Luo Xingguang, Kranzler Henry R, Zuo Lingjun, Lappalainen Jaakko, Yang Bao-zhu, Gelernter Joel
Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06516, USA.
Neuropsychopharmacology. 2006 May;31(5):1085-95. doi: 10.1038/sj.npp.1300925.
The alcohol dehydrogenase (ADH) family constitutes one of the key sets of enzymes responsible for the oxidation of alcohol. The ADH4 gene, an important member of this family, is a functional and positional candidate for alcohol dependence. The present study aimed to investigate the relationship between ADH4 gene variation and alcohol dependence and drug dependence in European-Americans (EAs) and African-Americans (AAs). Seven single nucleotide polymorphisms (SNPs) spanning the ADH4 gene were genotyped in 365 healthy controls (317 EAs and 48 AAs) and 561 subjects (400 EAs and 161 AAs) affected with alcohol dependence and/or drug dependence (436 with alcohol dependence; 356 with drug dependence). Hardy-Weinberg equilibrium (HWE) for the genotype frequency distributions of these markers was tested in all phenotype groups to evaluate association between ADH4 gene variation and phenotypes and to fine-map the disease risk locus. The allele, genotype, and haplotype frequency distributions of these markers were compared between cases and controls to confirm the associations. The genotype frequency distributions of ADH4 markers were in HWE in EA controls, but were in Hardy-Weinberg disequilibrium (HWD) (ie, deviation from HWE) in EA cases. Among all markers, SNP2 (rs1042363) at exon 9 or SNP6 (rs1800759) at the promoter showed the greatest degree of HWD, among patients with either alcohol dependence or drug dependence. Significant differences between EA cases and controls were seen for genotype (10(-6)<global p<0.044), but not any allele or haplotype, frequency distributions for all seven ADH4 markers. These findings suggest that ADH4 genotypes predispose to alcohol dependence and drug dependence in a recessive manner, a predisposition that is population specific. SNP2 or SNP6 was the marker genetically closest to the functional risk loci for both alcohol dependence and drug dependence.
乙醇脱氢酶（ADH）家族是负责酒精氧化的关键酶组之一。ADH4基因是该家族的一个重要成员，是酒精依赖的功能和定位候选基因。本研究旨在调查欧洲裔美国人（EA）和非裔美国人（AA）中ADH4基因变异与酒精依赖和药物依赖之间的关系。对365名健康对照者（317名EA和48名AA）以及561名患有酒精依赖和/或药物依赖的受试者（400名EA和161名AA）（436名酒精依赖者；356名药物依赖者）进行了跨越ADH4基因的7个单核苷酸多态性（SNP）的基因分型。在所有表型组中测试了这些标记的基因型频率分布的哈迪-温伯格平衡（HWE），以评估ADH4基因变异与表型之间的关联，并对疾病风险位点进行精细定位。比较病例组和对照组之间这些标记的等位基因、基因型和单倍型频率分布，以确认关联。ADH4标记的基因型频率分布在EA对照者中符合HWE，但在EA病例中处于哈迪-温伯格不平衡（HWD）（即偏离HWE）状态。在所有标记中，外显子9的SNP2（rs1042363）或启动子的SNP6（rs1800759）在酒精依赖或药物依赖患者中显示出最大程度的HWD。对于所有7个ADH4标记，EA病例组和对照组之间在基因型（10^(-6)＜总体p＜0.044）频率分布上存在显著差异，但在任何等位基因或单倍型频率分布上均无差异。这些发现表明，ADH4基因型以隐性方式易患酒精依赖和药物依赖，这种易感性具有人群特异性。SNP2或SNP6是在基因上最接近酒精依赖和药物依赖功能风险位点的标记。
