Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events

Riyaz S Patel^{1

2}, Amand F Schmidt^{1

3}, Vinicius Tragante³, Raymond O McCubrey⁴, Michael V Holmes^{5

6

7}, Laurence J Howe¹, Kenan Direk¹, Axel Åkerblom^{8

9}, Karin Leander¹⁰, Salim S Virani¹¹, Karol A Kaminski^{12

13}, Jochen D Muehlschlegel¹⁴, Marie-Pierre Dubé¹⁵, Hooman Allayee¹⁶, Peter Almgren¹⁷, Maris Alver¹⁸, Ekaterina V Baranova¹⁹, Hassan Behlouli²⁰, Bram Boeckx^{21

22}, Peter S Braund^{23

24}, Lutz P Breitling²⁵, Graciela Delgado²⁶, Nubia E Duarte²⁷, Line Dufresne^{20

28}, Niclas Eriksson⁸, Luisa Foco²⁹, Crystel M Gijsberts³⁰, Yan Gong³¹, Jaana Hartiala^{16

32}, Mahyar Heydarpour^{33

14}, Jaroslav A Hubacek³⁴, Marcus Kleber²⁶, Daniel Kofink³, Pekka Kuukasjärvi³⁵, Vei-Vei Lee³⁶, Andreas Leiherer^{37

38

39}, Petra A Lenzini⁴⁰, Daniel Levin⁴¹, Leo-Pekka Lyytikäinen^{42

43}, Nicola Martinelli⁴⁴, Ute Mons²⁵, Christopher P Nelson^{23

24}, Kjell Nikus^{45

46}, Anna P Pilbrow⁴⁷, Rafal Ploski⁴⁸, Yan V Sun^{49

50}, Michael W T Tanck⁵¹, W H Wilson Tang^{52

53}, Stella Trompet^{54

55}, Sander W van der Laan⁵⁶, Jessica van Setten⁵⁷, Ragnar O Vilmundarson^{58

59}, Chiara Viviani Anselmi⁶⁰, Efthymia Vlachopoulou⁶¹, Eric Boerwinkle⁶², Carlo Briguori⁶³, John F Carlquist^{4

64}, Kathryn F Carruthers⁶⁵, Gavino Casu^{60

66}, John Deanfield^{1

2}, Panos Deloukas^{67

68}, Frank Dudbridge⁶⁹, Natalie Fitzpatrick⁷⁰, Bruna Gigante⁷¹, Stefan James^{8

72}, Marja-Liisa Lokki⁶¹, Paulo A Lotufo⁷³, Nicola Marziliano⁶⁶, Ify R Mordi⁴¹, Joseph B Muhlestein^{4

64}, Chris Newton Cheh⁷⁴, Jan Pitha³⁴, Christoph H Saely^{70

37

38}, Ayman Samman-Tahhan⁷⁵, Pratik B Sandesara⁷⁵, Andrej Teren^{76

77}, Adam Timmis^{70

2}, Frans Van de Werf⁷⁸, Els Wauters⁷⁹, Arthur A M Wilde^{80

81}, Ian Ford⁸², David J Stott⁸³, Ale Algra⁸⁴, Maria G Andreassi⁸⁵, Diego Ardissino⁸⁶, Benoit J Arsenault^{87

88}, Christie M Ballantyne¹¹, Thomas O Bergmeijer⁸⁹, Connie R Bezzina⁸⁰, Simon C Body^{14

90}, Peter Bogaty^{91

92

93}, Gert J de Borst⁹⁴, Hermann Brenner²⁵, Ralph Burkhardt^{77

95}, Clara Carpeggiani⁸⁵, Gianluigi Condorelli⁹⁶, Rhonda M Cooper-DeHoff³¹, Sharon Cresci^{40

97}, Ulf de Faire¹⁰, Robert N Doughty⁹⁸, Heinz Drexel^{37

38

99}, James C Engert^{100

101

28}, Keith A A Fox¹⁰², Domenico Girelli⁴⁴, Emil Hagström^{8

9}, Stanley L Hazen^{52

103}, Claes Held^{8

9}, Harry Hemingway⁷⁰, Imo E Hoefer⁷¹, G Kees Hovingh¹⁰⁴, Julie A Johnson^{31

105}, Pim A de Jong¹⁰⁶, J Wouter Jukema^{55

107

108}, Marcin P Kaczor¹⁰⁹, Mika Kähönen^{110

110}, Jiri Kettner¹¹¹, Marek Kiliszek¹¹², Olaf H Klungel¹⁹, Bo Lagerqvist^{8

72}, Diether Lambrechts^{21

22}, Jari O Laurikka^{113

114}, Terho Lehtimäki^{42

43}, Daniel Lindholm^{8

9}, Bakhtawar K Mahmoodi⁸⁹, Anke H Maitland-van der Zee^{19

115}, Ruth McPherson^{116

117}, Olle Melander^{17

118}, Andres Metspalu^{119

18}, Witold Pepinski¹²⁰, Oliviero Olivieri⁴⁴, Grzegorz Opolski¹²¹, Colin N Palmer¹²², Gerard Pasterkamp¹²³, Carl J Pepine¹⁰⁵, Alexandre C Pereira²⁷, Louise Pilote^{20

