiological features. Etiology of IGM remains unclarified. Our patient was 37-year-old and 14 weeks pregnant. There was pain, redness and swelling in the right breast. The mass suggestive of malignancy was detected in sonography. Serum CA 125 and CA 15-3 levels were high. Genetic analysis was performed for the etiology. methylenetetrahydrofolate reductase (MTHFR) C 677 TT, β-fibrinogen-455 G>A, plasminogen activator inhibitor (PAI)-1 5 G/5 G, angiotensin-converting enzyme (ACE) I/D mutation was found. IGM was diagnosed by cor biopsy. An association was also reported between breast cancer and mutations in MTHFR-C 677 T, PAI-1, ACE genes. Genetic polymorphisms may involve in the development of IGM as it was seen in our case. Further studies should be conducted to better clarify this plausible association. PMID:27619324

  15. Lack of association between the methylenetetrahydropholate reductase gene A1298C polymorphism and neural tube defects in a Turkish study group.

    PubMed

    Yildiz, S H; Ozdemir Erdogan, M; Solak, M; Eser, O; Arıkan Terzi, E S; Eser, B; Kocabaş, V; Aslan, A

    2016-01-01

    The etiology underlying neural tube defects (NTDs) is not fully understood and is believed to involve a complex milieu of genetic and environmental factors. The A1298C polymorphism in the methylenetetrahydropholate reductase gene (MTHFR) has been associated with mild risk for NTDs. In this study, the genotype distribution of the MTHFR gene A1298C polymorphism and the levels of serum homocysteine, vitamin B12, and folate were evaluated in 33 children with NTDs, their mothers, and 46 healthy controls. Genotyping of the A1298C polymorphism was performed by real-time polymerase chain reaction. The A and C allele frequencies in children with NTDs and their mothers were similar to controls (P = 0.160). The 1298AA and 1298CC genotype frequencies (P = 0.551 and 0.062, respectively) in children with NTDs and their mothers did not differ from controls. On the other hand, the 1298AC genotype frequencies in children with NTDs and their mothers were significantly different from controls (P = 0.025). The genotype frequency of 1298AC was lower in children with NTDs than in controls. There was no significant association between clinical distribution of NTDs and 1298AA/AC/CC genotypes (P > 0.05). Serum vitamin B12 levels were higher in children with NTDs than their mothers and controls (P = 0.001). There were no differences among serum homocysteine and folate levels in all groups (P = 0.494 and 0.141, respectively). Both genetic and nutritional factors are important in the etiology of NTDs. Thus, the A1298C polymorphism cannot be regarded as a major risk factor for NTDs. PMID:27323133

  16. Polymorphisms of Genes Involved in the Folate Metabolic Pathway Impact the Occurrence of Unexplained Recurrent Pregnancy Loss.

    PubMed

    Luo, Li; Chen, Yueming; Wang, Li; Zhuo, Guangchao; Qiu, Chunning; Tu, Qiaofeng; Mei, Jin; Zhang, Wen; Qian, Xia; Wang, Xianjun

    2015-07-01

    Low levels of folate combined with high levels of homocysteine may cause unexplained recurrent pregnancy loss (URPL). However, the relationships between polymorphisms in genes of the folate metabolic pathway and URPL remain controversial. We conducted a case-control study to explore polymorphisms of the major folate pathway genes, including methylenetetrahydrofolate reductase (MTHFR) 677C>T, MTHFR 1298A>C, methionine synthase (MTR) 2756A>G, methionine synthase reductase (MTRR) 66A>G and reduced folate carrier 1 (RFC-1) 80A>G, and their associations with URPL. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to determine the distributions of MTHFR, MTR and RFC-1 polymorphisms, and the results were validated using direct sequencing. The polymorphisms in MTRR were determined using direct sequencing. Haplotypes were analyzed using SHEsis, an online tool for biological analysis. We found that the MTHFR 677T allele and the 677T/1298A/2756A/66A/80G haplotype were risk factors for URPL, while the MTR 2756G allele and the 677C/1298A/2756A/66A/80A haplotype exhibited protective effects on susceptibility to URPL in a Chinese Han population from the Hangzhou area. PMID:25544674

  17. Folate Intake, MTHFR Polymorphisms, and the Risk of Colorectal Cancer: A Systematic Review and Meta-Analysis

    PubMed Central

    Kennedy, Deborah A.; Stern, Seth J.; Matok, Ilan; Moretti, Myla E.; Sarkar, Moumita; Adams-Webber, Thomasin; Koren, Gideon

    2012-01-01

    Background. The objective was to determine whether relationships exist between the methylene-tetrahydrofolate reductase (MTHFR) polymorphisms and risk of colorectal cancer (CRC) and examine whether the risk is modified by level of folate intake. Methods. MEDLINE, Embase, and SCOPUS were searched to May 2012 using the terms “folic acid,” “folate,” “colorectal cancer,” “methylenetetrahydrofolate reductase,” “MTHFR.” Observational studies were included which (1) assessed the risk of CRC for each polymorphism and/or (2) had defined levels of folate intake for each polymorphism and assessed the risk of CRC. Results. From 910 references, 67 studies met our criteria; hand searching yielded 10 studies. The summary risk estimate comparing the 677CT versus CC genotype was 1.02 (95% CI 0.95–1.10) and for 677TT versus CC was 0.88 (95% CI 0.80–0.96) both with heterogeneity. The summary risk estimates for A1298C polymorphisms suggested no reduced risk. The summary risk estimate for high versus low total folate for the 677CC genotype was 0.70 (95% CI 0.56–0.89) and the 677TT genotype 0.63 (95% CI 0.41–0.97). Conclusion. These results suggest that the 677TT genotype is associated with a reduced risk of developing CRC, under conditions of high total folate intake, and this associated risk remains reduced for both MTHFR 677 CC and TT genotypes. PMID:23125859

  18. Genetic polymorphisms predicting the outcome of bone marrow transplants.

    PubMed

    Dickinson, Anne M; Middleton, Peter G; Rocha, Vanderson; Gluckman, Eliane; Holler, Ernst

    2004-12-01

    Analysis of non-histocompatibility leucocyte antigen (HLA) functional genomics, together with conventional risk factors in haematopoietic stem cell transplantation (HSCT) can lead to predicting outcome in HLA-matched sibling transplant recipients. Polymorphisms of cytokine genes including tumour necrosis factor alpha, interleukin-10, interferon gamma and interleukin (IL)-6, associate with more severe acute graft-versus-host disease (aGvHD). Donor genotype for IL-1 receptor antagonist (IL-1Ra) has been associated with reduced aGvHD severity. Other genotypes (patient IL-1Ra, IL-6 and donor IL-1 alpha) have been associated with chronic GvHD, or overall survival (Vitamin D receptor and oestrogen receptor). Polymorphisms within genes associated with host defence/inflammatory responses (mannose binding lectin genes, myeloperoxidase genes and the FC gamma receptors) have been associated with infections. Polymorphisms of pharmacogenes, such as methylenetetrahydrofolate-reductase, have been associated with aGvHD and other post-transplant complications. The NOD2 gene polymorphism, associated with Crohn's disease, has been shown to be associated with risk of gut GvHD. The majority of the studies have been carried out in single centre HLA-matched sibling cohorts and in relatively few matched unrelated donor transplants. This review gives an overall perspective of the current field of non-HLA genetics with regard to HSCT outcome, clinical relevance and potential application of the results to clinical management of HSCT. PMID:15566351

  19. Methylenetetrahydrofolate dehydrogenase from Clostridium formicoaceticum and methylenetetrahydrofolate dehydrogenase, methenyltetrahydrofolate cyclohydrolase (combined) from Clostridium thermoaceticum

    SciTech Connect

    Ljungdahl, L.G.; O'Brien, W.E.; Moore, M.R.; Liu, M.T.

    1980-01-01

    Methylenetetrahydrofolate dehydrogenase is widely distributed and has been found in every cell type investigated. The NAD-specific enzyme has been purified to homogeneity from Clostridium formicoaceticum and the NADP-specific enzyme has been obtained from Clostridium thermoaceticum. Other sources of the NADP-specific enzyme are Streptococcus species, Escherichia coli, Clostridium cylindrosporum, Salmonella typhimurium, yeast, liver from various animals, calf thymus, and plants. The NAD-specific enzyme has been demonstrated in Acetobacterium woodii, some methane bacteria, and in Ehrlich ascites tumor cells. Of considerable interest are the observations that in porcine and ovine livers, as well as in yeast, methylenetetrahydrofolate dehydrogenase purified to homogeneity also contains methylenetetrahydrofolate cyclohydrolase and formyltetrahydrofolate synthetase activities. Now it appears that the purified methylenetetrahydrofolate dehydrogenase from C. thermoaceticum also has cyclohydrolase but not synthetase activity. Methylenetetrahydrofolate dehydrogenase has been discussed previously in this series, as has methenyltetrahydrofolate cyclohydrolase. In C. formicoaceticum and C. thermoaceticum these tetrahydrofolate-dependent enzymes participate in a sequence of metabolic reactions by which carbon dioxide is reduced to the methyl group of 5-methyltetrahydrofolate which in turn is utilized for the synthesis of acetate. This pathway provides the mechanism for disposing of reducing equivalents generated in glycolysis.

  20. Relationship of MTHFR gene polymorphisms with renal and cardiac disease

    PubMed Central

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

    2015-01-01

    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

  1. "Polymorphisms in folate metabolism genes as maternal risk factor for neural tube defects: an updated meta-analysis".

