| Affiliation: | (1) Department of Anthropology, University of Florida, PO Box 117305, Gainesville, FL 32611, USA;(2) Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Sitka, Alaska, USA;(3) Department of Genetics, Yale University School of Medicine, New Haven, Conn., USA;(4) Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Ariz., USA;(5) National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Md., USA;(6) National Human Genome Center at Howard University, Washington, D.C., USA;(7) Department of Surgery, Washington University, St. Louis, Mo., USA;(8) Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Md., USA;(9) Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Mich., USA |
| Abstract: | Enzymes encoded by two gene families, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), mediate alcohol metabolism in humans. Allelic variants have been identified that alter metabolic rates and influence risk for alcoholism. Specifically, ADH1B*47His(previously ADH2-2) and ALDH2-2 have been shown to confer protection against alcoholism, presumably through accumulation of acetaldehyde in the blood and a resultant 'flushing response' to alcohol consumption. In the current study, variants at ADH1B(previously ADH2), ADH1C (previously ADH3), andALDH2 were assayed in DNA extracts from participants belonging to a Southwest American Indian tribe (n=490) with a high prevalence of alcoholism. Each subject underwent a clinical interview for diagnosis of alcohol dependence, as well as evaluation of intermediate phenotypes such as binge drinking and flushing response to alcohol consumption. Detailed haplotypes were constructed and tested against alcohol dependence and related intermediate phenotypes using both association and linkage analysis. ADH and ALDH variants were also assayed in three Asian and one African population (no clinical data) in order to provide an evolutionary context for the haplotype data. Both linkage and association analysis identified several ADH1C alleles and a neighboring microsatellite marker that affected risk of alcohol dependence and were also related to binge drinking. These data strengthen the support forADH as a candidate locus for alcohol dependence and suggest further productive study. |
