Genetic determinants of ethanol-induced liver damage

Background: Although a clear correlation exists between cumulative alcohol intake and liver disease, only some of the alcohol abusers develop signs of ethanol-induced liver damage. To identify some of the genetic variations p redisposing persons to alcoholic liver disease (ALD), a genetic study was p erformed in heavy drinkers from the cohort of the Dionysis study, a survey aimed at evaluating liver disease in the open population of two towns in No rthern Italy (6917 individuals). Materials and Methods: 158 heavy drinkers (similar to 85% of all heavy drin kers in the population; daily alcohol intake > 120 g in males and > 60 g in females) were investigated by the analysis of nine polymorphic regions, ma pping in exons III and IX of the alcohol-dehydrogenase (ADH)-2, gene, in ex on VIII of the ADH3 gene, in intron VI, in the promoter region of the cytoc hrome P4502E1 (CYP2E1) gene, and in the promoter region of the tumor necros is factor-ct gene. Results: Heavy drinkers with or without ALD significantl y differed for the distribution of alleles of the cytochrome P4502E1 (CYP2E 1) and alcohol-dehydrogenase-3 (ADH-3) genes. In one town, allele C2 in the promoter region of the CYP2E1 gene had a frequency of 0.06 in healthy heav y drinkers, of 0.19 in heavy drinkers with ALD (P = 0.012), and of 0.33 in heavy drinkers with cirrhosis (p = 0.033). In the other town, whose inhabit ants have different genetic derivation, a prominent association between ALD and homozygosity for allele ADH3*2 of ADH3 was found, with a prevalence of 0.31 in heavy drinkers with ALD and of 0.07 in healthy heavy drinkers cont rols (p = 0.004). Conclusions. Both heterozygosity for allele C2 of CYP2E1 and homozygosity f or allele ADH3*2 of ADH3 are independent risk factors for ALD in alcohol ab users. The relative contribution of these genotypes to ALD is dependent on their frequency in the population. Overall, heavy drinkers lacking either o f these two genotypes are 3.2 and 4.3 times more protected from developing ALD and cirrhosis respectively.