An analysis of the effect of mu-opioid receptor gene (OPRM1) promoter region DNA methylation on the response of naltrexone treatment of alcohol dependence

This study explored the effect of OPRM1 promoter region DNA methylation on the outcome of treatment with the opioid antagonist naltrexone (NTX) for alcohol dependence (AD). Ninety-three patients with DSM-IV AD [41 African Americans (AAs) and 52 European Americans (EAs)] received double-blind treatment with NTX or placebo for at least three months. Relapse to heavy drinking was assessed during the first 13 weeks of the trial. Peripheral blood methylation levels of 33 CpG units in the OPRM1 promoter region were quantified using Sequenom EpiTYPER technology. Bayesian logistic regression was used to analyze the effects of NTX treatment, CpG methylation, CpG methylation×NTX treatment, and age on AD relapse. The Random Forest machine learning algorithm was applied to select AD relapse predictors. No significant effect of individual OPRM1 promoter CpG units on AD relapse was observed in either AAs or EAs. Age was significantly associated with AD relapse in EAs, among whom older subjects had a lower relapse rate. Random forest analyses revealed that the prediction rate for AD relapse reached 66.0% with five top variables (age and four CpG units; ranked by their importance to AD relapse) in the prediction model. These findings suggest that methylation levels of individual OPRM1 promoter CpG units do not contribute significantly to inter-individual variation in NTX response. However, the age of subjects in combination with a cluster of specific OPRM1 promoter CpG units may affect NTX treatment outcome. Additional studies of OPRM1 DNA methylation changes during and after NTX treatment of AD are needed.