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. ? ? ? ?