124}, Arshed A Quyyumi⁷⁵, A Mark Richards^{47

125}, Marek Sanak¹⁰⁹, Markus Scholz^{77

126}, Agneta Siegbahn^{8

127}, Juha Sinisalo¹²⁸, J Gustav Smith^{129

130

131}, John A Spertus¹³², Alexandre F R Stewart^{58

59}, Wojciech Szczeklik¹⁰⁹, Anna Szpakowicz¹³, Jurriën M Ten Berg⁸⁹, George Thanassoulis^{120

101

28}, Joachim Thiery^{77

133}, Yolanda van der Graaf¹³⁴, Frank L J Visseren¹³⁵, Johannes Waltenberger¹³⁶; CARDIoGRAMPlusC4D Consortium; Pim Van der Harst¹³⁷, Jean-Claude Tardif^{138

139}, Naveed Sattar⁸³, Chim C Lang⁴¹, Guillaume Pare^{140

141}, James M Brophy^{20

124}, Jeffrey L Anderson^{4

64}, Winfried März^{26

142

143}, Lars Wallentin^{8

72}, Vicky A Cameron⁴⁷, Benjamin D Horne^{30

144}, Nilesh J Samani²³, Aroon D Hingorani¹, Folkert W Asselbergs^{1

70

3

57}

Affiliations

¹ Institute of Cardiovascular Science, Faculty of Population Health Science (R.S.P., A.F.S., L.J.H., K.D., J.D., A.D.H., F.W.A.).
² Bart's Heart Centre, St Bartholomew's Hospital, London, United Kingdom (R.S.P., J.D., A. Timmis).
³ Division Heart and Lungs, Department of Cardiology (A.F.S., V.T. D.K., F.W.A.).
⁴ Intermountain Heart Institute, Intermountain Medical Center, Salt Lake City, UT (R.O.M., J.F.C., J.B.M., J.L.A.).
⁵ Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health (M.V.H.), University of Oxford, United Kingdom.
⁶ Medical Research Council Population Health Research Unit (M.V.H.), University of Oxford, United Kingdom.
⁷ National Institute for Health Research Oxford Biomedical Research Centre (M.V.H.), University of Oxford, United Kingdom.
⁸ Uppsala Clinical Research Center (A.A., N.E., S.J., E.H., C.H., B.L., D. Lindholm, A. Siegbahn, L.W.), Uppsala University, Sweden.
⁹ Department of Medical Sciences, Cardiology (A.A., E.H., C.H., D. Lindholm), Uppsala University, Sweden.
¹⁰ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (K.L., U.d.F.).
¹¹ Section of Cardiology, Michael E. DeBakey Veterans Affairs Medical Center, Section of Cardiovascular Research, and Department of Medicine, Baylor College of Medicine, Houston, TX (S.S.V., C.M.B.).
¹² Department of Population Medicine and Civilization Disease Prevention (K.A.K.).
¹³ Department of Cardiology (K.A.K., A. Szpakowicz).
¹⁴ Harvard Medical School, Boston, MA (J.D.M., M.H. S.C.B.).
¹⁵ Université de Montréal, QC, Canada (M.-P.D.).
¹⁶ Departments of Preventive Medicine and Biochemistry and Molecular Medicine (H.A., J.H.), Keck School of Medicine of USC, Los Angeles, CA.
¹⁷ Department of Clinical Sciences, Lund University, Malmö, Sweden (P.A., O.M.).
¹⁸ Department of Biotechnology, Institute of Molecular and Cell Biology, University of Tartu, Estonia (M.A., A.M.).
¹⁹ Division of Pharmacoepidemiology and Clinical Pharmacology (E.V.B., O.H.K., A.H.M.-v.d.Z.), University Medical Center Utrecht, the Netherlands.
²⁰ Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Centre (H.B., L.D., L.P., J.M.B.).
²¹ Laboratory for Translational Genetics, Department of Human Genetics (B.B., D. Lambrechts).
²² Laboratory for Translational Genetics, VIB Center for Cancer Biology, VIB, Belgium (B.B., D. Lambrechts).
²³ Department of Cardiovascular Sciences (P.S.B., C.P.N., N.J.S.) and Department of Health Sciences, University of Leicester, United Kingdom.
²⁴ National Institute of Health Research (NIHR) Leicester Biomedical Research Centre (P.S.B., C.P.N.), Glenfield Hospital, Leicester, United Kingdom.
²⁵ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg (L.P.B., U.M., H.B.).
²⁶ Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (G.D., M. Kleber, W.M.).
²⁷ Heart Institute, University of Sao Paulo, Brazil (N.E.D., A.C.P.).
²⁸ Preventive and Genomic Cardiology, McGill University Health Centre, Montreal, QC, Canada (L.D., J.C.E., G.T.).
²⁹ Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, Italy (L.F.).
³⁰ Laboratory of Experimental Cardiology (C.M.G., B.D.H.).
³¹ Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics (Y.G., R.M.C.-D., J.A.J.).
³² Institute for Genetic Medicine (J.H.), Keck School of Medicine of USC, Los Angeles, CA.
³³ Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital (M.H.).
³⁴ Centre for Experimental Medicine, Institut for Clinical and Experimental Medicine, Prague, Czech Republic (J.A.H., J.P.).
³⁵ Department of Cardio-Thoracic Surgery (P.K.).
³⁶ Department of Biostatistics and Epidemiology, Texas Heart Institute, Houston (V.-V.L.).
³⁷ Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria (A.L., C.H.S., H.D.).
³⁸ Private University of the Principality of Liechtenstein, Triesen, Liechtenstein (A.L., C.H.S., H.D.).
³⁹ Medical Central Laboratories, Feldkirch, Austria (A.L.).
⁴⁰ Department of Genetics, Statistical Genomics Division (P.A.L., S.C.).