    PubMed

    Yadav, Upendra; Kumar, Pradeep; Yadav, Sushil Kumar; Mishra, Om Prakash; Rai, Vandana

    2015-02-01

    Epidemiological studies have evaluated the association between maternal methylenetetrahydrofolate reductase (MTHFR) C677T, A1298C and methionine synthase reductase (MTRR) A66G polymorphisms and risk of neural tube defects (NTDs) in offspring. However, the results from the published studies on the association between these three polymorphisms and NTD risk are conflicting. To derive a clearer picture of association between these three maternal polymorphisms and risk of NTD, we performed meta-analysis. A comprehensive search was conducted to identify all case-control studies of maternal MTHFR and MTRR polymorphisms and NTD risk. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. Overall, we found that maternal MTHFR C677T polymorphism (OR(TvsC) =1.20; 95% CI = 1.13-1.28) and MTRR A66G polymorphism (OR(GvsA) = 1.21; 95% CI = 0.98-1.49) were risk factors for producing offspring with NTD but maternal MTHFR A1298C polymorphism (OR(CvsA) = 0.91; 95% CI = 0.78-1.07) was not associated with NTD risk. However, in stratified analysis by geographical regions, we found that the maternal C677T polymorphism was significantly associated with the risk of NTD in Asian (OR(TvsC) = 1.43; 95% CI: 1.05-1.94), European (OR(TvsC) = 1.13; 95% CI: 1.04-1.24) and American (OR(TvsC) = 1.26; 95% CI: 1.13-1.41) populations. In conclusion, present meta-analysis supports that the maternal MTHFR C677T and MTRR A66G are polymorphisms contributory to risk for NTD. PMID:25005003

  2. Associations between 5,10-methylenetetrahydrofolate reductase codon 677 and 1298 genetic polymorphisms and environmental factors with reference to susceptibility to colorectal cancer: a case-control study in an Indian population.

    PubMed

    Wang, Jingwen; Gajalakshmi, Vendhan; Jiang, Jing; Kuriki, Kiyonori; Suzuki, Sadao; Nagaya, Teruo; Nakamura, Seiichi; Akasaka, Susumu; Ishikawa, Hideki; Tokudome, Shinkan

    2006-02-15

    Although the incidence rate of colorectal cancer is very low, and rectal cancer remains more common in India, a significant increase in its incidence has been reported for both men and women over the last 2 decades. We evaluated MTHFR genetic susceptibility and common environmental risk factors in the development of colon and rectal cancer, and assessed the interactions between gene and environmental factors with colorectal cancer in a case-control study in the Indian population. The study included 59 colon cancer cases, 243 rectal cancer cases and 291 controls. The variant MTHFR 677T allele is rare, while the 1298C allele is common among Indians. MTHFR 677T showed no association with colon cancer (OR = 0.82; 95% CI 0.28-2.05) and a nonstatistically significantly elevated risk with rectal cancer (OR = 1.51; 95% CI 0.86-2.68), and MTHFR 1298 CC genotype was found to be associated with a significantly decreased risk for both colon cancer (OR = 0.30, 95% CI 0.09-0.81) and rectal cancer (OR = 0.43, 95% CI 0.23-0.80). High intake of nonfried vegetables or fruits was inversely associated with both colon and rectal cancer risk. Especially, the combination of a high intake of nonfried vegetables and MTHFR 1298CC genotype was associated with the lowest rectal cancer risk (OR = 0.22, 95% CI 0.09-0.52). Regarding alcohol consumption, indigenous Indian alcohol drinkers (OR = 2.26, 95% CI 0.86-6.36), and those consuming alcohol for duration more than 20 years (OR = 1.55, 95% CI 0.73-3.33), were at a somewhat higher rectal cancer risk. Moreover, the consumed alcohol amount (gram-years) may be also associated with colon or rectal cancer risk. PMID:16152599

  3. Are MTHFR C677T and MTRR A66G Polymorphisms Associated with Overweight/Obesity Risk? From a Case-Control to a Meta-Analysis of 30,327 Subjects

    PubMed Central

    Fan, Shu-Jun; Yang, Bo-Yi; Zhi, Xue-Yuan; He, Miao; Wang, Da; Wang, Yan-Xun; Wang, Yi-Nuo; Wei, Jian; Zheng, Quan-Mei; Sun, Gui-Fan

    2015-01-01

    Several studies have examined the associations of methylenetetrahydrofolate reductase (MTHFR) C677T and methionine synthase reductase (MTRR) A66G polymorphisms with being overweight/obesity. However, the results are still controversial. We therefore conducted a case-control study (517 cases and 741 controls) in a Chinese Han population and then performed a meta-analysis by combining previous studies (5431 cases and 24,896 controls). In our case-control study, the MTHFR C677T polymorphism was not significantly associated with being overweight/obesity when examining homozygous codominant, heterozygous codominant, dominant, recessive and allelic genetic models. The following meta-analysis confirmed our case-control results. Heterogeneity was minimal in the overall analysis, and sensitivity analyses and publication bias tests indicated that the meta-analytic results were reliable. Similarly, both the case-control study and meta-analysis found no significant association between the MTRR A66G polymorphism and being overweight/obesity. However, sensitivity analyses showed that the associations between the MTRR A66G polymorphism and being overweight/obesity became significant in the dominant, heterozygous codominant and allelic models after excluding our case-control study. The results from our case-control study and meta-analysis suggest that both of the two polymorphisms are not associated with being overweight/obesity. Further large-scale population-based studies, especially for the MTRR A66G polymorphism, are still needed to confirm or refute our findings. PMID:26016497

  4. Are MTHFR C677T and MTRR A66G Polymorphisms Associated with Overweight/Obesity Risk? From a Case-Control to a Meta-Analysis of 30,327 Subjects.

    PubMed

    Fan, Shu-Jun; Yang, Bo-Yi; Zhi, Xue-Yuan; He, Miao; Wang, Da; Wang, Yan-Xun; Wang, Yi-Nuo; Wei, Jian; Zheng, Quan-Mei; Sun, Gui-Fan

    2015-01-01

    Several studies have examined the associations of methylenetetrahydrofolate reductase (MTHFR) C677T and methionine synthase reductase (MTRR) A66G polymorphisms with being overweight/obesity. However, the results are still controversial. We therefore conducted a case-control study (517 cases and 741 controls) in a Chinese Han population and then performed a meta-analysis by combining previous studies (5431 cases and 24,896 controls). In our case-control study, the MTHFR C677T polymorphism was not significantly associated with being overweight/obesity when examining homozygous codominant, heterozygous codominant, dominant, recessive and allelic genetic models. The following meta-analysis confirmed our case-control results. Heterogeneity was minimal in the overall analysis, and sensitivity analyses and publication bias tests indicated that the meta-analytic results were reliable. Similarly, both the case-control study and meta-analysis found no significant association between the MTRR A66G polymorphism and being overweight/obesity. However, sensitivity analyses showed that the associations between the MTRR A66G polymorphism and being overweight/obesity became significant in the dominant, heterozygous codominant and allelic models after excluding our case-control study. The results from our case-control study and meta-analysis suggest that both of the two polymorphisms are not associated with being overweight/obesity. Further large-scale population-based studies, especially for the MTRR A66G polymorphism, are still needed to confirm or refute our findings. PMID:26016497

  5. The 19-bp deletion polymorphism of dihydrofolate reductase (DHFR) and nonsyndromic cleft lip with or without cleft palate: evidence for a protective role

    PubMed Central

    RAFIGHDOOST, Firoozeh; RAFIGHDOOST, Amir; RAFIGHDOOST, Houshang; RIGI-LADEZ, Mohammad-Ayoob; HASHEMI, Mohammad; ESKANDARI-NASAB, Ebrahim

    2015-01-01

    Objective Nonsyndromic cleft lip with or without cleft palate (NS-CL/P) are among the most common congenital birth defects worldwide. Several lines of evidence point to the involvement of folate, as well as folate metabolizing enzymes in risk reduction of orofacial clefts. Dihydrofolate reductase (DHFR) enzyme participates in the metabolic cycle of folate and has a crucial role in DNA synthesis, a fundamental feature of gestation and development. A functional polymorphic 19-bp deletion within intron-1 of DHFR has been associated with the risk of common congenital malformations. The present study aimed to evaluate the possible association between DHFR 19-bp deletion polymorphism and susceptibility to NS-CL/P in an Iranian population. Material and Methods The current study recruited 100 NS-CL/P patients and 100 healthy controls. DHFR 19-bp deletion was determined using an allele specific-PCR method. Results We observed the DHFR 19-bp homozygous deletion genotype (D/D) vs. homozygous wild genotype (WW) was more frequent in controls than in NS-CL/P patients (25% vs. 13%), being associated with a reduced risk of NS-CL/P in both codominant (OR=0.33, P=0.027) and recessive (OR=0.45, P=0.046) tested inheritance models. We also stratified the cleft patients and reanalyzed the data. The association trend for CL+CL/P group compared to the controls revealed that the DD genotype in both codominant (OR=0.30, P=0.032) and recessive models (OR=0.35, P=0.031) was associated with a reduced risk of CL+CL/P. Conclusions Our results for the first time suggested the DHFR 19-bp D/D genotype may confer a reduced risk of NS-CL/P and might act as a protective factor against NS-CL/P in the Iranian subjects. PMID:26221921

  6. Correlation between the 677C>T polymorphism in the methylene tetrahydrofolate reductase gene and serum homocysteine levels in coronary heart disease.

