Genetic polymorphism of alcohol dehydrogenase in europeans: TheADH2*2 allele decreases the risk for alcoholism and is associated withADH3*1

Abstract

Polymorphism at the ADH2 and ADH3 loci of alcohol dehydrogenase (ADH) has been shown to have an effect on the predisposition to alcoholism in Asian individuals. However, the results are not conclusive for white individuals. We have analyzed the ADH genotype of 876 white individuals from Spain (n ‫؍‬ 251), France (n ‫؍‬ 160), Germany (n ‫؍‬ 184), Sweden (n ‫؍‬ 88), and Poland (n ‫؍‬ 193). Peripheral blood samples from healthy controls and groups of patients with viral cirrhosis and alcohol-induced cirrhosis, as well as alcoholics with no liver disease, were collected on filter paper. Genotyping of the ADH2 and ADH3 loci was performed using polymerase chain reactionrestriction fragment length polymorphism methods on white cell DNA. In healthy controls, ADH2*2 frequencies ranged from 0% (France) to 5.4% (Spain), whereas ADH3*1 frequencies ranged from 47.6% (Germany) to 62.5% (Sweden). Statistically significant differences were not found, however, between controls from different countries, nor between patients with alcoholism and/or liver disease. When all individuals were grouped in nonalcoholics (n ‫؍‬ 451) and alcoholics (n ‫؍‬ 425), ADH2*2 frequency was higher in nonalcoholics (3.8%) than in alcoholics (1.3%) (P ‫؍‬ .0016), whereas the ADH3 alleles did not show differences. Linkage disequilibrium was found between ADH2 and ADH3, resulting in an association of the alleles ADH2*2 and ADH3*1, both coding for the most active enzymatic forms. In conclusion, the ADH2*2 allele decreases the risk for alcoholism, whereas the ADH2*2 and ADH3*1 alleles are found to be associated in the European population. (HEPATOLOGY 2000;31:984-989.)Ingested alcohol is mostly metabolized in the liver by the successive action of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). Both enzymes exhibit genetic polymorphisms that influence the rate of conversion of ethanol to acetaldehyde, and of acetaldehyde to acetate. It has been consistently reported that ALDH2 is the most important alcohol-metabolizing gene affecting predisposition to alcoholism in Asian populations. The prevalence of the ALDH2*2 allele, which codes for a physiologically inactive mitochondrial ALDH form, is lower in alcoholics than in nonalcoholics. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] However, this allele has not been found in white individuals. 21 Regarding ADH, polymorphism is detected at the ADH2 and ADH3 loci. Alleles of ADH2 found in whites and Asians are ADH2*1 and ADH2*2, which encode for the low activity (␤1) and high activity (␤2) subunits, respectively. The kcat values for the resulting dimeric isozymes are very different: 9.2 min Ϫ1 for ␤1␤1 and 400 min Ϫ1 for ␤2␤2. 22 The ADH2*2 frequency is much higher in Asians (60%-80%) than in whites (0%-10%). 21 ADH3 alleles are ADH3*1 and ADH3*2, which produce the ␥1 and ␥2 subunits. The ␥1␥1 isozyme (kcat ϭ 87 min Ϫ1 ) is moderately more active than the ␥2␥2 isozyme (kcat ϭ 35 min Ϫ1 ). 22 ADH3*1 frequency is about 50% to 60% in whites and higher than 90% in Asians. 3,23 ...

Interaction between alcohol dehydrogenase II gene, alcohol consumption, and risk for breast cancer

“…Since we, like others (Gilder et al, 1993;Whitfield et al, 1998;Borras et al, 2000), observed no association between ADH2 polymorphism and alcohol consumption in women without breast cancer, we could assess the interaction between these factors and risk for breast cancer using the case-only analysis, which is more powerful to detect gene-environment interactions than a case -control study (Piegorsch et al, 1994). In contrast to a case -control analysis, our analytic strategy has also the advantage of assessing associations independently in women with identical data collection procedures (i.e.…”

“…In particular, the observed risk and interaction may not be entirely due to the ADH2 polymorphism itself, but also to the linkage of ADH2 with other genes that are associated with an increased risk for breast cancer. ADH2 has been observed to be linked to ADH3 (Borras et al, 2000) and the ADH3*1 genotype was observed to be a risk factor for breast cancer in premenopausal women (Freudenheim et al, 1999). However, given the stronger metabolic effects of ADH2, the ADH3 -breast cancer association might also be confounded by ADH2.…”

Alcoholism and alcohol drinking habits predicted from alcohol dehydrogenase genes

“…The hazard ratio of hospitalization for alcoholism in men and women with the slow alcohol degradation ADH1B Á 1/1 genotype was 3.9 (95% CI: 1.0-16) and 2.7 (95% CI: 0. [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20].…”

Alcohol dehydrogenase 1B (ADH1B) genotype, alcohol consumption and breast cancer risk by age 50 years in a German case–control study

“…However, since ADH1B genotype and alcohol intake are not independent in our study population, the modifying effect of the ADH1B genotype on breast cancer risk associated with alcohol consumption is overestimated in the case-only analysis, partly due to residual confounding by differences in alcohol consumption caused by the genotype (Albert et al, 2001). Indeed, indications for an association between ADH1B genotype and alcohol consumption, alcoholism or ADH1B genotype, alcohol and breast cancer C Lilla et al adverse reactions such as flushing were observed in previous studies (Whitfield et al, 1998;Borras et al, 2000;Loew et al, 2003;Neumark et al, 2004). There is still controversy in the literature regarding the effect of ADH1B genotype on alcohol pharmacokinetics in vivo.…”