I appreciate Dr. Shriver's insightful editorial on ethnic variation as a key to the biology of human disease [1]. His comments provide an important context for understanding the assets and limitations of studying within ethnic variability to increase knowledge of complex diseases such as alcoholism [2]. I completely agree with Dr. Shriver's general comments but want to clarify one point. He stated that my colleagues and I "address the mechanism underlying the unpleasant sensations and facial flush experienced by many Asian persons after the consumption of alcohol." In 1974, Ewing and colleagues were the first to relate alcohol-induced flushing and other symptoms of alcohol sensitivity among Asian persons with elevated acetaldehyde levels and to suggest that the symptoms were clinically similar to those seen with an alcohol-disulfiram reaction [3].

Since this report was published, it has been widely hypothesized that Asian persons who have alcohol-induced flushing are protected from alcoholism because they experience unpleasant alcohol reactions. In our ongoing study, which is assessing subjective and objective responses to moderate alcohol ingestion among Asian-American persons, participants with mutations in the aldehyde dehydrogenase gene (ALDH2*2 alleles) as a group self-report more intense, but not less pleasant, feelings of intoxication than do participants without this gene mutation, despite equivalent drinking histories and blood alcohol levels [4]. We have also found extremely aversive alcohol reactions in only 5 of 84 participants. Each of 3 participants homozygous for the ALDH2*2 allele and 2 of 32 heterozygous participants vomited after ingesting the alcohol beverage. Both of the ALDH2*2 heterozygotes were also homozygous for the "atypical" alcohol dehydrogenase (ADH2*2) allele. ALDH2*2 and ADH2*2 alleles are both associated with a lower risk for alcoholism [5]. We hypothesize that variability in response to alcohol is the mechanism whereby these genetic variants interact to protect against alcoholism among Asian persons who drink alcohol. We suggest, however, that what is important is not whether the response has positive or negative valence but the overall intensity of the response.