    PubMed

    Chen, Y Y; Wang, B N; Yu, X P

    2016-01-01

    The aim of the current study was to explore the correlation between serum homocysteine (HCY) levels and the methylene tetrahydrofolate reductase (MTHFR) gene 677C/T polymorphism and coronary heart disease (CHD). We consecutively enrolled 208 patients with CHD confirmed by CTA or coronary angiography from our hospital. An additional 200 healthy volunteers were enrolled as the control group. Serum HCY levels, MTHFR C677T genotype, and other related indicators were evaluated for the two groups. Compared to those in the control group, the serum HCY levels in the CHD patients were significantly higher (P < 0.05). The proportion of individuals with the heterozygous MTHFR CT genotype and homozygous mutant TT genotype among CHD patients was significantly higher than that in the control group (P < 0.05). In the acute coronary syndrome (ACS) subgroup, the proportion of those with the CT and TT genotypes was significantly higher than that of the stable CHD subgroup (P < 0.05). In summary, serum HCY levels were elevated in CHD patients, and the frequency of the CT and TT genotypes were also significantly increased, especially among the ACS subgroup. Taken together, this suggests that serum HCY levels and MTHFR C677T genotypes are correlated with CHD. PMID:27051002

  7. C677T (RS1801133 ) MTHFR gene polymorphism frequency in a colombian population

    PubMed Central

    Gómez-Gutierrez, Alberto; Gómez, Piedad Elena; Casas-Gomez, Maria Consuelo; Briceño, Ignacio

    2015-01-01

    Introduction: Abnormal levels of the enzyme methylenetetrahydrofolate reductase (MTHFR) are associated with an increased risk of both cardiovascular and cerebrovascular disease and higher concentrations of homocysteine. Abnormal levels are also related to birth defects, pregnancy complications, cancer and toxicity to methotrexate (MTX). Polymorphisms of MTHFR affect the activity of the enzyme. Genetic associations have been related to treatment efficacy. Objective: To establish the frequency of the C> T polymorphism at nucleotide 677 of the MTHFR gene in a group of Colombian individuals. Methods: Data from pharmacogenetic microarrays that include MTX sensibility-associated polymorphisms were retrospectively collected (Pathway Genomics®). The frequency of the C> T MTHFR rs1801133 marker polymorphism was analyzed. Results: Microarray data from 68 men and 84 women were analyzed. Comparisons of genotype C/C vs. C/T and T/T were statistically significantly different (p= 0.00, p= 0.026, respectively), as were C/T and T / T (p= 0.0001). Conclusions: Results for the C/C and C/T genotypes in a Colombian population are similar to other previously studied groups of healthy subjects. Subjects from our population might be at risk of developing diseases associated with MTHFR polymorphisms and might present toxicity and adverse effects if treated with MTX, which suggests the need to evaluate therapeutic alternatives based on individual pharmacogenetic studies. PMID:26309343

  8. A Study on MTHFR C677T Gene Polymorphism and Alcohol Dependence among Meiteis of Manipur, India

    PubMed Central

    Singh, Huidrom Suraj; Salam, Kabita; Saraswathy, Kallur Nava

    2014-01-01

    Chronic alcohol consumption is reported to be associated with increase in plasma homocysteine levels which is further influenced by the polymorphism in methylenetetrahydrofolate reductase (MTHFR) gene. The present study aims to understand the extent of the MTHFR C677T polymorphism in alcohol dependent (AD) cases of Meiteis of Manipur, a Mendelian population of India. MTHFR C677T polymorphism was screened in 313 controls and 139 alcohol dependent (AD) cases who all met DSM-IV criteria for alcohol dependence. Both AD cases and controls were unrelated up to 1st cousin. Among the control group, different drinking patterns like abstainer/nondrinkers (NDs), occasional drinkers (ODs), and moderate drinkers (MDs) are included. Both the groups were found to be in Hardy-Weinberg equilibrium (P > 0.05). Genotypic and allelic frequency distribution of MTHFR C677T polymorphism did not differ significantly between AD cases and controls (P > 0.05). However, individuals carrying mutant (T) allele show more than 1-fold increased risk for AD though not significant (OR = 1.43; 95% CI 0.41–5.01, P > 0.05). In conclusion, MTHFR C677T polymorphism is not found to be risk marker for AD in present studied population. However, higher prevalence of the mutant T allele may exacerbate deleterious health risk in future especially among alcohol drinkers. PMID:26317030

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

    PubMed Central

    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

    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

  10. Association between folate metabolism-related polymorphisms and colorectal cancer risk

    PubMed Central

    KIM, JONG WOO; JEON, YOUNG JOO; JANG, MOON JU; KIM, JUNG O; CHONG, SO YOUNG; KO, KWANG HYUN; HWANG, SEONG GYU; OH, DOYEUN; OH, JISU; KIM, NAM KEUN

    2015-01-01

    Folate has essential roles in DNA synthesis, repair and methylation. Folate metabolism-related gene variants may modulate the levels of this vitamin and affect the cancer risk. Thus, whether these polymorphisms play an important role in carcinogenesis, particularly colorectal cancer (CRC) development, has been a subject interest. The present study investigated the association between polymorphisms in the methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS) and the reduced folate carrier 1 (RFC1) genes and CRC risk. Polymorphisms in MTHFR (677C>T and 1298A>C), TS [1494del6 and the TS enhancer region (TSER)] and RFC1 (−43T>C, 80G>A and 696C>T) were characterized using polymerase chain reaction-restriction fragment length polymorphism in 477 CRC cases and 514 controls. Although no polymorphisms were significantly associated with the CRC risk in the overall sample, significant associations between folate metabolism-related polymorphisms and CRC risk were identified in the stratified analyses. The MTHFR 677CT/1298AC and MTHFR 1298AC+CC/TSER 2R3R genotypes in the presence of plasma folate levels ≤4.12 ng/ml were associated with significantly increased CRC risk. In addition, individuals with the MTHFR 677TT/TSER 3R3R or MTHFR 677/TSER 3R3R/TS 1494 0bp6bp+6bp6bp genotypes and diabetes mellitus (DM) were at an increased risk for CRC. Therefore, the data suggest that i) MTHFR polymorphisms combined with low plasma folate levels and ii) polymorphisms in folate metabolism-related genes combined with metabolic syndrome risk factors (hypertension and DM) increase the odds of developing CRC. PMID:26137281

  11. Association between MTHFR gene polymorphisms and the risk of autism spectrum disorders: a meta-analysis.

    PubMed

    Pu, Danhua; Shen, Yiping; Wu, Jie

    2013-10-01

    Methylenetetrahydrofolate reductase (MTHFR) is essential for DNA biosynthesis and the epigenetic process of DNA methylation, and its gene polymorphisms have been implicated as risk factors for birth defects, neurological disorders, and cancers. However, reports on the association of MTHFR polymorphisms with autism spectrum disorders (ASD) are inconclusive. Therefore, we investigated the relationship of the MTHFR polymorphisms (C677T and A1298C) and the risk of ASD by meta-analysis. Up to December 2012, eight case-control studies involving 1672 patients with ASD and 6760 controls were included for meta-analysis. The results showed that the C677T polymorphism was associated with significantly increased ASD risk in all the comparison models [T vs. C allele (frequency of allele): odds ratio (OR) = 1.42, 95% confidence interval (CI): 1.09-1.85; CT vs. CC (heterozygote): OR = 1.48, 95% CI: 1.09-2.00; TT vs. CC (homozygote): OR = 1.86, 95% CI: 1.08-3.20; CT+TT vs. CC (dominant model): OR = 1.56, 95% CI: 1.12-2.18; and TT vs. CC+CT (recessive model): OR = 1.51, 95% CI: 1.02-2.22], whereas the A1298C polymorphism was found to be significantly associated with reduced ASD risk but only in a recessive model (CC vs. AA+AC: OR = 0.73, 95% CI: 0.56-0.97). In addition, we stratified the patient population based on whether they were from a country with food fortification of folic acid or not. The meta-analysis showed that the C677T polymorphism was found to be associated with ASD only in children from countries without food fortification. Our study indicated that the MTHFR C677T polymorphism contributes to increased ASD risk, and periconceptional folic acid may reduce ASD risk in those with MTHFR 677C>T polymorphism. PMID:23653228

  12. The MTHFR C677T Polymorphism and Risk of Intracerebral Hemorrhage in a Chinese Han Population

    PubMed Central

    Hu, Xin; Tao, Chuanyuan; Xie, Zhiyi; Li, Yunke; Zheng, Jun; Fang, Yuan; Lin, Sen; Li, Hao; You, Chao

    2016-01-01

    Background Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism has been speculated to be and extensively investigated as a risk factor for various vascular diseases, including intracerebral hemorrhage (ICH). However, results from published studies regarding the role of C677T polymorphism in ICH risk in Chinese populations were contradictory rather than conclusive. Material/Methods In this study, a total of 180 ICH patients and 180 matched controls of Chinese Han ethnicity were enrolled. The MTHFR C677T polymorphism was genotyped by polymerase chain reaction-ligation detection reaction (PCR-LDR). A meta-analysis was conducted by combining our data with previous relevant studies in Chinese populations. Results In our case-control study, similar allele frequency (p=0.492) and genotype distribution (p=0.748) of MTHFR C677T polymorphism were detected between ICH patients and controls. Further analysis based on hematoma location did not show a significant association. When combined with previous studies, however, C677T polymorphism was found to be significantly associated with an increased risk for ICH in Chinese populations (recessive model: OR=1.57, 95%CI=1.29–1.91). When focusing on the Han ethnicity, carriers of the TT genotype had an increased risk of ICH (recessive model: OR=1.36, 95%CI=1.05–1.75). Conclusions In this case-control study we did not observe that the MTHFR C677T polymorphism was associated with ICH risk in people of Chinese Han ethnicity. However, when combined with previous published studies, a significant association of C677T polymorphism with an increased risk of ICH was detected in Chinese populations, and also in the subgroup analysis focusing on Han ethnicity. PMID:26757363

  13. Lack of association between MTHFR C677T polymorphism and breast cancer risk in Ahvaz, west south-Iran

    PubMed Central

    Mohammadzadeh, Ghorban; Karimi, Maryam; Bazyar, Mohammad; Hosseini, Seyed-Mohammad

    2016-01-01

    Background: Association between C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR), a key enzyme involved in folate metabolism and DNA methylation, and breast cancer risk are inconsistent. We investigated in a case-control study, possible effect of the common MTHFR C677T polymorphism on breast cancer risk in a sample of Iranian patients. Materials and Methods: The study subjects comprised of 123 breast cancer cases and 110 cancer-free control, who were matched for age and body mass index (BMI). C677T genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Lipid profile was measured in all subjects by standard method. Results: The genotypes distributions (CC, CT, and TT) were 55.3, 39, and 5.7% in breast cancer cases and 51.8, 44.5, and 3.6% in controls. Chi square analysis revealed that there was no significant association between breast cancer risk and MTHFR genotypes and alleles. Additionally, no significant association was observed between C677T genotypes and biochemistry parameters. A multinomial logistic regression model with MTHFR genotypes, lipid profiles, BMI and age as covariates revealed that there is no significant association between MTHFR genotypes and risk of breast cancer, but higher values of LDL and HDL significantly increase risk of breast cancer. Conclusions: Our findings do not support the hypothesis that genetic variation in the MTHFR C677T polymorphism is implicated in the breast cancer risk in a sample of Iranian patients. PMID:27014653

