Abstract 3934: Gene-Environment Interaction Regarding Ethanol Metabolizing Enzymes in the Japanese General Population
Objective: Epidemiological studies have shown that excessive alcohol consumption is a potent extrinsic factor to develop hypertension and dyslipidemia, while modest alcohol consumption tends to increase high-density lipoprotein (HDL) cholesterol levels, thereby leading to the reduced risk of coronary heart diseases. Also, some polymorphisms of the alcohol metabolism genes have been reported to exert significant impacts on the risk of alcoholism. We investigate the relevance of genetic susceptibility to drinking behavior and its influence on the sensitivity to the pressor effects and to the lipid-modifier effects of alcohol in the Japanese population.
Design and Methods: We initially screened SNPs in 4 alcohol metabolism genes including ADH1A, ADH1B, ADH1C and ALDH2 by re-sequencing of 48 Japanese subjects. From 35 SNPs thus identified, 10 tag-SNPs were chosen and used for large-scale association analysis in a total of 5724 subjects (mean age 48.8-years; male 60%), who were enrolled in a population-based setting. Genotype association was tested for drinking behavior (non-drinker, chance drinker and regular drinker) and subsequently for measurements of blood pressure, total cholesterol (TC), triglyceride (TG) and HDL with the subjects being stratified by drinking behavior and gender.
Results: Among 10 SNPs tested, significant association (p<0.001) with drinking behavior was observed for ADH1B Arg47His and ALDH2 Glu487Lys polymorphisms. All subjects homozygous with ALDH2 487Lys (n=318) turned out to be non-drinker and the combination of two SNPs genotype appeared to substantially influence people’s drinking behavior in a synergistic manner [e.g., combined OR=46.0 (95% CI, 6.3 334.2) in double mutant homozygous males]. ANCOVA and multivariate analysis revealed that ALDH2 Glu487Lys was significantly associated with blood pressure (p=0.009~0.03), TC (p=0.044) and HDL (p=0.014) after adjusting for confounding factors.
Conclusions: As a typical gene-environment interaction model, our data clearly demonstrate genetic impacts of two SNPs, whose functionality has been proven in vivo, on drinking behavior and one SNP on the sensitivity to the blood pressure and lipid-modifier effects of alcohol in the Japanese general population.