POLYMORPHISM OF ALCOHOL AND ALDEHYDE DEHYDROGENASE GENES AND ALCOHOLIC CIRRHOSIS IN CHINESE PATIENTS

Liver alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), t he principal enzymes responsible for the oxidation of ethanol, are pol ymorphic at the ADH2, ADH3 and ALDH2 loci in human beings. Our previou s studies have shown that, compared with nonalcoholic individuals, Chi nese alcoholic patients without liver disease had significantly lower frequencies of the ADH22 and ADH3*1 alleles, which encode high maximu m velocity beta(2)- and gamma(1)-ADH subunits, respectively, as well a s a lower frequency of the ALDH22 allele, which encodes an enzymatica lly 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 inves tigate the possible role of acetaldehyde in the pathogenesis of alcoho lic 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 rele vance to alcohol (n = 30). We developed a new restriction fragment len gth polymorphism method to genotype the mutant and normal ALDH2 allele s by using polymerase chain reaction-directed mutagenesis, which prove d to be simpler and faster than the conventional detection methods tha t use hybridization with allele-specific oligonucleotide probes. We fo und that the frequencies of the alleles ADH22 (57%), ADH3*1 (78%) and ALDH22 (9%) in the alcoholic cirrhotic patients were significantly l ower than those in the healthy controls and in the patients with cirrh osis from viral hepatitis and with gastric and duodenal ulcer. No sign ificant differences in the allele frequencies of these three genes bet ween the alcoholic cirrhotic patients and the alcohol-dependent subjec ts without severe liver injury were found, although the alcoholic cirr hosis group tended to have a higher incidence of ALDH21/*2 heterozygo tes (5 of 27) than did the alcohol-dependent group (6 of 50). The resu lts confirm previous studies that the ADH22, ADH3*1 and ALDH2*2 genes can affect predisposition to alcoholism in Chinese patients and sugge st that the mutant ALDH22 gene may influence susceptibility to alcoho lic cirrhosis.