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

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.

Figure 1

Relative sizes and positions of the seven human alcohol dehydrogenase (ADH) genes on the long arm of chromosome 4 (i.e., chromosome 4q). They are shown in the direction in which the genes are transcribed (arrows), but this is opposite to their orientation on chromosome 4q (i.e., ADH5 is closest to the region where the chromosome arms are joined [i.e., the centromere]). The distances between the genes are indicated in kilobasepairs (kb).

Figure 2

Linkage disequilibrium (LD) among single-nucleotide polymorphisms (SNPs) in the alcohol dehydrogenase (ADH) genes. The positions of the genes are indicated at the top. SNPs in which particular combinations of alleles are commonly inherited together have a high LD, depicted in the figure as darker-shaded boxes at the intersections of the SNPs that are being compared. SNPs in which combinations of alleles essentially are random have a lower LD (indicated by lighter shades). SNPs within genes generally are in high LD with each other, whereas SNPs in different genes typically have a lower LD between them. One region of moderately high LD spans most of the genes except ADH7. At one site of the ADH7 gene, frequent rearrangement of the genetic information (i.e., recombination) has occurred so that SNPs upstream of that site are randomly associated with SNPs downstream of that site (as indicated by the area of mostly white boxes). SOURCE: Modified from Edenberg et al. 2006.