Association of MTHFD1 G1958A (rs2236225) gene polymorphism with the risk of congenital heart disease: a systematic review and meta-analysis.

Background: We did this study to better clarify the correlations of methylenetetrahydrofolate dehydrogenase 1 (MTHFD1)-G1958A (rs2236225) gene polymorphism with the risk of congenital heart diseases (CHD) and its subgroups.

Methods: Relevant articles were searched in PubMed, Web of Science, Cochrane Library, Embase, CNKI, VIP database and Wanfang DATA until October 2023. We will use odds ratios (ORs) and 95% confidence intervals (CIs) to examine the potential associations of MTHFD1- G1958A gene polymorphism with CHD and its subgroups.

Results: We included a total of 9 eligible studies, encompassing 1917 children with CHD, 1863 healthy children, 1717 mothers of the children with CHD and 1666 mothers of healthy children. In our study, the meta-analysis of fetal group revealed no significant association between any of the five genetic models for the MTHFD1-G1958A polymorphism and the risk of CHD. Subgroup analysis showed that associations between the MTHFD1-G1958A polymorphism and Tetralogy of Fallot (TOF) risk in the homozygote model (AA vs. GG, OR = 2.82, 95%CI [1.16, 6.86], P = 0.02) and recessive model (AA vs. GG + GA, OR = 3.09, 95%CI [1.36, 7.03], P = 0.007). In addition, the MTHFD1-G1958A polymorphism was associated with the risk of CHD in racial subgroup, increasing the risk of CHD in Caucasians. In maternal analysis, 2 genetic models of MTHFD1-G1958A polymorphism increased the risk of CHD: the heterozygote model (GA vs. GG, OR = 1.22, 95%CI [1.04, 1.42], P = 0.01), and the dominance model (GA + AA vs. GG, OR = 1.17, 95%CI [1.01, 1.34], P = 0.03).

Conclusions: The fetal MTHFD1-G1958A (rs2236225) gene polymorphism increase their risk of TOF. The maternal MTHFD1-G1958A polymorphism has a strong correlation with the risk of CHD, and there are racial differences in this correlation. Compared with GG genotype, the GA genotype increases the risk of CHD.