Genetic associations of alcohol and aldehyde dehydrogenase with alcohol dependence and their mechanisms of action.

Two alcohol dehydrogenase genes (ADHIB and ADH1C on chromosome 4) and one aldehyde dehydrogenase gene (ALDH2 on chromosome 12) exhibit functional polymorphisms that are associated with lower rates of alcohol dependence. The ALDH22 allele,found almost exclusively in Asian populations, has the strongest relationship. The ADH1B2, ADH1B3, and ADHlCi alleles, found in varying prevalence in different ethnic groups, have also been associated with lower rates of alcohol dependence. Studies of the ADHIBand ADH1C haplotypes, however, have shown that ADH1CI is in linkage disequilibrium with ADHiB2, and the ADH1Ci allele does not appear to have significant unique associations with alcohol dependence. The hypothesized mechanism underlying the associations of the ADH1B and ALDH2 polymorphisms with alcohol dependence is that the isoenzymes encoded by these alleles lead to an accumulation of acetaldehyde during alcohol metabolism. Based on their kinetic properties, ALDH2 2 theoretically should lead to a slower removal of acetaldehyde than ALDH21, whereas ADH1B2 and ADH1B3 should lead to a more rapid production of acetaldehyde than ADHIBI. It is further hypothesized that elevations in acetaldehyde cause more intense reactions to alcohol and lead to lower levels of alcohol intake. Data are consistent with the hypothesis that elevations in acetaldehyde, increased sensitivity to alcohol, and lower levels of drinking reflect the mechanism by which the ALDH22 allele reduces risk for alcohol dependence. There is also some evidence supporting this mechanism for the ADH1B2 and ADHIB*3 alleles, but the results are less consistent. These findings highlight the value of trying to elucidate the mechanism by which genes ultimately give rise to differences in alcohol dependence through the examination of mediating behaviors.