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A polymorphism in the OPRM1 3'-untranslated region is associated with methadone efficacy in treating opioid dependence

By R. C. Crist, G. A. Doyle, E. C. Nelson, L. Degenhardt, N. G. Martin, G. W. Montgomery, A. J. Saxon, W. Ling and W. H. Berrettini


The μ-opioid receptor (MOR) is the primary target of methadone and buprenorphine. The primary neuronal transcript of the OPRM1 gene, MOR-1, contains a ~13 kb 3' untranslated region with five common haplotypes in European-Americans. We analyzed the effects of these haplotypes on the percentage of opioid positive urine tests in European-Americans (n=582) during a 24-week, randomized, open-label trial of methadone or buprenorphine/naloxone (Suboxone) for the treatment of opioid dependence. A single haplotype, tagged by rs10485058, was significantly associated with patient urinalysis data in the methadone treatment group. Methadone patients with the A/A genotype at rs10485058 were less likely to have opioid-positive urine drug screens than those in the combined A/G and G/G genotypes group (relative risk=0.76, 95% confidence intervals=0.73-0.80, P=0.0064). Genotype at rs10485058 also predicted self-reported relapse rates in an independent population of Australian patients of European descent (n=1215) who were receiving opioid substitution therapy (P=0.003). In silico analysis predicted that miR-95-3p would interact with the G, but not the A allele of rs10485058. Luciferase assays indicated miR-95-3p decreased reporter activity of constructs containing the G, but not the A allele of rs10485058, suggesting a potential mechanism for the observed pharmacogenetic effect. These findings suggest that selection of a medication for opioid dependence based on rs10485058 genotype might improve outcomes in this ethnic group

Topics: Morphine-Induced Analgesia, Receptor Oprm1, Naltrexone Response, Alcohol Dependence, Clinical-Trial, Messenger-Rna, Cocaine, Mice, Gene, Buprenorphine, 1311 Genetics, 1313 Molecular Medicine, 3004 Pharmacology
Publisher: 'Springer Science and Business Media LLC'
Year: 2018
DOI identifier: 10.1038/tpj.2016.89
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