From the Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland 20892, USA.
Alcohol Clin Exp Res. 2011 Feb;35(2):304-16. doi: 10.1111/j.1530-0277.2010.01346.x. Epub 2010 Nov 17.
Ethanol is metabolized by 2 rate-limiting reactions: alcohol dehydrogenases (ADH) convert ethanol to acetaldehyde that is subsequently metabolized to acetate by aldehyde dehydrogenases (ALDH). Approximately 50% of East Asians have genetic variants that significantly impair this pathway and influence alcohol dependence (AD) vulnerability. We investigated whether variation in alcohol metabolism genes might alter the AD risk in four non-East Asian populations by performing systematic haplotype association analyses to maximize the chances of capturing functional variation.
Haplotype-tagging SNPs were genotyped using the Illumina GoldenGate platform. Genotypes were available for 40 SNPs across the ADH genes cluster and 24 SNPs across the two ALDH genes in four diverse samples that included cases (lifetime AD) and controls (no Axis 1 disorders). The case control sample sizes were the following: Finnish Caucasians: 232, 194; African Americans: 267, 422; Plains American Indians: 226, 110; and Southwestern American (SW) Indians: 317, 72.
In all four populations, as well as HapMap populations, 5 haplotype blocks were identified across the ADH gene cluster: (i) ADH5-ADH4; (ii) ADH6-ADH1A-ADH1B; (iii) ADH1C; (iv) intergenic; (v) ADH7. The ALDH1A1 gene was defined by 4 blocks and ALDH2 by 1 block. No haplotype or SNP association results were significant after correction for multiple comparisons; however, several results, particularly for ALDH1A1 and ADH4, replicated earlier findings. There was an ALDH1A1 block 1 and 2 (extending from intron 5 to the 3' UTR) yin yang haplotype (haplotypes that have opposite allelic configuration) association with AD in the Finns driven by SNPs rs3764435 and rs2303317, respectively, and an ALDH1A1 block 3 (including the promoter region) yin yang haplotype association in SW Indians driven by 5 SNPs, all in allelic identity. The ADH4 SNP rs3762894 was associated with AD in Plains Indians.
The systematic evaluation of alcohol-metabolizing genes in four non-East Asian populations has shown only modest associations with AD, largely for ALDH1A1 and ADH4. A concentration of signals for AD with ALDH1A1 yin yang haplotypes in several populations warrants further study.
乙醇通过两种限速反应进行代谢：乙醇脱氢酶（ADH）将乙醇转化为乙醛，然后乙醛脱氢酶（ALDH）将乙醛代谢为乙酸盐。大约 50%的东亚人存在遗传变异，这些变异显著损害了这条途径，并影响了酒精依赖（AD）易感性。我们通过进行系统的单体型关联分析来研究酒精代谢基因的变异是否会改变四个非东亚人群的 AD 风险，以最大限度地捕获功能变异。
使用 Illumina GoldenGate 平台对单体型标记 SNP 进行基因分型。在四个不同的样本中，对 ADH 基因簇的 40 个 SNP 和两个 ALDH 基因的 24 个 SNP 进行了基因型分析，这些样本包括病例（终生 AD）和对照（无轴 1 障碍）。病例对照样本量如下：芬兰白人：232，194；非裔美国人：267，422；平原美洲印第安人：226，110；和西南美洲（SW）印第安人：317，72。
在所有四个群体以及 HapMap 群体中，横跨 ADH 基因簇鉴定出 5 个单体型块：（i）ADH5-ADH4；（ii）ADH6-ADH1A-ADH1B；（iii）ADH1C；（iv）基因间；（v）ADH7。ALDH1A1 基因由 4 个块定义，ALDH2 由 1 个块定义。在进行多次比较校正后，没有单体型或 SNP 关联结果具有统计学意义；然而，有几个结果，特别是对 ALDH1A1 和 ADH4 的结果，复制了早期的发现。在芬兰人中，ALDH1A1 块 1 和 2（从内含子 5 延伸到 3'UTR）阴阳单体型（具有相反等位基因构型的单体型）与 AD 相关，分别由 rs3764435 和 rs2303317 驱动，ALDH1A1 块 3（包括启动子区域）在 SW 印第安人中与 5 个 SNP 相关，均为等位基因同一性。ADH4 SNP rs3762894 与平原印第安人的 AD 相关。
对四个非东亚人群的酒精代谢基因进行系统评估表明，与 AD 相关的关联程度较小，主要与 ALDH1A1 和 ADH4 相关。几个群体中 ALDH1A1 阴阳单体型与 AD 的信号集中表明需要进一步研究。
