A Common Polymorphism in the MTHFD1 Gene Is a Modulator of Risk of Congenital Heart Disease

Abstract

Several environmental and genetic factors may influence the risk of congenital heart defects (CHDs), which can have a substantial impact on pediatric morbidity and mortality. We investigated the association of polymorphisms in the genes of the folate and methionine pathways with CHDs using different strategies: a case–control, mother–child pair design, and a family-based association study. The polymorphism rs2236225 in the MTHFD1 was confirmed as an important modulator of CHD risk in both, whereas polymorphisms in MTRR, FPGS, and SLC19A1 were identified as risk factors in only one of the models. A strong synergistic effect on the development of CHDs was detected for MTHFD1 polymorphism and a lack of maternal folate supplementation during early pregnancy. A common polymorphism in the MTHFD1 is a genetic risk factor for the development of CHD, especially in the absence of folate supplementation in early pregnancy.

Association of Maternal Folate Intake and Offspring MTHFD1 and MTHFD2 Genes with Congenital Heart Disease

“…This study also examined the interaction between folic acid intake and the rs828858 locus of the MTHFD2 gene in relation to the occurrence of CHD. Previous research demonstrated a strong synergistic effect between the MTHFD1 gene and maternal FAS on CHD [ 53 ]. Previous studies using hen models indicated that folic acid deficiency in hens could significantly increase MTHFD2 gene expression in their offspring, suggesting a potential correlation between maternal FAS and MTHFD2 gene expression in offspring [ 54 ].…”

Reply to F.I. Mulder et al

“…We have used this and other preliminary cutoffs in the past with good results. [3][4][5] Finally, the Hosmer-Lemeshow test was used to assess the correct calibration of the models, and in the case of ONCOTHROMB, x 2 was 7.3167, with the DF of 8 and P 5 .5029.…”