In addition to the relatively clear effects of genetic effects at the first stage of metabolism, even more robust findings are evident in terms of genetic influences at the second stage of alcohol metabolism, the oxidation of acetaldehyde into acetate. Two ALDH enzymes are responsible for metabolizing acetaldehyde and are encoded by the eponymous genes, ALDH2 and ALDH1A1, on chromosomes 12 and 9, respectively. ALDH2 has two variants, ALDH2-1 and ALDH2-2, and the latter results in an inactive form of the enzyme that cannot metabolize acetaldehyde into acetate. Further, this variant is dominant, so possession of even one ALDH2-2 copy results in almost no hepatic ALDH2 activity (Crabb et al, 1989). Consequently, ALDH2-2 carriers experience a build-up of acetaldehyde following alcohol consumption, again causing a syndrome of unpleasant effects, including flushing, headache, tachycardia, and nausea. From a functional standpoint, as with the case for polymorphisms affecting acetaldehyde levels via ADH genes, the aversive reaction to alcohol resulting from the ALDH2-2 allele has been robustly demonstrated to result in a substantial protective effect against alcoholism in a number of studies (e.g.,
