Genome 2000 基因體分析研討會

Interaction between the Functional Polymorphisms of the Alcohol Metabolic Genes in Protection against Alcoholism

SHIH-JIUN YIN (尹士俊)

Department of Biochemistry, National Defense Medical Center,
Taiwan, R.O.C.

The genes which encode the major enzymes of alcohol metabolism, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), exhibit functional polymorphism. The variant alleles ADH2*2 and ADH3*1, which encode high-activity ADH isoforms, and the ALDH2*2 allele, which encodes the low-activity form of ALDH2, protect against alcoholism in East Asians. To investigate possible interactions among these protective genes, we genotyped 340 alcoholic and 545 control Han Chinese living in Taiwan at the ADH2, ADH3 and ALDH2 loci. After the influence of ALDH2*2 was controlled for in a complete dominance or partial dominance model, multiple logistic regression analysis indicated that allelic variation at ADH3 exerts no significant effect on the risk of alcoholism. This can be accounted for by linkage between the ADH3*1 and ADH2*2 alleles, as demonstrated by evaluation of the relative haplotype frequencies of ADH2 and ADH3 in the alcoholics and controls. ALDH2*2 homozygosity, regardless of the ADH2 genotypes, was highly protective against alcoholism; no individual showing such homozygosity was found among the alcoholics. Logistic regression analyses of the remaining six combinatorial genotypes of the polymorphic ADH2 and ALDH2 loci indicated that individuals carrying one or two copies of ADH2*2 allele and a single copy of ALDH2*2 had the lowest risk (odds ratios, 0.04_0.05) for alcoholism, as compared with the ADH2*1/*1 and ALDH2*1/*1 genotype. The disease risk with the ADH2*2/*2_ALDH2*1/*1 genotype appeared to be about half of that with the ADH2*1/*2_ALDH2*1/*1 genotype. The results suggest that protection afforded by the ADH2*2 allele may be independent of that by ALDH2*2, whose influence can be mostly ascribed to accumulation of blood acetaldehyde after alcohol ingestion.