Further clarification of the contribution of the ADH1C gene to vulnerability of alcoholism and selected liver diseases.
- Authors
- Li, Dawei; Zhao, Hongyu; Gelernter, Joel
- Year
- 2012
- Journal
- Human genetics
- PMID
- 22476623
- DOI
- 10.1007/s00439-012-1163-5
- PMCID
- PMC3557796
The alcohol dehydrogenase 1C (ADH1C) subunit is an important member of the alcohol dehydrogenase family, a set of genes that plays a major role in the catabolism of ethanol. Numerous association studies have provided compelling evidence that ADH1C gene variation (formerly ADH3) is associated with altered genetic susceptibility to alcoholism and alcohol-related liver disease, cirrhosis, or pancreatitis. However, the results have been inconsistent, partially, because each study involved a limited number of subjects, and some were underpowered. Using cumulative data over the past two decades, this meta-analysis (6,796 cases and 6,938 controls) considered samples of Asian, European, African, and Native American origins to examine whether the aggregate genotype provide statistically significant evidence of association. The results showed strong evidence of association between ADH1C Ile350Val (rs698, formerly ADH1C *1/*2) and alcohol dependence (AD) and abuse in the combined studies. The overall allelic (Val vs. Ile or *2 vs. *1) P value was 1 × 10(-8) and odds ratio (OR) was 1.51 (1.31, 1.73). The Asian populations produced stronger evidence of association with an allelic P value of 4 × 10(-33) [OR 2.14 (1.89, 2.43)] with no evidence of heterogeneity, and the dominant and recessive models revealed even stronger effect sizes. The strong evidence remained when stricter criteria and sub-group analyses were applied, while Asians always showed stronger associations than other populations. Our findings support that ADH1C Ile may lower the risk of AD and alcohol abuse as well as alcohol-related cirrhosis in pooled populations, with the strongest and most consistent effects in Asians.
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. Three studies, including Chen 1997 (Atayal), Chen 1997 (Ami), and Chen 1997 (Paiwan), are not shown on the forest plots because the scale of the wide CIs can not fit into the current version of the plot. *, alcoholic patients without alcoholic liver disease, cirrhosis or pancreatitis.
Forest plots of ln(OR) with 95% CI for the dominant model ((ValVal + ValIle) vs. IleIle). Three studies, including Chen 1997 (Atayal), Chen 1997 (Ami), and Chen 1997 (Paiwan), are not shown on the forest plots because the scale of the wide CIs can not fit into the current version of the plot.*, the alcoholic patients without alcoholic liver disease, cirrhosis or pancreatitis.
Egger’s funnel plots of publication bias analysis for the allelic analysis of AD and alcohol abuse in Asians. 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.
Retrospective analysis for the allelic analysis. Analysis in retrospect was based on publication year since 1990.
Allele frequencies among different populations. Blue and red represent Ile350 and 350Val, respectively. Upper graphs are based on the patients and , lower graphs on controls. The geographical borders(Miyazaki et al. 1993) of Taiwan aboriginals were from a previous study.
Graphical representation of the LD structure of the ADH1C gene for the Asian populations. The LD structure, spanning 233 kb, was constructed using the Asian genotype data of 232 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 representing increasing D’ between the SNPs. The genes from left to right are ADH6, ADH1A, ADH1B, ADH1C and ADH7. The ADH1C gene, and ADH1C Ile350Val are shown in red; the selected ADH1C nonsynonymous SNPs are shown in blue; and the other genes are in black.
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