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Strong protective effect of the aldehyde dehydrogenase gene (ALDH2) 504lys (*2) allele against alcoholism and alcohol-induced medical diseases in Asians

Abstract

Alcohol is oxidized to acetaldehyde, which in turn is oxidized to acetate. The aldehyde dehydrogenase 2 gene (ALDH2) is the most important gene responsible for acetaldehyde metabolism. Individuals heterozygous or homozygous for the lys (A or *2) allele at the single nucleotide polymorphism (SNP) glu504lys (rs671) of ALDH2 have greatly reduced ability to metabolize acetaldehyde, which greatly decreases their risk for alcohol dependence (AD). Case–control studies have shown association between this SNP and alcohol dependence as well as alcohol-induced liver disease. However, some studies have produced insignificant results. Using cumulative data from the past 20 years predominately from Asian populations (from both English and Chinese publications), this meta-analysis sought to examine and update whether the aggregate data provide new evidence of statistical significance for the proposed association. Our results (9,678 cases and 7,331 controls from 53 studies) support a strong association of alcohol abuse and dependence, with allelic P value of 3 × 10−56 and OR of 0.23 (0.2, 0.28) under the random effects model. The dominant model (lys–lys + lys–glu vs. glu–glu) also showed strong association with P value of 1 × 10−44 and OR of 0.22 (0.18, 0.27). When stricter criteria and various sub-group analyses were applied, the association remained strong (for example, OR = 0.23 (0.18, 0.3) and P = 2 × 10−28 for the alcoholic patients with alcoholic liver disease, cirrhosis, or pancreatitis). These findings provide confirmation of the involvement of the human ALDH2 gene in the pathogenesis of AD as well as alcohol-induced medical illnesses in East-Asians.

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Acknowledgments

This work was supported by the research grants DA12849, DA12690, AA017535, AA12870, and AA11330 from the National Institutes of Health, USA. We also thank Dr. Xingguang Luo for very helpful comments on the manuscript.

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None.

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Correspondence to Dawei Li.

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Supplementary Figure 1 Egger’s funnel plots of publication bias analysis for the dominant model. (TIFF 243 kb)

Supplementary Figure 2 Retrospective analysis for the dominant model. Analysis in retrospect was based on publication year since 1991. (TIFF 9 kb)

Supplementary Figure 3 Graphical representation of the LD structure of the ALDH2 gene for the European populations. The LD structure, spanning 902 kb, was constructed using the European genotype data of 256 SNPs. The genes from left to right are: ATXN2, BRAP, ACAD10, ALDH2, MAPKAPK5, TMEM116, ERP29, C12orf30, TRAFD1, C12orf51. The ALDH2 gene and the SNP rs671 are shown in red; and rs1062136 (Val/Glu), which is a nonsynonymous SNP, is shown in blue. The other genes are in black. (TIFF 5353 kb)

Supplementary Figure 4 LD structure of ALDH2 rs671 in the Asian populations based on the 1000 Genomes Project. The x-axis represents the physical positions of the SNPs, the left y-axis represents the r2 values, and the right y-axis represents the recombination rate. The brightness of each point is proportional to the r2 value for that SNP. (JPEG 150 kb)

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Li, D., Zhao, H. & Gelernter, J. Strong protective effect of the aldehyde dehydrogenase gene (ALDH2) 504lys (*2) allele against alcoholism and alcohol-induced medical diseases in Asians. Hum Genet 131, 725–737 (2012). https://doi.org/10.1007/s00439-011-1116-4

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Keywords

  • Pancreatitis
  • Alcohol Dependence
  • Aldehyde Dehydrogenase
  • Alcoholic Liver Disease
  • Genotypic Analysis