Original Article

The Pharmacogenomics Journal advance online publication 13 December 2016; doi: 10.1038/tpj.2016.89

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

R C Crist1,8, G A Doyle1,8, E C Nelson2, L Degenhardt3, N G Martin4, G W Montgomery5, A J Saxon6, W Ling7 and W H Berrettini1

  1. 1Department of Psychiatry, Center for Neurobiology and Behavior, University of Pennsylvania School of Medicine, PA, Pennsylvania, USA
  2. 2Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA
  3. 3National Drug and Alcohol Research Centre, UNSW Australia, Sydney, New South Wales, Australia
  4. 4QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  5. 5The University of Queensland, Herston, Queensland, Australia
  6. 6Veteran's Affairs Puget Sound Health Care System, Seattle, WA, USA
  7. 7University of California, Los Angeles, Integrated Substance Abuse Programs, Los Angeles, CA, USA

Correspondence: Dr RC Crist, Department of Psychiatry, Center for Neurobiology and Behavior, University of Pennsylvania School of Medicine, Translational Research Laboratories 125 South 31st Street, Room 2109, Philadelphia, PA 19104, USA. E-mail: crist@mail.med.upenn.edu

8These authors contributed equally to this work.

Received 25 August 2016; Revised 7 November 2016; Accepted 14 November 2016
Advance online publication 13 December 2016

Top

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 ~13kb 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.