Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data

doi:10.1136/bmj.g4164

Meta-Analysis

. 2014 Jul 10:349:g4164.

doi: 10.1136/bmj.g4164.

Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data

Michael V Holmes¹, Caroline E Dale², Luisa Zuccolo³, Richard J Silverwood⁴, Yiran Guo⁵, Zheng Ye⁶, David Prieto-Merino², Abbas Dehghan⁷, Stella Trompet⁸, Andrew Wong⁹, Alana Cavadino¹⁰, Dagmar Drogan¹¹, Sandosh Padmanabhan¹², Shanshan Li¹³, Ajay Yesupriya¹⁴, Maarten Leusink¹⁵, Johan Sundstrom¹⁶, Jaroslav A Hubacek¹⁷, Hynek Pikhart¹⁸, Daniel I Swerdlow¹⁹, Andrie G Panayiotou²⁰, Svetlana A Borinskaya²¹, Chris Finan¹⁹, Sonia Shah²², Karoline B Kuchenbaecker²³, Tina Shah¹⁹, Jorgen Engmann¹⁹, Lasse Folkersen²⁴, Per Eriksson²⁴, Fulvio Ricceri²⁵, Olle Melander²⁶, Carlotta Sacerdote²⁵, Dale M Gamble²⁷, Sruti Rayaprolu²⁸, Owen A Ross²⁸, Stela McLachlan²⁹, Olga Vikhireva¹⁸, Ivonne Sluijs³⁰, Robert A Scott⁶, Vera Adamkova³¹, Leon Flicker³², Frank M van Bockxmeer³³, Christine Power¹⁰, Pedro Marques-Vidal³⁴, Tom Meade², Michael G Marmot³⁵, Jose M Ferro³⁶, Sofia Paulos-Pinheiro³⁷, Steve E Humphries³⁸, Philippa J Talmud³⁸, Irene Mateo Leach³⁹, Niek Verweij³⁹, Allan Linneberg⁴⁰, Tea Skaaby⁴⁰, Pieter A Doevendans⁴¹, Maarten J Cramer⁴¹, Pim van der Harst⁴², Olaf H Klungel¹⁵, Nicole F Dowling¹⁴, Anna F Dominiczak¹², Meena Kumari¹⁹, Andrew N Nicolaides⁴³, Cornelia Weikert¹¹, Heiner Boeing¹¹, Shah Ebrahim², Tom R Gaunt³, Jackie F Price²⁹, Lars Lannfelt⁴⁴, Anne Peasey¹⁸, Ruzena Kubinova⁴⁵, Andrzej Pajak⁴⁶, Sofia Malyutina⁴⁷, Mikhail I Voevoda⁴⁸, Abdonas Tamosiunas⁴⁹, Anke H Maitland-van der Zee¹⁵, Paul E Norman⁵⁰, Graeme J Hankey⁵¹, Manuela M Bergmann¹¹, Albert Hofman⁷, Oscar H Franco⁷, Jackie Cooper⁵², Jutta Palmen³⁸, Wilko Spiering⁵³, Pim A de Jong⁵⁴, Diana Kuh⁹, Rebecca Hardy⁹, Andre G Uitterlinden⁷, M Arfan Ikram⁷, Ian Ford⁵⁵, Elina Hyppönen⁵⁶, Osvaldo P Almeida⁵⁷, Nicholas J Wareham⁶, Kay-Tee Khaw⁵⁸, Anders Hamsten⁵⁹, Lise Lotte N Husemoen⁴⁰, Anne Tjønneland⁶⁰, Janne S Tolstrup⁶¹, Eric Rimm⁶², Joline W J Beulens³⁰, W M Monique Verschuren⁶³, N Charlotte Onland-Moret³⁰, Marten H Hofker⁶⁴, S Goya Wannamethee⁶⁵, Peter H Whincup⁶⁶, Richard Morris⁶⁵, Astrid M Vicente⁶⁷, Hugh Watkins⁶⁸, Martin Farrall⁶⁸, J Wouter Jukema⁸, James Meschia²⁷, L Adrienne Cupples⁶⁹, Stephen J Sharp⁶, Myriam Fornage⁷⁰, Charles Kooperberg⁷¹, Andrea Z LaCroix⁷¹, James Y Dai⁷¹, Matthew B Lanktree⁷², David S Siscovick⁷³, Eric Jorgenson⁷⁴, Bonnie Spring⁷⁵, Josef Coresh⁷⁶, Yun R Li⁷⁷, Sarah G Buxbaum⁷⁸, Pamela J Schreiner⁷⁹, R Curtis Ellison⁸⁰, Michael Y Tsai⁸¹, Sanjay R Patel⁸², Susan Redline⁸³, Andrew D Johnson⁸⁴, Ron C Hoogeveen⁸⁵, Hakon Hakonarson⁸⁶, Jerome I Rotter⁸⁷, Eric Boerwinkle⁸⁸, Paul I W de Bakker⁸⁹, Mika Kivimaki¹⁸, Folkert W Asselbergs⁹⁰, Naveed Sattar⁹¹, Debbie A Lawlor³, John Whittaker⁹², George Davey Smith³, Kenneth Mukamal⁹³, Bruce M Psaty⁹⁴, James G Wilson⁹⁵, Leslie A Lange⁹⁶, Ajna Hamidovic⁹⁷, Aroon D Hingorani¹⁹, Børge G Nordestgaard⁹⁸, Martin Bobak¹⁸, David A Leon², Claudia Langenberg⁶, Tom M Palmer⁹⁹, Alex P Reiner⁷¹, Brendan J Keating¹⁰⁰, Frank Dudbridge², Juan P Casas¹⁰¹; InterAct Consortium

