OBJECTIVE: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease. DESIGN: Mendelian randomisation meta-analysis of 56 epidemiological studies. PARTICIPANTS: 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers. MAIN OUTCOME MEASURES: Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption. RESULTS: Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)). CONCLUSIONS: Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.

Atherosclerosis Research Unit Center for Molecular Medicine Department of Medicine Karolinska Institutet Stockholm Sweden

Atherosclerosis Research Unit Center for Molecular Medicine Department of Medicine Karolinska Institutet Stockholm Sweden Center for Molecular Medicine Karolinska University Hospital Solna Stockholm Sweden

Baylor College of Medicine Department of Medicine Division of Atherosclerosis and Vascular Medicine Houston Texas 77030 USA

Beth Israel Deaconess Medical Center Boston Massachusetts USA

British Heart Foundation Glasgow Cardiovascular Research Centre University of Glasgow Glasgow UK

Cardiovascular Health Research Unit Departments of Medicine Epidemiology and Health Services University of Washington Seattle WA USA Group Health Research Institute Group Health Cooperative Seattle WA USA

Center for Applied Genomics Abramson Research Center The Children's Hospital of Philadelphia Philadelphia USA

Center for Applied Genomics Abramson Research Center The Children's Hospital of Philadelphia Philadelphia USA BGI Shenzhen Beishan Industrial Zone Yantian District Shenzhen 518083 China

Center for Experimental Medicine Institute for Clinical and Experimental Medicine Videnska 1958 9 Prague 4 14021 Czech Republic

Centre for Cancer Genetic Epidemiology Department of Public Health and Primary Care University of Cambridge Cambridge UK

Centre for Cardiovascular Genetics Institute of Cardiovascular Science University College London London UK

Centre for Cardiovascular Genetics Institute of Cardiovascular Science University College London London UK WC1E 6JF

Centre for Health Monitoring National Institute of Public Health 100 42 Prague Czech Republic

Centre for Paediatric Epidemiology and Biostatistics UCL Institute of Child Health London UK

Centre for Paediatric Epidemiology and Biostatistics UCL Institute of Child Health London UK School of Population Health and Sansom Institute for Health Research University of South Australia Adelaide SA 5000 Australia South Australian Health and Medical Research Institute Adelaide SA5000 Australia

Centre for Population Health Sciences University of Edinburgh Edinburgh EH8 9AG UK

College of Pharmacy The University of New Mexico Albuquerque NM USA

Cyprus International Institute for Environmental and Public Health in association with the Harvard School of Public Health Cyprus University of Technology 3603 Limassol Cyprus

Danish Cancer Society Strandboulevarden Copenhagen Denmark

Department of Biostatistics Boston University School of Public Health Boston Massachusetts USA National Heart Lung and Blood Institute's The Framingham Heart Study Framingham Massachusetts USA

Department of Cardiology Division Heart and Lungs University Medical Center Utrecht Utrecht The Netherlands

Department of Cardiology Division Heart and Lungs University Medical Center Utrecht Utrecht The Netherlands Durrer Center for Cardiogenetic Research ICIN Netherlands Heart Institute Utrecht The Netherlands Institute of Cardiovascular Science Faculty of Population Health Sciences University College London London UK

Department of Cardiology Leiden University Medical Center the Netherlands

Department of Cardiology University Medical Center Groningen Groningen The Netherlands

Department of Cardiology University Medical Center Groningen Groningen The Netherlands Department of Genetics University Medical Center Groningen Groningen The Netherlands Durrer Center for Cardiogenetic Research ICIN Netherlands Heart Institute Utrecht The Netherlands

Department of Clinical Biochemistry Royal Perth Hospital and School of Surgery the University of Western Australia

Department of Clinical Sciences Lund University Malmö Sweden

Department of Epidemiology and Department of Nutrition Harvard School of Public Health Boston MA USA Channing Division of Network Medicine Brigham and Women's Hospital and Harvard Medical School Boston MA USA

Department of Epidemiology and Population Studies Institute of Public Health Jagiellonian University Medical College 31 531 Krakow Poland

Department of Epidemiology and Public Health University College London London WC1E 6BT UK

