Polymorphism of alcohol and aldehyde dehydrogenase genes and alcoholic cirrhosis in chinese patients

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Abstract

Liver alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), the principal enzymes responsible for the oxidation of ethanol, are polymorphic at the ADH2, ADH3 and ALDH2 loci in human beings. Our previous studies have shown that, compared with nonalcoholic individuals, Chinese alcoholic patients without liver disease had significantly lower frequencies of the ADH2*2 and ADH3*1 alleles, which encode high maximum velocity β2- and γ1-ADH subunits, respectively, as well as a lower frequency of the ALDH2*2 allele, which encodes an enzymatically inactive subunit. The data strongly suggest that genetic variation in both ADH and ALDH may influence drinking behavior and the risk of alcoholism developing through acetaldehyde formation. To further investigate the possible role of acetaldehyde in the pathogenesis of alcoholic liver disease, we determined the ADH and ALDH genotype frequencies in patients with alcohol-related cirrhosis (n = 27), viral hepatitis-related cirrhosis (n = 29) and gastric and duodenal ulcer without relevance to alcohol (n = 30). We developed a new restriction fragment length polymorphism method to genotype the mutant and normal ALDH2 alleles by using polymerase chain reaction–directed mutagenesis, which proved to be simpler and faster than the conventional detection methods that use hybridization with allele-specific oligonucleotide probes. We found that the frequencies of the alleles ADH2*2 (57), ADH3*1 (78) and ALDH2*2 (9) in the alcoholic cirrhotic patients were significantly lower than those in the healthy controls and in the patients with cirrhosis from viral hepatitis and with gastric and duodenal ulcer. No significant differences in the allele frequencies of these three genes between the alcoholic cirrhotic patients and the alcohol-dependent subjects without severe liver injury were found, although the alcoholic cirrhosis group tended to have a higher incidence of ALDH2*1/*2 heterozygotes (5 of 27) than did the alcohol-dependent group (6 of 50). The results confirm previous studies that the ADH2*2, ADH3*1 and ALDH2*2 genes can affect predisposition to alcoholism in Chinese patients and suggest that the mutant ALDH2*2 gene may influence susceptibility to alcoholic cirrhosis. (Hepatology 1994;19:360–366).

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