Macgregor Stuart, Lind Penelope A, Bucholz Kathleen K, Hansell Narelle K, Madden Pamela A F, Richter Melinda M, Montgomery Grant W, Martin Nicholas G, Heath Andrew C, Whitfield John B
Genetic Epidemiology, Queensland Institute of Medical Research, Brisbane, Queensland, Australia.
Hum Mol Genet. 2009 Feb 1;18(3):580-93. doi: 10.1093/hmg/ddn372. Epub 2008 Nov 7.
Alcohol dependence (AD) is a complex disorder with environmental and genetic origins. The role of two genetic variants in ALDH2 and ADH1B in AD risk has been extensively investigated. This study tested for associations between nine polymorphisms in ALDH2 and 41 in the seven ADH genes, and alcohol-related flushing, alcohol use and dependence symptom scores in 4597 Australian twins. The vast majority (4296) had consumed alcohol in the previous year, with 547 meeting DSM-IIIR criteria for AD. There were study-wide significant associations (P<2.3 x 10(-4)) between ADH1B-Arg48His (rs1229984) and flushing and consumption, but only nominally significant associations (P<0.01) with dependence. Individuals carrying the rs1229984 G-allele (48Arg) reported a lower prevalence of flushing after alcohol (P=8.2 x 10(-7)), consumed alcohol on more occasions (P=2.7 x 10(-6)), had a higher maximum number of alcoholic drinks in a single day (P=2.7 x 10(-6)) and a higher overall alcohol consumption (P=8.9 x 10(-8)) in the previous year than those with the less common A-allele (48His). After controlling for rs1229984, an independent association was observed between rs1042026 (ADH1B) and alcohol intake (P=4.7 x 10(-5)) and suggestive associations (P<0.001) between alcohol consumption phenotypes and rs1693482 (ADH1C), rs1230165 (ADH5) and rs3762894 (ADH4). ALDH2 variation was not associated with flushing or alcohol consumption, but was weakly associated with AD measures. These results bridge the gap between DNA sequence variation and alcohol-related behavior, confirming that the ADH1B-Arg48His polymorphism affects both alcohol-related flushing in Europeans and alcohol intake. The absence of study-wide significant effects on AD results from the low P-value required when testing multiple single nucleotide polymorphisms and phenotypes.
酒精依赖（AD）是一种具有环境和遗传根源的复杂疾病。乙醛脱氢酶2（ALDH2）和乙醇脱氢酶1B（ADH1B）中的两种基因变异在酒精依赖风险中的作用已得到广泛研究。本研究检测了ALDH2基因中的9种多态性以及7种乙醇脱氢酶基因中的41种多态性与4597名澳大利亚双胞胎的酒精相关脸红、饮酒情况及依赖症状评分之间的关联。绝大多数（4296名）在过去一年中饮酒，其中547名符合《精神疾病诊断与统计手册》第三版修订本（DSM-IIIR）中酒精依赖的标准。乙醇脱氢酶1B-精氨酸48组氨酸（rs1229984）与脸红及饮酒量之间存在全研究范围的显著关联（P<2.3×10⁻⁴），但与酒精依赖仅存在名义上的显著关联（P<0.01）。携带rs1229984 G等位基因（48精氨酸）的个体报告称，饮酒后脸红的发生率较低（P=8.2×10⁻⁷），饮酒次数更多（P=2.7×10⁻⁶），前一年单日饮酒的最大量更高（P=2.7×10⁻⁶），总体酒精摄入量也更高（P=8.9×10⁻⁸），相比携带较不常见的A等位基因（48组氨酸）的个体。在控制rs1229984后，观察到rs1042026（ADH1B）与酒精摄入量之间存在独立关联（P=4.7×10⁻⁵），并且饮酒量表型与rs1693482（ADH1C）及rs1230165（ADH5）和rs3762894（ADH4）之间存在提示性关联（P<0.001）。ALDH2变异与脸红或饮酒量无关，但与酒精依赖指标存在弱关联。这些结果填补了DNA序列变异与酒精相关行为之间的空白，证实乙醇脱氢酶1B-精氨酸48组氨酸多态性既影响欧洲人的酒精相关脸红，也影响酒精摄入量。对酒精依赖缺乏全研究范围的显著影响，是由于在测试多个单核苷酸多态性和表型时所需的P值较低。
