BACKGROUND: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk. METHODS: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD. RESULTS: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUS-CHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction <0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09). CONCLUSIONS: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.

5th Department of Medicine Medical Faculty Mannheim Heidelberg University Mannheim Germany

AMC Heart Center

ATS Sardegna ASL 3 Nuoro

Bart's Heart Centre St Bartholomew's Hospital London United Kingdom

BHF Cardiovascular Research Centre Glenfield Hospital Leicester United Kingdom

CARDIoGRAMPlusC4D University of Groningen University Medical Center Groningen Netherlands

Cardiology Centre Institute for Clinical and Experimental Medicine Prague Czech Republic

Cardiology Department Parma University Hospital Italy

Cardiology Division Department of Internal Medicine

Cardiovascular Research Center and Center for Human Genetic Research Massachusetts General Hospital Boston and Program in Medical and Population Genetics Broad Institute Cambridge MA

Cardiovascular Research Institute National University of Singapore

Cardiovascular Sciences University of Edinburgh

Centre de recherche de l'Institut Universitaire de cardiologie et de pneumologie de Québec

Centre for Experimental Medicine Institut for Clinical and Experimental Medicine Prague Czech Republic

Centre for Genomic Health Queen Mary University of London

Centre for Outcomes Research and Evaluation Research Institute of the McGill University Health Centre

Centro de Pesquisa Clinica Hospital Universitario Universidade de Sao Paulo Brazil

Clinica Mediterranea Naples Italy

Clinical and Experimental Cardiology Amsterdam Cardiovascular Sciences Amsterdam UMC Department of Respiratory Medicine Academic Medical Center University of Amsterdam the Netherlands

Clinical Epidemiology and Biostatistics

Clinical Institute of Medical and Chemical Laboratory Diagnostics Medical University of Graz Austria

Clinical Trial Service Unit and Epidemiological Studies Unit Nuffield Department of Population Health University of Oxford United Kingdom

CNR Institute of Clinical Physiology Pisa Italy

Departement of Cardiovascular Sciences KU Leuven Belgium

Department of Anesthesia Pain and Critical Care Beth Israel Deaconess Medical Center Boston MA

Department of Anesthesiology Perioperative and Pain Medicine Brigham and Women's Hospital

Department of Biochemistry Microbiology and Immunology

Department of Biomedical Informatics

Department of Biomedical Informatics University of Utah Salt Lake City

Department of Biomedical Sciences Humanitas University Milan Italy

Department of Biostatistics and Epidemiology Texas Heart Institute Houston

Department of Biotechnology Institute of Molecular and Cell Biology University of Tartu Estonia

Department of Cardio Thoracic Surgery

Department of Cardio Thoracic Surgery Finnish Cardiovascular Research Center Faculty of Medicine and Life Sciences University of Tampere

Department of Cardio Thoracic Surgery Heart Center Tampere University Hospital Finland

Department of Cardiology

Department of Cardiology and Internal Diseases Military Institute of Medicine Warsaw Poland

Department of Cardiology Clinical Sciences Lund University and Skåne University Hospital Lund University Lund Sweden

Department of Cardiology Heart Center

Department of Cardiology Leiden University Medical Center

Department of Cardiology Medical University of Warsaw Poland

Department of Cardiovascular Medicine Heart and Vascular Institute and Center for Clinical Genomics

Department of Cardiovascular Medicine Heart and Vascular Institute and Center for Microbiome and Human Health Cleveland Clinic OH

Department of Cardiovascular Medicine Humanitas Clinical and Research Center Milan Italy

Department of Cardiovascular Medicine University of Münster Germany

Department of Cardiovascular Sciences and Department of Health Sciences University of Leicester United Kingdom

Department of Cellular and Molecular Medicine Lerner Research Institute

Department of Clinical Chemistry

Department of Clinical Chemistry and Hematology

Department of Clinical Chemistry Fimlab Laboratories Tampere Finland

Department of Clinical Chemistry UMC Utrecht Netherlands

Department of Clinical Physiology

Department of Clinical Sciences Lund University Malmö Sweden

Department of Epidemiology Emory University Rollins School of Public Health

Department of Forensic Medicine Medical University of Bialystok Poland

Department of Genetics Statistical Genomics Division

Department of Internal Medicine Jagiellonian University Medical College Kraków Poland

Department of Internal Medicine Skåne University Hospital Malmö Sweden

Department of Medical Genetics

Department of Medical Sciences Cardiology Uppsala University Sweden

Department of Medical Sciences Clinical Chemistry Uppsala University Sweden

Department of Medicine

Department of Medicine and Cardiology Academic Teaching Hospital Feldkirch Austria Heart Center Leipzig

Department of Medicine Cardiovascular Division Washington University School of Medicine St Louis MO

Department of Medicine Faculty of Medicine Université Laval Canada

Department of Medicine University of Verona Italy

Department of Neurology and Neurosurgery Brain Centre Rudolf Magnus and Julius Center for Health Sciences and Primary Care University Medical Center Utrecht the Netherlands

Department of Pathology and Molecular Medicine McMaster University

Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics

Department of Population Medicine and Civilization Disease Prevention

Department of Radiology University Medical Center Utrecht the Netherlands

Department of Vascular Medicine Academic Medical Center Amsterdam the Netherlands

