Genetic associations of alcohol and aldehyde dehydrogenase with alcohol dependence and their mechanisms of action
Genetic associations of alcohol and aldehyde dehydrogenase with alcohol dependence and their mechanisms of action
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DOI：
10.1097/01.ftd.0000179840.78762.33
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发表时间：
2005-12-01
影响因子：
2.5
通讯作者：
Wall, TL
中科院分区：
文献类型：
--
作者：
Wall, TL
两个酒精脱氢酶基因（4号染色体上的ADH1B和ADH1C）和一个醛脱氢酶基因（12号染色体上的ALDH2）表现出与较低酒精依赖率相关的功能多态性。几乎只在亚洲人群中发现的ALDH2*2等位基因与肥胖的关系最为密切。ADH1B*2、ADH1B*3和ADH1C*1等位基因在不同种族群体中发现的患病率不同，也与较低的酒精依赖率有关。然而，对ADH1B和ADH1C单倍型的研究表明，ADH1C*1与ADH1B*2存在连锁不平衡，ADH1C*1等位基因似乎与酒精依赖没有显著的独特关联。ADH1B和ALDH2多态性与酒精依赖关联的假设机制是，这些等位基因编码的同工酶导致酒精代谢过程中乙醛的积累。根据它们的动力学性质，ALDH2*2理论上应该比ALDH2*1更慢地去除乙醛，而ADH1B*2和ADH1B*3应该比ADH1B*L更快地产生乙醛。进一步的假设是，乙醛的升高会引起对酒精的更强烈的反应，并导致更低的酒精摄入量。数据与假设一致，即乙醛升高、酒精敏感性增加和饮酒水平降低反映了ALDH2*2等位基因降低酒精依赖风险的机制。也有一些证据支持ADH1B*2和ADH1B*3等位基因的这种机制，但结果不太一致。这些发现强调了试图通过检查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。
Two alcohol dehydrogenase genes (ADH1B and ADH1C on chromosome 4) and one aldehyde dehydrogenase gene (ALDH2 on chromosome 12) exhibit functional polymorpbisms that are associated with lower rates of alcohol dependence. The ALDH2*2 allele, found almost exclusively in Asian populations, has the strongest relationship. The ADH1B*2, ADH1B*3, and ADH1C*1 alleles, found in varying prevalence in different ethnic groups, have also been associated with lower rates of alcohol dependence. Studies of the ADH1B and ADH1C haplotypes, however, have shown that ADH1C*1 is in linkage disequilibrium with ADH1B*2, and the ADH1C*1 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 ALDH2*1, whereas ADH1B*2 and ADH1B*3 should lead to a more rapid production of acetaldehyde than ADH1B*L 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 ALDH2*2 allele reduces risk for alcohol dependence. There is also some evidence supporting this mechanism for the ADH1B*2 and ADH1B*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.