Department of Epidemiology Erasmus Medical Center Rotterdam The Netherlands

Department of Epidemiology Harvard School of Public Health Boston MA USA

Department of Epidemiology Johns Hopkins Bloomberg School of Public Health Johns Hopkins University Baltimore Maryland USA

Department of Genetics University of North Carolina School of Medicine at Chapel Hill Chapel Hill North Carolina 27514 USA

Department of Internal Medicine Internal Medicine CHUV Lausanne Switzerland

Department of Laboratory Medicine and Pathology University of Minnesota USA

Department of Medical Sciences Uppsala University Uppsala University Hospital SE 751 85 Uppsala Sweden

Department of Medicine McMaster University Hamilton Ontario Canada L8S4L8

Department of Neurology Sir Charles Gairdner Hospital Perth Australia School of Medicine and Pharmacology The University of Western Australia Nedlands Perth Australia

Department of Neuroscience Mayo Clinic Florida Jacksonville FL USA

Department of Physiology and Biophysics University of Mississippi Medical Center Jackson MS USA

Department of Population Studies Institute of Cardiology Lithuanian University of Health Sciences Kaunas LT 50161 Lithuania

Department of Preventive Cardiology Institute for Clinical and Experimental Medicine Prague 4 14021 Czech Republic

Department of Primary Care and Population Health UCL London UK

Department of Primary Care and Public Health and Primary Care University of Cambridge Cambridge UK

Department of Public Health and Caring Sciences Uppsala University Uppsala University Hospital SE 75185 Uppsala Sweden

Department of Radiology University Medical Center Utrecht Utrecht The Netherlands

Department of Surgery Penn Transplant Institute Perelman School of Medicine University of Pennsylvania Philadelphia PA19104 USA Center for Applied Genomics Abramson Research Center The Children's Hospital of Philadelphia Philadelphia USA

Department of Vascular Medicine University Medical Center Utrecht Utrecht The Netherlands

Dept Pathology and Medical Biology Medical Biology division Molecular Genetics University Medical Center Groningen and Groningen University Groningen The Netherlands

Division of Epidemiology School of Public Health University of Texas Health Science Center at Houston Texas USA

Division of Health Sciences Warwick Medical School University of Warwick Coventry UK

Division of Pharmacoepidemiology and Clinical Pharmacology Utrecht Institute for Pharmaceutical Sciences Utrecht University Utrecht The Netherlands

Division of Public Health Sciences Fred Hutchinson Cancer Research Center Seattle WA 98109 USA

Division of Research Kaiser Permanente Northern California Oakland CA USA

Division of Sleep and Circadian Disorders Brigham and Women's Hospital; Harvard Medical School Boston USA

Division of Sleep and Circadian Disorders Brigham and Women's Hospital; Harvard Medical School Boston USA Beth Israel Deaconess Medical Center Boston Massachusetts USA

Faculty of Epidemiology and Population Health London School of Hygiene and Tropical Medicine London WC1E 7HT UK

Faculty of Epidemiology and Population Health London School of Hygiene and Tropical Medicine London WC1E 7HT UK Centre for Statistical Methodology London School of Hygiene and Tropical Medicine London WC1E 7HT UK

Faculty of Epidemiology and Population Health London School of Hygiene and Tropical Medicine London WC1E 7HT UK Genetics R and D GlaxoSmithKline Stevenage UK

Genetic Epidemiology Group Institute of Cardiovascular Science Department of Epidemiology and Public Health University College London UK

Genetic Epidemiology Group Institute of Cardiovascular Science Department of Epidemiology and Public Health University College London UK Department of Surgery Penn Transplant Institute Perelman School of Medicine University of Pennsylvania Philadelphia PA19104 USA Center for Clinical Epidemiology and Biostatistics Perelman School of Medicine University of Pennsylvania Philadelphia PA 19104 USA

Genetic Epidemiology Group Institute of Cardiovascular Science Department of Epidemiology and Public Health University College London UK Faculty of Epidemiology and Population Health London School of Hygiene and Tropical Medicine London WC1E 7HT UK

German Institute of Human Nutrition Potsdam Rehbrücke Arthur Scheunert Allee 114 116 14558 Nuthetal Germany

