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The present study was designed to investigate whether genetic polymorphisms of the aryl hydrocarbon receptor (AHR) signaling pathway are involved in the molecular basis of essential hypertension (EH).A total of 2160 unrelated Russian individuals comprising 1341 EH patients and 819 healthy controls were recruited into the study. Seven common AHR pathway single-nucleotide polymorphisms (SNPs) such as rs2066853, rs2292596, rs2228099, rs1048943, rs762551, rs1056836, and rs1800566 were genotyped by TaqMan-based allele discrimination assays.We found that SNP rs2228099 of ARNT is associated with an increased risk of EH (odds ratio=1.20 95% confidence interval: 1.01–1.44, P=0.043) in a dominant genetic model, whereas polymorphism rs762551 of CYP1A2 showed an association with a decreased risk of disease in a recessive genetic model (odds ratio=0.68, 95% confidence interval: 0.52–0.89, P=0.006). A log-likelihood ratio test enabled identification of epistatic interaction effects on EH susceptibility for all SNPs. MB-MDR analysis showed that cigarette smoking, rs1048943, rs762551, rs1056836, and rs2228099 were significant contributing factors in 19, 18, 13, 13, and 11 interaction models, respectively. The best MDR model associated with EH risk included rs1048943, rs762551, rs1056836, and cigarette smoking (cross-validation consistency 100%, prediction error 45.7%, Ppermutation<0.0001). The mRNA expression and in-silico function prediction analyses have confirmed a regulatory potential for a majority of SNPs associated with EH susceptibility.Our pilot study was the first to show that gene–gene and gene–environment interactions in the AHR signaling pathway represent important determinants for the development of EH, and the pathway may become an attractive target for a pharmacological intervention in hypertensive patients in the future.