Classic studies, which have been replicated in many populations, have demonstrated that certain coding variations in two genes affecting alcohol metabolism have a strong protective effect—that is, they both substantially lower the risk for alcoholism. These variants affect a gene called ADH1B, which encodes a variant of ADH, and a gene called ALDH2, which encodes a variant of ALDH (Edenberg 2000, 2007; Hurley et al. 2002) (figure 2). The protective variant in the ALDH2 gene, known as ALDH2*2, involves a point mutation that results in the exchange of the amino acid glutamate at position 487 of the ALDH protein for the amino acid lysine. This mutation acts in a nearly dominant manner to render the enzyme almost inactive: even people who inherit only one copy of ALDH2*2 and one “normal” copy of the gene (i.e., people who are heterozygous for this mutation) produce an ALDH enzyme with extremely low enzyme activity (Crabb et al. 1989). As a result, these individuals exhibit highly elevated levels of acetaldehyde, which produces aversive reactions, including flushing, elevated heart rate (i.e., tachycardia), and nausea after
