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.

Figure 1

Forest plots of ln (OR) with 95% CI for the allelic analysis. Black squares indicate the ln (OR) (ln (OR) can be better fitted than OR), with the size of the square inversely proportional to its variance, and horizontal lines represent the 95% CIs. The pooled results are indicated by the unshaded black diamond. Six datasets including Chen 1997 (Atayal) (Chen et al. 1997), Chen 1997 (Bunun) (Chen et al. 1997), Chen 1997 (Paiwan) (Chen et al. 1997), Shen 1997 (b) (Elunchun) (Shen et al. 1997b), Fan 1998 (Elunchun) (Fan et al. 1998), and Konishi 2004(Konishi et al. 2004), are not shown on the forest plots because the wide CIs can not fit into the current version of the plots.

Figure 2

Forest plots of ln (OR) with 95% CI for the dominant model of (lys-lys + lys-glu) vs. glu-glu. Six datasets are not shown on the forest plots as described above.

Figure 3

Egger’s funnel plots of publication bias analysis for the allelic analysis. A larger deviation from the funnel curve of each study means more pronounced asymmetry. Results from small studies will scatter widely at the bottom of the graph, with the spread narrowing among larger studies.

Figure 4

Retrospective analysis of the alleles. Analysis in retrospect was based on publication year since 1991.

Figure 5

Graphical representation of the LD structure of the ALDH2 gene for the Asian populations. The LD structure, spanning 902kb, was constructed using the Asian genotype data of 351 SNPs. Vertical tick marks above the name indicate the relative genomic position of each SNP. The LD structure represents the pairwise calculation of D’ for each possible combination of SNPs. D’ < 0.5 is shown in white, D’ = 1.0 in dark red, with increasing shades of red between representing increasing D’ between the 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.

Figure 6

504lys allele frequencies among different populations. Blue and red represent 504lys and 504glu, respectively. Upper graphs are based on the cases, lower graphs on controls. The geographical borders (Miyazaki et al. 1993) of Taiwan aboriginals were from a previous study.