The discovery of functional polymorphisms in alcohol dehydrogenase IB (ADH1B) and aldehyde dehydrogenase 2 (ALDH2) represents one of the earliest and still most successful examples of pharmacogenetics as applied to drug addictions. These enzymes catalyze consecutive steps in alcohol metabolism (see Fig. 1); both have functional polymorphisms common in East Asians that additively alter the risk of alcoholism, with protective effects of 4–10 fold depending on the population (41). The two most common genetic variants in these enzymes are ADH1B His47Arg in which Arg47 is an increase-of-function allele, and ALDH2 Glu487Lys in which Lys487 is an inactive allele. Accumulation of acetaldehyde, the intermediate from ADH metabolism, potently releases histamine, triggering an aversive skin flushing reaction as well as headaches, nausea and palpitations that are thought to deter heavy alcohol use and development of dependence. Indeed, a number of studies have shown that genetic polymorphisms in ADH1B and ALDH2 that have functional impacts on enzyme function alter the risk of alcohol dependence (reviewed in (10), Supplementary Table 1, 3). Acetaldehyde is also a mutagen that can react with a variety of
