Genetic Variants in the Folate Pathway and the Risk of Neural Tube Defects: A Meta-Analysis of the Published Literature

<div><p>Background</p><p>Neural Tube Defects (NTDs) are among the most prevalent and most severe congenital malformations worldwide. Polymorphisms in key genes involving the folate pathway have been reported to be associated with the risk of NTDs. However, the results from these published studies are conflicting. We surveyed the literature (1996–2011) and performed a comprehensive meta-analysis to provide empirical evidence on the association.</p> <p>Methods and Findings</p><p>We investigated the effects of 5 genetic variants from 47 study populations, for a total of 85 case-control comparisons <i>MTHFR</i> C677T (42 studies; 4374 cases, 7232 controls), <i>MTHFR</i> A1298C (22 studies; 2602 cases, 4070 controls), <i>MTR</i> A2756G (9 studies; 843 cases, 1006 controls), <i>MTRR</i> A66G (8 studies; 703 cases, 1572 controls), and <i>RFC-1</i> A80G (4 studies; 1107 cases, 1585 controls). We found a convincing evidence of dominant effects of <i>MTHFR</i> C677T (OR 1.23; 95%CI 1.07–1.42) and suggestive evidence of <i>RFC-1</i> A80G (OR 1.55; 95%CI 1.24–1.92). However, we found no significant effects of <i>MTHFR</i> A1298C, <i>MTR</i> A2756G, <i>MTRR</i> A66G in risk of NTDs in dominant, recessive or in allelic models.</p> <p>Conclusions</p><p>Our meta-analysis strongly suggested a significant association of the variant <i>MTHFR</i> C677T and a suggestive association of <i>RFC-1</i> A80G with increased risk of NTDs. However, other variants involved in folate pathway do not demonstrate any evidence for a significant marginal association on susceptibility to NTDs.</p> </div

Simplified overview of folate metabolism pathway, highlighting enzymes with polymorphisms investigated in this study.

<p>MTHFR, methylene tetrahydrofolate reductase; MTR, methionine synthase; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine; MTRR, methionine synthase reductase; THF, tetrahydrofolate. RFC, the reduced folate carrier.</p

Pooled frequencies of the <i>MTHFR</i> C677T alleles and <i>MTHFR</i> A1298C alleles in controls stratified by ethnicity.

<p>Native A, Native America.</p

Stratified analysis of the association between <i>MTHFR</i> C677T polymorphism and Neural Tube Defects in dominant model.

a<p>Number of studies.</p>b<p>Genotyping including PCR-DHPLC, Dideoxy fingerprinting, Sequenom-based Mass Array assay and Melting Curve Analysis. NR, Not reported.</p

The cumulative forest plot of OR with 95%CI for <i>MTHFR</i> C677T polymorphism, <i>MTHFR</i> A1298C and Neural tube defects risk in dominant model.

<p>The cumulative forest plot of OR with 95%CI for <i>MTHFR</i> C677T polymorphism, <i>MTHFR</i> A1298C and Neural tube defects risk in dominant model.</p

Sensitive analysis of pooled OR for Genetic polymorphisms in MTHFR in the folate pathway.

<p>Sensitive analysis of pooled OR for Genetic polymorphisms in MTHFR in the folate pathway.</p

The overall forest plot of OR with 95%CI for <i>MTR</i> A2756G, <i>MTRR</i> A66G and <i>RFC-1</i> A80G polymorphism and Neural tube defects risk in dominant model.

<p>The overall forest plot of OR with 95%CI for <i>MTR</i> A2756G, <i>MTRR</i> A66G and <i>RFC-1</i> A80G polymorphism and Neural tube defects risk in dominant model.</p

Summarized odds ratios with confidence intervals of stratified studies for <i>MTHFR A1298C</i> polymorphism.

a<p>Number of studies.</p>b<p>Other genotyping including PCR-DHPLC, Sequenom-based Mass ARRAY assay and Dideoxy fingerprinting.</p

Flow chart of the literature search.

<p>Flow chart of the literature search.</p

The funnel plot of natural logarithm of OR against inverse standard error in each study.

<p>The funnel plot of natural logarithm of OR against inverse standard error in each study.</p