THE RSAI POLYMORPHISM OF CYP2E1 AND SUSCEPTIBILITY TO ALCOHOLIC LIVER-DISEASE IN CAUCASIANS - EFFECT ON AGE OF PRESENTATION AND DEPENDENCE ON ALCOHOL-DEHYDROGENASE GENOTYPE

Twin studies in Caucasians suggest that susceptibility to alcoholic li ver disease is, in part, genetically determined. Because most of the d eleterious effects of alcohol are caused by its metabolism, attention has focused upon genes encoding ethanol metabolizing enzymes. Caucasia ns are polymorphic at only two Of these gene loci - cytochrome P450 2E 1 (CYP2E1) and alcohol dehydrogenase 3 (ADH3). We examined the frequen cy of the RsaI polymorphism of CYP2E1 and ADH3 genotype in 264 patient s with alcoholic liver disease and 121 local control individuals. Ther e was a non-significant excess of the rare c2 CYP2E1 allele in patient s with advanced liver disease compared with control individuals/patien ts with steatosis only (0.029 versus 0.017/0.00). However, patients wi th the c2 allele presented at a younger age compared with those with t he wild type c1 allele only (42.3 +/- 1.6 years versus 49.0 +/- 0.6 ye ars; P = 0.001) with at least as advanced histology (93% cirrhotic ver sus 74%). Male patients had a higher frequency of the ADH32/*2 genoty pe (which encodes the less active gamma(2) subunit) than control indiv iduals [odds ratio (OR) 2.04 (1.11-3.76)], however, ADH3 genotype did not differ with histological stage or with age of presentation. Patien ts with advanced disease possessing the c2 allele had a significantly higher frequency of the ADH32/*2 genotype compared with c1 homozygote s [OR 3.71 (1.24-11.09)]. This study demonstrates that, although rare in Caucasians, possession of the mutant c2 allele of CYP2E1 increases the risk of alcoholic liver disease at a given level of cumulative alc ohol consumption. This risk appears to be particularly manifest in ind ividuals carrying the ADH32 allele, presumably reflecting increased m etabolism of ethanol by CYP2E1. In the absence of the c2 allele, ADH3 genotype does not influence the risk of advanced alcoholic liver disea se but, in males at least, may influence the risk of alcoholism. Pharm acogenetics 8:335-342 (C) 1998 Lippincott-Raven Publishers.