  14. Association of polymorphisms in one-carbon metabolism genes and postmenopausal breast cancer incidence.

    PubMed

    Stevens, Victoria L; McCullough, Marjorie L; Pavluck, Alexandre L; Talbot, Jeffrey T; Feigelson, Heather S; Thun, Michael J; Calle, Eugenia E

    2007-06-01

    The interconversion of folates by the one-carbon metabolism pathway is essential for the synthesis of precursors used in DNA synthesis, repair, and methylation. Perturbations in this pathway can disrupt these processes and are hypothesized to facilitate carcinogenesis. We investigated associations of 25 candidate polymorphisms in nine one-carbon metabolism genes with risk of postmenopausal breast cancer using 502 cases and 505 controls from the Cancer Prevention II Nutrition Cohort. Four single nucleotide polymorphisms (SNP) in three different genes were significantly associated with breast cancer. The nonsynonymous R134K SNP in methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthase [MTHFD1; odds ratio (OR), 1.40; 95% confidence interval (95% CI), 1.06-1.85 for CT + TT] and an intronic SNP in formyltetrahydrofolate dehydrogenase (FTHFD; OR, 2.23; 95% CI, 1.09-4.54 for CC) were associated with a significant increase in risk. Significantly decreased risk was associated with an intronic SNP in FTHFD (OR, 0.75; 95% CI, 0.58-0.98 for CT + CC) and the A360A SNP in cystathionine beta-synthase (CBS; OR, 0.63; 95% CI, 0.41-0.96 for TT). The presence of at least one variant from both the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C SNPs was also associated with increased risk (OR, 2.16; 95% CI, 1.34-3.48 for 677 CT + TT/1,298 AC + CC). Investigations into interactions of the associated SNPs with each other and with dietary factors yielded inconclusive results. Our findings indicate that genetic variation in multiple one-carbon metabolism genes may influence risk of postmenopausal breast cancer and may involve changes in methyl donor synthesis. However, larger studies are needed to further examine gene/gene and gene/diet interactions in this pathway. PMID:17548676

  15. Genetic polymorphisms and cerebrovascular disease in children with sickle cell anemia from Rio de Janeiro, Brazil.

    PubMed

    Filho, Isaac Lima da Silva; Leite, Ana Claudia Celestino Bezerra; Moura, Patrícia Gomes; Ribeiro, Georgina Severo; Cavalcante, Andréa Cony; Azevedo, Flávia Carolina Marques de; Andrada-Serpa, Maria José de

    2011-06-01

    The aim of the present work was to examine possible genetic risk factors related to the occurrence of cerebrovascular disease (CVD) in Brazilian population, the frequency of β(S)-globin gene haplotypes and co-inheritance with α-thalassemia (-α(3.7kb)) and single nucleotide polymorphism of methylenetetrahydrofolate reductase (MTHFR-C677T), Factor V Leiden (FV-G1691A) and prothrombin (PT-G20210A) genes in children from Rio de Janeiro. Ninety four children with sickle cell anemia (SCA) were included, 24 patients with cerebrovascular involvement and 70 patients without CVD as control group. The mean age of children at the time of the cerebrovascular event was similar to the control group. The frequency of -α(3.7kb) thalassemia was similar in both groups (p=0.751). Children with Bantu/Atypical β(S)-globin gene haplotype presented 15 times more chance (OR=15.4 CI 95% 2.9-81.6) of CVD than the other β(S)-globin gene haplotypes. The C677T polymorphism of MTHFR gene was similar in both groups (p=0.085). No mutation in the FV Leiden or PT genes was found. A large study seems necessary to establish the role of these genetic polymorphisms in Brazilian miscegenated population. PMID:21755116

  16. Dietary consumption of B vitamins, maternal MTHFR polymorphisms and risk for spontaneous abortion

    PubMed Central

    Rodríguez-Guillén, María del Rosario; Torres-Sánchez, Luisa; Chen, Jia; Galván-Portillo, Marcia; Silva-Zolezzi, Irma; Blanco-Muñoz, Julia; Hernández-Valero, María A.; López-Carrillo, Lizbeth

    2010-01-01

    Objective To asses he association between intake of folate and B vitamins and the incidence of spontaneous abortion (SA) according to the maternal methylenetetrahydrofolate reductase (MTHFR) polymorphisms (677 C>T and 1298 A>C). Material and Methods We conducted a nested case-control study within a perinatal cohort of women recruited in the state of Morelos, Mexico. Twenty-three women with SA were compared to 74 women whose pregnancy survived beyond week 20th. Intake of folate and B vitamins respectively, was estimated using a validated food frequency questionnaire. Maternal MTHFR polymorphisms were determined by PCR-RFLP and serum homocysteine levels by HPLC. Results Carriers of MTHFR 677TT and 1298AC genotypes respectively showed an increased risk of SA (OR 677TT vs. CC/CT=5.0; 95% CI: 1.2, 20.9 and OR 1298 AC vs. AA=5.5; 95% CI: 1.1, 26.6). Conclusions Our results support the role of MTHFR polymorphisms as a risk factor for SA, regardless of dietary intake of B vitamins. PMID:19180309

  17. Association between the MTHFR C677T gene polymorphism and essential hypertension in South West Cameroon.

    PubMed

    Ghogomu, S M; Ngolle, N E; Mouliom, R N; Asa, B F

    2016-01-01

    The association of the methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism and essential hypertension has been reported but with controversial results in diverse populations in Asia and Europe, thereby suggesting a dependency on ethnicity. The aim of this study was to investigate the association between the MTHFR C677T polymorphism and essential hypertension in a Cameroonian population (Bantu ethnic group) of the South West Region. Analysis of anthropometric and biochemical data in hypertensive and normotensive subjects revealed that age, systolic blood pressure, diastolic blood pressure, low-density lipoprotein cholesterol, serum total cholesterol, and triglycerides are independent risk factors for essential hypertension. Substitution of thymine for cytosine at position 667 of the MTHFR gene was determined by polymerase chain reaction-restriction fragment length polymorphism. Genotype frequencies were found to be 7.3% CC, 58.5% CT, and 34.1% TT for hypertensive subjects compared to 90.0% CC, 10.0% CT, and 0.0% TT for normotensives. Allele frequencies were obtained as 36.6% C and 63.4% T for hypertensive subjects and 95.0% C and 5.0% T for normotensive subjects. These results reveal that the T allele predisposes individuals to hypertension. Therefore, there is an association between variants of the MTHFR gene and hypertension in Cameroonian patients from the South West region. PMID:27051013

  18. Association of Hemostatic Gene Polymorphisms With Early-Onset Ischemic Heart Disease in Egyptian Patients.

    PubMed

    Alkhiary, Wael; Azzam, Hanan; Yossof, Mahmoud Mohammed Abdo; Aref, Salah; Othman, Maha; El-Sharawy, Solafa

    2016-09-01

    The association between hereditary thrombophilia and venous thrombosis is well established but controversial data exist with respect to arterial thrombosis. We performed a pilot study on 31 patients with acute myocardial infarction (AMI), 21 patients with unstable angina (UA), and 20 healthy volunteers to investigate the role of various hemostatic gene polymorphisms in young Egyptian patients, who survived their first ischemic heart disease (IHD). Thrombophilic gene polymorphisms were tested using multiplex polymerase chain reaction and reverse-hybridization technique. We showed an increased risk of AMI with factor V (FV) Leiden and prothrombin G20210A heterozygosity. The increased risks of UA was associated with GA and A allele of fibrinogen β-455G→A polymorphism. Conversely, factor XIII (FXIII) Val34Leu GT and T allele were protective in the UA group. Nevertheless, the prevalence of FV H1299R, plasminogen activator inhibitor 1 4G/5G, glycoprotein IIIa C1565T, 5,10-methylenetetrahydrofolate reductase C677T, and A1298C mutations did not differ between patients with IHD and controls. The data have clinical implications regarding screening and thromboprophylaxis in high-risk individuals younger than 40 years. PMID:25693916

  19. Homocysteine levels are associated with MTHFR A1298C polymorphism in Indian population.

    PubMed

    Kumar, Jitender; Das, Swapan K; Sharma, Priyanka; Karthikeyan, Ganesan; Ramakrishnan, Lakshmy; Sengupta, Shantanu

    2005-01-01

    An elevated level of homocysteine is an independent risk factor for cardiovascular diseases and is associated with other complex disorders. Homocysteine levels can be elevated due to dietary and/or genetic factors. A majority of Indian population have a low level of vitamin B12 (presumably due to vegetarian diet)--a critical nutritional factor, deficiency of which results in hyperhomocysteinemia. Hence, polymorphisms in the genes responsible for homocysteine metabolism can be perceived to have a greater impact in relation to hyperhomocysteinemia in Indian population. For this reason, the effects of diet and/or methylenetetrahydrofolate reductase (MTHFR) polymorphism were assessed in 200 individuals having varying homocysteine levels. Homocysteine levels were significantly elevated in individuals adhering to a vegetarian diet (P = 0.019) or having MTHFR A1298C polymorphism (P = 0.006). The minor allele frequency (MAF) of MTHFR C677T and A1298C was 0.15 and 0.44 respectively in this cohort. Since the MAF of these polymorphisms differed considerably from Caucasian and other Asian populations, frequencies of these polymorphisms were also determined in more than 400 individuals from different ethnic populations, selected from the entire country based on their geographical location and linguistic lineage, and was found to be similar to that of our cohort. The fact that MTHFR A1298C polymorphism is significantly associated with homocysteine levels, and that the CC genotype is present at a higher frequency in the Indian population, makes it extremely relevant in terms of its potential impact on hyperhomocysteinemia. PMID:16244782

  20. A 19-base pair deletion polymorphism in dihydrofolate reductase is associated with increased unmetabolized folic acid in plasma and decreased red blood cell folate

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Dihydrofolate reductase (DHFR) catalyzes the reduction of folic acid to tetrahydrofolate (THF). A 19-bp noncoding deletion allele maps to intron 1, beginning 60 bases from the splice donor site, and has been implicated in neural tube defects and cancer, presumably by influencing folate metabolism. T...

