Prodynorphin CpG-SNPs associated with alcohol dependence: elevated methylation in the brain of human alcoholics

摘要: The endogenous opioid system (EOS) including dynorphin peptides and κ-opioid receptor (KOR) plays a critical role in alcohol dependence. Aims of the thesis were to evaluate whether EOS undergoes molecular adaptations brain areas involved cognitive control addiction human dependent subjects, analyze impact genetic epigenetic factors on these adaptive changes. main findings that (1) dynorphin/KOR PDYN mRNA dynorphins dorsolateral prefrontal cortex (dl-PFC), hippocampus, KOR orbitofrontal (OFC), is upregulated alcoholics. No other significant changes found. (2) Three single nucleotide polymorphisms (SNPs), which show most association with dependence, form CpG sites are methylated at different levels. Methylation C, non-risk variant 3’-untranslated region (3’-UTR) SNP (rs2235749; C>T) was increased dl-PFC positively correlated dynorphins. DNA-binding factor differentially targeted T, risk allele unmethylated C this identified brain. We hypothesize influences genetic, environmental may be integrated through alterations methylation 3’jUTR CpG/SNP and, as consequence, affect transcription vulnerability develop (3) principal component analysis suggested expression related alcoholism, while hippocampus depend genotype promoter (rs1997794; T>C). low resides within non-canonical AP-1-binding element by JUND FOSB proteins, dominant AP-1 constituents T transition abrogated binding. variations relevant for diverse responses gene alcohol. (4) It proposed regulated intragenic DNA regulatory elements controlling DNA-protein interactions formation secondary structures. dynorphin-encoding sequence found have potential such structure vitro, affected region. This sensitive regulation initiation from alternative start located region, or splicing mRNA. In conclusion, has been site robust associated dependence addiction. Regulation area specific, apparently factors, possibly internal properties its ability