Abstract
Conotruncal heart defects (CTDs) are among the most severe birth defects worldwide. Studies of CTDs indicate both lifestyle behaviors and genetic variation contribute to the risk of CTDs. Based on a hybrid design using data from 616 case-parental and 1645 control-parental triads recruited for the National Birth Defects Prevention Study between 1997 and 2008, we investigated whether the occurrence of CTDs is associated with interactions between 921 maternal and/or fetal single nucleotide polymorphisms (SNPs) and maternal obesity and tobacco use. The maternal genotypes of the variants in the glutamate-cysteine ligase, catalytic subunit (GCLC) gene and the fetal genotypes of the variants in the glutathione S-transferase alpha 3 (GSTA3) gene were associated with an elevated risk of CTDs among obese mothers. The risk of delivering infants with CTDs among obese mothers carrying AC genotype for a variant in the GCLC gene (rs6458939) was 2.00 times the risk among those carrying CC genotype (95% confidence interval: 1.41, 2.38). The maternal genotypes of several variants in the glutathione-S-transferase (GST) family of genes and the fetal genotypes of the variants in the GCLC gene interacted with tobacco exposures to increase the risk of CTDs. Our study suggests that the genetic basis underlying susceptibility of the developing heart to the adverse effects of maternal obesity and tobacco use involve both maternal and embryonic genetic variants. These results may provide insights into the underlying pathophysiology of CTDs, and ultimately lead to novel prevention strategies.
Highlights
Congenital heart defects (CHDs) are among the most common and severe birth defects worldwide, with reported estimated prevalence of 9.1 per 1,000 live births after 1995 [1]
Hobbs et al [9] identified the maternal genotypes of 17 single nucleotide polymorphisms (SNPs) and the fetal genotypes of 17 SNPs associated with Conotruncal heart defects (CTDs) risks independently from interactions with maternal folic acid supplement use, obesity and tobacco use
The maternal genotypes of 10 SNPs and the fetal genotypes of 2 SNPs in the glutamate-cysteine ligase, catalytic subunit (GCLC) gene were found to be significantly associated with the risk of CTDs through main genetic effects [9]
Summary
Congenital heart defects (CHDs) are among the most common and severe birth defects worldwide, with reported estimated prevalence of 9.1 per 1,000 live births after 1995 [1]. Nonsyndromic CTDs are due to a multifactorial etiology involving a complex interplay between genetic susceptibilities and environmental factors [2,3]. One such interplay is between maternal folic acid supplement use and genetic variants in folate-related pathways. It has been reported that genetic variants in folate-related pathways modify the association between birth defects and maternal intake of folic acid containing supplements [9] Based on the finding that maternal periconceptional folic acid intake decreases the occurrence of CTDs [4,5], multiple studies have investigated associations between CTDs and polymorphisms in folate-related genes [6,7,8].
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