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

Alcohol Research & Health,  Wntr, 2007  by Howard J. Edenberg

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SUMMARY

ADHIB and ALDH2 are the genes most strongly associated with risk for alcoholism. Coding variants in both of these genes are strongly protective. They probably decrease alcoholism risk by increasing local acetaldehyde levels, either because ethanol is oxidized more rapidly or because acetaldehyde is oxidized more slowly. The exact balance between the rates of ethanol and acetaldehyde oxidation could be crucial in determining acetaldehyde concentrations within cells, such that small differences in the relative activities of ADH and ALDH might produce significant differences in acetaldehyde concentration (Kitson 1999). Because of this delicate balance, the effects of variations in ADH and ALDH genes on risk for alcoholism can be demonstrated independently--that is, researchers can determine differences in risk between people carrying different alleles of one gene but identical alleles of the other genes (e.g., Chen et al. 1999b; Thomasson et al. 1991).

The distribution of ADH1B and ALDH2 coding variants differs greatly among different populations; for both genes, the protective alleles most commonly are found in people of East Asian origin (for more information, see the article by Eng et al. in this issue). Variations in genes encoding other ADH enzymes influence alcoholism risk in other populations. For example, ADH4 variants strongly affect alcoholism risk in populations of European descent (Edenberg et al. 2006). Furthermore, noncoding variations in various alcohol-metabolizing enzymes likely also affect risk for alcoholism (Edenberg et al. 2006). These noncoding variants should be studied in more populations.

Although variations in individual ADH and ALDH genes can affect risk for alcoholism, it is important to remember that no one gene determines this risk. An increasing number of genes not related to ethanol metabolism also affect risk (Edenberg and Foroud 2006). Moreover, the contribution of any gene(s) to risk is modulated by other genes as well as by social and environmental factors.

ACKNOWLEDGEMENTS

Related work in the author's laboratory is supported by National Institute on Alcohol Abuse and Alcoholism grants R37 AA006460 and U10 AA008401.

FINANCIAL DISCLOSURE

The author declares that he has no competing financial interests.

REFERENCES

BIRLEY, A.J.; WHITFIELD, J.B.; NEALE, M.C.; ET AL. Genetic time-series analysis identifies a major QTL for in vivo alcohol metabolism not predicted by in vitro studies of structural protein polymorphism at the ADH1B or ADH1C loci. Behavioral Genetics 35(5):509-524, 2005. PMID: 1618-4481

CHEN, C.-C.; LU, R.-B.; CHEN, Y.-C.; ET AL., Interaction between the functional polymorphisms of the alcohol-metabolism genes in protection against alcoholism. American Journal of Human Genetics 65:795-807, 1999a. PMID: 10441588

CHEN, Y.C.; LU, R.B.; PENG, G.S.; ET AL., Alcohol metabolism and cardiovascular response in an alcoholic patient homozygous for the ALDH2*2 variant gene allele. Alcoholism: Climical and Experiemental Researeh 23(12):1853-1860, 1999b. PMID: 10630602