Polymorphism of ADH and ALDH Genes among Four Ethnic Groups in China and Effects upon the Risk for Alcoholism

Abstract

The alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs) that metabolize ethanol are polymorphic. Different alleles encode subunits of the enzymes that differ in their rate of metabolizing ethanol. These polymorphisms are distributed differently among populations and have been shown to influence the risk for alcoholism in some Asian populations. We have examined the allele frequencies at the ADH2, ADH3, and ALDH2 loci in four populations from China (Han, Mongolian, Korean, and Elunchun) and in alcoholics within each population. The four populations differ in allele frequencies, with the Elunchun having a much lower frequency of ADH2*2 alleles, and the Mongolian and Elunchun having a much lower frequency of ALDH2*2 alleles. Within each population, alleles at one or more of these three loci are protective against alcoholism, although the populations differ in which loci play significant roles. The protective allele at each locus (ALDH2*2, ADH2*2, and ADH3*1) encodes a subunit that either metabolizes ethanol to acetaldehyde more rapidly or slows the conversion of acetaldehyde to acetate. Taken as a whole, data demonstrate that genetic differences in the enzymes that metabolize alcohol can substantially affect the risk for alcoholism.

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

“…In sensitivity analysis, 5,26,29,31,45 the pattern of results was also similar. In a subgroup analysis for the men 6,32,39 (no study provided data for women), there was no association. However, the lack of association was due to the Caucasians, 6 , respectively), whereas for the Caucasians the associations were not significant.…”

“…Data from 50 studies that investigated the association between any of the ADH2, ADH3, CYP2E1, and ALDH2 polymorphisms and alcoholism, and alcohol-induced liver disease, met the inclusion criteria and were included in the meta-analysis. Thirty-three studies dealt with ADH2, 2 [2][3]6,8,11,[26][27][29][30][31][32]37,[39][40][41][42][43][44]46,47,51 and 20 studies in CYP2E1. 6,11,26,31,32,35,[41][42][43]54,[57][58][59][60][61][62][63][64][65]67 To investigate the association between any of the four loci considered and alcohol-induced liver disease, ten studies dealt with ADH2, 5,6,[31][32][33]35,…”

“…Eight studies in alcoholism 28,33,38,39,44,56,65,66 and two studies in liver disease 33,44 reported that the controls were age-or sex-matched. Studies were conducted in various populations of racial background: 24 involved Caucasians, 5 …”

“…For the ALDH2 polymorphism, all studied individuals but 1 among Mexican Americans 26 in alcoholism and 1 among Caucasians 31 in alcoholic liver disease, were homozygous for the *1/*1 genotype in Caucasians and Americans; therefore, the analysis was restricted to East Asians. [2][3][4]8,11,27,28,32,35,37,[39][40][41][42][43][44]46,56,57 There was heterogeneity among studies (P Ͻ .01), and the allele contrast was highly significant (RE OR ϭ 4.35 [95% CI 3.04, 6.23]). The recessive and dominant models for the effect of allele ALDH2*1 showed highly significant associations.…”

Evidence for a two-stage model of dependence using the NESARC and its implications for genetic association studies

“…Finally, the definitions of "abstainer" used in the study (one full drink for alcohol, any use over the lifecourse for drugs) may not have identified initial users of very small amounts (e.g., less than a full drink of alcohol or a single puff of cannabis) who had negative reactions that discouraged further use (Eissenberg and Balster, 2000). For example, many Asian studies of ALDH2, a gene affecting alcohol metabolism, explicitly included abstainers (e.g., Chen et al, 1999;Shen et al, 1997;Sun et al, 2002), and our understanding of ALDH2 could not have been gained without abstainers in the samples. Individuals homozygous for ALDH2*2 have such unpleasant reactions to alcohol that they cannot drink more than a small sip.…”