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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.

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Fig. 1: 44 CpG sites in the OPRM1 promoter region (734 bp).
Fig. 2: Importance of variables to relapse estimated by the Random Forest algorithm.
Fig. 3: Out-of-bag (OOB) error rates versus numbers of most important variables to relapse included in the Random Forest prediction model.


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We thank all participants in this study. We are grateful to Dr Joel Gelernter and his colleagues at Yale University School of Medicine for providing DNA samples and clinical data for the conduct of this study.

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Corresponding author

Correspondence to Huiping Zhang.

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Conflict of interest

This work was supported by grants (R21AA023068 and R01AA025080) from the National Institute on Alcohol Abuse and Alcoholism. HRK is a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative (ACTIVE), which during the past three years was supported by AbbVie, Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Ethypharm, Indivior, Lilly, Lundbeck, Otsuka, and Pfizer. HRK is named as an inventor on PCT patent application #15/878,640 entitled: “Genotype-guided dosing of opioid agonists,” filed January 24, 2018. All other authors declare that they have no conflict of interest. The authors alone are responsible for the content and writing of this paper.

Ethical approval

Ethics statements: The study was exempted from a specific ethical approval by Boston University School of Medicine in accordance with local/national guidelines. This study only involved DNA methylation data analysis, and the de-identified DNA samples were from our collaborator Dr Joel Gelernter at Yale University School of Medicine. Patient samples and demographic information were collected as part of previous studies (Krystal et al. [34]; Gelernter et al. [10]).

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Lin, Y., Kranzler, H.R., Farrer, L.A. et al. An analysis of the effect of mu-opioid receptor gene (OPRM1) promoter region DNA methylation on the response of naltrexone treatment of alcohol dependence. Pharmacogenomics J 20, 672–680 (2020).

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