23059056

PMC3523122

Background

The development of non-syndromic congenital heart defects (CHDs) involves a complex interplay of genetics, metabolism, and lifestyle. Previous studies have implicated maternal single nucleotide polymorphisms (SNPs) and altered metabolism in folate-related pathways as CHD risk factors.

Objective

We sought to discover associations between maternal SNPs and metabolites involved in the homocysteine, folate, and transsulfuration pathways, and determine if these associations differ between CHD cases and controls.

Design

Genetic, metabolic, demographic, and lifestyle information was available for 335 mothers with CHD-affected pregnancies and 263 mothers with unaffected pregnancies. Analysis was conducted on 1160 SNPs, 13 plasma metabolites, and 2 metabolite ratios. A two-stage multiple linear regression was fitted to each combination of SNP and metabolite/ratio.

Results

We identified 4 SNPs in the methionine adenosyltransferase II alpha (MAT2A) gene that were associated with methionine levels. Three SNPs in tRNA aspartic acid methyltransferase 1 (TRDMT1) gene were associated with total plasma folate levels. Glutamylcysteine (GluCys) levels were associated with multiple SNPs within the glutathione peroxidase 6 (GPX6) and O-6-methylguanine-DNA methyltransferase (MGMT) genes. The regression model revealed interactions between genotype and case-control status in the association of total plasma folate, total glutathione (GSH), and free GSH, to SNPs within the MGMT, 5,10-methenyltetrahydrofolate synthetase (MTHFS), and catalase (CAT) genes, respectively.

Conclusions

Our study provides further evidence that genetic variation within folate-related pathways accounts for inter-individual variability in key metabolites. We identified specific SNP-metabolite relationships that differed in mothers with CHD-affected pregnancies, compared to controls. Our results underscore the importance of multifactorial studies to define maternal CHD risk.

CDC Public Access

2R01HD039054-11A1/HD/NICHD NIH HHS/United States
5U01 DD000491-04/DD/NCBDD CDC HHS/United States
R01 HD039054/HD/NICHD NIH HHS/United States