⁴¹ Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Scotland, United Kingdom (D. Levin, I.R.M., C.C.L.).
⁴² Department of Clinical Chemistry (L.-P.L., T.L.).
⁴³ Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland (L.-P.L., T.L.).
⁴⁴ Department of Medicine, University of Verona, Italy (N. Martinelli, D.G., O.O.).
⁴⁵ Department of Cardiology (K.N.).
⁴⁶ Department of Cardiology, Heart Center (K.N.).
⁴⁷ The Christchurch Heart Institute, University of Otago Christchurch, New Zealand (A.P.B., A.M.R., V.A.C.).
⁴⁸ Department of Medical Genetics (R.P.).
⁴⁹ Department of Epidemiology, Emory University Rollins School of Public Health (Y.V.S.).
⁵⁰ Department of Biomedical Informatics (Y.V.S.).
⁵¹ Clinical Epidemiology and Biostatistics (M.W.T.T.).
⁵² Department of Cellular and Molecular Medicine, Lerner Research Institute (W.H.W.T., S.L.H.).
⁵³ Department of Cardiovascular Medicine, Heart and Vascular Institute and Center for Clinical Genomics (W.H.W.T.).
⁵⁴ Section of Gerontology and Geriatrics, Department of Internal Medicine (S.T.), Leiden University Medical Center.
⁵⁵ Department of Cardiology (S.T., J.W.J.), Leiden University Medical Center.
⁵⁶ Laboratory of Clinical Chemistry and Hematology, Division Laboratories, Pharmacy, and Biomedical Genetics (S.W.v.d.L.).
⁵⁷ Durrer Centre of Cardiogenetic Research, ICIN-Netherlands Heart Institute, Netherlands (J.v.S., F.W.B.).
⁵⁸ Ruddy Canadian Cardiovascular Genetics Centre (R.O.V., A.F.R.S.).
⁵⁹ Department of Biochemistry, Microbiology and Immunology (R.O.V., A.F.R.S.).
⁶⁰ Department of Cardiovascular Medicine, Humanitas Clinical and Research Center, Milan, Italy (C.V.A., G.C).
⁶¹ Transplantation Laboratory, Medicum (E.V., M.-L.L.).
⁶² University of Texas School of Public Health, Houston (E.B.).
⁶³ Clinica Mediterranea, Naples, Italy (C.B.).
⁶⁴ Cardiology Division, Department of Internal Medicine (J.F.C., J.B.M., J.L.A.).
⁶⁵ Cardiovascular Sciences (K.F.C.), University of Edinburgh.
⁶⁶ ATS Sardegna, ASL 3, Nuoro (G. Casu, N. Marziliano).
⁶⁷ William Harvey Research Institute, Barts and the London Medical School (P.D.), Queen Mary University of London.
⁶⁸ Centre for Genomic Health (P.D.), Queen Mary University of London.
⁶⁹ BHF Cardiovascular Research Centre (F.D.), Glenfield Hospital, Leicester, United Kingdom.
⁷⁰ Institute of Health Informatics, Faculty of Population Health Science, University College London, United Kingdom (N.F., C.H.S., A. Timmis, H.H., F.W.A.).
⁷¹ Department of Clinical Chemistry and Hematology (B.G., I.E.H.).
⁷² Department of Medical Sciences, Cardiology (S.J., B.L., L.W.), Uppsala University, Sweden.
⁷³ Centro de Pesquisa Clinica, Hospital Universitario, Universidade de Sao Paulo, Brazil (P.A.L.).
⁷⁴ Cardiovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital, Boston and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (C.N.C.).
⁷⁵ Division of Cardiology, Department of Medicine, Emory Clinical Cardiovascular Research Institute, Emory University School of Medicine, Atlanta, GA (A.S.-T., P.B.S., A.A.Q.).
⁷⁶ Department of Medicine and Cardiology, Academic Teaching Hospital Feldkirch, Austria. Heart Center Leipzig (A. Teren).
⁷⁷ LIFE Research Center for Civilization Diseases (A. Teren, R.B., M. Scholz, J.T.).
⁷⁸ Departement of Cardiovascular Sciences, KU Leuven, Belgium (F.V.d.W.).
⁷⁹ Respiratory Oncology Unit, Department of Respiratory Medicine, University Hospitals KU Leuven, Belgium (E.W.).
⁸⁰ AMC Heart Center (A.A.M.W., C.R.B.).
⁸¹ Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Saudi Arabia (A.A.M.W.).
⁸² Robertson Center for Biostatistics (I.F.).
⁸³ Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (D.J.S., N.S.).
⁸⁴ Department of Neurology and Neurosurgery, Brain Centre Rudolf Magnus and Julius Center for Health Sciences and Primary Care (A. Algra), University Medical Center Utrecht, the Netherlands.
⁸⁵ CNR Institute of Clinical Physiology, Pisa, Italy (M.G.A., C.C.).
⁸⁶ Cardiology Department, Parma University Hospital, Italy (D.A.).
⁸⁷ Centre de recherche de l'Institut Universitaire de cardiologie et de pneumologie de Québec (B.J.A.).
⁸⁸ Department of Medicine, Faculty of Medicine, Université Laval, Canada (B.J.A.).
⁸⁹ St. Antonius Hospital, Department of Cardiology, Nieuwegein, the Netherlands (T.O.B., B.K.M., J.M.t.B.).
⁹⁰ Department of Anesthesia, Pain and Critical Care, Beth Israel Deaconess Medical Center, Boston, MA (S.C.B.).
⁹¹ Service de cardiologie, Département multidisciplinaire de cardiologie, Instituteitut universitaire de cardiologie et de pneumologie de Québec, Canada (P.B.).
⁹² Unité d'évaluation cardiovasculaire, Institut national d'excellence en santé et en services sociaux (INESSS), Montreal Canada (P.B.).
