Gene-environmental interaction regarding alcohol-metabolizing enzymes in the Japanese general population.

Epidemiological studies have shown that excessive alcohol consumption is a potent risk factor to develop hypertension. In addition, 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 pressor effects of alcohol in the Japanese general population. We initially screened SNPs in four candidate genes by resequencing. From 35 SNPs thus identified, 10 tag SNPs were selected and used for large-scale association analysis in a total of 5724 subjects. Among the SNPs tested, significant association (P<0.001) with drinking behavior was observed for ADH1B Arg47His (rs1229984) and ALDH2 Glu487Lys (rs671) polymorphisms. All subjects with Lys homozygote (AA genotype) of rs671 turned out to be nondrinkers and the combination of two SNP genotypes appeared to substantially influence people's drinking behavior in a synergistic manner. rs671 was significantly associated with blood pressure (P=0.0001-0.0491) in subgroups of drinkers. In the context of gene-environment interaction, our data clearly show the genetic impacts of two SNPs on drinking behavior and of one SNP on the sensitivity to the pressor effects of alcohol in the Japanese general population.