Genetic variation and epigenetic modification of the prodynorphin gene in peripheral blood cells in alcoholism

Abstract

Dynorphins are critically involved in the development, maintenance and relapse of alcoholism. Alcohol-induced changes in the prodynorphin gene expression may be influenced by both gene polymorphisms and epigenetic modifications. The present study of human alcoholics aims to evaluate DNA methylation patterns in the prodynorphin gene (PDYN) promoter and to identify single nucleotide polymorphisms (SNPs) associated with alcohol dependence and with altered DNA methylation. Genomic DNA was isolated from peripheral blood cells of alcoholics and healthy controls, and DNA methylation was studied in the PDYN promoter by bisulfite pyrosequencing. In alcoholics, DNA methylation increased in three of the seven CpG sites investigated, as well as in the average of the seven CpG sites. Data stratification showed lower increase in DNA methylation levels in individuals reporting craving and with higher levels of alcohol consumption. Association with alcoholism was observed for rs2235751 and the presence of the minor allele G was associated with reduced DNA methylation at PDYN promoter in females and younger subjects. Genetic and epigenetic factors within PDYN are related to risk for alcoholism, providing further evidence of its involvement on ethanol effects. These results might be of relevance for developing new biomarkers to predict disease trajectories and therapeutic outcome.

Transcriptional Regulators as Targets for Alcohol Pharmacotherapies

“…Another study found decreased DNAm at repetitive DNA elements (Alu) associated with alcohol use in lymphocytes from healthy individuals (Zhu et al 2012). Candidate gene approaches in blood cells have demonstrated associations between increased DNAm and AUD at the promoters for alpha synuclein ( SNCA ), homocysteine-induced endoplasmic reticulum protein ( HERPUD1 ), serotonin transporter ( SLC6A4 ), monoamine oxidase A ( MAOA ), prodynorphin ( PDYN ), and aldehyde dehydrogenase 2 ( ALDH2 ) (Bleich et al 2006; Bonsch et al 2005; Philibert et al 2008a; Philibert et al 2008b; D’Addario et al 2017; Pathak et al 2017). More recently, genome-wide profiling of methylated regions in whole blood cells or human lymphoblast cell lines has demonstrated several significant differentially methylated regions or differentially methylated cytosines associated with high levels of alcohol drinking or dependence (Philibert et al 2012; Clark et al 2015; Liu et al 2016; Zhang et al 2013; Zhao et al 2013).…”

Role of the Dynorphin/Kappa Opioid Receptor System in the Motivational Effects of Ethanol

“…Variations in the prodynorphin gene have also been associated with negative craving for alcohol (i.e., seeking alcohol for relief from a negative emotional state) and alcohol dependence (Karpyak et al., ). DNA methylation (associated with reduced gene expression) in the prodynorphin gene was increased in alcoholics relative to control subjects in cortex and blood cells (D'Addario et al., ; Taqi et al., ). Future work using animal models may be valuable in clarifying whether allelic variants of OPRK1 or epigenetic factors (e.g., differential methylation of the prodynorphin gene) significantly contribute to risk for alcohol use disorder and/or treatment responsiveness.…”

Gene–methylation interactions: discovering region-wise DNA methylation levels that modify SNP-associated disease risk

“…These results were subsequently used to test for association between the top CpGs and genotypes. A few studies searched for an association between a specific genotype and DNAm at a chosen CpG from a neighboring region [ 28 – 30 ]. Another study adopted a more integrative approach by utilizing all the available genetic and methylation data to search for differentially methylated CpG sites and meQTLs associated with breast cancer [ 31 ].…”