The genetics of alcohol metabolism: role of alcohol dehydrogenase and aldehyde dehydrogenase variants.

TLDR

Alcohol metabolism is driven by the enzymes ADH and ALDH, which exist in multiple gene‑encoded forms with variants that differ in activity and ethnic distribution, thereby influencing alcohol consumption and alcoholism risk. The study seeks to determine how noncoding variants in ADH and ALDH genes affect alcohol metabolism and the risk of alcoholism. Alleles of ADH1B and ADH1C that encode highly active enzymes accelerate ethanol conversion to acetaldehyde, providing protection against alcoholism, while an inactive ALDH2 variant leads to acetaldehyde accumulation and also confers protection.

Abstract

The primary enzymes involved in alcohol metabolism are alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). Both enzymes occur in several forms that are encoded by different genes; moreover, there are variants (i.e., alleles) of some of these genes that encode enzymes with different characteristics and which have different ethnic distributions. Which ADH or ALDH alleles a person carries influence his or her level of alcohol consumption and risk of alcoholism. Researchers to date primarily have studied coding variants in the ADH1 B, ADH1C, and ALDH2 genes that are associated with altered kinetic properties of the resulting enzymes. For example, certain ADH1B and ADH1C alleles encode particularly active ADH enzymes, resulting in more rapid conversion of alcohol (i.e., ethanol) to acetaldehyde; these alleles have a protective effect on the risk of alcoholism. A variant of the ALDH2 gene encodes an essentially inactive ALDH enzyme, resulting in acetaldehyde accumulation and a protective effect. It is becoming clear that noncoding variants in both ADH and ALDH genes also may influence alcohol metabolism and, consequently, alcoholism risk; the specific nature and effects of these variants still need further study.