At the ADH1B His48Arg locus (rs1229984), the His48 allele directly leads to increased catalytic efficiency of ADH1B. Indeed, the rate of oxidation of ethanol to acetaldehyde is increased 100-fold in His48/His48 homozygotes compared to Arg48/Arg48 homozygotes. At the ALDH2 Glu487Lys locus (rs671), the Lys487 allele dominantly inactivates ALDH2. Higher ADH1B activity or lower ALDH2 activity lead to accumulation of acetaldehyde and flushing following consumption of small quantities of alcohol. In East Asian populations in which both His48 and Lys487 are highly abundant, and in Jewish populations in which His48 is abundant, many individuals carry genotypes protective against alcoholism. Recently, the protective effect of the His48 ADH1B variant on alcohol dependence was also demonstrated in European and African populations.59 Following up the connection of acetaldehyde to mutation, both the ADH1B and ALDH2 flushing alleles have been associated with enhanced risk of cancers of the oropharynx and esophagus.58 As seen in Fig. 7, rates of upper GI cancer are higher in parts of the world where the ALDH2 Lys487 allele is abundant.
