BACKGROUND: Genetic variation in the alcohol dehydrogenase (ADH) enzyme is associated with an aversion to alcohol and a lower risk of alcoholism among Asians. There is growing evidence of a functional role of the ADH2*2 allele in alcohol-drinking patterns among Jews, who have traditionally exhibited low rates of alcoholism and alcohol-related problems. The mechanism by which this allelic effect is mediated is not yet clearly understood. This study examined the effect of ADH2*2 on alcohol-elimination rates (AER) under experimental conditions. METHODS: Young adult male Jews (N = 109) received an intravenous alcohol infusion; metabolism was measured by using standard breath alcohol concentration tests. A clamping technique was used to achieve and maintain a target breath alcohol concentration of 50 mg/100 ml for a defined time period. The AER at steady state was calculated. The alcohol disappearance rate was also calculated from the descending limb slope. Polymerase chain reaction was used for allelic determination of the ADH2 and ADH3 loci. RESULTS: The mean AER among ADH2*2 carriers was significantly higher (8.09 +/- 1.4 g/hr) than among ADH2*1 homozygotes (7.14 +/- 1.5 g/hr; p = 0.003). Significance was retained on adjustment for potential confounding covariates. The ADH2 allele explains 8.5% of the AER variance in this population. Little AER difference was observed across ADH3 genotype groups. The slope of the descending limb increased with increasing copies of the ADH2*2 allele. CONCLUSIONS: The rate of alcohol elimination is significantly associated with the ADH2 genotype of Jewish males. Evidence for variation in alcohol metabolism across ADH genotypic groups provides support for the role of physiologic protective factors in alcohol drinking and suggests that reduced drinking among Jews may be genetically as well as environmentally determined. We believe that application of the novel "Indiana clamp" enhances AER measurement accuracy, allowing for detection of hitherto undetectable differences.
BACKGROUND: Genetic variation in the alcohol dehydrogenase (ADH) enzyme is associated with an aversion to alcohol and a lower risk of alcoholism among Asians. There is growing evidence of a functional role of the ADH2*2 allele in alcohol-drinking patterns among Jews, who have traditionally exhibited low rates of alcoholism and alcohol-related problems. The mechanism by which this allelic effect is mediated is not yet clearly understood. This study examined the effect of ADH2*2 on alcohol-elimination rates (AER) under experimental conditions. METHODS: Young adult male Jews (N = 109) received an intravenous alcohol infusion; metabolism was measured by using standard breath alcohol concentration tests. A clamping technique was used to achieve and maintain a target breath alcohol concentration of 50 mg/100 ml for a defined time period. The AER at steady state was calculated. The alcohol disappearance rate was also calculated from the descending limb slope. Polymerase chain reaction was used for allelic determination of the ADH2 and ADH3 loci. RESULTS: The mean AER among ADH2*2 carriers was significantly higher (8.09 +/- 1.4 g/hr) than among ADH2*1 homozygotes (7.14 +/- 1.5 g/hr; p = 0.003). Significance was retained on adjustment for potential confounding covariates. The ADH2 allele explains 8.5% of the AER variance in this population. Little AER difference was observed across ADH3 genotype groups. The slope of the descending limb increased with increasing copies of the ADH2*2 allele. CONCLUSIONS: The rate of alcohol elimination is significantly associated with the ADH2 genotype of Jewish males. Evidence for variation in alcohol metabolism across ADH genotypic groups provides support for the role of physiologic protective factors in alcohol drinking and suggests that reduced drinking among Jews may be genetically as well as environmentally determined. We believe that application of the novel "Indiana clamp" enhances AER measurement accuracy, allowing for detection of hitherto undetectable differences.
Authors: Ian R Gizer; Howard J Edenberg; David A Gilder; Kirk C Wilhelmsen; Cindy L Ehlers Journal: Alcohol Clin Exp Res Date: 2011-06-02 Impact factor: 3.455
Authors: Andrew J Birley; Michael R James; Peter A Dickson; Grant W Montgomery; Andrew C Heath; Nicholas G Martin; John B Whitfield Journal: Hum Mol Genet Date: 2009-02-04 Impact factor: 6.150
Authors: Denis M McCarthy; Sarah L Pedersen; Elizabeth A Lobos; Richard D Todd; Tamara L Wall Journal: Alcohol Clin Exp Res Date: 2010-05-04 Impact factor: 3.455
Authors: Stuart Macgregor; Penelope A Lind; Kathleen K Bucholz; Narelle K Hansell; Pamela A F Madden; Melinda M Richter; Grant W Montgomery; Nicholas G Martin; Andrew C Heath; John B Whitfield Journal: Hum Mol Genet Date: 2008-11-07 Impact factor: 6.150
Authors: V A Ramchandani; J Umhau; F J Pavon; V Ruiz-Velasco; W Margas; H Sun; R Damadzic; R Eskay; M Schoor; A Thorsell; M L Schwandt; W H Sommer; D T George; L H Parsons; P Herscovitch; D Hommer; M Heilig Journal: Mol Psychiatry Date: 2010-05-18 Impact factor: 15.992
Authors: Luisa Zuccolo; Nicola Fitz-Simon; Ron Gray; Susan M Ring; Kapil Sayal; George Davey Smith; Sarah J Lewis Journal: Hum Mol Genet Date: 2009-08-17 Impact factor: 6.150