MTHFD1 gene polymorphisms as risk factors involved in orofacial cleft: an independent case-control study and a...

Orofacial clefts (OFCs) were among the most familiar birth defects in the world, which had been reported to be influenced by the folic acid ingestion in pregnancy previously. Methylenetetrahydrofolate dehydrogenase1 (MTHFD1) gene was associated with the susceptibility of OFCs through a complex metabolism correlate with folic acid. The aim of our study was to evaluate the correlation of five single-nucleotide polymorphisms (SNPs) within MTHFD1 related to the OFCs risk in a Chinese population.

By the use of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), we genotyped 5 filtered SNPs (identified by Haploview 4.2 software with HapMap databases) on MTHFD1 gene: 118913T>C, 31136A>G, 58893A>G, 1958G>A and 61869T>C of 216 subjects (108 OFCs cases and 108 healthy controls) from a Chinese population. The association between these SNPs and OFCs risk was investigated by student t-test, one-way analysis of variance (ANOVA) and chi-square test with GraphPad Prism 5.0 software. Furthermore, we also performed a meta-analysis of relevant studies to investigate the association between MTHFD1 1958G>A and the susceptibility of OFCs.

Through the genotyping, the AA genotype was found significantly correlated with the susceptibility of OFCs compared with other SNPs on MTHFD1, yielding an OR of 2.71 (95% CI = 1.12-6.58, P = 0.025) under the homozygous model and an OR of 2.37 (95% CI = 1.06-5.30, P = 0.033) under the recessive model. While other selected SNPs 118913T>C and 31136A>G were also associated with an increased OFC risk, the results were not statistically significant (all P > 0.05). However, the overall result of meta-analysis did not support the conclusion that the 1958G>A variant could be a genetic susceptible factor for OFCs (A allele vs. G allele: OR = 1.02, 95% CI = 0.85-1.23, AA vs. GG: OR = 1.06, 95% CI = 0.69-1.63, GA vs. GG: OR = 1.02, 95% CI = 0.81-1.27, AA vs. GG+GA: OR = 0.94, 95% CI = 0.61-1.46, AA+GA vs. GG: OR = 0.94, 95% CI = 0.74-1.19).

The MTHFD1 1958G>A variant was significantly associated with the increased OFCs risk in Chinese population. However, this association was not supported by meta-analysis of all relevant studies. Further investigations about functional impact of this polymorphism were needed.