  1. 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

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

    2015-01-01

    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

  2. Homocysteine Metabolism Gene Polymorphisms (MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) Jointly Elevate the Risk of Folate Deficiency

    PubMed Central

    Li, Wen-Xing; Dai, Shao-Xing; Zheng, Jun-Juan; Liu, Jia-Qian; Huang, Jing-Fei

    2015-01-01

    Folate deficiency is strongly associated with cardiovascular disease. We aimed to explore the joint effect of the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, methionine synthase (MTR) A2756G, and methionine synthase reductase (MTRR) A66G polymorphisms on folate deficiency in a Chinese hypertensive population. A total of 480 subjects aged 28–75 were enrolled in this study from September 2005–December 2005 from six hospitals in different Chinese regions. Known genotypes were detected by PCR-RFLP methods and serum folate was measured by chemiluminescence immunoassay. Our results showed that MTHFR 677TT and MTR 2756AG + GG were independently associated with a higher risk of folate deficiency (TT vs. CC + CT, p < 0.001 and AG + GG vs. AA p = 0.030, respectively). However, the MTHFR A1298C mutation may confer protection by elevating the serum folate level (p = 0.025). Furthermore, patients carrying two or more risk genotypes showed higher odds of folate deficiency than null risk genotype carriers, especially those carrying four risk genotypes. These findings were verified by generalized multifactor dimensionality reduction (p = 0.0107) and a cumulative effects model (p = 0.001). The results of this study have shown that interactions among homocysteine metabolism gene polymorphisms lead to dramatic elevations in the folate deficiency risk. PMID:26266420

  3. Homocysteine Metabolism Gene Polymorphisms (MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) Jointly Elevate the Risk of Folate Deficiency.

    PubMed

    Li, Wen-Xing; Dai, Shao-Xing; Zheng, Jun-Juan; Liu, Jia-Qian; Huang, Jing-Fei

    2015-08-01

    Folate deficiency is strongly associated with cardiovascular disease. We aimed to explore the joint effect of the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, methionine synthase (MTR) A2756G, and methionine synthase reductase (MTRR) A66G polymorphisms on folate deficiency in a Chinese hypertensive population. A total of 480 subjects aged 28-75 were enrolled in this study from September 2005-December 2005 from six hospitals in different Chinese regions. Known genotypes were detected by PCR-RFLP methods and serum folate was measured by chemiluminescence immunoassay. Our results showed that MTHFR 677TT and MTR 2756AG + GG were independently associated with a higher risk of folate deficiency (TT vs. CC + CT, p < 0.001 and AG + GG vs. AA p = 0.030, respectively). However, the MTHFR A1298C mutation may confer protection by elevating the serum folate level (p = 0.025). Furthermore, patients carrying two or more risk genotypes showed higher odds of folate deficiency than null risk genotype carriers, especially those carrying four risk genotypes. These findings were verified by generalized multifactor dimensionality reduction (p = 0.0107) and a cumulative effects model (p = 0.001). The results of this study have shown that interactions among homocysteine metabolism gene polymorphisms lead to dramatic elevations in the folate deficiency risk. PMID:26266420

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

    PubMed Central

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

    2014-01-01

    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

  5. Association between the thrombophilic polymorphisms MTHFR C677T, Factor V Leiden, and prothrombin G20210A and recurrent miscarriage in Brazilian women.

    PubMed

    Gonçalves, R O; Fraga, L R; Santos, W V B; Carvalho, A F L; Veloso Cerqueira, B A V; Sarno, M; Toralles, M B P; Vieira, M J; Dutra, C G; Schüler-Faccini, L; Sanseverino, M T V; Gonçalves, M S; Vianna, F S L; Costa, O L N

    2016-01-01

    Some cases of recurrent first trimester miscarriage have a thrombotic etiology. The aim of this study was to investigate the prevalence of the most common thrombophilic mutations - factor V (FV) Leiden G1691A (FVL), prothrombin (FII) G20210A, and methylenetetrahydrofolate reductase (MTHFR) C677T - in women with recurrent miscarriages. In this case-control study, we included 137 women with two or more consecutive first-trimester miscarriages (£12 weeks of gestation) and 100 healthy women with no history of pregnancy loss, and with at least one living child. DNA was extracted from the patient samples, and the relevant genes (FVL, FII, and MTHFR) were amplified by PCR, followed by restriction fragment length polymorphism, to assess the polymorphisms in these genes. The allelic frequencies of polymorphisms were not significantly different between the case and control groups. Polymorphisms in the MTHFR, FVL, and FII genes were not associated with recurrent miscarriage during the first trimester of pregnancy in Brazilian women (P = 0.479; P = 0.491 and P = 0.107, respectively). However, the etiologic identification of genetic factors is important for genetic counseling. PMID:27525841

  6. MTHFR C677T and A1298C polymorphisms as predictors of radiotherapy response in head and neck squamous cell carcinoma.

    PubMed

    Anders, Q S; Stur, E; Agostini, L P; Garcia, F M; Reis, R S; Santos, J A; Mendes, S O; Maia, L L; Peterle, G T; Stange, V; Carvalho, M B; Tajara, E H; Santos, M; Silva-Conforti, A M A; Louro, I D

    2015-01-01

    The C677T and A1298C polymorphisms in methylene-tetrahydrofolate reductase (MTHFR), which regulates the release of active folate in the body, may have reduced activity. Given that folate participates in important intracellular pathways, such as nucleotide synthesis and biomolecule methylation, it seems plausible that patients with head and neck squamous cell carcinoma (HNSCC) may respond differently to radiotherapy treatments, based on genetic polymor-phisms. Therefore, this study sought to understand the role of these polymorphisms in HNSCC patient radiotherapy response. Genotypes were detected by PCR-RFLP after extraction of DNA from peripheral blood lymphocytes. Survival curves were analyzed by the Kaplan- Meier model, and significant differences were analyzed by the Wil-coxon test. Response to radiotherapy in patients with laryngeal SCC was significantly associated with the MTHFR C677T polymorphism (P = 0.030). Indeed, the presence of at least one T allele decreases the mortality rate up to 3-fold. Therefore, we propose that MTHFR C677T may represent a putative biomarker for radiotherapy prognosis in la-ryngeal SCC patients. PMID:26535623

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

    PubMed Central

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

    2015-01-01

    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

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

    NASA Astrophysics Data System (ADS)

    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

    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.

  9. Dietary intake of folate and co-factors in folate metabolism, MTHFR polymorphisms, and reduced rectal cancer.

    PubMed

    Murtaugh, Maureen A; Curtin, Karen; Sweeney, Carol; Wolff, Roger K; Holubkov, Richard; Caan, Bette J; Slattery, Martha L

    2007-03-01

    Little is known about the contribution of polymorphisms in the methylenetetrahydrofolate reductase gene (MTHFR) and the folate metabolism pathway in rectal cancer alone. Data were from participants in a case-control study conducted in Northern California and Utah (751 cases and 979 controls). We examined independent associations and interactions of folate, B vitamins, methionine, alcohol, and MTHFR polymorphisms (MTHFR C677T and A1298C) with rectal cancer. Dietary folate intake was associated with a reduction in rectal cancer OR 0.66, 95% CI 0.48-0.92 (>475 mcg day compared to < or = 322 mcg) as was a combination of nutrient intakes contributing to higher methyl donor status (OR 0.79, 95% CI 0.66-0.95). Risk was reduced among women with the 677 TT genotype (OR 0.54, 95% CI 0.30-0.9), but not men (OR 1.11, 95% CI 0.70-1.76) and with the 1298 CC genotype in combined gender analysis (OR 0.67, 95% CI 0.46-0.98). These data are consistent with a protective effect of increasing dietary folate against rectal cancer and suggest a protective role of the MTHFR 677 TT genotype in women and 1298 CC in men and women. Folate intake, low methyl donor status, and MTHFR polymorphisms may play independent roles in the etiology of rectal cancer. PMID:17245555

  10. Folate and One-Carbon Metabolism Gene Polymorphisms and Their Associations With Oral Facial Clefts

    PubMed Central

    Boyles, Abee L.; Wilcox, Allen J.; Taylor, Jack A.; Meyer, Klaus; Fredriksen, Åse; Ueland, Per Magne; Drevon, Christian A.; Vollset, Stein Emil; Lie, Rolv Terje

    2008-01-01

    Folate metabolism plays a critical role in embryonic development. Prenatal folate supplementation reduces the risk of neural tube defects and probably oral facial clefts. Previous studies of related metabolic genes have associated polymorphisms in cystathionine-beta-synthase (CBS) and 5,10-methylenetetrahydrofolate reductase (MTHFR) with cleft risk. We explored associations between genes related to one-carbon metabolism and clefts in a Norwegian population-based study that included 362 families with cleft lip with or without cleft palate (CL/P) and 191 families with cleft palate only (CPO). We previously showed a 39% reduction in risk of CL/P with folic acid supplementation in this population. In the present study we genotyped 12 polymorphisms in nine genes related to one-carbon metabolism and looked for associations of clefting risk with fetal polymorphisms, maternal polymorphisms, as well as parent-of-origin effects, using combined likelihood-ratio tests (LRT). We also stratified by maternal periconceptional intake of folic acid (>400 μg) to explore gene-exposure interactions. We found a reduced risk of CL/P with mothers who carried the CBS C699T variant (rs234706); relative risk was 0.94 with one copy of the T allele (95% CI 0.63-1.4) and 0.50 (95% CI 0.26-0.96) with two copies (P = 0.008). We found no evidence of interaction of this variant with folate status. We saw no evidence of risk from the MTHFR C677T variant (rs1801133) either overall or after stratifying by maternal folate intake. No associations were found between any of the polymorphisms and CPO. Genetic variations in the nine metabolic genes examined here do not confer a substantial degree of risk for clefts. Published 2008 Wiley-Liss, Inc.† PMID:18203168

