The pattern of enhanced response to alcohol in individuals with ALDH2*2 and ADH1B*2 alleles is supportive of the hypothesized mechanistic pathway for how these variant alleles protect individuals from heavy drinking and alcohol-related problems. The results from this study indicate individuals with ALDH2*2 and ADH1B*2 alleles have more intense, and perhaps more aversive, responses to alcohol from the very onset of drinking and that this heightened response occurs even from small amounts of alcohol. These findings provide new support for one of the initial steps of the mechanistic model, the heightened subjective response to alcohol in individuals with these variant alleles. In the proposed mechanistic model, the endophenotype alcohol sensitivity is more proximal to the gene effects than the phenotype of alcohol dependence, and thus may better reflect the etiologic process by which genetic expression gives rise to differential vulnerability for alcohol dependence (Gottesman & Gould, 2003). Increased knowledge of the effects of alcohol metabolizing genes on early and low dose effects of alcohol may help researchers form a better understanding of how these variant alleles ultimately protect against the development of alcohol-related problems and AUDs.
