Maternal Obesity and Tobacco Use Modify the Impact of Genetic Variants on the Occurrence of Conotruncal Heart Defects

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.

Maternal Body Mass Index and Risk of Congenital Heart Defects in Infants: A Dose-Response Meta-Analysis

“…Data from epidemiology research suggest that folate, glutathione, and homocysteine metabolism related genetic variants in maternal and fetal may have great impact on the heart development [57]. It had been reported that obesity mothers who carried mutant genotype AC for glutamate-cysteine ligase, catalytic subunit ( GCLC ) gene (rs6458939) significantly increased the risk of conotruncal defects (CTDs) in infants, compared with those obesity mothers who carried the CC genotype [58]. Another possible mechanism is that maternal metabolic environment plays an important role in fetal developments [59].…”

Genetics of congenital heart disease

“…Tobacco smoke and maternal obesity were recently evaluated as environmental exposures interacting with both maternal and fetal variants of 60 genes involved in metabolic pathways associated with CTDs (folate, homocysteine, and trans-sulfuration) [18]. No SNP was associated with risk of CTD in the absence of tobacco exposure, and no protective SNP was identified.…”

Genetics of Congenital Heart Disease

“…In isolation, these results offer an unclear image of the biological impact of harboring any given CNV and, therefore, limit genotype-phenotype associations and predictions. Tobacco smoke and maternal obesity were recently evaluated as environmental exposures interacting with both maternal and fetal variants of 60 genes involved in metabolic pathways associated with CTDs (folate, homocysteine, and trans-sulfuration) [18]. No SNP was associated with risk of CTD in the absence of tobacco exposure, and no protective SNP was identified.…”