Alcohol Consumption, Genetic Variants in Alcohol Deydrogenases, and Risk of Cardiovascular Diseases: A Prospective Study and Meta-Analysis Dagmar Drogan 1 *, Abigail J. Sheldrick 2,5 , Madlen Schu ¨ tze 1 , Sven Knu ¨ ppel 1 , Frank Andersohn 3 , Romina di Giuseppe 1 , Bianca Herrmann 1,6 , Stefan N. Willich 3 , Edeltraut Garbe 4 , Manuela M. Bergmann 1 , Heiner Boeing 1 , Cornelia Weikert 1,3 1 Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany, 2 Institute of Clinical Pharmacology and Toxicology; Charite ´ University Medical Center, Berlin, Germany, 3 Institute for Social Medicine, Epidemiology and Health Economics, Charite ´ University Medical Center, Berlin, Germany, 4 Department of Clinical Epidemiology, Bremen Institute for Prevention Research and Social Medicine, Bremen, Germany, 5 Department of Psychiatry, Psychotherapy and Psychosomatics, Medical School, RWTH Aachen University, Aachen, Germany, 6 Department 4.1 Biology in Materials Protection and Environmental Issues, Federal Institute for Materials Research and Testing, Berlin, Germany Abstract Objective: First, to investigate and compare associations between alcohol consumption and variants in alcohol dehydrogenase (ADH) genes with incidence of cardiovascular diseases (CVD) in a large German cohort. Second, to quantitatively summarize available evidence of prospective studies on polymorphisms in ADH1B and ADH1C and CVD-risk. Methods: We conducted a case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort including a randomly drawn subcohort (n = 2175) and incident cases of myocardial infarction (MI; n = 230) or stroke (n = 208). Mean follow-up time was 8.262.2 years. The association between alcohol consumption, ADH1B or ADH1C genotypes, and CVD-risk was assessed using Cox proportional hazards regression. Additionally, we report results on associations of variants in ADH1B and ADH1C with ischemic heart disease and stroke in the context of a meta-analysis of previously published prospective studies published up to November 2011. Results: Compared to individuals who drank .0 to 6 g alcohol/d, we observed a reduced risk of MI among females consuming .12 g alcohol/d (HR = 0.31; 95% CI: 0.10–0.97) and among males consuming .24 to 60 g/d (HR = 0.57; 95% CI: 0.33–0.98) or .60 g alcohol/d (HR = 0.30; 95% CI: 0.12–0.78). Stroke risk was not significantly related to alcohol consumption .6 g/d, but we observed an increased risk of stroke in men reporting no alcohol consumption. Individuals with the slow- coding ADH1B*1/1 genotype reported higher median alcohol consumption. Yet, polymorphisms in ADH1B or ADH1C were not significantly associated with risk of CVD in our data and after pooling results of eligible prospective studies [ADH1B*1/1: RR = 1.35 (95% CI: 0.98–1.88; p for heterogeneity: 0.364); ADH1C*2/2: RR = 1.07 (95% CI: 0.90–1.27; p for heterogeneity: 0.098)]. Conclusion: The well described association between alcohol consumption and CVD-risk is not reflected by ADH polymorphisms, which modify the rate of ethanol oxidation. Citation: Drogan D, Sheldrick AJ, Schu ¨ tze M, Knu ¨ ppel S, Andersohn F, et al. (2012) Alcohol Consumption, Genetic Variants in Alcohol Deydrogenases, and Risk of Cardiovascular Diseases: A Prospective Study and Meta-Analysis. PLoS ONE 7(2): e32176. doi:10.1371/journal.pone.0032176 Editor: Weili Zhang, Chinese Academy of Medical Sciences, China Received September 19, 2011; Accepted January 23, 2012; Published February 21, 2012 Copyright: ß 2012 Drogan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The recruitment phase of the EPIC-Potsdam Study was supported by the Federal Ministry of Science, Germany (01 EA 9401), and the European Union (SOC 95201408 05F02). The follow-up was supported by the German Cancer Aid (70-2488-Ha I) and the European Community (SOC 98200769 05F02). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: drogan@dife.de Introduction Considerable epidemiologic evidence links moderate alcohol consumption to a reduced risk of coronary heart disease (CHD) and stroke [1]. Because alcohol consumption is related to many potentially confounding factors, the causal effect of alcohol consumption on CVD risk is difficult to assess in observational studies. Long-term randomized controlled trials investigating the effects of regular alcohol consumption on hard cardiovascular endpoints are unlikely to be ever carried out. However, short- to medium-term intervention studies have demonstrated a favorable effect of ethanol on lipids, haemostasis, and insulin sensitivity [2]. As biologically plausible mediators these mechanisms may be viewed as an indirect support for a protective effect of moderate alcohol use on cardiovascular events. In addition, genetic variants associated with average alcohol consumption and/or circulating ethanol levels may act as unconfounded and precisely measured markers of the exposure and thereby contributing to strengthen causal inference [3]. In this respect, genes coding for alcohol dehydrogenases (ADH) deserve PLoS ONE | www.plosone.org 1 February 2012 | Volume 7 | Issue 2 | e32176