Multicenter Study

. 2019 Oct 29;19(1):240.

doi: 10.1186/s12872-019-1187-z.

Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

Amand F Schmidt^{1

2

3}, Michael V Holmes⁴, David Preiss⁴, Daniel I Swerdlow^{5

6}, Spiros Denaxas^{7

8

9

10}, Ghazaleh Fatemifar^{7

8

9}, Rupert Faraway⁵, Chris Finan^{5

7}, Dennis Valentine^{7

11}, Zammy Fairhurst-Hunter¹², Fernando Pires Hartwig¹³, Bernardo Lessa Horta¹³, Elina Hypponen^{14

15

16}, Christine Power¹⁵, Max Moldovan¹⁶, Erik van Iperen^{17

18}, Kees Hovingh¹⁹, Ilja Demuth^{20

21}, Kristina Norman^{22

23

24}, Elisabeth Steinhagen-Thiessen²⁰, Juri Demuth²⁵, Lars Bertram^{26

27}, Christina M Lill^{28

29

30}, Stefan Coassin³¹, Johann Willeit³², Stefan Kiechl³², Karin Willeit^{32

33}, Dan Mason³⁴, John Wright³⁴, Richard Morris³⁵, Goya Wanamethee³⁵, Peter Whincup³⁶, Yoav Ben-Shlomo³⁷, Stela McLachlan³⁸, Jackie F Price³⁸, Mika Kivimaki³⁹, Catherine Welch³⁹, Adelaida Sanchez-Galvez³⁹, Pedro Marques-Vidal⁴⁰, Andrew Nicolaides^{41

42}, Andrie G Panayiotou⁴³, N Charlotte Onland-Moret⁴⁴, Yvonne T van der Schouw⁴⁴, Giuseppe Matullo^{45

46}, Giovanni Fiorito^{45

46}, Simonetta Guarrera^{45

46}, Carlotta Sacerdote⁴⁷, Nicholas J Wareham⁴⁸, Claudia Langenberg⁴⁸, Robert A Scott⁴⁸, Jian'an Luan⁴⁸, Martin Bobak³⁹, Sofia Malyutina^{49

50}, Andrzej Pająk⁵¹, Ruzena Kubinova⁵², Abdonas Tamosiunas⁵³, Hynek Pikhart³⁹, Niels Grarup⁵⁴, Oluf Pedersen⁵⁴, Torben Hansen⁵⁴, Allan Linneberg^{55

56}, Tine Jess⁵⁶, Jackie Cooper⁵⁷, Steve E Humphries⁵⁷, Murray Brilliant⁵⁸, Terrie Kitchner⁵⁸, Hakon Hakonarson⁵⁹, David S Carrell⁶⁰, Catherine A McCarty⁶¹, Kirchner H Lester⁶², Eric B Larson⁶⁰, David R Crosslin⁶³, Mariza de Andrade⁶⁴, Dan M Roden⁶⁵, Joshua C Denny⁶⁶, Cara Carty⁶⁷, Stephen Hancock⁶⁸, John Attia^{68

69}, Elizabeth Holliday^{68

69}, Rodney Scott⁶⁸, Peter Schofield⁷⁰, Martin O'Donnell⁷¹, Salim Yusuf⁷¹, Michael Chong⁷¹, Guillaume Pare⁷¹, Pim van der Harst^{17

18

72

73}, M Abdullah Said⁷³, Ruben N Eppinga⁷³, Niek Verweij⁷³, Harold Snieder⁷⁴; Lifelines Cohort authors; Tim Christen⁷⁵, D O Mook-Kanamori⁷⁵; ICBP Consortium; Stefan Gustafsson⁷⁶, Lars Lind^{77

78}, Erik Ingelsson^{76

77}, Raha Pazoki^{79

80}, Oscar Franco⁷⁹, Albert Hofman⁷⁹, Andre Uitterlinden⁷⁹, Abbas Dehghan⁷⁹, Alexander Teumer^{81

82}, Sebastian Baumeister^{81

83}, Marcus Dörr^{82

84}, Markus M Lerch⁸⁵, Uwe Völker^{82

86}, Henry Völzke^{81

82}, Joey Ward⁸⁷, Jill P Pell⁸⁷, Tom Meade⁸⁸, Ingrid E Christophersen⁸⁹, Anke H Maitland-van der Zee^{90

91}, Ekaterina V Baranova⁹², Robin Young⁹², Ian Ford⁹², Archie Campbell⁹³, Sandosh Padmanabhan⁹⁴, Michiel L Bots⁴³, Diederick E Grobbee⁴³, Philippe Froguel^{95

96}, Dorothée Thuillier⁹⁵, Ronan Roussel^{97

98

99}, Amélie Bonnefond⁹⁵, Bertrand Cariou¹⁰⁰, Melissa Smart¹⁰¹, Yanchun Bao¹⁰², Meena Kumari¹⁰³, Anubha Mahajan¹⁰², Jemma C Hopewell¹², Sudha Seshadri¹⁰³; METASTROKE Consortium of the ISGC; Caroline Dale¹¹, Rui Providencia E Costa¹¹, Paul M Ridker¹⁰⁴, Daniel I Chasman¹⁰⁴, Alex P Reiner¹⁰⁵, Marylyn D Ritchie¹⁰⁶, Leslie A Lange¹⁰⁷, Alex J Cornish¹⁰⁸, Sara E Dobbins¹⁰⁸, Kari Hemminki^{109