Affiliations

¹ 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.
² Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, WC1E 7HT, UK.
³ MRC Integrative Epidemiology Unit (IEU) at the Universty of Bristol, Oakfield House, Bristol BS8 2BN, UK.
⁴ Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, WC1E 7HT, UK Centre for Statistical Methodology, London School of Hygiene & Tropical Medicine, London, WC1E 7HT, UK.
⁵ 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.
⁶ MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
⁷ Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
⁸ Department of Cardiology, Leiden University Medical Center, the Netherlands.
⁹ MRC Unit for Lifelong Health and Ageing at UCL, London, UK.
¹⁰ Centre for Paediatric Epidemiology and Biostatistics, UCL Institute of Child Health, London, UK.
¹¹ German Institute of Human Nutrition Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany.
¹² Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK.
¹³ Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA Juan-P.Casas@lshtm.ac.uk.
¹⁴ Office of Public Health Genomics, Office of Epidemiology, Surveillance, and Laboratory Services, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
¹⁵ Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
¹⁶ Department of Medical Sciences, Uppsala University, Uppsala University Hospital, SE-751 85 Uppsala, Sweden.
¹⁷ Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Videnska 1958/9, Prague 4, 14021, Czech Republic.
¹⁸ Department of Epidemiology and Public Health, University College London, London, WC1E 6BT, UK.
¹⁹ Genetic Epidemiology Group, Institute of Cardiovascular Science, Department of Epidemiology and Public Health, University College London, UK.
²⁰ Cyprus International Institute for Environmental and Public Health in association with the Harvard School of Public Health, Cyprus University of Technology, 3603 Limassol, Cyprus.
²¹ Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia.
²² UCL Genetics Institute, Department of Genetics Environment and Evolution, London, WC1E 6BT, UK.
²³ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
²⁴ Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
²⁵ Unit of Cancer Epidemiology, San Giovanni Battista Hospital and Center for Cancer Prevention (CPO-Piemonte), 10129, Torino, Italy.
²⁶ Department of Clinical Sciences, Lund University, Malmö, Sweden.
²⁷ Mayo Clinic Department of Neurology, Jacksonville, FL 32224, USA.
²⁸ Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.
²⁹ Centre for Population Health Sciences, University of Edinburgh, Edinburgh EH8 9AG, UK.
³⁰ Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, The Netherlands.
³¹ Department of Preventive Cardiology, Institute for Clinical and Experimental Medicine, Prague 4, 14021, Czech Republic.
³² Western Australian Centre for Health & Ageing, Centre for Medical Research, University of Western Australia, Perth, Australia.
³³ Department of Clinical Biochemistry, Royal Perth Hospital and School of Surgery, the University of Western Australia.
³⁴ Department of Internal Medicine, Internal Medicine, CHUV, Lausanne, Switzerland.
³⁵ UCL Institute of Health Equity, Department of Epidemiology & Public Health, London WC1E 7HB, UK.
³⁶ Instituto Medicina Molecular, Faculdade de Medicina Universidade de Lisboa, 1649-028 Lisbon, Portugal Servico Neurologia, Hospital de Santa Maria, 1649-035 Lisbon, Portugal.
³⁷ Instituto Nacional de Saude Doutor Ricardo Jorge, 1649-016 Lisbon, Portugal Faculdade Ciencias Universidade Lisboa, 1749-016 Lisbon, Portugal.
³⁸ Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK.
³⁹ Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands.
⁴⁰ Research Centre for Prevention and Health, Capital Region of Denmark, Glostrup University Hospital, Glostrup, Denmark.
⁴¹ Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
⁴² 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.
⁴³ 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.
⁴⁴ Department of Public Health & Caring Sciences, Uppsala University, Uppsala University Hospital, SE-75185 Uppsala, Sweden.
⁴⁵ Centre for Health Monitoring, National Institute of Public Health, 100 42 Prague, Czech Republic.
⁴⁶ Department of Epidemiology and Population Studies, Institute of Public Health, Jagiellonian University Medical College, 31-531 Krakow, Poland.
⁴⁷ 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.
⁴⁸ 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.
⁴⁹ Department of Population Studies, Institute of Cardiology, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania.
