Genetic variation and epigenetic modification of the prodynorphin gene in peripheral blood cells in alcoholism.
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.
Karolinska Institutet, Department of Clinical Neuroscience, Center for Molecular Medicine, Stockholm, Sweden; Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Italy. Electronic address: claudio.daddario@ki.se.
Claudio
C
D'Addario
Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
Klementy
K
Shchetynsky
Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Italy.
Mariangela
M
Pucci
School of Pharmacy, University of Camerino, Italy.
Carlo
C
Cifani
Karolinska Institutet, Department of Clinical Neuroscience, Center for Molecular Medicine, Stockholm, Sweden.
Agneta
A
Gunnar
Karolinska Institutet, Department of Clinical Neuroscience, Center for Molecular Medicine, Stockholm, Sweden.
Vladana
V
Vukojević
Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
Leonid
L
Padyukov
Karolinska Institutet, Department of Clinical Neuroscience, Center for Molecular Medicine, Stockholm, Sweden.
Lars
L
Terenius
D000328:Adult; D000367:Age Factors; D000437:Alcoholism / Q000097:blood* / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation / Q000235:genetics*; D004745:Enkephalins / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011498:Protein Precursors / Q000235:genetics*; D012737:Sex Factors
D004745:Enkephalins; D011498:Protein Precursors; C033660:preproenkephalin
Alcoholism; DNA methylation; Human peripheral blood cells; Prodynorphin; Single nucleotide polymorphism