Department of Biochemistry and Molecular Biology , Indiana University School of Medicine, Indianapolis, Indiana.
Department of Medical and Molecular Genetics , Indiana University School of Medicine, Indianapolis, Indiana.
Alcohol Clin Exp Res. 2018 Dec;42(12):2281-2297. doi: 10.1111/acer.13904. Epub 2018 Nov 11.
Alcohol use disorders (AUDs) are complex traits, meaning that variations in many genes contribute to the risk, as does the environment. Although the total genetic contribution to risk is substantial, most individual variations make only very small contributions. By far the strongest contributors are functional variations in 2 genes involved in alcohol (ethanol [EtOH]) metabolism. A functional variant in alcohol dehydrogenase 1B (ADH1B) is protective in people of European and Asian descent, and a different functional variant in the same gene is protective in those of African descent. A strongly protective variant in aldehyde dehydrogenase 2 (ALDH2) is essentially only found in Asians. This highlights the need to study a wide range of populations. The likely mechanism of protection against heavy drinking and AUDs in both cases is alteration in the rate of metabolism of EtOH that at least transiently elevates acetaldehyde. Other ADH and ALDH variants, including functional variations in ADH1C, have also been implicated in affecting drinking behavior and risk for alcoholism. The pattern of linkage disequilibrium in the ADH region and the differences among populations complicate analyses, particularly of regulatory variants. This critical review focuses upon the ADH and ALDH genes as they affect AUDs.
酒精使用障碍（AUD）是一种复杂的特征，这意味着许多基因的变异都会增加患病风险，环境也是如此。尽管遗传因素对风险的总贡献很大，但大多数个体变异的贡献非常小。到目前为止，最强的贡献者是参与酒精（乙醇[EtOH]）代谢的 2 个基因中的功能变异。在欧洲和亚洲血统的人群中，酒精脱氢酶 1B（ADH1B）的一个功能变体具有保护作用，而在同一基因中的另一个不同的功能变体在非洲血统的人群中具有保护作用。醛脱氢酶 2（ALDH2）中的一个强保护性变体基本上只在亚洲人中发现。这突出表明需要研究广泛的人群。在这两种情况下，针对大量饮酒和 AUD 的保护机制可能是改变 EtOH 的代谢速度，至少会短暂地提高乙醛的水平。其他 ADH 和 ALDH 变体，包括 ADH1C 的功能变体，也与饮酒行为和酗酒风险有关。ADH 区域的连锁不平衡模式和不同人群之间的差异使分析变得复杂，特别是对调节变体的分析。这篇批判性综述主要关注影响 AUD 的 ADH 和 ALDH 基因。