⁹³ Instituteitut universitaire de cardiologie et de pneumologie de Québec, Laval University, Québec City, Canada (P.B.).
⁹⁴ Department of Vascular Surgery, University Medical Center Utrecht, University Utrecht, the Netherlands (G.J.d.B.).
⁹⁵ Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Germany (R.B.).
⁹⁶ Department of Biomedical Sciences, Humanitas University, Milan, Italy (G. Condorelli).
⁹⁷ Department of Medicine, Cardiovascular Division Washington University School of Medicine, St Louis, MO (S.C.).
⁹⁸ Heart Health Research Group, University of Auckland, New Zealand (R.N.D.).
⁹⁹ Drexel University College of Medicine, Philadelphia, PA (H.D.).
¹⁰⁰ Research Institute of the McGill University Health Centre (J.C.E.).
¹⁰¹ Division of Cardiology, Department of Medicine, Royal Victoria Hospital (J.C.E., G.T.).
¹⁰² Emeritus Professor of Cardiology (K.A.A.F.), University of Edinburgh.
¹⁰³ Department of Cardiovascular Medicine, Heart and Vascular Institute and Center for Microbiome and Human Health, Cleveland Clinic, OH (S.L.H.).
¹⁰⁴ Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands (G.K.H.).
¹⁰⁵ Division of Cardiovascular Medicine, College of Medicine, University of Florida (J.A.J., C.J.P.).
¹⁰⁶ Department of Radiology (P.A.d.J.), University Medical Center Utrecht, the Netherlands.
¹⁰⁷ Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden (J.W.J.).
¹⁰⁸ Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands (J.W.J.).
¹⁰⁹ Department of Internal Medicine, Jagiellonian University Medical College, Kraków, Poland (M.P.K., M. Sanak, W.S.).
¹¹⁰ Department of Clinical Physiology (M. Kähönen).
¹¹¹ Cardiology Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic (J.K.).
¹¹² Department of Cardiology and Internal Diseases, Military Institute of Medicine, Warsaw, Poland (M. Kiliszek).
¹¹³ Department of Cardio-Thoracic Surgery, Finnish Cardiovascular Research Center, Faculty of Medicine and Life Sciences, University of Tampere (J.O.L.).
¹¹⁴ Department of Cardio-Thoracic Surgery, Heart Center, Tampere University Hospital, Finland (J.O.L).
¹¹⁵ Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Department of Respiratory Medicine, Academic Medical Center, University of Amsterdam, the Netherlands (A.H.M.-v.d.Z.).
¹¹⁶ University of Ottawa Heart Institute (R.M.).
¹¹⁷ Departments of Medicine and Biochemistry, Microbiology and Immunology, University of Ottawa, ON, Canada (R.M.).
¹¹⁸ Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden (O.M.).
¹¹⁹ Estonian Genome Center, Institute of Genomics (A.M.).
¹²⁰ Department of Forensic Medicine, Medical University of Bialystok, Poland (W.P., G.T.).
¹²¹ Department of Cardiology, Medical University of Warsaw, Poland (G.O.).
¹²² Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, Dundee (C.N.P.).
¹²³ Department of Clinical Chemistry, UMC Utrecht, Netherlands (G. Pasterkamp).
¹²⁴ Department of Medicine (L.P., J.M.B.).
¹²⁵ Cardiovascular Research Institute, National University of Singapore (A.M.R.).
¹²⁶ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Germany (M. Scholz).
¹²⁷ Department of Medical Sciences, Clinical Chemistry (A. Siegbahn), Uppsala University, Sweden.
¹²⁸ Heart and Lung Center, Helsinki University Hospital University of Helsinki, Finland (J.S.).
¹²⁹ Department of Cardiology, Clinical Sciences, Lund University and Skåne University Hospital (J.G.S.), Lund University, Lund, Sweden.
¹³⁰ Wallenberg Center for Molecular Medicine (J.G.S.), Lund University, Lund, Sweden.
¹³¹ Lund University Diabetes Center (J.G.S.), Lund University, Lund, Sweden.
¹³² Saint Luke's Mid America Heart Institute and the University of Missouri-Kansas City and Saint Luke's Health System, Kansas City, MO (J.A.S.).
¹³³ Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital, Leipzig (J.T.).
¹³⁴ Julius Center for Health Sciences and Primary Care (Y.v.d.G.), University Medical Center Utrecht, the Netherlands.
¹³⁵ Department of Vascular Medicine, University Medical Center Utrecht and Utrecht University, the Netherlands (F.L.J.V.).
¹³⁶ Department of Cardiovascular Medicine, University of Münster, Germany (J.W.).
¹³⁷ CARDIoGRAMPlusC4D. University of Groningen, University Medical Center, Groningen, Netherlands (P.V.d.H.).
¹³⁸ Montreal Heart Institute (J.-C.T.).
¹³⁹ Faculty of Medicine (J.-C.T.).
¹⁴⁰ Department of Pathology and Molecular Medicine, McMaster University (G. Pare).
¹⁴¹ Population Health Research Institute, Hamilton, ON, Canada (G. Pare).
¹⁴² Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany (W.M.).
¹⁴³ Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Austria (W.M.).
¹⁴⁴ Department of Biomedical Informatics, University of Utah, Salt Lake City (B.D.H.).

