engleski

Genetic variants of the dopaminergic system and alcohol dependence and alcohol abuse-related phenotypes

Alcoholism, including alcohol addiction and dependence, is related to altered function of dopaminergic system such as dopamine receptors, metabolic enzymes and dopamine transporter. The aim of the study was to evaluate the association between the polymorphisms of the selected genes of dopaminergic system: variable number of tandem repeats (VNTR) in the third exon of dopamine receptor D4 (DRD4) gene (DRD4 VNTR), Val108/158Met of catechol-o-methyltransferase gene (COMT Val108/158Met), VNTR in the 3’-untranslated region of dopamine transporter (DAT) gene (DAT VNTR), and -1021C/T of dopamine beta-hydroxylase gene (DBH -1021C/T) with alcohol dependence and/or alcohol abuse-related phenotypes. The study included large groups of ethnically homogenous Caucasian subjects: 690 patients with alcohol dependence diagnosed using the SCID for DSM-IV criteria, and 580 healthy subjects who served as controls. Alcoholism related phenotypes were evaluated by a psychiatrist using clinical evaluation, clinician-administered interview and psychiatric and/or self-report scales: withdrawal, aggressive behavior, severity of alcohol dependence, delirium tremens, comorbid depression, current suicidal behavior, life-time suicide attempt, onset (early/late) of alcohol dependence. Genotyping of the VNTR polymorphisms in DRD4 and DAT genes were determined by polymerase chain reaction and 2% agarose gel electrophoresis, while COMT Val108/158Met and DBH -1021C/T were determined by real time PCR in ABI Prism 7300 Real time PCR System apparatus, according to manufacturer’s procedures. The results were evaluated using χ2-test, standardized residuals, multiple regression analysis, Mann-Whitney test, and Cramer’s V or C statistic. Present study detected significant association between DRD4 VNTR, but not other studied polymorphisms, and alcoholism, since there was an increased frequency of DRD4 VNTR long allele carriers in patients with alcohol dependence compared to control subjects. Alcoholism-related phenotypes were significantly associated with COMT Val108/158Met polymorphism. There was an over-presentation of the COMT Met/Met genotype among patients with current suicidal behavior and in suicide attempters, and increased frequency of the COMT Val/Val genotype in patients with an early onset of alcohol dependence. These findings suggest that DRD4 VNTR could be used as a peripheral biomarker of alcoholism, while COMT Val108/158Met could be a biomarker of suicidal behavior, and that alcoholism-related phenotypes were well chosen to study the association with selected gene polymorphisms.

COMT Val108/158Met; DRD4 VNTR; DAT VNTR; DBH -1021 C/T; alcoholism; alcohol related phenotypes

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