ADH1B: From alcoholism, natural selection, and cancer to the human phenome

Abstract

The ADH1B (Alcohol Dehydrogenase 1B (class I), Beta Polypeptide) gene and its best-known functional alleles, Arg48His (rs1229984, ADH1B*2) and Arg370Cys (rs2066702, ADH1B*3), have been investigated in relation to many phenotypic traits; most frequently including alcohol metabolism and alcohol drinking behaviors, but also human evolution, liver function, cancer, and, recently, the comprehensive human phenome. To understand ADH1B functions and consequences, we provide here a bioinformatic analysis of its gene regulation and molecular functions, literature review of studies focused on this gene, and a discussion regarding future research perspectives. Certain ADH1B alleles have large effects on alcohol metabolism, and this relationship particularly encourages further investigations in relation to alcoholism and alcohol-associated cancer to understand better the mechanisms by which alcohol metabolism contributes to alcohol abuse and carcinogenesis. We also observed that ADH1B has complex mechanisms that regulate its expression across multiple human tissues, and these may be involved in cardiac and metabolic traits. Evolutionary data strongly suggest that the selection signatures at the ADH1B locus are primarily related to effects other than those on alcohol metabolism. This is also supported by the involvement of ADH1B in multiple molecular pathways and by the findings of our recent phenome-wide association study. Accordingly, future studies should also investigate other functions of ADH1B potentially relevant for the human phenome. © 2017 Wiley Periodicals, Inc.

Replication of the Interaction of PRKG1 and Trauma Exposure on Alcohol Misuse in an Independent African American Sample

“…This framework suggests that rs1729578 may be a “plasticity” gene, which may increase an individual's susceptibility to environmental influences, rather than a “vulnerability” gene, which heightens risk for psychological conditions following adversity and shows little or no effects in nonadverse environments; however, this interpretation is speculative and further study is needed to examine the mechanism by which this G×E operates. Notably, this pattern of findings is consistent with the pattern of findings published by Polimanti and colleagues (), who also demonstrated a cross‐over interaction wherein mean scores of alcohol misuse decreased across alleles in the non‐trauma‐exposed group and increased across alleles in the trauma‐exposed group, providing replicated support for the potential effects of rs1729578 as a “plasticity” gene.…”

“…In addition to the interaction effect being observed in only one out of the three analyzed alcohol outcomes, a limitation of this study was that our finding was no longer statistically significant once an FDR was applied to account for multiple testing across alcohol phenotypes. Additionally, although the sample tested 916 and 361 trauma‐exposed and unexposed individuals, respectively, there was limited power to replicate the effect sizes reported by Polimanti and colleagues (). Since discovery studies tend to overestimate true effect size and the current study estimated a larger effect size, it is possible that the replication may have been a false‐positive.…”

Ancestry‐specific and sex‐specific risk alleles identified in a genome‐wide gene‐by‐alcohol dependence interaction study of risky sexual behaviors

“…This approach can be useful to identify molecular mechanisms related to loci associated to alcohol drinking behaviors [Polimanti and Gelernter, 2017]. Because different ancestry groups can show different risk alleles for a given trait but often nevertheless present the same genetic architecture, we used the GW-GxAD meta-analysis in EAs as the discovery sample and the GW-GxAD meta-analysis in AAs for replication.…”

The roles of alcohol dehydrogenase in patients with atrial fibrillation

“…The enzyme activity of ADH1B is higher in patients with ADH1B*2 genotype, which leads to a higher level of acetaldehyde, cytotoxic effects, and altered calcium hemostasis. In addition, ADH may also have some distinct physiological roles in metabolizing different substrates such as retinol or lipid peroxidation products, in addition to alcohol or its metabolites , . Accordingly, the overexpression of ADH or higher enzyme activity of ADH1B*2 genotype might increase oxidative stress .…”

“…In addition, ADH may also have some distinct physiological roles in metabolizing different substrates such as retinol or lipid peroxidation products, in addition to alcohol or its metabolites. 14,27 Accordingly, the overexpression of ADH or higher enzyme activity of ADH1B*2 genotype might increase oxidative stress. 28 The cytotoxic effects, altered calcium homeostasis, and increase oxidative stress will lead to shortening of action potential duration and spontaneous depolarization of cardiomyocytes, which underlies the mechanisms of AF attack or recurrence.…”