⁵⁰ School of Surgery, University of Western Australia, Perth, Australia.
⁵¹ Department of Neurology, Sir Charles Gairdner Hospital, Perth, Australia School of Medicine and Pharmacology, The University of Western Australia, Nedlands, Perth, Australia.
⁵² Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK WC1E 6JF.
⁵³ Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
⁵⁴ Department of Radiology, University Medical Center Utrecht, Utrecht, The Netherlands.
⁵⁵ Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK.
⁵⁶ 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.
⁵⁷ Western Australian Centre for Health & Ageing, Centre for Medical Research, University of Western Australia, Perth, Australia School of Psychiatry & Clinical Neurosciences (M573), University of Western Australia, Perth 6009, Australia Department of Psychiatry, Royal Perth Hospital, Perth, Australia.
⁵⁸ Department of Primary Care and Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁵⁹ Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden Center for Molecular Medicine, Karolinska University Hospital Solna, Stockholm, Sweden.
⁶⁰ Danish Cancer Society, Strandboulevarden, Copenhagen, Denmark.
⁶¹ National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark.
⁶² 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.
⁶³ National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.
⁶⁴ Dept Pathology and Medical Biology, Medical Biology division, Molecular Genetics, University Medical Center Groningen and Groningen University, Groningen, The Netherlands.
⁶⁵ Department of Primary Care & Population Health, UCL, London, UK.
⁶⁶ Population Health Research Institute, St George's, University of London, London, UK.
⁶⁷ 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.
⁶⁸ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK Department of Cardiovascular Medicine, University of Oxford, Oxford, UK.
⁶⁹ 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.
⁷⁰ Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Texas, USA.
⁷¹ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
⁷² Department of Medicine, McMaster University, Hamilton, Ontario, Canada L8S4L8.
⁷³ New York Academy of Medicine, New York, NY 10021, USA.
⁷⁴ Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
⁷⁵ Northwestern University, Feinberg School of Medicine, Department of Preventive Medicine, Chicago, IL, USA.
⁷⁶ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
⁷⁷ Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, USA Juan-P.Casas@lshtm.ac.uk.
⁷⁸ School of Health Sciences, Jackson State University, Jackson, MS, USA.
⁷⁹ School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.
⁸⁰ Preventive Medicine and Epidemiology, Evans Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
⁸¹ Department of Laboratory Medicine and Pathology, University of Minnesota, USA.
⁸² Division of Sleep and Circadian Disorders, Brigham and Women's Hospital; Harvard Medical School, Boston USA Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
⁸³ Division of Sleep and Circadian Disorders, Brigham and Women's Hospital; Harvard Medical School, Boston USA.
⁸⁴ National Heart, Lung, and Blood Institute's The Framingham Heart Study, Framingham, Massachusetts, USA.
⁸⁵ Baylor College of Medicine, Department of Medicine, Division of Atherosclerosis & Vascular Medicine, Houston, Texas 77030, USA.
⁸⁶ Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, USA.
⁸⁷ Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, Calif, USA.
⁸⁸ Division of Epidemiology, School of Public Health, University of Texas Health Science Center at Houston, Texas, USA.
⁸⁹ 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.
⁹⁰ 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.
⁹¹ British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
⁹² Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, WC1E 7HT, UK Genetics, R&D, GlaxoSmithKline, Stevenage, UK.
⁹³ Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
⁹⁴ 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.
⁹⁵ Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
⁹⁶ Department of Genetics, University of North Carolina School of Medicine at Chapel Hill, Chapel Hill, North Carolina 27514, USA.
⁹⁷ College of Pharmacy, The University of New Mexico, Albuquerque, NM, USA.
⁹⁸ 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.
⁹⁹ Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK.
¹⁰⁰ 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.
¹⁰¹ 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 & Tropical Medicine, London, WC1E 7HT, UK Juan-P.Casas@lshtm.ac.uk.

