Department of Psychiatry and Psychotherapy, University of Mainz, Untere Zahlbacher Str. 8, 55131, Mainz, Germany.
J Neural Transm (Vienna). 2013 Aug;120(8):1161-9. doi: 10.1007/s00702-013-0996-y. Epub 2013 Mar 17.
Alcohol-related diseases cause significant harm in the western world. Up to 65 % of the phenotypic variance is genetically determined. Few candidate genes have been identified, comprising ADH4, ALDH2, COMT, CRHR1, DAT (SLC6A3), GABRA2 and MAOA. While abnormalities in the dopaminergic mesolimbic reward system are considered important mediators of alcoholism, studies analyzing variants of dopamine receptors showed conflicting results. Other modulators of the reward system are synaptosomal genes. Among candidate genes, polygenic variants of the Vesicular Monamine Transporter 2 (VMAT2) gene locus associated with alterations of drinking behavior were published. These variants comprise single nucleotide polymorphisms (SNPs) within the promoter region and the open reading frame. In this study, we confirm the association of VMAT2 SNP rs363387 (allelic association: p = 0.015) with alcohol dependence. This SNP defines several haplotypes including up to four SNPs (minimal p = 0.0045). In addition, numeric effects in the subgroups of males and patients with positive family history were found. We suggest that several rs363387 T-allele containing haplotypes increase the risk of alcohol dependence (OR 1.53), whereas G-allele containing haplotypes confer protection against alcohol dependence. Taken together, there is supporting evidence for a contribution of VMAT2 gene variants to phenotypes of alcohol dependence.
酒精相关疾病在西方国家造成了重大危害。高达 65%的表型变异是由遗传决定的。已经确定了少数候选基因，包括 ADH4、ALDH2、COMT、CRHR1、DAT（SLC6A3）、GABRA2 和 MAOA。虽然多巴胺能中脑边缘奖励系统的异常被认为是酒精中毒的重要介质，但分析多巴胺受体变异的研究结果相互矛盾。奖励系统的其他调节剂是突触体基因。在候选基因中，与饮酒行为改变相关的囊泡单胺转运体 2（VMAT2）基因座的多态性变体已经发表。这些变体包括启动子区域和开放阅读框内的单核苷酸多态性（SNP）。在这项研究中，我们证实了 VMAT2 SNP rs363387（等位基因关联：p=0.015）与酒精依赖的关联。该 SNP 定义了几个单倍型，包括多达四个 SNP（最小 p=0.0045）。此外，还在男性亚组和阳性家族史患者亚组中发现了数值效应。我们认为，含有 rs363387 T 等位基因的几个单倍型增加了酒精依赖的风险（OR 1.53），而含有 G 等位基因的单倍型则对酒精依赖具有保护作用。总的来说，有证据表明 VMAT2 基因变异对酒精依赖表型有一定的影响。