PMID: 30897348
PMCID: PMC6625876
DOI: 10.1161/CIRCGEN.119.002471

Meta-Analysis

Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events

Riyaz S Patel et al. Circ Genom Precis Med. 2019 Apr.

. 2019 Apr;12(4):e002471.

doi: 10.1161/CIRCGEN.119.002471. Epub 2019 Mar 21.

Authors

Affiliations

¹ Institute of Cardiovascular Science, Faculty of Population Health Science (R.S.P., A.F.S., L.J.H., K.D., J.D., A.D.H., F.W.A.).
² Bart's Heart Centre, St Bartholomew's Hospital, London, United Kingdom (R.S.P., J.D., A. Timmis).
³ Division Heart and Lungs, Department of Cardiology (A.F.S., V.T. D.K., F.W.A.).
⁴ Intermountain Heart Institute, Intermountain Medical Center, Salt Lake City, UT (R.O.M., J.F.C., J.B.M., J.L.A.).
⁵ Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health (M.V.H.), University of Oxford, United Kingdom.
⁶ Medical Research Council Population Health Research Unit (M.V.H.), University of Oxford, United Kingdom.
⁷ National Institute for Health Research Oxford Biomedical Research Centre (M.V.H.), University of Oxford, United Kingdom.
⁸ Uppsala Clinical Research Center (A.A., N.E., S.J., E.H., C.H., B.L., D. Lindholm, A. Siegbahn, L.W.), Uppsala University, Sweden.
⁹ Department of Medical Sciences, Cardiology (A.A., E.H., C.H., D. Lindholm), Uppsala University, Sweden.
¹⁰ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (K.L., U.d.F.).
¹¹ Section of Cardiology, Michael E. DeBakey Veterans Affairs Medical Center, Section of Cardiovascular Research, and Department of Medicine, Baylor College of Medicine, Houston, TX (S.S.V., C.M.B.).
¹² Department of Population Medicine and Civilization Disease Prevention (K.A.K.).
¹³ Department of Cardiology (K.A.K., A. Szpakowicz).
¹⁴ Harvard Medical School, Boston, MA (J.D.M., M.H. S.C.B.).
¹⁵ Université de Montréal, QC, Canada (M.-P.D.).
¹⁶ Departments of Preventive Medicine and Biochemistry and Molecular Medicine (H.A., J.H.), Keck School of Medicine of USC, Los Angeles, CA.
¹⁷ Department of Clinical Sciences, Lund University, Malmö, Sweden (P.A., O.M.).
¹⁸ Department of Biotechnology, Institute of Molecular and Cell Biology, University of Tartu, Estonia (M.A., A.M.).
¹⁹ Division of Pharmacoepidemiology and Clinical Pharmacology (E.V.B., O.H.K., A.H.M.-v.d.Z.), University Medical Center Utrecht, the Netherlands.
²⁰ Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Centre (H.B., L.D., L.P., J.M.B.).
²¹ Laboratory for Translational Genetics, Department of Human Genetics (B.B., D. Lambrechts).
²² Laboratory for Translational Genetics, VIB Center for Cancer Biology, VIB, Belgium (B.B., D. Lambrechts).
²³ Department of Cardiovascular Sciences (P.S.B., C.P.N., N.J.S.) and Department of Health Sciences, University of Leicester, United Kingdom.
²⁴ National Institute of Health Research (NIHR) Leicester Biomedical Research Centre (P.S.B., C.P.N.), Glenfield Hospital, Leicester, United Kingdom.
²⁵ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg (L.P.B., U.M., H.B.).
²⁶ Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (G.D., M. Kleber, W.M.).
²⁷ Heart Institute, University of Sao Paulo, Brazil (N.E.D., A.C.P.).
²⁸ Preventive and Genomic Cardiology, McGill University Health Centre, Montreal, QC, Canada (L.D., J.C.E., G.T.).
²⁹ Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, Italy (L.F.).
³⁰ Laboratory of Experimental Cardiology (C.M.G., B.D.H.).
³¹ Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics (Y.G., R.M.C.-D., J.A.J.).
³² Institute for Genetic Medicine (J.H.), Keck School of Medicine of USC, Los Angeles, CA.
³³ Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital (M.H.).
³⁴ Centre for Experimental Medicine, Institut for Clinical and Experimental Medicine, Prague, Czech Republic (J.A.H., J.P.).
³⁵ Department of Cardio-Thoracic Surgery (P.K.).
³⁶ Department of Biostatistics and Epidemiology, Texas Heart Institute, Houston (V.-V.L.).
³⁷ Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria (A.L., C.H.S., H.D.).
³⁸ Private University of the Principality of Liechtenstein, Triesen, Liechtenstein (A.L., C.H.S., H.D.).
³⁹ Medical Central Laboratories, Feldkirch, Austria (A.L.).
⁴⁰ Department of Genetics, Statistical Genomics Division (P.A.L., S.C.).
⁴¹ Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Scotland, United Kingdom (D. Levin, I.R.M., C.C.L.).
⁴² Department of Clinical Chemistry (L.-P.L., T.L.).
⁴³ Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland (L.-P.L., T.L.).
⁴⁴ Department of Medicine, University of Verona, Italy (N. Martinelli, D.G., O.O.).
