Genetic Variation in Alcohol Dehydrogenase and the Beneficial Effect of Moderate Alcohol Consumption on Myocardial Infarction

doi:10.1056/NEJM200102223440802

Volume 344:549-555		February 22, 2001		Number 8

Genetic Variation in Alcohol Dehydrogenase and the Beneficial Effect of Moderate Alcohol Consumption on Myocardial Infarction

Lisa M. Hines, S.M., Meir J. Stampfer, M.D., Dr.P.H., Jing Ma, M.D., Ph.D., J. Michael Gaziano, M.D., Paul M. Ridker, M.D., Susan E. Hankinson, Sc.D., Frank Sacks, M.D., Eric B. Rimm, Sc.D., and David J. Hunter, M.B., B.S., Sc.D.

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ABSTRACT

Background A polymorphism in the gene for alcohol dehydrogenasetype 3 (ADH3 ) alters the rate of alcohol metabolism. We investigatedthe relation among the ADH3 polymorphism, the level of alcoholconsumption, and the risk of myocardial infarction in a nestedcase–control study based on data from the prospectivePhysicians' Health Study.

Methods We identified 396 patients with eligible newly diagnosedcases of myocardial infarction among men in the Physicians'Health Study. Of these patients, 374 were matched with 2 randomlyselected control subjects each and the remaining 22 with 1 controleach (total, 770 controls). The ADH3 genotype ( ${gamma}$ ₁ ${gamma}$ ₁, ${gamma}$ ₁ ${gamma}$ ₂, or ${gamma}$ ₂ ${gamma}$ ₂)was determined in all subjects. We examined the relations amongthe level of alcohol intake, the ADH3 genotype, and plasma high-densitylipoprotein (HDL) levels in this study population and in a similarcohort of women.

Results As compared with homozygosity for the allele associatedwith a fast rate of ethanol oxidation ( ${gamma}$ ₁), homozygosity forthe allele associated with a slow rate of ethanol oxidation( ${gamma}$ ₂) was associated with a reduced risk of myocardial infarction(relative risk, 0.65; 95 percent confidence interval, 0.43 to0.99). Moderate alcohol consumption was associated with a decreasedrisk of myocardial infarction in all three genotype groups ( ${gamma}$ ₁ ${gamma}$ ₁, ${gamma}$ ₁ ${gamma}$ ₂, and ${gamma}$ ₂ ${gamma}$ ₂); however, the ADH3 genotype significantly modifiedthis association (P=0.01 for the interaction). Among men whowere homozygous for the ${gamma}$ ₁ allele, those who consumed at leastone drink per day had a relative risk of myocardial infarctionof 0.62 (95 percent confidence interval, 0.34 to 1.13), as comparedwith the risk among men who consumed less than one drink perweek. Men who consumed at least one drink per day and were homozygousfor the ${gamma}$ ₂ allele had the greatest reduction in risk (relativerisk, 0.14; 95 percent confidence interval, 0.04 to 0.45). Suchmen also had the highest plasma HDL levels (P for interaction= 0.05). We confirmed the interaction among the ADH3 genotype,the level of alcohol consumption, and the HDL level in an independentstudy of postmenopausal women (P=0.02).

Conclusions Moderate drinkers who are homozygous for the slow-oxidizingADH3 allele have higher HDL levels and a substantially decreasedrisk of myocardial infarction.

Source Information

From the Departments of Epidemiology (L.M.H., M.J.S., S.E.H., E.B.R., D.J.H.) and Nutrition (M.J.S., F.S., E.B.R., D.J.H.), Harvard School of Public Health; the Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital (M.J.S., J.M., S.E.H., F.S., E.B.R., D.J.H.); the Divisions of Preventive Medicine and Cardiology, Harvard Medical School (J.M.G, P.M.R.); and the Massachusetts Veterans Epidemiologic Research and Information Center, Department of Veterans Affairs Boston Healthcare System (J.M.G.) — all in Boston.

Address reprint requests to Ms. Hines at the Channing Laboratory, 181 Longwood Ave., Boston, MA 02115, or at lhines{at}hsph.harvard.edu.

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