Recent experimental studies showed that ablation of the aryl hydrocarbon receptor (AhR) as well as its activation by exogenous ligands disrupt the molecular networks involved in heart formation and function, leading to congenital heart disease (CHD). However, no evidence is available about the role of AhR in humans. We assessed the prevalence of a functional AhR genetic variant (p.Arg554Lys) in CHD patients as well as its joint effects with parental exposure. A total of 128 CHD patients (76 males; age 6.2 ± 6.7 years) and 274 controls (160 males; age at birth) were genotyped for the AhR polymorphism by using the TaqMan® Drug Metabolism Genotyping assay. Both case and control parents completed a structured questionnaire on demographic, lifestyle and preconception exposures. Genotype (p = 0.001) and allele (p < 0.0001) distributions of AhR p.Arg554Lys differed significantly between patients and controls. A significant elevated CHD risk was found under dominant (OR = 2.9, 95% CI 1.9-4.6, p < 0.0001) and additive genetic models (OR = 6.2, 95% CI 2-19, p = 0.001). There was a significant interaction between 554-Lys allele and paternal smoking exposure (ORsmoking = 1.6, 95% CI = 0.9-2.9; ORallele = 2.6, 95% CI = 1.3-5; ORinteraction = 4.9, 95% CI = 2.4-9.9, p interaction < 0.0001). Additionally, 554-Lys allele exacerbated the effect of maternal periconceptional exposure (ORexposure = 1.6, 95% CI = 0.8-3; ORallele = 2.6, 95% CI = 1.5-4.5; ORinteraction = 5.7; 95% CI = 2.6-12, p interaction < 0.0001). Our findings showed that the AhR p.Arg554Lys polymorphism, alone and in combination with parental exposures, is associated with the CHD risk, highlighting the significant role of AhR in the cardiovascular development.
Keywords: Aryl hydrocarbon receptor; Congenital heart disease; Periconceptional exposure; Polymorphism.