Abstract
ObjectivesThe methylenetetrahydrofolate dehydrogenase (MTHFD1) gene, as one of the key genes involved in the folate pathway, has been reported to play a critical role in the pathogenesis of neural tube defects (NTDs). However, the results of published studies are contradictory and inconclusive. Thus, this meta-analysis aimed to evaluate the effect of the common polymorphism in the MTHFD1 gene, the G1958A (R653Q, dbSNP ID: rs2236225) variant, on the risk of NTDs in all eligible studies.MethodsRelevant literature published before January 3, 2014 was retrieved from the MEDLINE, EMBASE, Cochrane Library, and CBM databases. Pooled crude odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were calculated to evaluate the association between the MTHFD1 G1958A polymorphism and NTDs risk.ResultsWe performed a meta-analysis of nine studies with a total of 4,302 NTDs patients and 4,238 healthy controls. Our results demonstrated a significant correlation between the MTHFD1 G1958A polymorphism and NTDs in an overall meta-analysis. For family-based studies, the study subjects were classified as NTD cases, mothers with NTDs offspring, and fathers with NTDs offspring. We found no association between any of the fathers’ genotypes and NTDs, whereas there was a clear excess of the 1958A allele in the mothers of children with NTDs compared with controls individuals.ConclusionsIn summary, our meta-analysis strongly suggests that the MTHFD1 G1958A polymorphism might be associated with maternal risk for NTDs in Caucasian populations. However, the evidence of this association should be interpreted with caution due to the selective nature of publication of genetic association studies.
Highlights
Neural tube defects (NTDs) are among the most common congenital malformations at birth and present as a wide range of phenotypes, primarily including anencephaly, spina bifida and encephalocele [1]
After removing duplicate records (n = 23) and articles without full texts (n = 10), 115 titles and abstract were reviewed; of these, 99 articles were excluded for the following reasons: 55 were not case-control studies, 16 were not relevant to NTDs, and 28 were not relevant to the MTHFD1 G1958A polymorphism
Five studies investigated the association of the MTHFD1 G1958A polymorphism in NTDs cases [16,17,18,19,29], five in mothers with NTDs offspring [16,17,18,19,29] and four in fathers with NTDs offspring [16,17,18,29]
Summary
Neural tube defects (NTDs) are among the most common congenital malformations at birth and present as a wide range of phenotypes, primarily including anencephaly, spina bifida and encephalocele [1]. Epidemiological studies have revealed that periconceptional vitamin supplementation with folic acid substantially lowers the percentage of women with NTD-affected pregnancies [4,5], which has led to intense research on the genetic variants of enzymes involved in the folate metabolic pathway. It is hypothesized that polymorphisms within folate-dependent enzymes might have an impact on NTDs risk, the exact mechanism of these genetic factors has not been completely elucidated. Numerous investigations of genes that are involved in folate metabolism have identified at least one polymorphism, C677T (A222V; dbSNP ID: rs1801133) in the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene, that may be associated with an approximately doubled risk of NTDs [6,7,8,9,10]. The presence of this principal MTHFR variant does not appear to account for a large proportion of the etiologic factors for NTDs [12], indicating that besides MTHFR, additional folate-related genes are likely to be involved
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