Association between MTHFD1 polymorphisms and neural tube defect susceptibility

Objectives: Neural tube defect (NTD) is a common disease among neonates with multiplex symptom and complex origins, and the exact mechanism of NTD has not been definitely elucidated. Nevertheless, it is hypothesized that NTD risk can be prevented by periconceptional folic acid in folate metabolism. The methylenetetrahydrofolate dehydrogenase (MTHFD1) gene has been proved to play an important role in folate metabolism, which was strongly associated with the high risk for NTD. We focused on three folate metabolism-related single-nucleotide polymorphisms (SNPs) on the MTHFD1 gene to evaluate the associations between MTHFD1 polymorphisms and NTD susceptibility. Methods: We genotyped blood samples from 222 specimens (including 122 NTD-affected infants and 100 healthy controls) in a case-control study. We investigated the association between NTD and three selected tag-SNPs on MTHFD1 gene: 401A>G (rs1950902), 2305C>T (rs17857382) and 1958G>A (rs2236225) by the SNapShot method. These SNPs were identified by Haploview 42 software with HapMap databases, and then these associations were evaluated by the Mann-Whitney test, one-way analysis of variance (ANOVA) and chi-square test. Furthermore, a meta-analysis of the association between MTHFD1 1958G>A and NTD risk was also performed. Results: In our study, an increased risk of NTD was observed for 1958G>A of MTHFD1 (AA vs. GG: OR = 2.63,95% CI = 2.61-5.70; AA vs. GG + GA: OR = 2.10,95% CI = 1.07-4.14; A vs. G: OR = 1.62, 95% CI = 1.11-2.36). However, the other two SNPs (401A>G and 2305C>T) displayed no statistically significant association with NTD risk. The overall result of the meta-analysis indicated that the 1958G>A variant might not be a genetic susceptible factor for the Caucasian population. Conclusions: Our analysis implicated that MTHFD1 1958G>A was significantly associated with the susceptibility of NTD in a Chinese population. In addition, the AA homozygote carriers were more likely to suffer NTD, compared with the others with GA or GG genotypes. Validation of the risk effect and functional impact of this polymorphism is needed in future investigations. (C) 2014 Elsevier B.V. All rights reserved.