Institute for Translational Genomics and Population Sciences Los Angeles BioMedical Research Institute and Department of Pediatrics Harbor UCLA Medical Center Torrance Calif USA

Institute of Cardiovascular and Medical Sciences College of Medical Veterinary and Life Sciences University of Glasgow Glasgow G12 8TA UK

Institute of Internal and Preventative Medicine Siberian Branch of Russian Academy of Medical Sciences Novosibirsk Russia 630089 Dept of Internal Medicine Novosibirsk State Medical University Novosibirsk Russia 630091

Institute of Internal and Preventative Medicine Siberian Branch of Russian Academy of Medical Sciences Novosibirsk Russia 630089 Faculty of Medicine Novosibirsk State University Novosibirsk Russia 630090

Institute of Molecular Medicine University of Texas Health Science Center at Houston Texas USA

Instituto Medicina Molecular Faculdade de Medicina Universidade de Lisboa 1649 028 Lisbon Portugal Servico Neurologia Hospital de Santa Maria 1649 035 Lisbon Portugal

Instituto Nacional de Saude Doutor Ricardo Jorge 1649 016 Lisbon Portugal Faculdade Ciencias Universidade Lisboa 1749 016 Lisbon Portugal

Instituto Nacional de Saude Doutor Ricardo Jorge 1649 016 Lisbon Portugal Instituto Gulbenkian Ciencia P 2780 156 Oeiras Portugal Biofig Center for Biodiversity Functional and Integrative Genomics Campus da FCUL 1749 016 Lisboa Portugal

Julius Center for Health Sciences and Primary Care University Medical Center Utrecht The Netherlands

Julius Center for Health Sciences and Primary Care University Medical Center Utrecht The Netherlands Department of Medical Genetics Center for Molecular Medicine University Medical Center Utrecht Utrecht The Netherlands

Mayo Clinic Department of Neurology Jacksonville FL 32224 USA

MRC Epidemiology Unit Institute of Metabolic Science Addenbrooke's Hospital Cambridge UK

MRC Integrative Epidemiology Unit at the Universty of Bristol Oakfield House Bristol BS8 2BN UK

MRC Unit for Lifelong Health and Ageing at UCL London UK

National Heart Lung and Blood Institute's The Framingham Heart Study Framingham Massachusetts USA

National Institute for Public Health and the Environment Bilthoven the Netherlands

National Institute of Public Health University of Southern Denmark Copenhagen Denmark

New York Academy of Medicine New York NY 10021 USA

Northwestern University Feinberg School of Medicine Department of Preventive Medicine Chicago IL USA

Office of Public Health Genomics Office of Epidemiology Surveillance and Laboratory Services Centers for Disease Control and Prevention Atlanta GA 30333 USA

Population Health Research Institute St George's University of London London UK

Preventive Medicine and Epidemiology Evans Department of Medicine Boston University School of Medicine Boston Massachusetts USA

Research Centre for Prevention and Health Capital Region of Denmark Glostrup University Hospital Glostrup Denmark

Robertson Centre for Biostatistics University of Glasgow Glasgow UK

School of Health Sciences Jackson State University Jackson MS USA

School of Public Health University of Minnesota Minneapolis Minnesota USA

School of Surgery University of Western Australia Perth Australia

The Copenhagen General Population Study Herlev Hospital Copenhagen Denmark Faculty of Health Sciences Copenhagen University Hospital University of Copenhagen Copenhagen Denmark Department of Clinical Biochemistry Herlev Hospital Copenhagen University Hospital Denmark

UCL Genetics Institute Department of Genetics Environment and Evolution London WC1E 6BT UK

UCL Institute of Health Equity Department of Epidemiology and Public Health London WC1E 7HB UK

Unit of Cancer Epidemiology San Giovanni Battista Hospital and Center for Cancer Prevention 10129 Torino Italy

Vascular Screening and Diagnostic Centre Ayios Dometios Nicosia Cyprus Deparment of Vascular Surgery Imperial College London SW7 2BX UK Cyprus Cardiovascular Disease Educational and Research trust Nicosia Cyprus

Vavilov Institute of General Genetics Russian Academy of Sciences Moscow Russia

Wellcome Trust Centre for Human Genetics University of Oxford Oxford UK Department of Cardiovascular Medicine University of Oxford Oxford UK

