A Three-Way Interaction among Maternal and Fetal Variants Contributing to Congenital Heart Defects

Abstract

SUMMARY Congenital heart defects (CHDs) develop through a complex interplay between genetic variants, epigenetic modifications and maternal environmental exposures. Genetic studies of CHDs have commonly tested single genetic variants for association with CHDs. Less attention has been given to complex gene-by-gene and gene-by-environment interactions. In this study, we applied a recently developed likelihood-ratio Mann-Whitney (LRMW) method to detect joint actions among maternal variants, fetal variants and maternal environmental exposures, allowing for high-order statistical interactions. All subjects are participants from the National Birth Defect Prevention Study, including 623 mother-offspring pairs with CHD-affected pregnancies and 875 mother-offspring pairs with unaffected pregnancies. Each individual has 872 single nucleotide polymorphisms encoding for critical enzymes in the homocysteine, folate, and transsulfuration pathways. By using the LRMW method, three variants (fetal rs625879, maternal rs2169650 and maternal rs8177441) were identified with a joint association to CHD risk (nominal P-value=1.13e-07). These 3 variants are located within gene BHMT2, GSTP1 and GPX3, respectively. Further examination indicated that maternal SNP rs2169650 may interact with both fetal SNP rs625879 and maternal SNP rs8177441. Our findings suggest that the risk of CHD may be influenced by both the intra-generational interaction within the maternal genome and the inter-generational interaction between maternal and fetal genomes.

1-CMDb: A Curated Database of Genomic Variations of the One-Carbon Metabolism Pathway

“…The folate cycle is involved in the synthesis of thymidine nucleotides and integrates DNA methylation and methionine synthesis. Polymorphisms in the multiple genes involved in the one-carbon pathway and their associations have been studied [16][17][18] . Folate supply activated onecarbon units required in nucleic acid biosynthesis, mitochondrial and chloroplast protein biosynthesis, amino acid metabolism, methyl group biogenesis, and vitamin metabolism [19] .…”

A missense mutation in TCN2 is associated with decreased risk for congenital heart defects and may increase cellular uptake of vitamin B12 via Megalin

“…Therefore, not only the TCN2 230T allele in mother's side could elevate plasma holo-TC, but also babies with TCN2 230T allele could be further benefited as probably more VB12 is transported across the yolk sac and placenta into the developing fetus. Since the maternal and fetal genes could interact each other to influence the phenotypes of mothers and babies [ 57 ], it is necessary to investigate the interaction of c.230A>T in the mother and offspring and other non-genetic factors in association with CHD risk in the future. However, the transporting processes of maternal-embryonic VB12 are still poorly understood.…”

Epigenetics and Congenital Heart Diseases

“…Folate deficiency has a direct impact on genetic regulation, as evidenced by the global hypomethylation levels observed in offspring of folate-deficient mothers [ 81 ]. Similarly, hypomorphic polymorphisms in folate-cycle enzymes such as MTHFR (methylenetetrahydrofolate reductase) [ 82 ] or MTRR have been established as risk factors for cardiac defects, and directly linked to DNA methylation levels [ 83 ]. Conversely, maternal supplementation with polyvitamins in the periconceptional period effectively rescues this phenotype, with an estimated drop in fetal risk of 30% [ 84 ].…”