title: Allelic variation at alcohol metabolism genes ( ADH1B, ADH1C, ALDH2) and alcohol dependence in an American Indian population.
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), and ALDH2 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 for ADH as a candidate locus for alcohol dependence and suggest further productive study.
authors.affiliation: Department of Anthropology, University of Florida, PO Box 117305, Gainesville, FL 32611, USA. mulligan@anthro.ufl.edu
authors.forename: Connie J
authors.initials: CJ
authors.lastname: Mulligan
authors.forename: Robert W
authors.initials: RW
authors.lastname: Robin
authors.forename: Michael V
authors.initials: MV
authors.lastname: Osier
authors.forename: Nyamkhishig
authors.initials: N
authors.lastname: Sambuughin
authors.forename: Lev G
authors.initials: LG
authors.lastname: Goldfarb
authors.forename: Rick A
authors.initials: RA
authors.lastname: Kittles
authors.forename: Diane
authors.initials: D
authors.lastname: Hesselbrock
authors.forename: David
authors.initials: D
authors.lastname: Goldman
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Long
mesh_terms: D000426:Alcohol Dehydrogenase / Q000235:genetics*; D000437:Alcoholism / Q000175:diagnosis / Q000235:genetics*; D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000431:Ethanol / Q000506:poisoning; D005787:Gene Frequency; D008040:Genetic Linkage; D005819:Genetic Markers; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D007198:Indians, North American; D015810:Linkage Disequilibrium
chemical_list: D005819:Genetic Markers; D000431:Ethanol; D000426:Alcohol Dehydrogenase; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial