Recent human genetic studies suggest that a predisposition to alcohol abuse and/or
to develop alcoholism may be inherited. Pedigree analysis, linkage, and association
studies have helped to detect marker loci and candidate genes that may prove useful
in identifying individuals at risk. In particular, molecular genetic research into
the causes of alcoholism has drawn attention to the potentially important role of
alcohol-and acetaldehyde-metabolizing enzymes, alcohol dehydrogenase (ADH) and aldehyde
dehydrogenase (ALDH). Functional polymorphisms have been observed at various genes
encoding these enzyme proteins, all of which act to alter the rate of synthesis of
the toxic metabolite acetaldehyde, or decrease its further oxidation.
The occurrence of functional polymorphisms in alcohol-metabolizing enzymes makes them
favored candidate genes suitable for further molecular genetic research. A positive
selection of such genetic polymorphisms in some populations might act as a protective
factor against alcohol abuse and alcohol-related disease outcomes. For example, individuals
who show initial sensitivity to alcohol by virtue of their genetically controlled
abnormality of ALDH2*2 allele are discouraged from excessive alcohol consumption.
On the other hand, persons with the heterozygous ALDH2*2 genotype (ALDH2*1/2*2) are
at higher risk for developing alcohol abuse-related end-organ damage than those with
a homozygous ALDH2* 1/2*1 genotype. Moreover, the frequency of c2 allele of cytochrome
P45 02E1 was found to be higher in patients with nonfibrotic alcoholic liver disease
than in patients with severe hepatic fibrosis or liver cirrhosis. Identification of
putative alcoholism vulnerability genes by direct analysis of candidate genes and
genetic linkage may therefore help improve approaches to prevention and treatment.