  11. Meta-analysis of the association of MTHFR polymorphisms with multiple myeloma risk.

    PubMed

    Ma, Li-Min; Ruan, Lin-Hai; Yang, Hai-Ping

    2015-01-01

    The association of methylenetetrahydrofolate reductase (MTHFR) polymorphisms with multiple myeloma (MM) risk has been explored, but the results remain controversial. Thus, a meta-analysis was performed to provide a comprehensively estimate. The case-control studies about MTHFR C677T and A1298C polymorphisms with MM risk were collected by searching PubMed, Elsevier, China National Knowledge Infrastructure and Wanfang Databases. Odds ratios (ORs) with 95% confidence intervals (CIs) were applied to assess the strength of association. Overall, no significant association was found between MTHFR A1298C polymorphism and MM risk under all four genetic models (AC vs. AA, OR = 0.99, 95%CI = 0.82-1.20; CC vs. AA, OR = 1.14, 95%CI = 0.77-1.68; recessive model, OR = 1.10, 95%CI = 0.76-1.59; dominant model, OR = 1.01, 95%CI = 0.84-1.22). The risk was also not significantly altered for C677T polymorphism and MM in overall comparisons (CT vs. CC, OR = 1.04, 95%CI = 0.93-1.17; TT vs. CC, OR = 1.16, 95%CI = 0.98-1.37; recessive model, OR = 1.13, 95%CI = 0.98-1.32; dominant model, OR = 1.07, 95%CI = 0.96-1.20). In subgroup analyses by ethnicity, no significant association was observed in both Caucasians and Asians. This meta-analysis suggested that MTHFR polymorphisms were not associated with MM risk. PMID:26022785

  12. Meta-analysis of the association of MTHFR polymorphisms with multiple myeloma risk

    PubMed Central

    Ma, Li-Min; Ruan, Lin-Hai; Yang, Hai-Ping

    2015-01-01

    The association of methylenetetrahydrofolate reductase (MTHFR) polymorphisms with multiple myeloma (MM) risk has been explored, but the results remain controversial. Thus, a meta-analysis was performed to provide a comprehensively estimate. The case-control studies about MTHFR C677T and A1298C polymorphisms with MM risk were collected by searching PubMed, Elsevier, China National Knowledge Infrastructure and Wanfang Databases. Odds ratios (ORs) with 95% confidence intervals (CIs) were applied to assess the strength of association. Overall, no significant association was found between MTHFR A1298C polymorphism and MM risk under all four genetic models (AC vs. AA, OR = 0.99, 95%CI = 0.82-1.20; CC vs. AA, OR = 1.14, 95%CI = 0.77-1.68; recessive model, OR = 1.10, 95%CI = 0.76-1.59; dominant model, OR = 1.01, 95%CI = 0.84-1.22). The risk was also not significantly altered for C677T polymorphism and MM in overall comparisons (CT vs. CC, OR = 1.04, 95%CI = 0.93-1.17; TT vs. CC, OR = 1.16, 95%CI = 0.98-1.37; recessive model, OR = 1.13, 95%CI = 0.98-1.32; dominant model, OR = 1.07, 95%CI = 0.96-1.20). In subgroup analyses by ethnicity, no significant association was observed in both Caucasians and Asians. This meta-analysis suggested that MTHFR polymorphisms were not associated with MM risk. PMID:26022785

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

    PubMed Central

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

    2015-01-01

    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

  14. Interaction of MTHFR C677T and A1298C, and MTR A2756G gene polymorphisms in breast cancer risk in a population in Northeast Brazil.

    PubMed

    de Cássia Carvalho Barbosa, Rita; da Costa, Débora Menezes; Cordeiro, Denise Ellen Francelino; Vieira, Ana Patricia Freitas; Rabenhorst, Silvia Helena Barem

    2012-11-01

    Polymorphisms in genes encoding enzymes of folate metabolism are a focus of breast cancer risk studies due of the role of these enzymes in DNA methylation, synthesis, and repair. MTHFR, encoding for 5,10-methylenetetrahydrofolate reductase, is one of the most studied genes in this regard, but findings are controversial, and the majority of studies have analyzed polymorphisms individually. In this case control study, we examined the combination of the polymorphisms MTHFR C677T and A1298C with MTR A2756G, where MTR, methionine synthase, is an important enzyme of the folate cycle in the methylation pathway. One hundred and forty-two patients with breast cancer and controls were included and the genotypes were determined using PCR-RFLP. In the population studied, individuals carrying the polymorphic allele in the heterozygous state for both enzymes, MTHFR C677T and MTR A2756G, had an increased risk [odds ratio, OR=2.77 (95% confidence interval, CI=1.19-6.52)] for disease, compared to those with the wild genotype. In addition, individuals carrying the MTR 2756 genotype AG had an increased risk when this was combined with the MTHFR 1298 genotype CC [OR=5.13 (95% CI=0.87-38.82)]. No significant results were found from the analyses associating the MTHFR C677T and A1298C genotypes. However, when stratifying the patients by age (50 years old as the cut-off), patients over 50 years old had greater risk, with the presence of both MTHFR polymorphisms in the heterozygous state [OR=5.33 (95% CI=1.42-21.03)]. This study points out the importance of the interactions between the MTHFR C677T, MTHFR A1298C and MTR A2756G polymorphisms, and also highlights the relevance of the MTR A2756G polymorphism and age in breast cancer risk. PMID:23155246

  15. Relationship between MTHFR C677T and A1298C gene polymorphisms and complications of type 2 diabetes mellitus in an Emirati population

    PubMed Central

    El Hajj Chehadeh, Sarah W.; Jelinek, Herbert F.; Al Mahmeed, Wael A.; Tay, Guan K.; Odama, Unini O.; Elghazali, Gehad E.B.; Al Safar, Habiba S.

    2016-01-01

    Purpose Type 2 diabetes mellitus (T2DM) is the most common form of diabetes with clinical consequences giving rise to chronic multiple organ complications. Methylenetetrahydrofolate reductase (MTHFR) polymorphisms are genetic variations that have been linked to T2DM, and micro/macrovascular complications. The link between MTHFR and T2DM however is strongly dependent on the ethnic group studied. The objective of this study was to investigate the possible association between two MTHFR polymorphisms (C677T and A1298C) and T2DM and specifically examine if there are any associations with clinical and demographic characteristics among patients in the United Arab Emirates (UAE). Methods The study included 169 T2DM patients and 209 healthy controls. Genomic DNA was isolated and genotyped using TaqMan real-Time PCR assays for the MTHFR C677T and A1298C polymorphisms. Results There were no significant differences in genotype and haplotype distributions observed between groups. A significant association was observed between the C677T polymorphism and history of cerebrovascular accident (CVA) (p = 0.0330), history of nephropathy (p = 0.0280) and levels of LDL cholesterol (p = 0.0409). Also, the A1298C polymorphism was associated with hypertriglyceridemia (p = 0.0305) in T2DM patients. Conclusion These findings demonstrate that the MTHFR gene polymorphisms are not related to T2DM in the Emirati population. However, these polymorphisms can be used as risk markers for CVA, nephropathy, high LDL cholesterol and triglycerides in T2DM patients and allow timely treatment. PMID:27222819

  16. Geographical and Ethnic Distributions of the MTHFR C677T, A1298C and MTRR A66G Gene Polymorphisms in Chinese Populations: A Meta-Analysis

    PubMed Central

    Zeng, Dingyuan

    2016-01-01

    Background The geographical and ethnic distributions of the polymorphic methylenetetrahydrofolate reductase (MTHFR) mutations (C677T and A1298C) and methionine synthase reductase (MTRR) mutation (A66G) remain heterogeneous in China. The goal of this study was to estimate the pooled frequencies of the alleles and associated genotypes of these gene polymorphisms among healthy populations in Mainland China. Objective and Methods We systematically reviewed published epidemiological studies on the distributions of 3 genetic variants in Chinese healthy populations living in Mainland China through a meta-analysis. The relevant electronic databases were searched. All of the raw data of the eligible citations were extracted. The frequency estimates were stratified by geography, ethnicity and sex. Results Sixty-six studies were identified with a total of 92277 study participants. The meta-analysis revealed that the frequencies of the MTHFR C677T, A1298C, and MTRR A66G gene polymorphisms varied significantly between different ethnic groups and along geographical gradients. The frequencies of the 677T allele and 677TT genotype increased along the southern-central-northern direction across Mainland China (all Pvalues≤0.001). The frequencies of the 1298C, 1298CC, 66G and 66GG genotypes decreased along the south-central-north direction across the country (all Pvalues≤0.001). Conclusions Our meta-analysis strongly indicates significant geographical and ethnic variations in the frequencies of the C677T, A1298C, and A66G gene polymorphisms in the folate metabolism pathway among Chinese populations. PMID:27089387

  17. Polymorphism in one-carbon metabolism pathway affects survival of gastric cancer patients: Large and comprehensive study.

    PubMed

    Zhao, Tingting; Gu, Dongying; Xu, Zhi; Huo, Xinying; Shen, Lili; Wang, Chun; Tang, Yongfei; Wu, Peng; He, Jason; Gong, Weida; He, Ming-Liang; Chen, Jinfei

    2015-04-20

    Although it has been shown that polymorphisms in one-carbon metabolism (OCM) pathway are associated with gastric cancer (GC), their interactions and contributions for patients' survival are elusive. In this study, we investigated the effects of polymorphisms and their interactions on the survival of GC patients, including genes of Methylenetetrahydrofolate reductase (MTHFR 677C > T, 1298A > C), Methionine synthase reductase (MTRR 66A > G), Methionine synthase (MTR 2756A > G), and Thymidylate synthase (TS 3'-UTR ins6 > del6, 5'-UTR 2R > 3R). We recruited 919 GC patients from 1998 to 2006. The Kaplan-Meier plots, Cox regression analyses and the log-rank tests were carried out in this study. MTHFR 1298CC genotype showed protective effect (HR = 0.444, 95% CI = 0.210-0.940). MTRR 66 GA + GG genotypes decreased the risk of death (HR = 0.793, 95% CI = 0.651-0.967) in general, and in subgroups with more pronounced diffuse type, greater depth of invasion (T2/T3/T4), higher level lymph node metastasis (N1/N2/N3), advanced TNM stages (II/III level) and 5-Fu treatment. However, the improved survival disappeared when GC patients simultaneously had MTR 2756 GA + GG genotypes (HR = 1.063, 95% CI = 0.750-1.507). Although MTRR 66GA genotype was not associated with the survival of GC patients, patients with simultaneous MTRR 66GA and MTR 2756AA genotypes exhibited significant risk reduction of death (HR = 0.773, 95% CI = 0.609-0.981). MTHFR 1298 CA + CC combined with TS 5-UTR 2R3R + 3R3R genotypes (HR = 0.536, 95% CI = 0.315-0.913) also increased patient survival rates. Our results suggest that the MTRR 66A > G and MTHFR 1298A > C polymorphisms may be useful prognostic biomarkers for GC patients. PMID:25840420

