title: A polymorphism in the OPRM1 3'-untranslated region is associated with methadone efficacy in treating opioid dependence.
abstract: 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.
authors.affiliation: Department of Psychiatry, Center for Neurobiology and Behavior, University of Pennsylvania School of Medicine, PA, Pennsylvania, USA.
authors.forename: R C
authors.initials: RC
authors.lastname: Crist
authors.affiliation: Department of Psychiatry, Center for Neurobiology and Behavior, University of Pennsylvania School of Medicine, PA, Pennsylvania, USA.
authors.forename: G A
authors.initials: GA
authors.lastname: Doyle
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: E C
authors.initials: EC
authors.lastname: Nelson
authors.affiliation: National Drug and Alcohol Research Centre, UNSW Australia, Sydney, New South Wales, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Degenhardt
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: N G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: The University of Queensland, Herston, Queensland, Australia.
authors.forename: G W
authors.initials: GW
authors.lastname: Montgomery
authors.affiliation: Veteran's Affairs Puget Sound Health Care System, Seattle, WA, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Saxon
authors.affiliation: University of California, Los Angeles, Integrated Substance Abuse Programs, Los Angeles, CA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Ling
authors.affiliation: Department of Psychiatry, Center for Neurobiology and Behavior, University of Pennsylvania School of Medicine, PA, Pennsylvania, USA.
authors.forename: W H
authors.initials: WH
authors.lastname: Berrettini
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D000328:Adult; D000483:Alleles; D000701:Analgesics, Opioid / Q000627:therapeutic use*; D001315:Australia; D002047:Buprenorphine / Q000627:therapeutic use; D000069479:Buprenorphine, Naloxone Drug Combination / Q000627:therapeutic use; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008691:Methadone / Q000627:therapeutic use*; D009292:Narcotic Antagonists / Q000627:therapeutic use; D058850:Opiate Substitution Treatment / Q000379:methods; D009293:Opioid-Related Disorders / Q000188:drug therapy* / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D017450:Receptors, Opioid, mu / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D000701:Analgesics, Opioid; D000069479:Buprenorphine, Naloxone Drug Combination; D009292:Narcotic Antagonists; C485764:OPRM1 protein, human; D017450:Receptors, Opioid, mu; D002047:Buprenorphine; D008691:Methadone