Western Australian Centre for Health and Ageing Centre for Medical Research University of Western Australia Perth Australia

Western Australian Centre for Health and Ageing Centre for Medical Research University of Western Australia Perth Australia School of Psychiatry and Clinical Neurosciences University of Western Australia Perth 6009 Australia Department of Psychiatry Royal Perth Hospital Perth Australia

Comment In

BMJ. 2014 Jul 10;349:g4334. doi: 10.1136/bmj.g4334. PubMed

Comment In

Nat Rev Cardiol. 2014 Sep;11(9):495. doi: 10.1038/nrcardio.2014.106. PubMed

Comment In

Evid Based Med. 2015 Feb;20(1):38. doi: 10.1136/ebmed-2014-110086. PubMed

Comment In

MMW Fortschr Med. 2014 Oct 23;156(18):32. PubMed

See more in PubMed

Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2224-60. PubMed PMC

Rehm J, Baliunas D, Borges GL, Graham K, Irving H, Kehoe T, et al. The relation between different dimensions of alcohol consumption and burden of disease: an overview. Addiction 2010;105:817-43. PubMed PMC

Freiberg MS, Samet JH. Alcohol and coronary heart disease: the answer awaits a randomized controlled trial. Circulation 2005;112:1379-81. PubMed

O’Keefe JH, Bybee KA, Lavie CJ. Alcohol and cardiovascular health: the razor-sharp double-edged sword. J Am Coll Cardiol 2007;50:1009-14. PubMed

Hansel B, Thomas F, Pannier B, Bean K, Kontush A, Chapman MJ, et al. Relationship between alcohol intake, health and social status and cardiovascular risk factors in the Urban Paris-Ile-de-France Cohort: is the cardioprotective action of alcohol a myth? Eur J Clin Nutr 2010;64:561-8. PubMed

Corrao G, Rubbiati L, Bagnardi V, Zambon A, Poikolainen K. Alcohol and coronary heart disease: a meta-analysis. Addiction 2000;95:1505-23. PubMed

Ronksley PE, Brien SE, Turner BJ, Mukamal KJ, Ghali WA. Association of alcohol consumption with selected cardiovascular disease outcomes: a systematic review and meta-analysis. BMJ 2011;342:d671. PubMed PMC

Boffetta P, Garfinkel L. Alcohol drinking and mortality among men enrolled in an American Cancer Society prospective study. Epidemiology 1990;1:342-8. PubMed

Shaper AG, Wannamethee G, Walker M. Alcohol and mortality in British men: explaining the U-shaped curve. Lancet 1988;2:1267-73. PubMed

Jackson R, Broad J, Connor J, Wells S. Alcohol and ischaemic heart disease: probably no free lunch. Lancet 2005;366:1911-2. PubMed

Brien SE, Ronksley PE, Turner BJ, Mukamal KJ, Ghali WA. Effect of alcohol consumption on biological markers associated with risk of coronary heart disease: systematic review and meta-analysis of interventional studies. BMJ 2011;342:d636. PubMed PMC

Briel M, Ferreira-Gonzalez I, You JJ, Karanicolas PJ, Akl EA, Wu P, et al. Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis. BMJ 2009;338:b92. PubMed PMC

Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012;367:2089-99. PubMed

Hingorani A, Humphries S. Nature’s randomised trials. Lancet 2005;366:1906-8. PubMed

Davey Smith G, Ebrahim S. ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol 2003;32:1-22. PubMed

Edenberg HJ. The genetics of alcohol metabolism: role of alcohol dehydrogenase and aldehyde dehydrogenase variants. Alcohol Res Health 2007;30:5-13. PubMed PMC

Yokoyama A, Yokoyama T, Mizukami T, Matsui T, Kimura M, Matsushita S, et al. Blood ethanol levels of nonabstinent Japanese alcoholic men in the morning after drinking and their ADH1B and ALDH2 genotypes. Alcohol Alcoholism 2013. 10.1093/alcalc/agt136. PubMed DOI

Macgregor S, Lind PA, Bucholz KK, Hansell NK, Madden PA, Richter MM, et al. Associations of ADH and ALDH2 gene variation with self report alcohol reactions, consumption and dependence: an integrated analysis. Hum Molecular Genetics 2009;18:580-93. PubMed PMC