  18. Maternal folate, alcohol and energy metabolism-related gene polymorphisms and the risk of recurrent pregnancy loss.

    PubMed

    Sata, F; Yamada, H; Kishi, R; Minakami, H

    2012-10-01

    Epidemiological studies have suggested that the condition of recurrent pregnancy loss (RPL) may be multifactorial, with both genetic predisposition and environmental factors potentially involved in its pathogenesis. The aim of this study is to elucidate the associations between maternal folate, alcohol and energy metabolism-related gene polymorphisms and the risk of RPL. This case-control study, which involved 116 cases with two or more instances of RPL and 306 fertile controls, was performed in the city of Sapporo, Japan. The associations between eight single nucleotide polymorphisms of folate, alcohol and energy metabolism-related genes [methylenetetrahydrofolate reductase (MTHFR), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR), alcohol dehydrogenase 1B (ADH1B), aldehyde dehydrogenase 2 (ALDH2), beta-3-adrenergic receptor (ADRB3) and peroxisome proliferator-activated receptor gamma (PPARG)], and RPL were assessed. Without consideration of cigarette smoking or alcohol use, the risk of RPL significantly decreased in women with the MTHFR rs1801133 TT, MTR rs1805087 AG or ALDH2 rs671 AA genotype (P < 0.05). The risk of RPL associated with cigarette smoking and alcohol use decreased significantly in women carrying the MTHFR rs1801133 T allele [odds ratio (OR), 0.51; 95% confidence interval (CI), 0.27-0.95]. Similarly, the risk of RPL significantly decreased in women carrying the MTR rs1805087 G allele (OR, 0.44; 95% CI, 0.23-0.85). Our findings suggest that maternal gene polymorphisms related to folate metabolism may decrease the risk of RPL. Molecular epidemiological studies are needed to unequivocally elucidate the multifactorial effects of both genetic and environmental factors on human fecundity. PMID:25102261

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

    PubMed

    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

    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

  20. Thioredoxin reductase.

    PubMed

    Mustacich, D; Powis, G

    2000-02-15

    The mammalian thioredoxin reductases (TrxRs) are a family of selenium-containing pyridine nucleotide-disulphide oxidoreductases with mechanistic and sequence identity, including a conserved -Cys-Val-Asn-Val-Gly-Cys- redox catalytic site, to glutathione reductases. TrxRs catalyse the NADPH-dependent reduction of the redox protein thioredoxin (Trx), as well as of other endogenous and exogenous compounds. The broad substrate specificity of mammalian TrxRs is due to a second redox-active site, a C-terminal -Cys-SeCys- (where SeCys is selenocysteine), that is not found in glutathione reductase or Escherichia coli TrxR. There are currently two confirmed forms of mammalian TrxRs, TrxR1 and TrxR2, and it is possible that other forms will be identified. The availability of Se is a key factor determining TrxR activity both in cell culture and in vivo, and the mechanism(s) for the incorporation of Se into TrxRs, as well as the regulation of TrxR activity, have only recently begun to be investigated. The importance of Trx to many aspects of cell function make it likely that TrxRs also play a role in protection against oxidant injury, cell growth and transformation, and the recycling of ascorbate from its oxidized form. Since TrxRs are able to reduce a number of substrates other than Trx, it is likely that additional biological effects will be discovered for TrxR. Furthermore, inhibiting TrxR with drugs may lead to new treatments for human diseases such as cancer, AIDS and autoimmune diseases. PMID:10657232

  1. MTHFR polymorphisms, dietary folate intake, and breast cancer risk: results from the Shanghai Breast Cancer Study.

    PubMed

    Shrubsole, Martha J; Gao, Yu-Tang; Cai, Qiuyin; Shu, Xiao Ou; Dai, Qi; Hébert, James R; Jin, Fan; Zheng, Wei

    2004-02-01

    Folate plays an important role in DNA methylation, synthesis, and repair; intake has been associated with breast cancer. The folate-metabolizing enzyme, methylenetetrahydrofolate reductase (MTHFR) is polymorphic at nucleotides 677 (C-->T) and 1298 (A-->C), resulting in allozymes with decreased activity. We evaluated these two common polymorphisms and their effects on the folate intake and breast cancer risk association in a population-based case-control study of 1144 breast cancer cases and 1236 controls using a PCR-RFLP-based assay. All subjects completed in-person interviews, which included a food frequency questionnaire. Unconditional logistic regression models were used to calculate odds ratios and their 95% confidence intervals, after adjusting for potential confounding factors. Cases and controls were similar in the distribution of MTHFR polymorphisms at codons 677 (41.4% cases and 41.8% controls carried the T allele) and 1298 (17.6% cases and 17.5% controls carried the C allele). An inverse association of breast cancer risk with folate intake was observed in all genotype groups, particularly among subjects with the 677TT genotype. Compared with those with the 677CC genotype and high folate, the adjusted odds ratios (95% confidence intervals) associated with low folate intake were 1.94 (1.15-3.26), 2.17 (1.34-3.51), and 2.51 (1.37-4.60) for subjects who had CC, CT, and TT genotypes (p for interaction, 0.05). No modifying effect of A1298C genotypes on the association of folate intake with breast cancer risk was observed. Results of this study suggest that the MTHFR C677T polymorphisms may modify the association between dietary folate intake and breast cancer risk. PMID:14973091

  2. MTHFR genetic polymorphism as a risk factor in Egyptian mothers with Down syndrome children.

    PubMed

    Meguid, Nagwa A; Dardir, Ahmed A; Khass, Mohamed; Hossieny, Lamia El; Ezzat, Afaf; El Awady, Mostafa K

    2008-01-01

    Recent reports linking Down syndrome (DS) to maternal polymorphisms at the methylenetetrahydrofolate reductase (MTHFR) gene locus have generated great interest among investigators in the field. The present study aimed at evaluation of MTHFR 677C/T and 1298A/C polymorphisms in the MTHFR gene as maternal risk factors for DS. Forty two mothers of proven DS outcomes and forty eight control mothers with normal offspring were included. Complete medical and nutritional histories for all mothers were taken with special emphasis on folate intake. Folic acid intake from food or vitamin supplements was significantly low (below the Recommended Daily Allowance) in the group of case mothers compared to control mothers. Frequencies of MTHFR 677T and MTHFR 1298C alleles were significantly higher among case mothers (32.1% and 57.1%, respectively) compared to control mothers (18.7% and 32.3%, respectively). Heterozygous and homozygous genotype frequencies of MTHFR at position 677 (CT and TT) were higher among case mothers than controls (40.5% versus 25% and 11.9% versus 6.2%, respectively) with an odds ratio of 2.34 (95% confidence interval [CI] 0.93-5.89) and 2.75 (95% CI 0.95-12.77), respectively. Interestingly, the homozygous genotype frequency (CC) at position 1298 was significantly higher in case mothers than in controls (33.3% versus 2.1% respectively) with an odds ratio of 31.5 (95% CI 3.51 to 282.33) indicating that this polymorphism may have more genetic impact than 677 polymorphism. Heterozygous genotype (AC) did not show significant difference between the two groups. We here report on the first pilot study of the possible genetic association between DS and MTHFR 1298A/C genotypes among Egyptians. Further extended studies are recommended to confirm the present work. PMID:18057532

  3. Postgraduate Symposium: The MTHFR C677T polymorphism, B-vitamins and blood pressure.

    PubMed

    Wilson, C P; McNulty, H; Scott, J M; Strain, J J; Ward, M

    2010-02-01

    High blood pressure (BP) and elevated homocysteine are reported as independent risk factors for CVD and stroke in particular. The main genetic determinant of homocysteine concentrations is homozygosity (TT genotype) for the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene, typically found in approximately 10% of Western populations. The B-vitamins folate, vitamin B12 and vitamin B6 are the main nutritional determinants of homocysteine, with riboflavin more recently identified as a potent modulator specifically in individuals with the TT genotype. Although observational studies have reported associations between homocysteine and BP, B-vitamin intervention studies have shown little or no BP response despite decreases in homocysteine. Such studies, however, have not considered the MTHFR C677T polymorphism, which has been shown to be associated with BP. It has been shown for the first time that riboflavin is an important determinant of BP specifically in individuals with the TT genotype. Research generally suggests that 24 h ambulatory BP monitoring provides a more accurate measure of BP than casual measurements and its use in future studies may also provide important insights into the relationship between the MTHFR polymorphism and BP. Further research is also required to investigate the association between specific B-vitamins and BP in individuals with different MTHFR genotypes in order to confirm whether any genetic predisposition to hypertension is correctable by B-vitamin intervention. The present review will investigate the evidence linking the MTHFR C677T polymorphism to BP and the potential modulating role of B-vitamins. PMID:19954568

  4. Polymorphism of cytosolic serine hydroxymethyltransferase, estrogen and breast cancer risk among Chinese women in Taiwan.

