| Summary: | 博士 === 國防醫學院 === 醫學科學研究所 === 88 === Alcoholism is a complex behavior trait influenced by multiple genes as well as by by sociocultural factors. Alcohol metabolism is one of the biological determinants that can significantly influence drinking behavior and the development of alcoholism. To date, ADH and ALDH are the only so-called alcoholism genes. The genes which encode the major enzymes of alcohol metabolism, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), exhibit functional polymorphism. The variant alleles ADH2*2 and ADH3*1 which encode high-activity ADH isoforms as well as the ALDH2*2 allele which encodes the low-activity form of ALDH2 protect against alcoholism in East Asians. To investigate possible interactions among these protective genes, 420 alcohol dependent and 689 control Han Chinese living in Taiwan were genotyped at the ADH2, ADH3 and ALDH2 loci. After controlling for the influence of ALDH2*2 in a complete dominance or partial dominance model, multiple logistic regression analysis indicated that the allelic variation at ADH3 exerts no significant effect on risk of developing alcoholism. This finding can be accounted for by linkage between the ADH3*1 and ADH2*2 genes, as demonstrated by evaluation of the relative haplotype frequencies of ADH2 and ADH3 in the alcoholics and controls. Logistic regression analyses of combinatorial genotypes of the polymorphic ADH2 and ALDH2 loci indicated that individuals carrying two copies of ADH2*2 allele and two copies of ALDH2*2 had the lowest risk (odds ratio = 0.01) for alcoholism, as compared with the ADH2*1/*1 and ALDH2*1/*1 genotype. The disease risk with the ADH2*2/*2－ALDH2*1/*1 genotype appeared to be about half of that with the ADH2*1/*2－ALDH2*1/*1 genotype. The results suggest that protection afforded by the ADH2*2 allele may be independent of that by ALDH2*2, whose influence can be mostly ascribed to accumulation of blood acetaldehyde after alcohol ingestion.
Allelic variation of ALDH gene can significantly affect vulnerability for the development of alcoholism. The variant ALDH2*2 gene allele, expressed in a dominant fashion, can accumulate more acetaldehyde in ethanol metabolism, hence more protection against development of alcoholism. Despite having partially ALDH2*2 variant alleles, some individuals became alcoholism. Recent investigation of ALDH2 genotypes in our study revealed 10-20% alcoholics with the heterozygous ALDH2*1/*2 genotype. We also found an alcoholic patient with homozygosity of the variant ALDH2*2 allele which had been believed to be fully protective against alcoholism in the Asians. To explore addictive mechanism of alcohol heterozygous or homozygous for ALDH2*2, we evaluated ethanol metabolism, cardiovascular responses and subjective feelings of alcoholics following alcohol challenge with a moderate dose of ethanol (0.5 g/kg). Blood ethanol concentration was determined by headspace gas chromatography and acetaldehyde concentration by high-performance liquid chromatography with detection of the derivatized fluorescent product. Cardiovascular hemodynamic parameters were measured by two-dimensional Doppler echocardiography. Following alcohol challenge, the ethanol pharmacokinetic parameters showed no significant difference in alcoholics and controls with different ALDH2 genotypes. No blood acetaldehyde accumulations were found in the ALDH2*1/*1 alcoholics and controls. ALDH2*1/*2 alcoholics and controls exhibited markedly high blood acetaldehyde (peak concentration ~ 60 mM), no differences were noted between alcoholic and control groups. Cardiovascular hemodynamic parameters revealed no marked change in the ALDH2*1/*1 groups, but showed significant alterations in the ALDH2*1/*2 groups. Alcoholic patients with ALDH2*1/*2 or ALDH2*2/*2 genotypes displayed significantly less intense cardiovascular responses compared with the corresponding nonalcoholic controls. The results imply physiological tolerance or innate hyposensitivity to the accumulation of blood acetaldehyde following alcohol ingestion appears to be crucial for development of alcoholism in individuals heterozygous or homozygous for the ALDH2*2 variant gene allele.
Alcohol sensitivity is thought to be a behavioral trait marker for susceptibility to develop alcoholism. Genetic variations of alcohol-metabolism genes result in individual differences of alcohol sensitivity. The functional polymorphism of ALDH2 gene is important in testing the hypothesis that high-level alcohol sensitivity is protective against alcoholism. To investigate ethanol/acetaldehyde responses and their possible interactions in individuals with variant alleles of ADH2 and ALDH2 genes, we developed a measurement scale to evaluate the physiological/psychological responses following alcohol ingestion. To explore the dose effects of alcohol in nonalcoholic subjects possessing different ADH2 and ALDH2 genotypes, 60 adult men were recruited for alcohol challenge in two dose sessions (0.3 g /kg or 0.5 g/kg). Blood ethanol and acetaldehyde concentrations were determined and subjective perceptions were self-reported following alcohol challenge. The results showed that subjects with ALDH2*1/*2 genotype had a more intense response to alcohol than ALDH2*1/*1, but not necessarily negative. The functional polymorphism of ADH2 gene did not significantly correlate with alterations in blood acetaldehyde level or subjective perceptions.
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