⁴⁵ Department of Cardiology (K.N.).
⁴⁶ Department of Cardiology, Heart Center (K.N.).
⁴⁷ The Christchurch Heart Institute, University of Otago Christchurch, New Zealand (A.P.B., A.M.R., V.A.C.).
⁴⁸ Department of Medical Genetics (R.P.).
⁴⁹ Department of Epidemiology, Emory University Rollins School of Public Health (Y.V.S.).
⁵⁰ Department of Biomedical Informatics (Y.V.S.).
⁵¹ Clinical Epidemiology and Biostatistics (M.W.T.T.).
⁵² Department of Cellular and Molecular Medicine, Lerner Research Institute (W.H.W.T., S.L.H.).
⁵³ Department of Cardiovascular Medicine, Heart and Vascular Institute and Center for Clinical Genomics (W.H.W.T.).
⁵⁴ Section of Gerontology and Geriatrics, Department of Internal Medicine (S.T.), Leiden University Medical Center.
⁵⁵ Department of Cardiology (S.T., J.W.J.), Leiden University Medical Center.
⁵⁶ Laboratory of Clinical Chemistry and Hematology, Division Laboratories, Pharmacy, and Biomedical Genetics (S.W.v.d.L.).
⁵⁷ Durrer Centre of Cardiogenetic Research, ICIN-Netherlands Heart Institute, Netherlands (J.v.S., F.W.B.).
⁵⁸ Ruddy Canadian Cardiovascular Genetics Centre (R.O.V., A.F.R.S.).
⁵⁹ Department of Biochemistry, Microbiology and Immunology (R.O.V., A.F.R.S.).
⁶⁰ Department of Cardiovascular Medicine, Humanitas Clinical and Research Center, Milan, Italy (C.V.A., G.C).
⁶¹ Transplantation Laboratory, Medicum (E.V., M.-L.L.).
⁶² University of Texas School of Public Health, Houston (E.B.).
⁶³ Clinica Mediterranea, Naples, Italy (C.B.).
⁶⁴ Cardiology Division, Department of Internal Medicine (J.F.C., J.B.M., J.L.A.).
⁶⁵ Cardiovascular Sciences (K.F.C.), University of Edinburgh.
⁶⁶ ATS Sardegna, ASL 3, Nuoro (G. Casu, N. Marziliano).
⁶⁷ William Harvey Research Institute, Barts and the London Medical School (P.D.), Queen Mary University of London.
⁶⁸ Centre for Genomic Health (P.D.), Queen Mary University of London.
⁶⁹ BHF Cardiovascular Research Centre (F.D.), Glenfield Hospital, Leicester, United Kingdom.
⁷⁰ Institute of Health Informatics, Faculty of Population Health Science, University College London, United Kingdom (N.F., C.H.S., A. Timmis, H.H., F.W.A.).
⁷¹ Department of Clinical Chemistry and Hematology (B.G., I.E.H.).
⁷² Department of Medical Sciences, Cardiology (S.J., B.L., L.W.), Uppsala University, Sweden.
⁷³ Centro de Pesquisa Clinica, Hospital Universitario, Universidade de Sao Paulo, Brazil (P.A.L.).
⁷⁴ Cardiovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital, Boston and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (C.N.C.).
⁷⁵ Division of Cardiology, Department of Medicine, Emory Clinical Cardiovascular Research Institute, Emory University School of Medicine, Atlanta, GA (A.S.-T., P.B.S., A.A.Q.).
⁷⁶ Department of Medicine and Cardiology, Academic Teaching Hospital Feldkirch, Austria. Heart Center Leipzig (A. Teren).
⁷⁷ LIFE Research Center for Civilization Diseases (A. Teren, R.B., M. Scholz, J.T.).
⁷⁸ Departement of Cardiovascular Sciences, KU Leuven, Belgium (F.V.d.W.).
⁷⁹ Respiratory Oncology Unit, Department of Respiratory Medicine, University Hospitals KU Leuven, Belgium (E.W.).
⁸⁰ AMC Heart Center (A.A.M.W., C.R.B.).
⁸¹ Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Saudi Arabia (A.A.M.W.).
⁸² Robertson Center for Biostatistics (I.F.).
⁸³ Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (D.J.S., N.S.).
⁸⁴ Department of Neurology and Neurosurgery, Brain Centre Rudolf Magnus and Julius Center for Health Sciences and Primary Care (A. Algra), University Medical Center Utrecht, the Netherlands.
⁸⁵ CNR Institute of Clinical Physiology, Pisa, Italy (M.G.A., C.C.).
⁸⁶ Cardiology Department, Parma University Hospital, Italy (D.A.).
⁸⁷ Centre de recherche de l'Institut Universitaire de cardiologie et de pneumologie de Québec (B.J.A.).
⁸⁸ Department of Medicine, Faculty of Medicine, Université Laval, Canada (B.J.A.).
⁸⁹ St. Antonius Hospital, Department of Cardiology, Nieuwegein, the Netherlands (T.O.B., B.K.M., J.M.t.B.).
⁹⁰ Department of Anesthesia, Pain and Critical Care, Beth Israel Deaconess Medical Center, Boston, MA (S.C.B.).
⁹¹ Service de cardiologie, Département multidisciplinaire de cardiologie, Instituteitut universitaire de cardiologie et de pneumologie de Québec, Canada (P.B.).
⁹² Unité d'évaluation cardiovasculaire, Institut national d'excellence en santé et en services sociaux (INESSS), Montreal Canada (P.B.).
⁹³ Instituteitut universitaire de cardiologie et de pneumologie de Québec, Laval University, Québec City, Canada (P.B.).
