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 predisposing persons to alcoholic liver disease (ALD), a genetic study was performed 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 Northern Italy (6917 individuals).


METHODS
158 heavy drinkers (approximately 85% of all heavy drinkers in the population; daily alcohol intake > 120 g in males and >60 g in females) were investigated by the analysis of nine polymorphic regions, mapping in exons III and IX of the alcohol-dehydrogenase (ADH)-2 gene, in exon VIII of the ADH3 gene, in intron VI, in the promoter region of the cytochrome P4502E1 (CYP2E1) gene, and in the promoter region of the tumor necrosis factor-alpha gene.


RESULTS
Heavy drinkers with or without ALD significantly differed for the distribution of alleles of the cytochrome P4502E1 (CYP2E1) 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 heavy 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 inhabitants 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 controls (p = 0.004). CONCLUSIONS. Both heterozygosity for allele C2 of CYP2E1 and homozygosity for allele ADH3*2 of ADH3 are independent risk factors for ALD in alcohol abusers. The relative contribution of these genotypes to ALD is dependent on their frequency in the population. Overall, heavy drinkers lacking either of these two genotypes are 3.2 and 4.3 times more protected from developing ALD and cirrhosis respectively.
Monzoni
A
A
Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology), Trieste, Italy.
Masutti
F
F
Saccoccio
G
G
Bellentani
S
S
Tiribelli
C
C
Giacca
M
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D000426:Alcohol Dehydrogenase / Q000235:genetics; D000428:Alcohol Drinking / Q000009:adverse effects* / Q000235:genetics*; D000483:Alleles; D006528:Carcinoma, Hepatocellular / Q000235:genetics; D002874:Chromosome Mapping; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics; D000431:Ethanol / Q000009:adverse effects*; D005091:Exons; D005260:Female; D005355:Fibrosis / Q000235:genetics; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007438:Introns; D008099:Liver / Q000187:drug effects* / Q000293:injuries*; D008107:Liver Diseases / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D000637:Transaminases / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D000431:Ethanol; D000426:Alcohol Dehydrogenase; D019392:Cytochrome P-450 CYP2E1; D005723:gamma-Glutamyltransferase; D000637:Transaminases