An intronic variant in OPRD1 predicts treatment outcome for opioid dependence in African-Americans

Abstract

Although buprenorphine and methadone are both effective treatments for opioid dependence, their efficacy can vary significantly among patients. Genetic differences may explain some of the variability in treatment outcome. Understanding the interactions between genetic background and pharmacotherapy may result in more informed treatment decisions. This study is a pharmacogenetic analysis of the effects of genetic variants in OPRD1, the gene encoding the δ-opioid receptor, on the prevalence of opioid-positive urine tests in African-Americans (n=77) or European-Americans (n=566) undergoing treatment for opioid dependence. Patients were randomly assigned to treatment with either methadone or buprenorphine/naloxone (Suboxone) over a 24-week open-label clinical trial, in which illicit opioid use was measured by weekly urinalysis. In African-Americans, the intronic SNP rs678849 predicted treatment outcome for both medications. Methadone patients with the CC genotype were less likely to have opioid-positive urine tests than those in the combined CT and TT genotypes group (relative risk (RR)=0.52, 95% confidence interval (CI)=0.44-0.60, p=0.001). In the buprenorphine treatment group, however, individuals with the CC genotype were more likely to have positive opioid drug screens than individuals in the combined CT and TT genotypes group (RR=2.17, 95% CI=1.95-2.68, p=0.008). These findings indicate that the genotype at rs678849 predicts African-American patient response to two common treatments for opioid dependence, suggesting that matching patients to treatment type based on the genotype at this locus may improve overall treatment efficacy. This observation requires confirmation in an independent population.

Figure 1

Diagram of the OPRD1 gene (Chr1: 29138654-29190208) and the six SNPs genotyped in this study. Gray boxes indicate exons and boxes with diagonal lines indicate untranslated regions. The residue numbers and encoded amino acids of the synonymous and non-synonymous variants are included after the SNP IDs. SNP and exon locations taken from the February 2009 build of the human genome in UCSC Genome Browser (http://www.genome.ucsc.edu).

Figure 2

Weekly urinalysis data for African-Americans based on rs678849 genotype. Patients were treated for opioid dependence with either methadone (a) or buprenorphine (b) for 24 weeks. Weekly urine drug screens were administered for the presence of opioids other than the one prescribed. The average percentage of opioid-positive urine tests during each week is provided for individuals with either the C/C genotype or the C/T and T/T genotypes, which were combined due to the low number of T/T patients (n=3). Time, age, gender, maximal dose, and treatment group were analyzed as covariates. (a) Methadone patients with the CC genotype (n=21) were less likely to have opioid-positive urine drug screens than patients with the C/T or T/T genotypes (n=15; RR=0.52, 95% CI=0.44–0.60, p=0.001). (b) Buprenorphine patients with the CC genotype (n=24) were more likely to have opioid-positive drug screens than patients with the C/T or T/T genotypes (n=17; RR=2.17, 95% CI=1.95–2.68, p=0.008).