⁹⁴ Department of Vascular Surgery, University Medical Center Utrecht, University Utrecht, the Netherlands (G.J.d.B.).
⁹⁵ Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Germany (R.B.).
⁹⁶ Department of Biomedical Sciences, Humanitas University, Milan, Italy (G. Condorelli).
⁹⁷ Department of Medicine, Cardiovascular Division Washington University School of Medicine, St Louis, MO (S.C.).
⁹⁸ Heart Health Research Group, University of Auckland, New Zealand (R.N.D.).
⁹⁹ Drexel University College of Medicine, Philadelphia, PA (H.D.).
¹⁰⁰ Research Institute of the McGill University Health Centre (J.C.E.).
¹⁰¹ Division of Cardiology, Department of Medicine, Royal Victoria Hospital (J.C.E., G.T.).
¹⁰² Emeritus Professor of Cardiology (K.A.A.F.), University of Edinburgh.
¹⁰³ Department of Cardiovascular Medicine, Heart and Vascular Institute and Center for Microbiome and Human Health, Cleveland Clinic, OH (S.L.H.).
¹⁰⁴ Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands (G.K.H.).
¹⁰⁵ Division of Cardiovascular Medicine, College of Medicine, University of Florida (J.A.J., C.J.P.).
¹⁰⁶ Department of Radiology (P.A.d.J.), University Medical Center Utrecht, the Netherlands.
¹⁰⁷ Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden (J.W.J.).
¹⁰⁸ Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands (J.W.J.).
¹⁰⁹ Department of Internal Medicine, Jagiellonian University Medical College, Kraków, Poland (M.P.K., M. Sanak, W.S.).
¹¹⁰ Department of Clinical Physiology (M. Kähönen).
¹¹¹ Cardiology Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic (J.K.).
¹¹² Department of Cardiology and Internal Diseases, Military Institute of Medicine, Warsaw, Poland (M. Kiliszek).
¹¹³ Department of Cardio-Thoracic Surgery, Finnish Cardiovascular Research Center, Faculty of Medicine and Life Sciences, University of Tampere (J.O.L.).
¹¹⁴ Department of Cardio-Thoracic Surgery, Heart Center, Tampere University Hospital, Finland (J.O.L).
¹¹⁵ Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Department of Respiratory Medicine, Academic Medical Center, University of Amsterdam, the Netherlands (A.H.M.-v.d.Z.).
¹¹⁶ University of Ottawa Heart Institute (R.M.).
¹¹⁷ Departments of Medicine and Biochemistry, Microbiology and Immunology, University of Ottawa, ON, Canada (R.M.).
¹¹⁸ Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden (O.M.).
¹¹⁹ Estonian Genome Center, Institute of Genomics (A.M.).
¹²⁰ Department of Forensic Medicine, Medical University of Bialystok, Poland (W.P., G.T.).
¹²¹ Department of Cardiology, Medical University of Warsaw, Poland (G.O.).
¹²² Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, Dundee (C.N.P.).
¹²³ Department of Clinical Chemistry, UMC Utrecht, Netherlands (G. Pasterkamp).
¹²⁴ Department of Medicine (L.P., J.M.B.).
¹²⁵ Cardiovascular Research Institute, National University of Singapore (A.M.R.).
¹²⁶ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Germany (M. Scholz).
¹²⁷ Department of Medical Sciences, Clinical Chemistry (A. Siegbahn), Uppsala University, Sweden.
¹²⁸ Heart and Lung Center, Helsinki University Hospital University of Helsinki, Finland (J.S.).
¹²⁹ Department of Cardiology, Clinical Sciences, Lund University and Skåne University Hospital (J.G.S.), Lund University, Lund, Sweden.
¹³⁰ Wallenberg Center for Molecular Medicine (J.G.S.), Lund University, Lund, Sweden.
¹³¹ Lund University Diabetes Center (J.G.S.), Lund University, Lund, Sweden.
¹³² Saint Luke's Mid America Heart Institute and the University of Missouri-Kansas City and Saint Luke's Health System, Kansas City, MO (J.A.S.).
¹³³ Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital, Leipzig (J.T.).
¹³⁴ Julius Center for Health Sciences and Primary Care (Y.v.d.G.), University Medical Center Utrecht, the Netherlands.
¹³⁵ Department of Vascular Medicine, University Medical Center Utrecht and Utrecht University, the Netherlands (F.L.J.V.).
¹³⁶ Department of Cardiovascular Medicine, University of Münster, Germany (J.W.).
¹³⁷ CARDIoGRAMPlusC4D. University of Groningen, University Medical Center, Groningen, Netherlands (P.V.d.H.).
¹³⁸ Montreal Heart Institute (J.-C.T.).
¹³⁹ Faculty of Medicine (J.-C.T.).
¹⁴⁰ Department of Pathology and Molecular Medicine, McMaster University (G. Pare).
¹⁴¹ Population Health Research Institute, Hamilton, ON, Canada (G. Pare).
¹⁴² Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany (W.M.).
¹⁴³ Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Austria (W.M.).
¹⁴⁴ Department of Biomedical Informatics, University of Utah, Salt Lake City (B.D.H.).

