A Functional Aryl Hydrocarbon Receptor Genetic Variant, Alone and in Combination with Parental Exposure, is a Risk Factor for Congenital Heart Disease
CARDIOVASCULAR TOXICOLOGY
Authors: Pulignani, Silvia; Borghini, Andrea; Vecoli, Cecilia; Foffa, Ilenia; Ait-Ali, Lamia; Andreassi, Maria Grazia
Abstract
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(A (R)) 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.
Associations of Polymorphic Variants of the Biotransformation Genes with the Components of the Glutathione System in Men with Infertility
INTERNATIONAL JOURNAL OF BIOMEDICINE
Authors: Kurashova, N. A.; Dolgikh, M. I.; Ershova, O. A.; Gavrilova, O. A.; Osipova, E. V.; Dashiev, B. G.; Bairova, T. A.; Kolesnikov, S. I.; Kolesnikov, L. I.
Abstract
The aim of this research was to investigate the glutathione system components and their association with polymorphisms GST genes in men with infertility. Materials and Methods: One hundred and sixty Russian men of reproductive age (Caucasians) who came to the public health institution Republican Perinatal Center in Ulan-Ude with an infertility problem of one year and more after marriage were included in the main group. The control group included 104 men with proven fertility. DNA samples were genotyped for polymorphisms in GSTP1, GSTT1 and GSTM1genes and activity of glutathione system enzymes was determined. Results: The most informative genetic and metabolic indicators in Caucasian males with infertility were combinations of the null genotypes GSTT1(*0/*0)+GSTM1(*0/*0) associated with a decrease of GST activity in blood and ejaculate and an increase of GSH and GPO in the blood. Another combination is GSTP1(Ile105Val)+GSTP1(Ala114Val), which is associated with suppression of the blood and ejaculate GPO activity and a decrease in blood concentration of GSH.
COA
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