Alcohol-Metabolising Genes and Alcoholism Among Taiwanese Han Men: Independent Effect of ADH2, ADH3 and ALDH2

Chen, Wei-Jen; Loh, El Wui; Hsu, Yun-Pung P.; Chen, Chiao Chicy; Yu, Jianguo; Cheng, Andrew T. A.

doi:10.1192/bjp.168.6.762

Cited by 153 publications

(134 citation statements)

References 17 publications

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“…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.…”

Section: Adh2mentioning

confidence: 99%

“…Although the majority of studies reviewed in this meta-analysis reported on more than two of the investigated polymorphisms, only four of them provided analyses of haplotypes. 7,8,37,40 Seven studies [5][6][7][8]31,37,40 investigated the existence of linkage disequilibrium, and six demonstrated linkage disequilibrium between ADH2 and ADH3. 5,7,8,31,37,40 Because all studies provided unadjusted estimates, adjusted pooled OR were not calculated.…”

Section: Summary Statisticsmentioning

confidence: 99%

“…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,…”

Section: Eligible Studiesmentioning

confidence: 99%

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

et al. 2006

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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-

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Section: Adh2mentioning

confidence: 99%

Section: Summary Statisticsmentioning

confidence: 99%

Section: Eligible Studiesmentioning

confidence: 99%

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

et al. 2006

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“…There is one exception: the "flushing syndrome" variants at the aldehyde (ALDH) and alcohol (ADH) dehydrogenase loci in Asian individuals do provide genes of major effect in this population. Individuals with these gene variants are at much lower risk for becoming dependent on alcohol than individuals with other genotypes [13] in Chinese [14,15], Korean [16], Japanese [17][18][19][20][21][22] and other populations [23,24]. Homozygous ALDH2*2 individuals are strongly protected from alcohol dependence [17,18].…”

Section: Complex Genetic Influences On Human Addiction Vulnerabilimentioning

confidence: 99%

“Higher order” addiction molecular genetics: Convergent data from genome-wide association in humans and mice

Uhl

Drgon

Johnson

et al. 2008

Biochemical Pharmacology

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Family, adoption and twin data each support substantial heritability for addictions. Most of this heritable influence is not substance-specific. The overlapping genetic vulnerability for developing dependence on a variety of addictive substances suggests large roles for "higher order" pharamacogenomics in addiction molecular genetics. We and others have now completed genomewide association (GWA) studies of DNAs from individuals with dependence on a variety of addictive substances vs appropriate controls. Recently reported replicated GWA observations identify a number of genes based on comparisons between controls and European-American and African-American polysubstance abusers. Here we review the convergence between these results and data that compares control samples and a) alcohol dependent European Americans, b) methamphetamine dependent Asians and c) nicotine dependent samples from European backgrounds. We also compare these human data to quantitative trait locus (QTL) results from studies of addiction-related phenotypes in mice that focus on alcohol, methamphetamine and barbiturates. These comparisons support a genetic architecture built from largely-polygenic contributions of common allelic variants to dependence on a variety of legal and illegal substances. Many of the gene variants identified in this way are likely to alter specification and maintenance of neuronal connections. KeywordsAssociation genome scanning; substance dependence; microarray; pooled; neuronal connections * To whom correspondence should be addressed at: Molecular Neurobiology, Box 5180, Baltimore, MD 21224 phone: (410) 550-2843 x 146, fax: (410) 550-1535, guhl@intra.nida.nih.gov. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access A. Studies of human addiction vulnerabilitiesVulnerability to addictions is a complex trait with strong genetic influences that are largely shared by abusers of different legal and illegal addictive substances [1][2][3][4]. This conclusion comes from family, adoption and twin studies. Family studies clearly document that first degree relative (eg sibs) of addicts display greater risk for developing substance dependence than more distant relatives [1,5]. Adoption studies consistently find greater similarities between substance abuse phenotypes with biological relatives than with adoptive family members [1]. In twin studies, differences in concordance between genetically identical and fraternal twins also support heritability for vulnerability to addictions [3,[6][7][8][9][10][11][12]. Twin data allows quantitation of the amount, about 50%, of ad...

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“…The selection of study subjects has been described in detail elsewhere. 7,8 Subjects who met the DSM-III-R diagnostic criteria for alcohol dependence, all with various extents of withdrawal symptoms, were included as cases, and controls were subjects who had never drunk or only occasionally drank small quantities, and were matched to the cases by ethnicity and sex. The mean age for cases was 39.4 years (range 21-69), and that for controls was 57.6 years (range 41-84).…”

Section: Association Of the Gammaaminobutyric Acid A Receptor Gene CLmentioning

confidence: 99%

Association of the gamma-aminobutyric acid A receptor gene cluster with alcohol dependence in Taiwanese Han

et al. 2002

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Molecular Psychiatryimplying an effect on the variance instead of on the mean. 10A second advantage of including measured genotypes in etiological models is that it may improve our understanding of psychiatric conditions. Measured genotypes represent a whole new class of epidemiological risk variables that may provide additional predictive power, shed new light on traditional research issues, and make it possible to examine the mechanisms that describe how genes and environmental risk variables co-act. In comparison with traditional epidemiological risk variables, measured genotypes have advantageous methodological properties arising from the fact that phenotypes or environmental factors cannot cause variations in genotypes. This property facilitates the evaluation of causal relations between health problems and their putative risk factors. 7 EJCG van den Oord

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Alcohol-Metabolising Genes and Alcoholism Among Taiwanese Han Men: Independent Effect of ADH2, ADH3 and ALDH2

Abstract: These findings clearly indicate that all three alcohol-metabolising genes contribute to susceptibility to alcoholism.

Cited by 153 publications

References 17 publications

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

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

“Higher order” addiction molecular genetics: Convergent data from genome-wide association in humans and mice

Association of the gamma-aminobutyric acid A receptor gene cluster with alcohol dependence in Taiwanese Han

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