PMID: 25011450
PMCID: PMC4091648
DOI: 10.1136/bmj.g4164

Meta-Analysis

Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data

Michael V Holmes et al. BMJ. 2014.

. 2014 Jul 10:349:g4164.

doi: 10.1136/bmj.g4164.

Authors

Affiliations

¹ 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.
² Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, WC1E 7HT, UK.
³ MRC Integrative Epidemiology Unit (IEU) at the Universty of Bristol, Oakfield House, Bristol BS8 2BN, UK.
⁴ Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, WC1E 7HT, UK Centre for Statistical Methodology, London School of Hygiene & Tropical Medicine, London, WC1E 7HT, UK.
⁵ 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.
⁶ MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
⁷ Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
⁸ Department of Cardiology, Leiden University Medical Center, the Netherlands.
⁹ MRC Unit for Lifelong Health and Ageing at UCL, London, UK.
¹⁰ Centre for Paediatric Epidemiology and Biostatistics, UCL Institute of Child Health, London, UK.
¹¹ German Institute of Human Nutrition Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany.
¹² Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK.
¹³ Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA Juan-P.Casas@lshtm.ac.uk.
¹⁴ Office of Public Health Genomics, Office of Epidemiology, Surveillance, and Laboratory Services, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
¹⁵ Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
¹⁶ Department of Medical Sciences, Uppsala University, Uppsala University Hospital, SE-751 85 Uppsala, Sweden.
¹⁷ Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Videnska 1958/9, Prague 4, 14021, Czech Republic.
¹⁸ Department of Epidemiology and Public Health, University College London, London, WC1E 6BT, UK.
¹⁹ Genetic Epidemiology Group, Institute of Cardiovascular Science, Department of Epidemiology and Public Health, University College London, UK.
²⁰ Cyprus International Institute for Environmental and Public Health in association with the Harvard School of Public Health, Cyprus University of Technology, 3603 Limassol, Cyprus.
²¹ Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia.
²² UCL Genetics Institute, Department of Genetics Environment and Evolution, London, WC1E 6BT, UK.
²³ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
²⁴ Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
²⁵ Unit of Cancer Epidemiology, San Giovanni Battista Hospital and Center for Cancer Prevention (CPO-Piemonte), 10129, Torino, Italy.
²⁶ Department of Clinical Sciences, Lund University, Malmö, Sweden.
²⁷ Mayo Clinic Department of Neurology, Jacksonville, FL 32224, USA.
²⁸ Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.
²⁹ Centre for Population Health Sciences, University of Edinburgh, Edinburgh EH8 9AG, UK.
³⁰ Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, The Netherlands.
³¹ Department of Preventive Cardiology, Institute for Clinical and Experimental Medicine, Prague 4, 14021, Czech Republic.
³² Western Australian Centre for Health & Ageing, Centre for Medical Research, University of Western Australia, Perth, Australia.
³³ Department of Clinical Biochemistry, Royal Perth Hospital and School of Surgery, the University of Western Australia.
³⁴ Department of Internal Medicine, Internal Medicine, CHUV, Lausanne, Switzerland.
³⁵ UCL Institute of Health Equity, Department of Epidemiology & Public Health, London WC1E 7HB, UK.
³⁶ Instituto Medicina Molecular, Faculdade de Medicina Universidade de Lisboa, 1649-028 Lisbon, Portugal Servico Neurologia, Hospital de Santa Maria, 1649-035 Lisbon, Portugal.
³⁷ Instituto Nacional de Saude Doutor Ricardo Jorge, 1649-016 Lisbon, Portugal Faculdade Ciencias Universidade Lisboa, 1749-016 Lisbon, Portugal.
³⁸ Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK.
³⁹ Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands.
⁴⁰ Research Centre for Prevention and Health, Capital Region of Denmark, Glostrup University Hospital, Glostrup, Denmark.
⁴¹ Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
⁴² 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.
⁴³ 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.
⁴⁴ Department of Public Health & Caring Sciences, Uppsala University, Uppsala University Hospital, SE-75185 Uppsala, Sweden.
⁴⁵ Centre for Health Monitoring, National Institute of Public Health, 100 42 Prague, Czech Republic.
⁴⁶ Department of Epidemiology and Population Studies, Institute of Public Health, Jagiellonian University Medical College, 31-531 Krakow, Poland.
⁴⁷ 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.
⁴⁸ 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.
