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.

Keywords: congenital heart defects; folate supplementation; genetic risk factors; methylene-tetrahydrofolate dehydrogenase 1.

Figure 1

The folate metabolic pathways. Blue ellipses, enzymes; green rectangles, metabolites; written in red, names of genes selected for genotype analysis; underlined, genes that showed a significant association with certain types of CHD (contruncal, septal, and LVOTO). ABCB1, P-glycoprotein; ABCC3, multidrug resistant protein 3; SLC19A1; solute-carrier family 19; FPGS, folypolyglutamyl synthase; FOLglu, polyglutamylated folic acid; DHF, dihydrofolate; DHFR, dihydrofolate reductase; THF, tetrahydrofolate; MTHFD1, trifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase/synthase; 10-CHO-THF, 10-formyl tetrahydrofolate; 5,10 = CH-THF, methenyl tetrahydrofolate; 5,10-CH2 = THF, methylene tetrahydrofolate; 5-CH3-THF, 5-methyl tetrahydrofolate; MTR, 5-methyl tetrahydrofolate-homocysteine methyltransferase; MTRR, 5-methyl tetrahydrofolate-homocysteine methyltransferase reductase; MAT2A, methionine adenosyltransferase II alpha; SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine; GNMT, glycine N-methyltransferase; DNMT3B, DNA (cytosine-5-)-methyltransferase 3 beta; ACHYL1, S-adenosylhomocysteine hydrolase-like 1; BHMT, betaine-homocysteine S-methyltransferase; diMeGly, dimethylglycine; Me, methyl; LVOTO, left ventricular outflow tract obstruction; CHD, congenital heart defect.

Figure 2

Incidence of CHD in the subgroups of the children, according to MTHFD1 genotype and maternal folate supplementation in early pregnancy. The highest incidence of CHD (91.7%) was seen for the MTHFD1 rs2236225 GG children whose mothers did not take any folate supplements. In contrast, the lowest incidences (~44%) were seen for the children of mothers who started folate intake early, irrespective of the MTHFD1 genotype, and in the MTHFD1 AG/AA children of mothers who started folate intake later than 3 weeks post conception.