Department of Vascular Medicine University Medical Center Utrecht and Utrecht University the Netherlands

Department of Vascular Surgery University Medical Center Utrecht University Utrecht the Netherlands

Departments of Medicine and Biochemistry Microbiology and Immunology University of Ottawa ON Canada

Departments of Preventive Medicine and Biochemistry and Molecular Medicine Keck School of Medicine of USC Los Angeles CA

Division Heart and Lungs Department of Cardiology

Division of Cardiology Department of Medicine Emory Clinical Cardiovascular Research Institute Emory University School of Medicine Atlanta GA

Division of Cardiology Department of Medicine Royal Victoria Hospital

Division of Cardiovascular Medicine College of Medicine University of Florida

Division of Clinical Epidemiology and Aging Research German Cancer Research Center

Division of Molecular and Clinical Medicine School of Medicine University of Dundee Scotland United Kingdom

Division of Pharmacoepidemiology and Clinical Pharmacology University Medical Center Utrecht the Netherlands

Drexel University College of Medicine Philadelphia PA

Durrer Centre of Cardiogenetic Research ICIN Netherlands Heart Institute Netherlands

Einthoven Laboratory for Experimental Vascular Medicine LUMC Leiden

Emeritus Professor of Cardiology University of Edinburgh

Estonian Genome Center Institute of Genomics

Faculty of Medicine

Harvard Medical School Boston MA

Heart and Lung Center Helsinki University Hospital University of Helsinki Finland

Heart Health Research Group University of Auckland New Zealand

Heart Institute University of Sao Paulo Brazil

Institute for Biomedicine Eurac Research Affiliated Institute of the University of Lübeck Bolzano Italy

Institute for Genetic Medicine Keck School of Medicine of USC Los Angeles CA

Institute for Medical Informatics Statistics and Epidemiology University of Leipzig Germany

Institute of Cardiovascular and Medical Sciences University of Glasgow United Kingdom

Institute of Cardiovascular Science Faculty of Population Health Science

Institute of Clinical Chemistry and Laboratory Medicine University Hospital Regensburg Germany

Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden

Institute of Health Informatics Faculty of Population Health Science University College London United Kingdom

Institute of Laboratory Medicine Clinical Chemistry and Molecular Diagnostics University Hospital Leipzig

Instituteitut universitaire de cardiologie et de pneumologie de Québec Laval University Québec City Canada

Intermountain Heart Institute Intermountain Medical Center Salt Lake City UT

Interuniversity Cardiology Institute of the Netherlands Utrecht the Netherlands

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

Laboratory for Translational Genetics Department of Human Genetics

Laboratory for Translational Genetics VIB Center for Cancer Biology VIB Belgium

Laboratory of Clinical Chemistry and Hematology Division Laboratories Pharmacy and Biomedical Genetics

Laboratory of Experimental Cardiology

LIFE Research Center for Civilization Diseases

Lund University Diabetes Center Lund University Lund Sweden

Medical Central Laboratories Feldkirch Austria

Medical Research Council Population Health Research Unit University of Oxford United Kingdom

Montreal Heart Institute

National Institute for Health Research Oxford Biomedical Research Centre University of Oxford United Kingdom

National Institute of Health Research Glenfield Hospital Leicester United Kingdom

Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics Division of Molecular and Clinical Medicine Ninewells Hospital and Medical School Dundee

Population Health Research Institute Hamilton ON Canada

Preventive and Genomic Cardiology McGill University Health Centre Montreal QC Canada

Princess Al Jawhara Al Brahim Centre of Excellence in Research of Hereditary Disorders Jeddah Saudi Arabia

Private University of the Principality of Liechtenstein Triesen Liechtenstein

Research Institute of the McGill University Health Centre

Respiratory Oncology Unit Department of Respiratory Medicine University Hospitals KU Leuven Belgium

Robertson Center for Biostatistics

Ruddy Canadian Cardiovascular Genetics Centre

Saint Luke's Mid America Heart Institute and the University of Missouri Kansas City and Saint Luke's Health System Kansas City MO

Section of Cardiology Michael E DeBakey Veterans Affairs Medical Center Section of Cardiovascular Research and Department of Medicine Baylor College of Medicine Houston TX

Section of Gerontology and Geriatrics Department of Internal Medicine Leiden University Medical Center

Service de cardiologie Département multidisciplinaire de cardiologie Instituteitut universitaire de cardiologie et de pneumologie de Québec Canada

St Antonius Hospital Department of Cardiology Nieuwegein the Netherlands

Synlab Academy Synlab Holding Deutschland GmbH Mannheim Germany

The Christchurch Heart Institute University of Otago Christchurch New Zealand

Transplantation Laboratory Medicum

Unité d'évaluation cardiovasculaire Institut national d'excellence en santé et en services sociaux

Université de Montréal QC Canada

University of Ottawa Heart Institute

University of Texas School of Public Health Houston

Uppsala Clinical Research Center Uppsala University Sweden

Vorarlberg Institute for Vascular Investigation and Treatment

Wallenberg Center for Molecular Medicine Lund University Lund Sweden

William Harvey Research Institute Barts and the London Medical School Queen Mary University of London

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