enzyme activity20, 24, 25. Most of the ALDH2 enzyme, which functions as a tetramer, is inactivated and degraded when a person carries even a single ALDH2*504K allele25. This leads to a major buildup of acetaldehyde in the circulation. It is similar to having disulfiram (Antabuse®) in one's system at all times. ALDH2*504K has repeatedly been demonstrated to have a protective effect against AUDs20, 21, 26, 27. But the protection against alcoholism afforded by a single copy of ALDH2*504K is not complete, and is affected by societal circumstances. Higuchi28 demonstrated that the relative protection afforded by carrying a single copy of this allele declined dramatically in Japan between 1970 and 1992, a period that coincides with increasing social pressure for drinking as part of the business culture. The protection against alcoholism afforded by carrying two copies of the ALDH2*2 allele is essentially complete, with those individuals typically unable to consume more than a very small amount of alcohol. The effects of the ALDH2*504K allele are a dramatic demonstration both of the strong effect a genetic variant can have on risk for alcohol dependence, and also of how the effects of a protective allele can be overridden by environmental and social factors.
