The Genetics Program, Boston University School of Medicine, Boston, MA, USA.
Alcohol Clin Exp Res. 2009 May;33(5):848-57. doi: 10.1111/j.1530-0277.2009.00904.x. Epub 2009 Mar 6.
Alcohol dependence is a major cause of morbidity and mortality worldwide and has a strong familial component. Several linkage and association studies have identified chromosomal regions and/or genes that affect alcohol consumption, notably in genes involved in the 2-stage pathway of alcohol metabolism.
Here, we use multiple regression models to test for associations and interactions between 2 alcohol-related phenotypes and SNPs in 17 genes involved in alcohol metabolism in a sample of 1,588 European American subjects.
The strongest evidence for association after correcting for multiple testing was between rs1229984, a nonsynonymous coding SNP in ADH1B, and DSM-IV symptom count (p = 0.0003). This SNP was also associated with maximum number of drinks in 24 hours (p = 0.0004). Each minor allele at this SNP predicts 45% fewer DSM-IV symptoms and 18% fewer max drinks. Another SNP in a splice site in ALDH1A1 (rs8187974) showed evidence for association with both phenotypes as well (p = 0.02 and 0.004, respectively), but neither association was significant after accounting for multiple testing. Minor alleles at this SNP predict greater alcohol consumption. In addition, pairwise interactions were observed between SNPs in several genes (p = 0.00002).
We replicated the large effect of rs1229984 on alcohol behavior, and although not common (MAF = 4%), this polymorphism may be highly relevant from a public health perspective in European Americans. Another SNP, rs8187974, may also affect alcohol behavior but requires replication. Also, interactions between polymorphisms in genes involved in alcohol metabolism are likely determinants of the parameters that ultimately affect alcohol consumption.
酒精依赖是全球发病率和死亡率的主要原因，且具有很强的家族成分。几项连锁和关联研究已经确定了影响酒精消耗的染色体区域和/或基因，特别是在涉及酒精代谢两阶段途径的基因中。
在这里，我们使用多元回归模型来检验 17 个与酒精代谢相关的基因中的 2 个与酒精相关的表型与 SNPs 之间的关联和相互作用，在一个包含 1588 名欧洲裔美国人的样本中进行。
在进行多次测试校正后，与 ADH1B 中一个非同义编码 SNP(rs1229984)与 DSM-IV 症状计数之间最强的关联证据(p=0.0003)。该 SNP 还与 24 小时内最大饮酒量相关(p=0.0004)。该 SNP 的每个次要等位基因预测 DSM-IV 症状减少 45%，最大饮酒量减少 18%。ALDH1A1 中的剪接位点的另一个 SNP(rs8187974)也显示出与这两种表型相关的证据(p=0.02 和 0.004，分别)，但在进行多次测试校正后，这两个关联均不显著。该 SNP 的次要等位基因预测饮酒量增加。此外，还观察到几个基因中的 SNPs 之间存在成对相互作用(p=0.00002)。
我们复制了 rs1229984 对酒精行为的巨大影响，尽管这种多态性并不常见(MAF=4%)，但从欧洲裔美国人的公共卫生角度来看，这种多态性可能具有高度相关性。另一个 SNP(rs8187974)也可能影响酒精行为，但需要复制。此外，参与酒精代谢的基因中的多态性之间的相互作用可能是最终影响酒精消耗的参数的决定因素。
