The genes most strongly implicated and best characterized are those encoding the key enzymes of alcohol metabolism, ADHs and ALDHs. A variation in the gene encoding mitochondrial ALDH2 (i.e., the ALDH2*2 allele)2 renders the resulting enzyme nearly inactive so that the levels of acetaldehyde circulating in the body increase substantially when alcohol is consumed. This acetaldehyde accumulation underlies the strongly aversive flushing reaction (for more information, see the article by Hurley and Edenberg, pp. 339–344). An abundance of physiological and molecular data has demonstrated how this allele affects alcohol metabolism. People carrying a single copy of the ALDH2*2 allele in their genome are highly protected against alcoholism. Yet this strong effect still can be modified by the environment, as clearly shown by Higuchi and colleagues (1994), who found that the level of protection afforded by ALDH2*2 in the Japanese population dropped significantly with time as the social pressures for drinking increased. People carrying two copies of the ALDH2*2 allele, however, become so ill after consuming alcohol that their risk of becoming alcohol dependent is near zero.