⁴⁹ Department of Population Studies, Institute of Cardiology, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania.
⁵⁰ School of Surgery, University of Western Australia, Perth, Australia.
⁵¹ Department of Neurology, Sir Charles Gairdner Hospital, Perth, Australia School of Medicine and Pharmacology, The University of Western Australia, Nedlands, Perth, Australia.
⁵² Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK WC1E 6JF.
⁵³ Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
⁵⁴ Department of Radiology, University Medical Center Utrecht, Utrecht, The Netherlands.
⁵⁵ Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK.
⁵⁶ 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.
⁵⁷ Western Australian Centre for Health & Ageing, Centre for Medical Research, University of Western Australia, Perth, Australia School of Psychiatry & Clinical Neurosciences (M573), University of Western Australia, Perth 6009, Australia Department of Psychiatry, Royal Perth Hospital, Perth, Australia.
⁵⁸ Department of Primary Care and Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁵⁹ Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden Center for Molecular Medicine, Karolinska University Hospital Solna, Stockholm, Sweden.
⁶⁰ Danish Cancer Society, Strandboulevarden, Copenhagen, Denmark.
⁶¹ National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark.
⁶² 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.
⁶³ National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.
⁶⁴ Dept Pathology and Medical Biology, Medical Biology division, Molecular Genetics, University Medical Center Groningen and Groningen University, Groningen, The Netherlands.
⁶⁵ Department of Primary Care & Population Health, UCL, London, UK.
⁶⁶ Population Health Research Institute, St George's, University of London, London, UK.
⁶⁷ 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.
⁶⁸ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK Department of Cardiovascular Medicine, University of Oxford, Oxford, UK.
⁶⁹ 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.
⁷⁰ Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Texas, USA.
⁷¹ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
⁷² Department of Medicine, McMaster University, Hamilton, Ontario, Canada L8S4L8.
⁷³ New York Academy of Medicine, New York, NY 10021, USA.
⁷⁴ Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
⁷⁵ Northwestern University, Feinberg School of Medicine, Department of Preventive Medicine, Chicago, IL, USA.
⁷⁶ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
⁷⁷ Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, USA Juan-P.Casas@lshtm.ac.uk.
⁷⁸ School of Health Sciences, Jackson State University, Jackson, MS, USA.
⁷⁹ School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.
⁸⁰ Preventive Medicine and Epidemiology, Evans Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
⁸¹ Department of Laboratory Medicine and Pathology, University of Minnesota, USA.
⁸² Division of Sleep and Circadian Disorders, Brigham and Women's Hospital; Harvard Medical School, Boston USA Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
⁸³ Division of Sleep and Circadian Disorders, Brigham and Women's Hospital; Harvard Medical School, Boston USA.
⁸⁴ National Heart, Lung, and Blood Institute's The Framingham Heart Study, Framingham, Massachusetts, USA.
⁸⁵ Baylor College of Medicine, Department of Medicine, Division of Atherosclerosis & Vascular Medicine, Houston, Texas 77030, USA.
⁸⁶ Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, USA.
⁸⁷ Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, Calif, USA.
⁸⁸ Division of Epidemiology, School of Public Health, University of Texas Health Science Center at Houston, Texas, USA.
⁸⁹ 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.
⁹⁰ 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.
⁹¹ British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
⁹² Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, WC1E 7HT, UK Genetics, R&D, GlaxoSmithKline, Stevenage, UK.
⁹³ Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
⁹⁴ 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.
⁹⁵ Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
⁹⁶ Department of Genetics, University of North Carolina School of Medicine at Chapel Hill, Chapel Hill, North Carolina 27514, USA.
⁹⁷ College of Pharmacy, The University of New Mexico, Albuquerque, NM, USA.
⁹⁸ 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.
⁹⁹ Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK.
¹⁰⁰ 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.
¹⁰¹ 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 & Tropical Medicine, London, WC1E 7HT, UK Juan-P.Casas@lshtm.ac.uk.