Bierut LJ, Goate AM, Breslau N, Johnson EO, Bertelsen S, Fox L, et al. ADH1B is associated with alcohol dependence and alcohol consumption in populations of European and African ancestry. Molecular Psychiatry 2012;17:445-50. PubMed PMC

Lawlor DA, Nordestgaard BG, Benn M, Zuccolo L, Tybjaerg-Hansen A, Davey Smith G. Exploring causal associations between alcohol and coronary heart disease risk factors: findings from a Mendelian randomization study in the Copenhagen General Population Study. Eur Heart J 2013;34:2519-28. PubMed

Kato N, Takeuchi F, Tabara Y, Kelly TN, Go MJ, Sim X, et al. Meta-analysis of genome-wide association studies identifies common variants associated with blood pressure variation in east Asians. Nature Genetics 2011;43:531-8. PubMed PMC

Chen L, Davey Smith G, Harbord RM, Lewis SJ. Alcohol intake and blood pressure: a systematic review implementing a Mendelian randomization approach. PLoS Med 2008;5:e52. PubMed PMC

Drogan D, Sheldrick AJ, Schutze M, Knuppel S, Andersohn F, di Giuseppe R, et al. Alcohol consumption, genetic variants in alcohol deydrogenases, and risk of cardiovascular diseases: a prospective study and meta-analysis. PloS One 2012;7:e32176. PubMed PMC

Keating BJ, Tischfield S, Murray SS, Bhangale T, Price TS, Glessner JT, et al. Concept, design and implementation of a cardiovascular gene-centric 50 k SNP array for large-scale genomic association studies. PloS One 2008;3:e3583. PubMed PMC

InterAct Consortium, Langenberg C, Sharp S, Forouhi NG, Franks PW, Schulze MB, et al. Design and cohort description of the InterAct Project: an examination of the interaction of genetic and lifestyle factors on the incidence of type 2 diabetes in the EPIC Study. Diabetologia 2011;54:2272-82. PubMed PMC

Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557-60. PubMed PMC

Del Boca FK, Darkes J. The validity of self-reports of alcohol consumption: state of the science and challenges for research. Addiction 2003;98(suppl 2):1-12. PubMed

Glymour MM, Tchetgen EJ, Robins JM. Credible Mendelian randomization studies: approaches for evaluating the instrumental variable assumptions. AmJ Epidemiol 2012;175:332-9. PubMed PMC

Hindorff LA, MacArthur J, Morales J, Junkins HA, Hall PN, Klemm AK, et al. A catalog of published genome-wide association studies. National Human Genome Research Institute. www.genome.gov/gwastudies (accessed Feb 2013).

Marmot MG, Davey Smith G, Stansfeld S, Patel C, North F, Head J, et al. Health inequalities among British civil servants: the Whitehall II study. Lancet 1991;337:1387-93. PubMed

Voight BF, Kang HM, Ding J, Palmer CD, Sidore C, Chines PS, et al. The metabochip, a custom genotyping array for genetic studies of metabolic, cardiovascular, and anthropometric traits. PLoS Gen 2012;8:e1002793. PubMed PMC

Room R. Smoking and drinking as complementary behaviours. Biomed Pharmacother 2004;58:111-5. PubMed

Tolstrup JS, Gronbaek M, Nordestgaard BG. Alcohol intake, myocardial infarction, biochemical risk factors, and alcohol dehydrogenase genotypes. Circ Cardiovasc Genet 2009;2:507-14. PubMed

Husemoen LL, Jorgensen T, Borch-Johnsen K, Hansen T, Pedersen O, Linneberg A. The association of alcohol and alcohol metabolizing gene variants with diabetes and coronary heart disease risk factors in a white population. PLoS One 2010;5:e11735. PubMed PMC

Quertemont E, Didone V. Role of acetaldehyde in mediating the pharmacological and behavioral effects of alcohol. Alcohol Res Health 2006;29:258-65. PubMed PMC

Education and coronary heart disease: mendelian randomisation study

Alcohol and lung cancer risk among never smokers: A pooled analysis from the international lung cancer consortium and the SYNERGY study