Health-related effects of genetic variations of alcohol-metabolizing enzymes in African Americans

Alcohol Research & Health, Wntr, 2007 by Denise M. Scott, Robert E. Taylor

Alcohol metabolism involves two key enzymes--alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). There are several types of ADH and ALDH, each of which may exist in several variants (i.e., isoforms) that differ in their ability to break down alcohol and its toxic metabolite acetaldehyde. The isoforms are encoded by different gene variants (i.e., alleles) whose distribution among ethnic groups differs. One variant of ADH is ADH1B, which is encoded by several alleles. An allele called ADH1B*3 is unique to people of African descent and certain Native American tribes. This allele is associated with more rapid breakdown of alcohol, leading to a transient accumulation of acetaldehyde. African Americans carrying this allele are less likely to have a family history of alcoholism and experience a less rewarding subjective response to alcohol. Moreover, children of mothers with this allele are less vulnerable to alcohol-related birth defects. The enzyme ALDH1 also is encoded by several alleles. Two of these alleles that are found in African Americans--ALDH1A1*2 and ALDH1A1*3--may be associated with a reduced risk of alcoholism. KEY WORDS: Alcohol and other drug (AOD) use, abuse, and dependence; drinking behavior; African American; ethanol metabolism; alcohol dehydrogenase (ADH); aldehyde dehydrogenase (ALDH); acetaldehyde; genetic factors; genetic polymorphisms; allele; ADH1B; ADH1B*3; ALDH1A1*2; ALDH1A1*3; protective factors; alcohol flush reaction

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Alcohol metabolism is one of the biological determinants that can influence drinking behavior and the development of alcohol dependence and alcohol-induced organ damage (Yin and Agarwal 2001). Oxidative alcohol metabolism depends on two key enzymes--alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). ADH converts alcohol to the highly toxic metabolite acetaldehyde, which then is metabolized by ALDH to acetate and eventually to carbon dioxide (C[O.sub.2]) and water. For both ADH and ALDH, several variants (i.e., isoforms) exist that differ in their ability to break down alcohol and acetaldehyde, respectively. For example, certain ADH isoforms are particularly active and rapidly break down alcohol to acetaldehyde; conversely, certain ALDH isoforms have very low activity and break down acetaldehyde slowly. In both of these cases, acetaldehyde will accumulate after alcohol consumption, exerting its toxic effects (e.g., causing a flushing syndrome characterized by facial flushing, nausea, and rapid heartbeat.) These effects deter people from alcohol consumption and therefore have a protective effect against alcoholism.

Because alcohol metabolism can significantly influence drinking behavior and the risk for alcoholism (Yin and Agarwal 2001), it is important to understand how genetic factors influence metabolism. The different ADH and ALDH isoforms are encoded by different genes, each of which again may be present in different variations (i.e., alleles). The occurrence of alternate alleles in a population is termed polymorphism. The activity and distribution of the ADH and ALDH alleles and of the proteins they encode have been intensively studied. For example, researchers have identified differences across ethnic groups in the frequencies with which individual genes or gene variants occur (Osier et al. 2002; Chou et al. 1999). This brief article examines the prevalence and effects of genetic variants of ADH and ALDH genes in African Americans.

ADH POLYMORPHISMS IN AFRICAN AMERICANS

There are numerous types of ADH, which, based on their structural similarities, can be categorized into five classes. (For more information on the classification and subtypes of ADH and ALDH enzymes, see the article by Edenberg.) The class I ADH enzymes include ADH1A, ADH1B, and ADH1C, which are considered the most important ADH isoforms in alcohol metabolism because they are present in the largest amounts and account for the majority of alcohol metabolism in humans (Jornvall and Hoog 1995). The genes encoding the class I ADH enzymes are called ADH1A, ADH1B, and ADH1C. For some of these genes, several alleles have been identified, particularly for the ADH1B gene. For this gene, there are three main alleles--ADH1B*1, ADH1B*2, and ADH1B*3--that result in significant differences in alcohol metabolism.

The prevalence of the alleles varies in different ethnic populations. ADH1B*1 is the most common allele and occurs in varying frequencies in all populations. The ADH1B*2 allele is present in the majority of Far East Asians (Goedde et al. 1997) and in smaller percentages of Caucasians (Borras et al. 2000), people of Jewish descent (Shea et al. 2001; Hasin et al. 2002), and African Americans (Luo et al. 2006). Finally, ADH1B*3 has been found in people of African descent and certain tribes of Native Americans (Thomasson et al. 1995; Ehlers et al. 2001, 2003).

Research into the genetics of alcohol metabolism in the African-American population is very limited; however, several studies, which are reviewed below, have examined important aspects of alcohol use that may be linked to the ADH1B*3 allele.