PMID: 30897348
PMCID: PMC6625876
DOI: 10.1161/CIRCGEN.119.002471

Abstract

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.

Keywords: chromosome; genetic; myocardial infarction; risk factor; secondary prevention; variation.

PubMed Disclaimer

Figures

**Figure 1.**
Association between chromosome 9p21 and subsequent coronary heart disease (CHD) events in all participants with baseline CHD (GENIUS-CHD [Genetics of Subsequent Coronary Heart Disease]) compared with association in CHD cases and CHD-free controls (CARDIoGRAMPlusC4D). For the CARDIoGRAMPlusC4D consortium (Coronary Artery Disease Genome wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) meta-analysis estimate, 6 studies (LURIC, LIFE-Heart [The Leipzig Heart Study], GoDARTS [Genetics of Diabetes Audit and Research in Tayside Scotland], OHGS [Ottawa Heart Genomics Study], PROSPER [Prospective Study of Pravastatin in the Elderly at Risk], WTCCC [Welcome Trust Case Control Consortium]) were excluded as they were also included in GENIUS-CHD. Estimates for GENIUS-CHD are also presented by subtype of CHD at baseline, including acute coronary syndrome (ACS), stable coronary artery disease (CAD) without prior myocardial infarction (MI; CAD/no MI), and stable CAD with prior MI (CAD/MI). All estimates were adjusted for age and sex.

**Figure 2.**
**Association between chromosome 9p21 and secondary outcomes in participants with baseline CHD, within GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease).** All meta-analysis estimates were adjusted for age and sex. CHD indicates coronary heart disease; CVD, cardiovascular disease; MI, myocardial infarction; and OR, odds ratio.

See this image and copyright information in PMC

References

1. Nikpay M, et al. A comprehensive 1,000 genomes-based genome-wide association meta-analysis of coronary artery disease. Nat Genet. 2015;47:1121–1130. doi: 10.1038/ng.3396. - PMC - PubMed
1. Helgadottir A, et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science. 2007;316:1491–1493. doi: 10.1126/science.1142842. - PubMed
1. McPherson R, et al. A common allele on chromosome 9 associated with coronary heart disease. Science. 2007;316:1488–1491. doi: 10.1126/science.1142447. - PMC - PubMed
1. Samani NJ, et al. WTCCC and the Cardiogenics Consortium. Genomewide association analysis of coronary artery disease. N Engl J Med. 2007;357:443–453. doi: 10.1056/NEJMoa072366. - PMC - PubMed
1. Palomaki GE, et al. Association between 9p21 genomic markers and heart disease: a meta-analysis. JAMA. 2010;303:648–656. doi: 10.1001/jama.2010.118. - PubMed

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Medical
- MedlinePlus Health Information

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events

Affiliations

Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical