Dataset Information

Association between C677T polymorphism of methylene tetrahydrofolate reductase and congenital heart disease: meta-analysis of 7697 cases and 13,125 controls.

ABSTRACT: BACKGROUND:Association between the C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene and congenital heart disease (CHD) is contentious. METHODS AND RESULTS:We compared genotypes between CHD cases and controls and between mothers of CHD cases and controls. We placed our results in context by conducting meta-analyses of previously published studies. Among 5814 cases with primary genotype data and 10 056 controls, there was no evidence of association between MTHFR C677T genotype and CHD risk (odds ratio [OR], 0.96 [95% confidence interval, 0.87-1.07]). A random-effects meta-analysis of all studies (involving 7697 cases and 13 125 controls) suggested the presence of association (OR, 1.25 [95% confidence interval, 1.03-1.51]; P=0.022) but with substantial heterogeneity among contributing studies (I(2)=64.4%) and evidence of publication bias. Meta-analysis of large studies only (defined by a variance of the log OR <0.05), which together contributed 83% of all cases, yielded no evidence of association (OR, 0.97 [95% confidence interval, 0.91-1.03]) without significant heterogeneity (I(2)=0). Moreover, meta-analysis of 1781 mothers of CHD cases (829 of whom were genotyped in this study) and 19 861 controls revealed no evidence of association between maternal C677T genotype and risk of CHD in offspring (OR, 1.13 [95% confidence interval, 0.87-1.47]). There was no significant association between MTHFR genotype and CHD risk in large studies from regions with different levels of dietary folate. CONCLUSIONS:The MTHFR C677T polymorphism, which directly influences plasma folate levels, is not associated with CHD risk. Publication biases appear to substantially contaminate the literature with regard to this genetic association.

SUBMITTER: Mamasoula C

PROVIDER: S-EPMC3855044 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Association between C677T polymorphism of methylene tetrahydrofolate reductase and congenital heart disease: meta-analysis of 7697 cases and 13,125 controls.

Mamasoula Chrysovalanto C Prentice R Reid RR Pierscionek Tomasz T Pangilinan Faith F Mills James L JL Druschel Charlotte C Pass Kenneth K Russell Mark W MW Hall Darroch D Töpf Ana A Brown Danielle L DL Zelenika Diana D Bentham Jamie J Cosgrove Catherine C Bhattacharya Shoumo S Riveron Javier Granados JG Setchfield Kerry K Brook J David JD Bu'Lock Frances A FA Thornborough Chris C Rahman Thahira J TJ Doza Julian Palomino JP Tan Huay L HL O'Sullivan John J Stuart A Graham AG Blue Gillian G Winlaw David D Postma Alex V AV Mulder Barbara J M BJ Zwinderman Aelko H AH van Engelen Klaartje K Moorman Antoon F M AF Rauch Anita A Gewillig Marc M Breckpot Jeroen J Devriendt Koen K Lathrop G Mark GM Farrall Martin M Goodship Judith A JA Cordell Heather J HJ Brody Lawrence C LC Keavney Bernard D BD

Circulation. Cardiovascular genetics 20130722 4

<h4>Background</h4>Association between the C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene and congenital heart disease (CHD) is contentious.<h4>Methods and results</h4>We compared genotypes between CHD cases and controls and between mothers of CHD cases and controls. We placed our results in context by conducting meta-analyses of previously published studies. Among 5814 cases with primary genotype data and 10 056 controls, there was no evidence of association between ...[more]

PMID: 23876493

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Project description:RationaleEnvironmental exposures strongly influence the development and progression of asthma. We have previously demonstrated that mice exposed to a diet enriched with methyl donors during vulnerable periods of fetal development can enhance the heritable risk of allergic airway disease through epigenetic changes. There is conflicting evidence on the role of folate (one of the primary methyl donors) in modifying allergic airway disease.ObjectivesWe hypothesized that blocking folate metabolism through the loss of methylene-tetrahydrofolate reductase (Mthfr) activity would reduce the allergic airway disease phenotype through epigenetic mechanisms.MethodsAllergic airway disease was induced in C57BL/6 and C57BL/6Mthfr-/- mice through house dust mite (HDM) exposure. Airway inflammation and airway hyperresponsiveness (AHR) were measured between the two groups. Gene expression and methylation profiles were generated for whole lung tissue. Disease and molecular outcomes were evaluated in C57BL/6 and C57BL/6Mthfr-/- mice supplemented with betaine.Measurements and main resultsLoss of Mthfr alters single carbon metabolite levels in the lung and serum including elevated homocysteine and cystathionine and reduced methionine. HDM-treated C57BL/6Mthfr-/- mice demonstrated significantly less airway hyperreactivity (AHR) compared to HDM-treated C57BL/6 mice. Furthermore, HDM-treated C57BL/6Mthfr-/- mice compared to HDM-treated C57BL/6 mice have reduced whole lung lavage (WLL) cellularity, eosinophilia, and Il-4/Il-5 cytokine concentrations. Betaine supplementation reversed parts of the HDM-induced allergic airway disease that are modified by Mthfr loss. 737 genes are differentially expressed and 146 regions are differentially methylated in lung tissue from HDM-treated C57BL/6Mthfr-/- mice and HDM-treated C57BL/6 mice. Additionally, analysis of methylation/expression relationships identified 503 significant correlations.ConclusionCollectively, these findings indicate that the loss of folate as a methyl donor is a modifier of allergic airway disease, and that epigenetic and expression changes correlate with this modification. Further investigation into the mechanisms that drive this observation is warranted.

