Wall Tamara L
Department of Psychiatry, University of California and the Psychology Service, Veterans Affairs San Diego Healthcare System 92161, USA.
Ther Drug Monit. 2005 Dec;27(6):700-3. doi: 10.1097/01.ftd.0000179840.78762.33.
Two alcohol dehydrogenase genes (ADHIB and ADH1C on chromosome 4) and one aldehyde dehydrogenase gene (ALDH2 on chromosome 12) exhibit functional polymorphisms that are associated with lower rates of alcohol dependence. The ALDH22 allele,found almost exclusively in Asian populations, has the strongest relationship. The ADH1B2, ADH1B3, and ADHlCi alleles, found in varying prevalence in different ethnic groups, have also been associated with lower rates of alcohol dependence. Studies of the ADHIBand ADH1C haplotypes, however, have shown that ADH1CI is in linkage disequilibrium with ADHiB2, and the ADH1Ci allele does not appear to have significant unique associations with alcohol dependence. The hypothesized mechanism underlying the associations of the ADH1B and ALDH2 polymorphisms with alcohol dependence is that the isoenzymes encoded by these alleles lead to an accumulation of acetaldehyde during alcohol metabolism. Based on their kinetic properties, ALDH2 2 theoretically should lead to a slower removal of acetaldehyde than ALDH21, whereas ADH1B2 and ADH1B3 should lead to a more rapid production of acetaldehyde than ADHIBI. It is further hypothesized that elevations in acetaldehyde cause more intense reactions to alcohol and lead to lower levels of alcohol intake. Data are consistent with the hypothesis that elevations in acetaldehyde, increased sensitivity to alcohol, and lower levels of drinking reflect the mechanism by which the ALDH22 allele reduces risk for alcohol dependence. There is also some evidence supporting this mechanism for the ADH1B2 and ADHIB*3 alleles, but the results are less consistent. These findings highlight the value of trying to elucidate the mechanism by which genes ultimately give rise to differences in alcohol dependence through the examination of mediating behaviors.
两个乙醇脱氢酶基因（位于4号染色体上的ADH1B和ADH1C）和一个乙醛脱氢酶基因（位于12号染色体上的ALDH2）表现出与酒精依赖率较低相关的功能性多态性。几乎仅在亚洲人群中发现的ALDH22等位基因，其相关性最强。在不同种族群体中以不同频率出现的ADH1B2、ADH1B3和ADH1C1等位基因，也与较低的酒精依赖率相关。然而，对ADH1B和ADH1C单倍型的研究表明，ADH1C1与ADH1B2处于连锁不平衡状态，且ADH1C1等位基因似乎与酒精依赖没有显著的独特关联。ADH1B和ALDH2多态性与酒精依赖相关的潜在机制推测是，这些等位基因编码的同工酶会导致酒精代谢过程中乙醛的积累。根据其动力学特性，理论上ALDH22导致乙醛清除速度比ALDH21慢，而ADH1B2和ADH1B3导致乙醛生成速度比ADH1B1快。进一步推测，乙醛水平升高会引起对酒精更强烈的反应，并导致酒精摄入量降低。数据与以下假设一致：乙醛水平升高、对酒精敏感性增加以及饮酒量降低反映了ALDH22等位基因降低酒精依赖风险的机制。也有一些证据支持ADH1B2和ADH1B*3等位基因的这一机制，但结果不太一致。这些发现凸显了通过研究中介行为来阐明基因最终导致酒精依赖差异的机制的价值。