PMID: 25011450
PMCID: PMC4091648
DOI: 10.1136/bmj.g4164

Abstract

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.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: Prof Whittaker is 90% employed by GlaxoSmithKline and own shares in GlaxoSmithKline. All other coauthors report no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Figures

None — **Fig 1** Meta-analysis pooled estimates of the association between *ADH1B* rs1229984 (A-allele carriers v non-carriers) and cardiovascular disease biomarkers showing association on crude analysis, stratified by alcohol intake

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Comment in

Alcohol and cardiovascular disease.
Glymour MM. Glymour MM. BMJ. 2014 Jul 10;349:g4334. doi: 10.1136/bmj.g4334. BMJ. 2014. PMID: 25011451 No abstract available.
Risk factors. Reducing alcohol intake improves heart health.
Huynh K. Huynh K. Nat Rev Cardiol. 2014 Sep;11(9):495. doi: 10.1038/nrcardio.2014.106. Epub 2014 Jul 29. Nat Rev Cardiol. 2014. PMID: 25072907 No abstract available.
Mendelian randomisation meta-analysis sheds doubt on protective associations between 'moderate' alcohol consumption and coronary heart disease.
Chikritzhs TN, Naimi TS, Stockwell TR, Liang W. Chikritzhs TN, et al. Evid Based Med. 2015 Feb;20(1):38. doi: 10.1136/ebmed-2014-110086. Epub 2014 Nov 4. Evid Based Med. 2015. PMID: 25371403 No abstract available.
[Alcohol in any amount harms the heart].
Holzgreve H. Holzgreve H. MMW Fortschr Med. 2014 Oct 23;156(18):32. MMW Fortschr Med. 2014. PMID: 25464536 German. No abstract available.

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References

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[1] 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. - PMC - PubMed

[2] 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. - PMC - PubMed

[3] 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. - PMC - PubMed

[4] 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. - PMC - PubMed

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

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

[7] 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

[8] 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

[9] 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

[10] 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

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Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data

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