Polymorphism at the ADH2 and ADH3 loci of alcohol dehydrogenase (ADH) has been shown to have an effect on the predisposition to alcoholism in Asian individuals. However, the results are not conclusive for white individuals. We have analyzed the ADH genotype of 876 white individuals from Spain (n ؍ 251), France (n ؍ 160), Germany (n ؍ 184), Sweden (n ؍ 88), and Poland (n ؍ 193). Peripheral blood samples from healthy controls and groups of patients with viral cirrhosis and alcohol-induced cirrhosis, as well as alcoholics with no liver disease, were collected on filter paper. Genotyping of the ADH2 and ADH3 loci was performed using polymerase chain reactionrestriction fragment length polymorphism methods on white cell DNA. In healthy controls, ADH2*2 frequencies ranged from 0% (France) to 5.4% (Spain), whereas ADH3*1 frequencies ranged from 47.6% (Germany) to 62.5% (Sweden). Statistically significant differences were not found, however, between controls from different countries, nor between patients with alcoholism and/or liver disease. When all individuals were grouped in nonalcoholics (n ؍ 451) and alcoholics (n ؍ 425), ADH2*2 frequency was higher in nonalcoholics (3.8%) than in alcoholics (1.3%) (P ؍ .0016), whereas the ADH3 alleles did not show differences. Linkage disequilibrium was found between ADH2 and ADH3, resulting in an association of the alleles ADH2*2 and ADH3*1, both coding for the most active enzymatic forms. In conclusion, the ADH2*2 allele decreases the risk for alcoholism, whereas the ADH2*2 and ADH3*1 alleles are found to be associated in the European population. (HEPATOLOGY 2000;31:984-989.)Ingested alcohol is mostly metabolized in the liver by the successive action of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). Both enzymes exhibit genetic polymorphisms that influence the rate of conversion of ethanol to acetaldehyde, and of acetaldehyde to acetate. It has been consistently reported that ALDH2 is the most important alcohol-metabolizing gene affecting predisposition to alcoholism in Asian populations. The prevalence of the ALDH2*2 allele, which codes for a physiologically inactive mitochondrial ALDH form, is lower in alcoholics than in nonalcoholics. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] However, this allele has not been found in white individuals. 21 Regarding ADH, polymorphism is detected at the ADH2 and ADH3 loci. Alleles of ADH2 found in whites and Asians are ADH2*1 and ADH2*2, which encode for the low activity (1) and high activity (2) subunits, respectively. The kcat values for the resulting dimeric isozymes are very different: 9.2 min Ϫ1 for 11 and 400 min Ϫ1 for 22. 22 The ADH2*2 frequency is much higher in Asians (60%-80%) than in whites (0%-10%). 21 ADH3 alleles are ADH3*1 and ADH3*2, which produce the ␥1 and ␥2 subunits. The ␥1␥1 isozyme (kcat ϭ 87 min Ϫ1 ) is moderately more active than the ␥2␥2 isozyme (kcat ϭ 35 min Ϫ1 ). 22 ADH3*1 frequency is about 50% to 60% in whites and higher than 90% in Asians. 3,23 ...