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BMJ. 2014 Jul 10;349:g4164. doi: 10.1136/bmj.g4164.

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

Holmes MV1, Dale CE2, Zuccolo L3, Silverwood RJ4, Guo Y5, Ye Z6, Prieto-Merino D2, Dehghan A7, Trompet S8, Wong A9, Cavadino A10, Drogan D11, Padmanabhan S12, Li S13, Yesupriya A14, Leusink M15, Sundstrom J16, Hubacek JA17, Pikhart H18, Swerdlow DI19, Panayiotou AG20, Borinskaya SA21, Finan C19, Shah S22, Kuchenbaecker KB23, Shah T19, Engmann J19, Folkersen L24, Eriksson P24, Ricceri F25, Melander O26, Sacerdote C25, Gamble DM27, Rayaprolu S28, Ross OA28, McLachlan S29, Vikhireva O18, Sluijs I30, Scott RA6, Adamkova V31, Flicker L32, Bockxmeer FM33, Power C10, Marques-Vidal P34, Meade T2, Marmot MG35, Ferro JM36, Paulos-Pinheiro S37, Humphries SE38, Talmud PJ38, Mateo Leach I39, Verweij N39, Linneberg A40, Skaaby T40, Doevendans PA41, Cramer MJ41, van der Harst P42, Klungel OH15, Dowling NF14, Dominiczak AF12, Kumari M19, Nicolaides AN43, Weikert C11, Boeing H11, Ebrahim S2, Gaunt TR3, Price JF29, Lannfelt L44, Peasey A18, Kubinova R45, Pajak A46, Malyutina S47, Voevoda MI48, Tamosiunas A49, Maitland-van der Zee AH15, Norman PE50, Hankey GJ51, Bergmann MM11, Hofman A7, Franco OH7, Cooper J52, Palmen J38, Spiering W53, de Jong PA54, Kuh D9, Hardy R9, Uitterlinden AG7, Ikram MA7, Ford I55, Hyppönen E56, Almeida OP57, Wareham NJ6, Khaw KT58, Hamsten A59, Husemoen LL40, Tjønneland A60, Tolstrup JS61, Rimm E62, Beulens JW30, Verschuren WM63, Onland-Moret NC30, Hofker MH64, Wannamethee SG65, Whincup PH66, Morris R65, Vicente AM67, Watkins H68, Farrall M68, Jukema JW8, Meschia J27, Cupples LA69, Sharp SJ6, Fornage M70, Kooperberg C71, LaCroix AZ71, Dai JY71, Lanktree MB72, Siscovick DS73, Jorgenson E74, Spring B75, Coresh J76, Li YR77, Buxbaum SG78, Schreiner PJ79, Ellison RC80, Tsai MY81, Patel SR82, Redline S83, Johnson AD84, Hoogeveen RC85, Hakonarson H86, Rotter JI87, Boerwinkle E88, de Bakker PI89, Kivimaki M18, Asselbergs FW90, Sattar N91, Lawlor DA3, Whittaker J92, Davey Smith G3, Mukamal K93, Psaty BM94, Wilson JG95, Lange LA96, Hamidovic A97, Hingorani AD19, Nordestgaard BG98, Bobak M18, Leon DA2, Langenberg C6, Palmer TM99, Reiner AP71, Keating BJ100, Dudbridge F2, Casas JP101; InterAct Consortium.

Author information

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.

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.

PMID:
25011450
PMCID:
PMC4091648
[Indexed for MEDLINE]
Free PMC Article

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