RESUMEN
Dopaminergic neurotransmission plays a crucial role in the genesis and maintenance of alcohol dependence. Epigenetic regulation via promoter specific DNA methylation of the dopamine transporter gene (DAT) may influence altered dopaminergic neurotransmission in alcoholism. Aim of the present study was to investigate DNA promoter methylation of DAT in early alcohol withdrawal and in relation to alcohol craving. We analyzed blood samples of 76 patients admitted for detoxification treatment and compared them to 35 healthy controls. Methylation specific quantitative real-time PCR was used to measure the promoter specific DNA methylation of the dopamine transporter. We assessed the extent of alcohol craving using the obsessive compulsive drinking scale (OCDS). Compared to healthy controls we found a significant hypermethylation of the DAT-promoter (Mann-Whitney U-test: p=0.001). Ln-transformed methylation of the DAT-promoter was negatively associated with the OCDS (linear regression: Beta=-0.275, p=0.016), particularly with the obsessive subscale (Beta=-0.300, p=0.008). Findings of the present study show that the epigenetic regulation of the DAT-promoter is altered in patients undergoing alcohol withdrawal. Furthermore, hypermethylation of the DAT-promoter may play an important role in dopaminergic neurotransmission and is associated with decreased alcohol craving.
Asunto(s)
Alcoholismo/genética , Alcoholismo/psicología , Metilación de ADN/genética , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Regiones Promotoras Genéticas/genética , Síndrome de Abstinencia a Sustancias/genética , Adulto , Conducta Compulsiva/genética , Conducta Compulsiva/psicología , Femenino , Regulación de la Expresión Génica/genética , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Conducta Obsesiva/genética , Conducta Obsesiva/psicología , Reacción en Cadena de la Polimerasa/métodos , Síndrome de Abstinencia a Sustancias/psicologíaRESUMEN
Understanding genome-wide links between genotype and phenotype has generally been difficult due to both the complexity of phenotypes, and until recently, inaccessibility to large numbers of genes that might underlie a trait. To address this issue, we establish the association between particular RNAi phenotypes in Caenorhabditis elegans and sequence characteristics of the corresponding proteins and DNA. We find that genes showing RNAi phenotypes are long and highly expressed with little noncoding DNA and high rates of synonymous site substitution (KS). In addition, genes conferring RNAi phenotypes have significantly lower rates of nonsynonymous site substitution (KA). Collectively, these sequence features explain nearly 20% of the difference between the sets of loci that display or lack a RNAi-mediated effect, and reflect aspects both of the RNAi mechanism and the biological function of the genes. For example, the particularly low rate of evolution of genes in the sterility RNAi phenotype class suggests a role of C. elegans life history in shaping these patterns of sequence and expression characteristics on phenotypes. This approach also allows prediction of a set of heretofore-uncharacterized loci for which we expect future RNAi studies to reveal phenotypic effects (i.e., false negatives in present screens).