Do alcohol-metabolizing enzyme gene polymorphisms increase the risk of alcoholism and alcoholic liver disease?

Abstract

Case-control studies that have investigated the association between alcoholism and alcoholinduced liver damage and the ADH2, ADH3, CYP2E1, and ADLH2 polymorphisms have reported controversial or inconclusive results. Thus, we conducted a meta-analysis of 50 association studies of the above polymorphisms. We explored potential sources of heterogeneity and bias, performed subgroup analyses by racial background and sex, performed sensitivity analyses for studies not in Hardy-Weinberg equilibrium, and performed a subgroup analysis for cases that met strict criteria for alcoholism. The present meta-analysis underscores significant associations of ADH2*1, ADH3*2, and ALDH2* . When strict criteria were imposed, the pattern of results remained unaltered. For liver disease, there were no significant associations for ADH2*1, ADH3*2, or ALDH2*1 in all subpopulations. The CYP2E1 polymorphism showed no association whatsoever. There is evidence that alleles are mainly dominant. In conclusion, there was heterogeneity between studies in alcoholism for ADH2, ADH3, and ALDH2, and lack of bias in all polymorphisms. The above findings reinforce the need for more rigorous studies, and for regular synthesis of studies' results. O ver the last few years, an increasing number of studies have provided compelling evidence for the involvement of genetically defined predisposing factors in alcoholism and alcohol-induced cirrhosis. The strongest support comes from the fact that not all subjects with a high daily intake of alcohol develop alcohol-induced liver disease. Mostly metabolized in the liver by the successive action of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), the rate of conversion of ingested ethanol to acetaldehyde, and of acetaldehyde to acetate, is influenced by genetic polymorphisms at both loci. ALDH2 is the most important gene that affects predisposition to alcoholism in Asian populations. Thus, the prevalence in these populations of the inactive ALDH enzymatic form encoded by the ALDH2*2 allele appears to protect against alcoholism. 1 Furthermore, alcoholics with this inactive allele may be at great risk for advanced alcoholic liver disease. [2][3][4] Regarding the ADH gene cluster, polymorphisms are also detected at the ADH2 and ADH3 loci with two alleles (referred to as *1 and *2) each. Alleles ADH2*2 and ADH3*1 encode, respectively, for the highly active ␤ 2 and ␥ 1 allozymes, 5 and a low prevalence of both alleles has been reported in alcoholic Asians-although some studies did not detect associations between ADH3 polymor-

Alcoholism and alcohol drinking habits predicted from alcohol dehydrogenase genes

“…Among men, we found relative estimates for alcoholism from two to three among ADH1B Á 1 homozygotes, which is comparable to results from a recent meta-analysis consisting predominantly of East Asian studies. 29 Also, the odds ratio (OR) for heavy drinking for men was 3.1 which agrees with what is previously found among Asian men. 30 Separate estimates for women were not available for any of the end points in previous studies.…”

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

“…Studies have reported genetic polymorphisms in the genes encoding enzymes responsible for alcohol metabolism; alcohol dehydrogenase, CYP450 2E1, and the mitochondrial low K m aldehyde dehydrogenase [123]. Unfortunately, only weak associations between these polymorphisms and increased alcohol hepatotoxicity have been shown [124].…”

Genetic polymorphism of alcohol-metabolizing enzyme and alcohol dependence in Polish men

“…Alcohol metabolism is one of the biological determinants that can significantly influence drinking behavior and the development of alcohol dependence (2). Alcohol dehydrogenase (ADH), aldehyde dehydrogenase and microsomal ethanol-oxidizing system (MEOS/CYP2E1) allele and genotypes occur at different frequencies in particular ethnic groups, and their role in the development of alcohol dependence differs between races and populations (3)(4)(5)(6)(7)(8)(9)(10)(11). These enzymes play a role in the variation in health effect outcomes seen in different populations owing to alcohol consumption.…”