Paternal genetic variants and risk of obstructive heart defects: A parent-of-origin approach

Abstract

Previous research on risk factors for obstructive heart defects (OHDs) focused on maternal and infant genetic variants, prenatal environmental exposures, and their potential interaction effects. Less is known about the role of paternal genetic variants or environmental exposures and risk of OHDs. We examined parent-of-origin effects in transmission of alleles in the folate, homocysteine, or transsulfuration pathway genes on OHD occurrence in offspring. We used data on 569 families of liveborn infants with OHDs born between October 1997 and August 2008 from the National Birth Defects Prevention Study to conduct a family-based case-only study. Maternal, paternal, and infant DNA were genotyped using an Illumina Golden Gate custom single nucleotide polymorphism (SNP) panel. Relative risks (RR), 95% confidence interval (CI), and likelihood ratio tests from log-linear models were used to estimate the parent-of-origin effect of 877 SNPs in 60 candidate genes in the folate, homocysteine, and transsulfuration pathways on the risk of OHDs. Bonferroni correction was applied for multiple testing. We identified 3 SNPs in the transsulfuration pathway and 1 SNP in the folate pathway that were statistically significant after Bonferroni correction. Among infants who inherited paternally-derived copies of the G allele for rs6812588 in the RFC1 gene, the G allele for rs1762430 in the MGMT gene, and the A allele for rs9296695 and rs4712023 in the GSTA3 gene, RRs for OHD were 0.11 (95% CI: 0.04, 0.29, P = 9.16x10^-7), 0.30 (95% CI: 0.17, 0.53, P = 9.80x10^-6), 0.34 (95% CI: 0.20, 0.57, P = 2.28x10^-5), and 0.34 (95% CI: 0.20, 0.58, P = 3.77x10^-5), respectively, compared to infants who inherited maternally-derived copies of the same alleles. We observed statistically significant decreased risk of OHDs among infants who inherited paternal gene variants involved in folate and transsulfuration pathways. Obstructive heart defects are birth defects that cause obstruction to the blood flow of the developing heart. Common OHDs include coarctation of the aorta, aortic stenosis and pulmonary stenosis. While there is a fair amount of literature indicating an association between maternal genetic variants and OHDs, less is known about the role of paternal genetic variants in the etiology of OHDs. We used a genotype clustering algorithm, SNPMClust, that was developed in-house at the Arkansas Center for Birth Defects Research and Prevention to study the role of paternal genetic variants in the folate, homocysteine and transsulfuration pathways. Maternal, paternal, and infant DNA specimens were collected from participants of the National Birth Defects Prevention Study, a large population-based case-control study in the United States, and were genotyped using an Illumina Golden Gate custom single nucleotide polymorphism (SNP) panel. We identified 4 SNPs in the folate and transsulfuration pathways, rs6812588, rs1762430, rs9296695, and rs4712023, that were associated with a statistically significant decreased risk of OHDs for infants who inherited a paternally-derived copy of the variant allele compared to infants who inherited a maternal copy of the variant allele. In conclusion, we observed a significantly decreased risk and less epigenetic influence of paternal genetic variants on OHDs compared to maternally-derived variants.