    PubMed

    Cheng, Chun-Wen; Yu, Jyh-Cherng; Huang, Chiun-Sheng; Shieh, Jia-Ching; Fu, Yi-Ping; Wang, Hsiao-Wei; Wu, Pei-Ei; Shen, Chen-Yang

    2008-09-01

    Cytosolic serine hydroxymethyltransferase (cSHMT) is key to intersection of folate-metabolic pathway, participating in the pyrimidine synthesis for DNA repair. Based on the hypothesis that variants of the cSHMT C1420T together with methionine synthase (MS A2756G) and 5,10-methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) are associated with breast cancer, we performed a multigenic case-control study of the effects to breast cancer risk of four polymorphisms of folate-metabolizing genes against duration of estrogen exposure. Support of our hypothesis came from the following observations: (i) Allelic frequency of cSHMT C1420T was higher in the controls than in the cases, manifesting a 0.56-fold risk reduction in breast cancer (95%CI = 0.39-0.80); and this association was more significant in those women are susceptible to time of estrogen exposure. (ii) A joint effect of the cSHMT and MS polymorphisms significantly reduced susceptibility to breast cancer (aOR = 0.55; 95%CI = 0.34-0.88). (iii) There was a trend toward a reduced risk of breast cancer in women carrying a greater number of putative low-risk genotypes (Ptrend = 0.048). (iv) This synergistic effects on risk reduction was significantly interacted with length of estrogen exposure, exhibiting a longer time of estrogen exposure (> or =30 years), menarche-to-FFTP interval (>11 years), age at the first full-term pregnancy (< or =25 years), and body mass index (< or =24). In conclusion, our study provides support to account for the preferential role of cSHMT polymorphism to lower risk of female breast cancer, and such reduced risk would be more significant in carriers with the polymorphisms of MS and MTHFR genes. PMID:17896178

  5. Meta-analysis of associations between MTHFR and GST polymorphisms and susceptibility to multiple sclerosis.

    PubMed

    Lee, Young Ho; Seo, Young Ho; Kim, Jae-Hoon; Choi, Sung Jae; Ji, Jong Dae; Song, Gwan Gyu

    2015-11-01

    We examined whether methylenetetrahydrofolate reductase (MTHFR) and glutathione S-transferase (GST) polymorphisms are associated with susceptibility to multiple sclerosis (MS). We performed a meta-analysis on the association between MS and the following genotypes: MTHFR C677T, A1298C, and GSTP1 A313G polymorphisms, and GSTM1 and GSTT1 null alleles. Fifteen comparisons involving 2,486 patients and 2,861 controls were considered. Meta-analysis of all study subjects considered together showed no association between MS and the MTHFR 677 T allele (OR = 1.014, 95 % CI 0.803-1.280, p = 0.909). Stratification by ethnicity showed no similar association in Caucasian and Arab populations. Likewise, no link was found between MS and the MTHFR 1298 C allele in the total data (OR = 2.477, 95 % CI 0.507-12.10, p = 0.263), nor when it was stratified by ethnicity. No association with MS was observed in relation to the GSTM1 null genotype in Caucasian populations (OR = 1.229, 95 % CI 0.693-2.181, p = 0.481), nor with the GSTP1 A313G polymorphism (OR for G allele = 1.133, 95 % CI 0.903-1.421, p = 0.281). However, there was an association between MS and the GSTT1 null genotype in data obtained from Caucasian populations (OR = 1.945, 95 % CI 1.452-2.605, p = 8.6 × 10(-7)). GSTT1 null genotype is associated with MS in Caucasian populations; however, no association was found between MS and polymorphisms of MTHFR, GSTM1, and GSTP1. PMID:26150166

  6. Association of MTHFR A1298C polymorphism with conotruncal heart disease.

    PubMed

    Sayin Kocakap, Beyza D; Sanli, Cihat; Cabuk, Feryal; Koc, Murat; Kutsal, Ali

    2015-10-01

    Congenital heart diseases are common congenital anomalies with 1% prevalence worldwide and are associated with significant childhood morbidity and mortality. Among a wide range of aetiologically heterogeneous conditions, conotruncal anomalies account for approximately one-third of all congenital heart defects. The aetiology of conotruncal heart diseases is complex, with both environmental and genetic causes. Hyperhomocysteinaemia, which is often accompanied by the defects of folic acid metabolism, is known to cause conotruncal heart anomalies. In this study, we have evaluated three polymorphisms in the following two hyperhomocysteinaemia-related genes: methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) and nicotinamide N-methyl transferase (NNMT rs694539) in 79 children with conotruncal heart disease and 99 children without conotruncal heart disease. Genotype distribution of the MTHFR A1298C polymorphism showed a statistically significant difference between the two groups. In the case group, AC and CC genotypes were higher than the control group (p<0.05). We have found that MTHFR A1298C polymorphism is associated with conotruncal heart disease; C allele (p=0.028), AC (OR[95% CI]=2.48[1.24-4.95], p=0.010), CC (OR[95% CI]=3.01[1.16-7.83], p=0.023), and AC+CC (OR[95% CI]=2.60[1.36-4.99], p=0.004) genotypes are more frequent in the patient group. Genotype distributions of the MTHFR C677T and NNMT rs694539 polymorphisms were similar in the two groups when evaluated separately and also according to the dominant genetic model (p>0.05). Our results suggest that MTHFR 1298C allele is a risk factor for conotruncal heart disease. PMID:25547204

  7. 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

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

    2012-01-01

    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…

  8. Role of MTHFR C677T gene polymorphism in the susceptibility of schizophrenia: An updated meta-analysis.

    PubMed

    Yadav, Upendra; Kumar, Pradeep; Gupta, Sanjay; Rai, Vandana

    2016-04-01

    Methylenetetrahydrofolate reductase (MTHFR) is the key enzyme of folate/homocysteine metabolic pathway. C677T polymorphism of MTHFR gene was reported as risk factor for congenital defects, metabolic and neuropsychiatric disorders. Numerous case-control studies investigated C677T polymorphism as risk factor for schizophrenia but results of these studies were contradictory. To draw a conclusion, a meta-analysis of all available case-control studies was performed. PubMed, Google Scholar, Springer Link and Elsevier databases were searched for eligible case-control studies. Pooled odds ratio with 95%CI was used as an association measure and all statistical analyses were performed by Open Meta-Analyst and MIX software. Total 38 studies with 10,069 cases and 13,372 controls were included in the present meta-analysis. Results of meta-analysis showed significant associated between C677T polymorphism and risk of schizophrenia (ORTvsC=1.18, 95%CI=1.10-1.27, p=<0.001; ORCTvsCC=1.10, 95%CI=1.04-1.17, p=<0.001; ORTTvsCC=1.40, 95%CI=1.20-1.64, p=<0.001; ORTT+CTvsCC=1.19, 95%CI=1.09-1.30, p=<0.001). We also performed subgroup and sensitivity analyses. Subgroup analysis was done according to ethnicity and significant association was found between C677T polymorphism and risk of schizophrenia in all three ethnic populations-African (OR=2.51; 95%CI=1.86-3.40; p=<0.001), Asian (OR=1.21; 95%CI=1.10-1.33; p=<0.001) and Caucasian (OR=1.07; 95%CI=1.01-1.14; p=0.01). In conclusion the results of the present meta-analysis suggested that the MTHFR C677T polymorphism is a risk factor for schizophrenia. PMID:27025471

  9. MTHFR C677T and A1298C polymorphisms and risk of lung cancer: a comprehensive evaluation.

    PubMed

    Yang, Y; Yang, L J; Deng, M Z; Luo, Y Y; Wu, S; Xiong, L; Wang, D; Liu, Y; Liu, H

    2016-01-01

    Results from previous studies on the association between methylenetetrahydrofolate reductase (MTHFR) polymorphisms C677T and A1298C and lung cancer have been conflicting. The aim of this meta-analysis was to clarify the effect of MTHFR polymorphisms on the risk of lung cancer. An electronic search of PubMed, EMBASE, the Cochrane library, and the China Knowledge Resource Integrated Database for papers on C677T and A1298C and susceptibility to lung cancer was performed. The STATA software (Version 13.0) was used for statistical analysis. Statistical heterogeneity, tests of publication bias, and a sensitivity analysis were performed. Twenty-six studies on C677T (12,324 cases and 12,532 controls) and thirteen studies on A1298C (6773 cases and 8207 controls) were included in the meta-analysis. The MTHFR C677T polymorphism showed significant pooled ORs for the homozygote comparison (TT versus CC: OR = 1.518, 95%CI = 1.220-1.890), heterozygote comparison (CT versus CC: OR = 1.053, 95%CI = 0.940-1.179), dominant model (CT + TT versus CC: OR = 1.143, 95%CI = 1.013-1.291), recessive model (TT versus CT + CC: OR = 1.435, 95%CI = 1.190-1.730), and additive model (T versus C: OR = 1.176, 95%CI = 1.066-1.298). In summary, our meta-analysis showed that the MTHFR C677T polymorphism is associated with a significant increase in lung cancer risk in Asian and overall populations, but not in Caucasian populations. However, no significant association between the MTHFR A1298C polymorphism and lung cancer risk was found in either the Caucasian or Asian group with any genetic models. PMID:27173216

  10. Short Communication: Lack of association between MTHFR gene polymorphisms and response to methotrexate treatment in Pakistani patients with rheumatoid arthritis.

    PubMed

    Iqbal, Mohammad Perwaiz; Ali, Azra Arif; Mehboobali, Naseema; Iqbal, Khalida

    2015-09-01

    Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms have been reported to be associated with response to methotrexate (MTX) in certain populations of patients with rheumatoid arthritis (RA). This study aims at investigating any relationship of two single nucleotide polymorphisms (SNPs) in MTHFR gene, C677T and A1298C with response to therapy with MTX in Pakistani RA patients. Allelic frequencies of the two polymorphisms (C677T and A1298C) were determined in 67 RA patients (9 males and 58 females; mean age 42.87 ± 13.5 years) who had previously participated in a prospective clinical trial. Fifty-one patients had received MTX and were followed up for response up to 6 months. Genotyping of the two MTHFR polymorphisms was carried out using PCR-RFLP, while fasting concentration of plasma homocysteine was determined using a kit method. Twenty-eight patients were found to be "good responders", while twenty-three were "poor responders". MTHFR 1298C and MTHFR 677T alleles' frequencies in "good responders" were not different from frequencies in "poor responders" (0.574 vs. 0.521; p=0.6 and 0.197 vs. 0.196; p=0.75, respectively). Plasma homocysteine levels in female RA patients were significantly higher compared to general population in Karachi (13.1 ± 6.7 µmol/l vs. 11.4 ± 5.3 µmol/l; p<0.001). MTHFR C677T and A1298C polymorphisms are not associated with response to MTX in a population of Pakistani RA patients. PMID:26408898