Analyses of polymorphisms of intron 2 of OPRK1 (kappa-opioid receptor gene) in association with opioid and cocaine dependence diagnoses in an African-American population. (18th January 2022)

• Record Type: Journal Article
• Authors: Yuferov, Vadim; Butelman, Eduardo R.; Randesi, Matthew; Ott, Jürg; Kreek, Mary Jeanne
• Is Part Of: Neuroscience letters. Volume 768(2022)
• Publication Date: 2022-01-18
• Subjects: Neurology -- Periodicals; Neurology -- Periodicals; Research -- Periodicals; Neurologie -- Périodiques; Neuroanatomie -- Périodiques; Neuropharmacologie -- Périodiques; Neurophysiologie -- Périodiques; Neurology; Periodicals; Electronic journals; 617.48
• DOI: 10.1016/j.neulet.2021.136364
• Languages: English
• ISSNs: 0304-3940

Abstract

Highlights: The kappa-opioid receptor (KOR)/dynorphin system is regulated by stress and heavy exposure to drugs including opioid and cocaine. Activation of the KOR system can result in anhedonia and dysphoria, and in relapse-like behaviors. Regions of intron 2 of the gene encoding KOR ( OPRK1 ) have potential regulatory functions and respond to activation by glucocorticoids. In this study, polymorphisms in intron 2 of OPRK1 were associated with increased vulnerability to cocaine dependence diagnoses, in a sample of persons of African-American ethnicity. Abstract: Rationale: The dynorphin/kappa-opioid receptor (KOR) system (encoded by PDYN and OPRK1 genes respectively) is highly regulated by repeated exposure to drugs of abuse, including mu-opioid agonists and cocaine. These changes in the dynorphin/KOR system can then influence the rewarding effects of these drugs of abuse. Activation of the dynorphin/KOR system is also thought to have a role in the pro-addictive effects of stress. Recent in vitro assays showed that the OPRK1 intron 2 may function as a genomic enhancer in the regulation KOR expression, and contains a glucocorticiod-responsive sequence site. We hypothesize that SNPs in intron 2 of OPRK1 are associated with categorical opioid or cocaine dependence diagnoses, as well as with dimensional aspects of drug use (i.e., magnitude of drug exposure). Methods: This study includes 577 subjects ≥ 18 years old, with African ancestry (AA) from the USA. They were divided into three groups: 152 control subjects, 142 persons with lifetime opioid dependence diagnosis (OD), and 283 subjects with lifetime cocaine dependence diagnosis (CD). Five SNPs (rs16918909, rs7016778, rs997917, rs6473797, rs10111937) that span 10 Kb nucleotides in intron 2 of OPRK1 were used for the association analyses. Genotyping was performed with the Smokescreen® array or sequencing of PCR-amplified DNA fragments. Association analyses for OD and CD diagnoses and the OPRK1 intron 2 alleles were carried out with Fisher's exact test. The Kreek-McHugh-Schluger-Kellogg (KMSK) scales were used for dimensional measure of maximum exposure to specific drugs, using Mann-Whitney tests. Results: Two SNPs, rs997917 and rs10111937 showed point-wise significant allelic association (p < 0.05) with CD diagnosis, and rs10111937 showed a point-wise significance in association with OD. None of these single SNP associations with categorical diagnoses were significant after correction for multiple testing (pcorr > 0.05). However, significant associations of several genotype patterns (diplotypes) were found with cocaine dependence, but none for opioid dependence. The most significant genotype pattern with cocaine dependence diagnosis occurred for rs6473797 and rs10111937 (pcorr = 0.036, odds ratio = 1.92, FDR < 0.05), and survived correction for multiple testing. Dimensional analyses with KMSK scores show that persons with either rs997917 or rs10111937 variants had greater exposure to cocaine, compared to those with prototype allele (Mann-Whitney tests, point-wise). Conclusions: This study provides additional support of potential importance of regulatory regions of intron 2 of the OPRK1 gene in development of cocaine and opioid dependence diagnoses, in a population with African-American ancestry.