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Abstract

Alcoholism is an etiologically and clinically heterogeneous disorder in which compulsive alcohol seeking and use represent core symptoms. Exposure to alcohol is a necessary precondition, but environment and heritability factors can also play a dramatic role in controlling individual vulnerability to develop alcohol abuse. Increasing evidence shows that the endogenous opioid system (EOS) is implicated in the development and maintenance of alcoholism, but molecular mechanisms underlying ethanol-induced adaptive transformations in the EOS are not sufficiently well understood. In this study we attempted to investigate the association between alcoholism and genetic and epigenetic regulation of the opioid peptide precursor prodynorphin (PDYN) gene in peripheral blood mononuclear cells (PBMCs). TaqMan Single Nucleotide Polymorphism (SNP) Genotyping Assays (Life Technologies) were used for genotyping PDYN SNPs in Swedish patients with DSM-IV diagnosis of alcohol dependence. Methylation analysis was conducted using Pyrosequencing (Qiagen) in a subset of our sample and matched non-alcoholic controls. We have observed the association of alcohol-dependence with PDYN rs2281285, just in the females, and rs2235751 variants. The methylation analysis revealed increased in DNA methylation at PDYN gene promoter in alcoholics when compared to healthy controls. Moreover, we have observed that the presence of the minor allele in rs2281285 and rs2235751 was linked with a reduced methylation of PDYN gene promoter. Our findings suggest a complex relationship between genetic and epigenetic markers at PDYN gene, which may enhance or mask a possible predisposition effect on the risk for alcoholism. Further research is needed to investigate the nature of the complex genetic and epigenetic interactions and their relevance for individual differences in susceptibility to alcohol dependence and selection of treatment strategies.

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