Strong association of the alcohol dehydrogenase 1B gene (ADH1B) with alcohol dependence and alcohol-induced medical diseases

Abstract

Background: The alcohol dehydrogenase 1B gene (ADH1B) is hypothesized to affect predisposition to alcohol dependence (AD) and abuse. A variant of the ADH1B gene (rs1229984 or Arg48His; previously referred to as Arg [*1] and His [*1]) has been reported to be associated with reduced rates of alcohol and drug dependence. Different studies have produced inconclusive results regarding association between rs1229984 (or rs2066702) and substance dependence.

Methods: Using the cumulative association study literature from the past 21 years from both English- and Chinese-language publications, this meta-analysis seeks to clarify the contradictory findings and to examine whether the aggregate data provide new evidence of significant association.

Results: The results, based on a large sample size (9638 cases and 9517 controls), suggested strong associations with alcohol dependence and abuse as well as alcohol-induced liver diseases, with an allelic (Arg vs. His) p value being 1 × 10(-36) and odds ratio (OR) (95% confidence intervals [CI]) 2.06 (1.84-2.31) under the random effects model. The dominant and recessive models produced larger ORs of 2.17 and 3.05, respectively. When more stringent criteria and subgroup analyses were imposed, the associations remained consistent and were strongest in various Asian groups (allelic p = 7 × 10(-42) and OR (95% CI) = 2.24 [1.99-2.51] with ORs of 2.16 and 4.11 for dominant and recessive models, respectively).

Conclusions: Our findings provide further strong evidence for the involvement of the ADH1B gene in the pathogenesis of alcohol dependence and abuse as well as for some alcohol-induced medical diseases in the multiple ethnic populations--in particular, certain Asian populations.

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. Two studies, including Day 1991 and Ehlers 2007 (East Indian Trinidadian) (Cys), are not shown on the forest plots because the scale of the wide CIs can not fit into the current plot. ^*, alcoholic patients without alcoholic liver disease, cirrhosis or pancreatitis.

Figure 2

Retrospective analysis for the allelic analysis. Analysis in retrospect was based on publication year since 1990.

Figure 3

His48 allele frequencies among different populations. Blue and red represent His48 and Arg48, respectively. Upper graphs are based on the patients and , lower graphs on controls. Only those 57 studies that described their geographic origins specifically are shown on the map. The geographical borders(111) of Taiwan aboriginals were based on a previous study.