Alcohol-Metabolizing Gene Variation, Lipids, Hemostatic Factors and CVD

描述（由申请人提供）：我们建议利用社区动脉粥样硬化风险（ARIC）研究的大型双种族人群来确定先前研究的酒精代谢基因中的功能变异以及其他非同质变异是否会改变酒精摄入对脂质水平、止血因子和心血管疾病（CVD）风险的影响。我们将对I类和II类酒精脱氢酶基因（ADH1B, ADH1C, ADH4），醛脱氢酶基因（ALDH1, ALDH2）和细胞色素P4502E1基因（CYP2E1）中的16个功能和/或非同质变体进行基因分型，所有这些基因都是负责肝脏中酒精转化为乙酸的两种主要酒精代谢系统的酶。我们将使用方差分析作为主要的统计方法来评估基因变异对饮酒与血脂水平/止血因子之间关联的潜在影响，并在模型中纳入相互作用项。我们将使用Cox比例风险模型来分析酒精代谢基因的遗传变异对饮酒与冠心病和卒中生存之间关系的影响。ARIC研究的丰富资源使我们能够扩展本应用程序中提出的初步分析，以便我们重新评估所消费的酒精饮料（葡萄酒/啤酒/烈酒）类型的所有目标。饮酒与心血管疾病之间的关系是有争议的，低至中度饮酒对心脏保护作用的潜在机制被认为涉及酒精诱导的脂质（即高密度脂蛋白胆固醇）和止血因子（即纤维蛋白原）的变化。最近的研究表明，酒精代谢基因的遗传变异改变了乙醇氧化的速率，较慢的酒精清除率改善了酒精对高密度脂蛋白胆固醇和纤维蛋白原的影响。ARIC研究为研究酒精代谢基因变异对大量白人和非裔美国人饮酒与血脂、止血因子和心血管疾病风险之间关系的潜在影响提供了丰富的资源。

DESCRIPTION (provided by applicant): We propose to utilize the large bi-ethnic population of the Atherosclerosis Risk in Communities (ARIC) study to determine whether previously studied functional variants, as well as additional non-synonymous variants, within alcohol-metabolizing genes modify the effect of alcohol consumption on lipid levels, hemostatic factors and cardiovascular disease (CVD) risk. We will genotype sixteen functional and/or non-synonymous variants in the class I and II alcohol dehydrogenase genes (ADH1B, ADH1C, ADH4), the aldehyde dehydrogenase genes (ALDH1, ALDH2) and the cytochrome P4502E1 gene (CYP2E1), all of which are enzymes of the two major alcohol metabolism systems responsible for the conversion of alcohol to acetate in the liver. We will use analysis of variance as our main statistical method for evaluating the potential effect modification of genetic variation on associations between alcohol consumption and lipid levels / hemostatic factors, with the inclusion of interaction terms in the model. We will use the Cox proportional hazards model to analyze the effect modification of genetic variation in alcohol-metabolizing genes on the relationship between alcohol consumption and incident CHD and stroke survival. The rich resource of the ARIC study provides us with the ability to extend the initial analyses put forth in this application such that we will re-evaluate all aims specific to the type of alcoholic beverage consumed (wine / beer / spirits). The relationship between alcohol consumption and CVD is controversial, with the mechanisms underlying the cardioprotective effects of low to moderate alcohol consumption believed to involve alcohol-induced changes in lipids (i.e., HDL cholesterol) and hemostatic factors (i.e., fibrinogen). Recent studies have shown that genetic variation within alcohol-metabolism genes alters the rate of ethanol oxidation, with slower alcohol clearance rates improving alcohol's effect on HDL cholesterol and fibrinogen. The ARIC study provides a rich resource for investigating the potential effect modification of alcohol-metabolizing gene variation on the relationship between alcohol consumption and lipids, hemostatic factors, and risk of CVD in a large population of whites and African Americans.