Alcohol Dehydrogenases, Aldehyde Dehydrogenases, and Alcohol Use Disorders: A Critical Review

Abstract

Alcohol use disorders (AUDs) are complex traits, meaning that variations in many genes contribute to the risk, as does the environment. Although the total genetic contribution to risk is substantial, most individual variations make only very small contributions. By far the strongest contributors are functional variations in 2 genes involved in alcohol (ethanol [EtOH]) metabolism. A functional variant in alcohol dehydrogenase 1B (ADH1B) is protective in people of European and Asian descent, and a different functional variant in the same gene is protective in those of African descent. A strongly protective variant in aldehyde dehydrogenase 2 (ALDH2) is essentially only found in Asians. This highlights the need to study a wide range of populations. The likely mechanism of protection against heavy drinking and AUDs in both cases is alteration in the rate of metabolism of EtOH that at least transiently elevates acetaldehyde. Other ADH and ALDH variants, including functional variations in ADH1C, have also been implicated in affecting drinking behavior and risk for alcoholism. The pattern of linkage disequilibrium in the ADH region and the differences among populations complicate analyses, particularly of regulatory variants. This critical review focuses upon the ADH and ALDH genes as they affect AUDs.

Keywords: ADH Genes; ALDH Genes; Alcohol Consumption; Alcohol Dependence; Alcohol Metabolism; Linkage Disequilibrium.

Figure 1.. Primary pathway of alcohol metabolism.

The oxidation of alcohol to acetaldehyde is reversible in vitro, but in vivo the overall reaction goes strongly toward acetate due to the activity of ALDH2. The ADH and ALDH enzymes that carry out most of the metabolism are shown.

Figure 2.. Expression of ADH mRNA in selected tissues.

Data are in median transcripts per million transcripts (tpm), from GTEx version 7 (gtexportal.org, exported 15 April 2018) (GTEx Consortium, 2013). ADH genes are shown in numerical order, left to right, within each tissue. Inset shows enlarged image of stomach, brain (maximum tpm across all brain tissues) and whole blood.

Figure 3.. ADH region of chromosome 4.

ADH genes are arranged head-to-tail along chromosome 4, and transcribed in the opposite direction. Numbers below the line are distances between genes, in kb.

Figure 4.. Expression of key ALDH RNAs in selected tissues.

Data are median tpm, from GTEx version 7 (exported 15 April 2018) (GTEx Consortium, 2013).