Interaction between the Functional Polymorphisms of the Alcohol-Metabolism Genes in Protection against Alcoholism

Chen, Chiao Chicy; Lu, Ru Band; Chen, Yi Chyan; Wang, Ming Fang; Chang, Yue Cune; Li, Ting Kai; Yin, Shih‐Jiun

doi:10.1086/302540

Cited by 431 publications

(419 citation statements)

References 69 publications

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“…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].…”

Section: Resultsmentioning

confidence: 99%

Alcoholism and alcohol drinking habits predicted from alcohol dehydrogenase genes

et al. 2007

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Alcohol drinking habits and alcoholism are partly genetically determined. Alcohol is degraded primarily by alcohol dehydrogenase (ADH) wherein genetic variation that affects the rate of alcohol degradation is found in ADH1B and ADH1C. It is biologically plausible that these variations may be associated with alcohol drinking habits and alcoholism. By genotyping 9080 white men and women from the general population, we found that men and women with ADH1B slow vs fast alcohol degradation drank more alcohol and had a higher risk of everyday drinking, heavy drinking, excessive drinking and of alcoholism. For example, the weekly alcohol intake was 9.8 drinks (95% confidence interval (CI): 9.1-11) among men with the ADH1B Á 1/1 genotype compared to 7.5 drinks (95% CI: 6.4-8.7) among men with the ADH1B Á 1/2 genotype, and the odds ratio (OR) for heavy drinking was 3.1 (95% CI: 1.7-5.7) among men with the ADH1B Á 1/1 genotype compared to men with the ADH1B Á 1/2 genotype. Furthermore, individuals with ADH1C slow vs fast alcohol degradation had a higher risk of heavy and excessive drinking. For example, the OR for heavy drinking was 1.4 (95% CI: 1.1-1.8) among men with the ADH1C Á 1/2 genotype and 1.4 (95% CI: 1.0-1.9) among men with the ADH1B Á 2/2 genotype, compared with men with the ADH1C Á 1/1 genotype. Results for ADH1B and ADH1C genotypes among men and women were similar. Finally, because slow ADH1B alcohol degradation is found in more than 90% of the white population compared to less than 10% of East Asians, the population attributable risk of heavy drinking and alcoholism by ADH1B Á 1/1 genotype was 67 and 62% among the white population compared with 9 and 24% among the East Asian population.

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Section: Resultsmentioning

confidence: 99%

Alcoholism and alcohol drinking habits predicted from alcohol dehydrogenase genes

et al. 2007

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“…6,7 A sequence of backward and forward stepwise regression analyses incorporated two-way and three-way interaction effects into the model. The resulting final model contains the seven markers through linear and quadratic main effects and interaction terms that cumulatively account for 11.6% of the total phenotypic variance ( Table 3).…”

Section: Resultsmentioning

confidence: 99%

Multi-locus interactions predict risk for post-PTCA restenosis: an approach to the genetic analysis of common complex disease

et al. 2002

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The complexity of recognizing the potential contribution of a number of possible predictors of complex disorders is increasingly challenging with the application of large-scale single nucleotide polymorphism (SNP) typing. In the search for putative genetic factors predisposing to coronary artery restenosis following balloon angioplasty, we determined genotypes for 94 SNPs representing 62 candidate genes, in a prospectively assembled cohort of 342 cases and 437 controls. Using a customized coupled-logistic regression procedure accounting for both additive and interactive effects, we identified seven SNPs in seven genes that, together, showed a statistically significant association with restenosis incidence (P Ͻ0.0001), accounting for 11.6% of overall variance observed. Among them are candidate genes for cardiovascular pathophysiology (apolipoprotein-species and NOS), inflammatory response (TNF receptor and CD14), and cell-cycle control (p53 and p53-associated protein). Our results emphasize the need to account for complex multi-gene influences and interactions when assessing the molecular pathology of multifactorial medical entities.

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“…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%

“…On the other hand, the results are far less conclusive for Caucasians because here allele ADH2*2 is found at very low frequency. 6 In addition, there is evidence that ADH2*2 and ADH3*1 alleles are in linkage disequilibrium, 7,8 which clearly indicates that their contribution to the associated risk of alcoholism is not independent.…”

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confidence: 99%

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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Interaction between the Functional Polymorphisms of the Alcohol-Metabolism Genes in Protection against Alcoholism

Cited by 431 publications

References 69 publications

Alcoholism and alcohol drinking habits predicted from alcohol dehydrogenase genes

Alcoholism and alcohol drinking habits predicted from alcohol dehydrogenase genes

Multi-locus interactions predict risk for post-PTCA restenosis: an approach to the genetic analysis of common complex disease

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

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