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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.

ABSTRACT: 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.

SUBMITTER: Lin Y

PROVIDER: S-EPMC7415483 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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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.

Lin Yufei Y Kranzler Henry R HR Farrer Lindsay A LA Xu Hongqin H Henderson David C DC Zhang Huiping H

The pharmacogenomics journal 20200207 5

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 promot ...[more]

PMID: 32029903

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Project description:ContextNaltrexone hydrochloride treatment for alcohol dependence works for some individuals but not for everyone. Asn40Asp, a functional polymorphism of the mu-opioid receptor gene (OPRM1), might predict naltrexone response.ObjectiveTo evaluate whether individuals with alcoholism who are heterozygous (Asp40/Asn40) or homozygous (Asp40/Asp40) for the OPRM1 Asp40 allele respond better to naltrexone.DesignPharmacogenetic analysis conducted between January 1, 2001, and January 31, 2004.SettingEleven academic sites in the COMBINE Study.ParticipantsRecently abstinent volunteers who met all 3 of the following conditions: (1) DSM-IV criteria for primary alcohol dependence; (2) participation in the COMBINE Study; and (3) availability of DNA.InterventionsAlcoholic subjects were treated for 16 weeks with 100 mg of naltrexone hydrochloride (234 Asn40 homozygotes and 67 with at least 1 copy of the Asp40 allele) or placebo (235 Asn40 homozygotes and 68 with at least 1 copy of the Asp40 allele). All participants received medical management (MM) alone or with combined behavioral intervention (CBI).Main outcome measuresTime trends in percentage of days abstinent, percentage of heavy drinking days, and rates of good clinical outcome.ResultsAlcoholic subjects with an Asp40 allele receiving MM alone (no CBI) had an increased percentage of days abstinent (P = .07) and a decreased percentage of heavy drinking days (P = .04) if treated with naltrexone vs placebo, while those with the Asn40/Asn40 genotype showed no medication differences. If treated with MM alone and naltrexone, 87.1% of Asp40 carriers had a good clinical outcome, compared with only 54.8% of individuals with the Asn40/Asn40 genotype (odds ratio, 5.75; confidence interval, 1.88-17.54), while, if treated with placebo, 48.6% of Asp40 carriers and 54.0% of individuals with the Asn40/Asn40 genotype had a good clinical outcome (interaction between medication and genotype, P = .005). No gene x medication interactions were observed in those treated with both MM and CBI.ConclusionsThese results confirm and extend the observation that the functionally significant OPRM1 Asp40 allele predicts naltrexone treatment response in alcoholic individuals. This relationship might be obscured, however, by other efficacious treatments. OPRM1 genotyping in alcoholic individuals might be useful to assist in selecting treatment options.Trial registrationclinicaltrials.gov Identifier: NCT00006206.

Project description:INTRODUCTION:The perioperative pain experience shows great interindividual variability and is difficult to predict. The mu-1 opioid receptor gene (OPRM1) is known to play an important role in opioid-pain pathways. Since deoxyribonucleic acid (DNA) methylation is a potent repressor of gene expression, DNA methylation was evaluated at the OPRM1 promoter, as a predictor of preoperative, acute, and chronic postsurgical pain (CPSP). METHODS:A prospective observational cohort study was conducted in 133 adolescents with idiopathic scoliosis undergoing spine fusion under standard protocols. Data regarding pain, opioid consumption, anxiety, and catastrophizing (using validated questionnaires) were collected before and 2-3 months postsurgery. Outcomes evaluated were preoperative pain, acute postoperative pain (area under curve [AUC] for pain scores over 48 hours), and CPSP (numerical rating scale >3/10 at 2-3 months postsurgery). Blood samples collected preoperatively were analyzed for DNA methylation by pyrosequencing of 22 CpG sites at the OPRM1 gene promoter. The association of each pain outcome with the methylation percentage of each CpG site was assessed using multivariable regression, adjusting for significant (P<0.05) nongenetic variables. RESULTS:Majority (83%) of the patients reported no pain preoperatively, while CPSP occurred in 36% of the subjects (44/121). Regression on dichotomized preoperative pain outcome showed association with methylation at six CpG sites (1, 3, 4, 9, 11, and 17) (P<0.05). Methylation at CpG sites 4, 17, and 18 was associated with higher AUC after adjusting for opioid consumption and preoperative pain score (P<0.05). After adjusting for postoperative opioid consumption and preoperative pain score, methylation at CpG sites 13 and 22 was associated with CPSP (P<0.05). DISCUSSION:Novel CPSP biomarkers were identified in an active regulatory region of the OPRM1 gene that binds multiple transcription factors. Inhibition of binding by DNA methylation potentially decreases the OPRM1 gene expression, leading to a decreased response to endogenous and exogenous opioids, and an increased pain experience.

Dataset Information

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

Publications

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

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