Project description:Background: The relationship between methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C polymorphism with the risk of intracerebral hemorrhage (ICH) has remained to be controversial in recent years. This meta-analysis is aimed to confirm the association of these. Methods: Systematically searching the related studies from the PubMed, Embase, Cochrane Library, China national knowledge internet database from 1 January 1990 to 1 June 2022. The odd ratio (ORs) and 95% confidence interval (CIs) of gene-disease correlation in various gene models were calculated by fixed or random effect model of meta-analysis. We included 20 case-control studies in this meta-analysis with a total of 1,989 ICH patients and 4,032 health controls originated from Asian, Caucasian, and African populations. Results: The statistical analysis demonstrated the association of MTHFR C677T gene polymorphism with ICH in allele model [ORT VS. C = 1.20 (95%CI: 1.06-1.36)]; homozygote model [OR TT VS. CC = 1.50 (95%CI: 1.20-1.88)]; dominant model [OR CT+ TT VS. CC = 1.23 (95%CI: 1.03-1.48)] and recessive model [ORTT VS. CT+CC = 1.37 (95%CI: 1.17-1.60)]. Besides, we also found the relationship of MTHFR C677T gene polymorphism with Asian in four comparison model (ORT VS. C = 1.19.95%CI:1.09-1.37, ORTT VS. CC = 1.46.95%CI: 1.15-1.85, OR CT+ TT VS. CC = 1.25.95%CI: 1.01-1.54, ORTT VS. CT+CC = 1.34.95%CI: 1.54-1.17) and Caucasian in four comparison model (ORT VS. C = 1.90.95%CI: 1.22-2.97, ORTT VS. CC = 2.67.95%CI: 1.42-5.00, OR CT+ TT VS. CC = 1.56.95%CI: 1.05-2.32, ORTT VS. CT+CC = 2.25.95%CI: 1.46-4.00). But no statistically significant correlation between A1298C polymorphism and the occurrence of ICH was detected in four studies. Conclusion: MTHFR C677T gene polymorphism increases the risk of ICH in Asian and Caucasian populations but has no impact on the incidence in African communities. More importantly, the risk of ICH increases in TT genotype individuals in comparison to CT and CC genotype individuals in Asian and Caucasian populations.

Project description:BackgroundMethylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the metabolism of folate. The non-synonymous single nucleotide polymorphism (nsSNP), C677T (Ala>Val, rs1801133), has been verified to impair enzyme activity. The association with cancer susceptibility, including hepatocellular carcinoma (HCC), has also been widely studied. The results, however, were inconsistent. To shed light on the influence of MTHFR C677T polymorphism on HCC, a meta-analysis was conducted.MethodsThe meta-analysis of C677T consisted of 10 studies (1814 cases/2862 controls). The association was measured by using random-effect (RE) or fixed-effect (FE) odds ratio (OR) combined with 95% confidence intervals (CIs) according to the studies' heterogeneity.ResultsUsing genetic model analysis, C677T polymorphism was found to increase the risk of HCC in a complete overdominant model, which indicates that heterozygotes CT are at a lesser risk of HCC than either homozygotes CC or TT. Meta-analyses of the 10 studies showed that the TT genotype increased the risk of HCC as compared to the CT genotype: FE OR was 1.20 (95%CI: 1.00-1.45, p for heterogeneity = 0.21). When subgroup analysis was done between the HCC cases and the chronic liver disease (CLD) patients of four studies, meta-analysis showed that individuals with the TT genotype had increased HCC risk compared with those with the CT genotype: FE OR (TT vs. CT) reached 1.81 (1.22-2.71, p for heterogeneity = 0.25). Meanwhile, the C677T polymorphism also increased HCC risk in a recessive model when cases were compared to CLD patients of four studies: RE OR reached 1.85 (95%CI: 1.00-3.42, p for heterogeneity = 0.06). Overall, there was some extent heterogeneity when analyses were performed in various models. There was no publication bias.ConclusionMTHFR C677T polymorphism increased the risk of HCC in an overdominant model, and might be a risk factor for HCC occurrence, especially in CLD patients. The association warranted further studies.

Dataset Information

Association between C677T polymorphism of methylene tetrahydrofolate reductase and congenital heart disease: meta-analysis of 7697 cases and 13,125 controls.

Publications

Association between C677T polymorphism of methylene tetrahydrofolate reductase and congenital heart disease: meta-analysis of 7697 cases and 13,125 controls.

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