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      Effect of the allelic variants of aldehyde dehydrogenase ALDH2*2 and alcohol dehydrogenase ADH1B*2 on blood acetaldehyde concentrations

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          Abstract

          Alcoholism is a complex behavioural disorder. Molecular genetics studies have identified numerous candidate genes associated with alcoholism. It is crucial to verify the disease susceptibility genes by correlating the pinpointed allelic variations to the causal phenotypes. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are the principal enzymes responsible for ethanol metabolism in humans. Both ADH and ALDH exhibit functional polymorphisms among racial populations; these polymorphisms have been shown to be the important genetic determinants in ethanol metabolism and alcoholism. Here, we briefly review recent advances in genomic studies of human ADH/ALDH families and alcoholism, with an emphasis on the pharmacogenetic consequences of venous blood acetaldehyde in the different ALDH2 genotypes following the intake of various doses of ethanol. This paper illustrates a paradigmatic example of phenotypic verifications in a protective disease gene for substance abuse.

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          Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology.

          Alvin Matsumoto, Min You, D Crabb … (2004)
          Alcohol dehydrogenase (ADH) and mitochondrial aldehyde dehydrogenase (ALDH2) are responsible for metabolizing the bulk of ethanol consumed as part of the diet and their activities contribute to the rate of ethanol elimination from the blood. They are expressed at highest levels in liver, but at lower levels in many tissues. This pathway probably evolved as a detoxification mechanism for environmental alcohols. However, with the consumption of large amounts of ethanol, the oxidation of ethanol can become a major energy source and, particularly in the liver, interferes with the metabolism of other nutrients. Polymorphic variants of the genes for these enzymes encode enzymes with altered kinetic properties. The pathophysiological effects of these variants may be mediated by accumulation of acetaldehyde; high-activity ADH variants are predicted to increase the rate of acetaldehyde generation, while the low-activity ALDH2 variant is associated with an inability to metabolize this compound. The effects of acetaldehyde may be expressed either in the cells generating it, or by delivery of acetaldehyde to various tissues by the bloodstream or even saliva. Inheritance of the high-activity ADH beta2, encoded by the ADH2*2 gene, and the inactive ALDH2*2 gene product have been conclusively associated with reduced risk of alcoholism. This association is influenced by gene-environment interactions, such as religion and national origin. The variants have also been studied for association with alcoholic liver disease, cancer, fetal alcohol syndrome, CVD, gout, asthma and clearance of xenobiotics. The strongest correlations found to date have been those between the ALDH2*2 allele and cancers of the oro-pharynx and oesophagus. It will be important to replicate other interesting associations between these variants and other cancers and heart disease, and to determine the biochemical mechanisms underlying the associations.
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            Association of alcohol dehydrogenase genes with alcohol dependence: a comprehensive analysis.

            Laura Almasy, Bernice Porjesz, Victor Hesselbrock … (2006)
            Linkage evidence indicated that gene(s) located on chromosome 4q, in the region of the alcohol dehydrogenase (ADH) genes, affected risk for alcoholism. We genotyped 110 single nucleotide polymorphisms (SNPs) across the seven ADH genes and analyzed their association with alcoholism in a set of families with multiple alcoholic members, using the pedigree disequilibrium test. There was strong evidence that variations in ADH4 are associated with alcoholism: 12 SNPs were significantly associated. The region of strongest association ran from intron 1 to 19.5 kb beyond the 3' end of the gene. Haplotype tag SNPs were selected for the block in the ADH4 gene that provided evidence of association and subsequently used in association analysis; the haplotype was significantly associated with alcoholism (P=0.01) There was weaker evidence that variations in ADH1A and ADH1B might also play a role in modifying risk. Among African-Americans, there was evidence that the ADH1B*3 allele was protective.
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              The genetics of alcoholism: identifying specific genes through family studies.

              Tatiana M. Foroud, Howard Edenberg (2006)
              Alcoholism is a complex disorder with both genetic and environmental risk factors. Studies in humans have begun to elucidate the genetic underpinnings of the risk for alcoholism. Here we briefly review strategies for identifying individual genes in which variations affect the risk for alcoholism and related phenotypes, in the context of one large study that has successfully identified such genes. The Collaborative Study on the Genetics of Alcoholism (COGA) is a family-based study that has collected detailed phenotypic data on individuals in families with multiple alcoholic members. A genome-wide linkage approach led to the identification of chromosomal regions containing genes that influenced alcoholism risk and related phenotypes. Subsequently, single nucleotide polymorphisms (SNPs) were genotyped in positional candidate genes located within the linked chromosomal regions, and analyzed for association with these phenotypes. Using this sequential approach, COGA has detected association with GABRA2, CHRM2 and ADH4; these associations have all been replicated by other researchers. COGA has detected association to additional genes including GABRG3, TAS2R16, SNCA, OPRK1 and PDYN, results that are awaiting confirmation. These successes demonstrate that genes contributing to the risk for alcoholism can be reliably identified using human subjects.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Hum Genomics
                Journal ID (iso-abbrev): Hum. Genomics
                Title: Human Genomics
                Publisher: BioMed Central
                ISSN (Print): 1473-9542
                ISSN (Electronic): 1479-7364
                Publication date Collection: 2009
                Publication date (Electronic): 1 January 2009
                Volume: 3
                Issue: 2
                Pages: 121-127
                Affiliations
                [1 ]Department of Neurology, Tri-Service General Hospital, 325 Chenggong Road Section 2, Taipei 114, Taiwan
                [2 ]Department of Biochemistry, National Defense Medical Center, 161 Minchuan East Road Section 6, Taipei 114, Taiwan
                Article
                Publisher ID: 1479-7364-3-2-121
                DOI: 10.1186/1479-7364-3-2-121
                PMC ID: 3525274
                PubMed ID: 19164089
                SO-VID: 11e29366-3c0d-4f4b-b71e-fc014bc259c2
                Copyright © Copyright ©2009 Henry Stewart Publications
                History
                Date received : 30 July 2008
                Date accepted : 30 July 2008
                Categories
                Subject: Review

                ScienceOpen disciplines: Genetics
                Keywords: alcohol dehydrogenase,aldehyde dehydrogenase,blood acetaldehyde,ethanol metabolism,alcoholism,single nucleotide polymorphism
                Data availability:
                ScienceOpen disciplines: Genetics
                Keywords: alcohol dehydrogenase, aldehyde dehydrogenase, blood acetaldehyde, ethanol metabolism, alcoholism, single nucleotide polymorphism

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