110}, Ben Kinnersley¹⁰⁸, Marc Sanson^{111

112}, Karim Labreche^{111

112}, Matthias Simon¹¹³, Melissa Bondy¹¹⁴, Philip Law¹⁰⁸, Helen Speedy¹⁰⁸, James Allan¹¹⁵, Ni Li¹⁰⁸, Molly Went¹⁰⁸, Niels Weinhold¹¹⁶, Gareth Morgan¹¹⁶, Pieter Sonneveld¹¹⁷, Björn Nilsson¹¹⁸, Hartmut Goldschmidt¹¹⁹, Amit Sud¹⁰⁸, Andreas Engert¹²⁰, Markus Hansson^{121

122}, Harry Hemingway^{7

8

9

123}, Folkert W Asselbergs^{5

124

7

125}, Riyaz S Patel^{5

7

126}, Brendan J Keating¹²⁷, Naveed Sattar⁹⁴, Richard Houlston¹⁰⁸, Juan P Casas¹²⁸, Aroon D Hingorani^{5

7}

Affiliations

¹ Institute of Cardiovascular Science, University College London, 222 Euston Road, London, NW1 2DA, UK. amand.schmidt@ucl.ac.uk.
² Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. amand.schmidt@ucl.ac.uk.
³ UCL's BHF Research Accelerator Centre, London, UK. amand.schmidt@ucl.ac.uk.
⁴ Medical Research Council Population Health Research Unit, Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁵ Institute of Cardiovascular Science, University College London, 222 Euston Road, London, NW1 2DA, UK.
⁶ Department of Medicine, Imperial College London, London, UK.
⁷ UCL's BHF Research Accelerator Centre, London, UK.
⁸ Health Data Research UK, University College London, 222 Euston Road, London, NW1 2DA, UK.
⁹ Institute of Health Informatics, University College London, 222 Euston Road, London, NW1 2DA, UK.
¹⁰ The Alan Turing Institute, British Library, 96 Euston Rd, London, NW1 2DB, UK.
¹¹ University College London, Farr Institute of Health Informatics, London, UK.
¹² Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford, OX3 7LF, UK.
¹³ Postgraduate Program in Epidemiology, Federal University of Pelotas, Pelotas, Brazil.
¹⁴ Centre for Population Health Research, Sansom Institute for Health Research, University of South Australia, Adelaide, Australia.
¹⁵ Population, Policy and Practice, UCL GOS Institute of Child Health, London, UK.
¹⁶ South Australian Health and Medical Research Institute, Adelaide, Australia.
¹⁷ Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, The Netherlands.
¹⁸ Department of Clinical Epidemiology, Biostatistics And Bioinformatics, Academic Medical Center Amsterdam, Amsterdam, the Netherlands.
¹⁹ Department of vascular medicine, Academic Medical Center Amsterdam, Amsterdam, the Netherlands.
²⁰ Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Lipid Clinic at the Interdisciplinary Metabolism Center, Berlin, Germany.
²¹ Charité - Universitätsmedizin Berlin, BCRT - Berlin Institute of Health Center for Regenerative Therapies, Berlin, Germany.
²² Institute of Nutritional Science, University of Potsdam, 14558, Nuthetal, Germany.
²³ Geriatrics Research Group, Charité - Universitätsmedizin Berlin, 13347, Berlin, Germany.
²⁴ Department of Nutrition and Gerontology, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558, Nuthetal, Germany.
²⁵ E.CA Economics GmbH, Berlin, Germany.
²⁶ Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics & Cardiogenetics, University of Lübeck, Lübeck, Germany.
²⁷ Center for Lifespan Changes in Brain and Cognition (LCBC), Dept. Psychology, University of Oslo, Oslo, Norway.
²⁸ Genetic and Molecular Epidemiology Group, Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics & Cardiogenetics, University of Lübeck, Lübeck, Germany.
²⁹ Institute of Human Genetics, Lübeck, Germany.
³⁰ Ageing Epidemiology Research Unit, School of Public Health, Imperial College, London, UK.
³¹ Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, 6020, Innsbruck, Austria.
³² Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
³³ Department of Neurology, Inselspital, University Hospital Bern, University of Bern, Bern, Switzerland.
³⁴ Bradford Institute for Health Research, Bradford Royal Infirmary, Bradford, UK.
³⁵ Department Primary Care & Population Health, University College London, London, UK.
³⁶ Population Health Research Institute, St George's, University of London, London, UK.
³⁷ Population Health Sciences, University of Bristol, Bristol, UK.
³⁸ Centre for Population Health Sciences, The Usher Institute, University of Edinburgh, Edinburgh, UK.
³⁹ Department of Epidemiology and Public Health, UCL Institute of Epidemiology and Health Care, University College London, London, UK.
⁴⁰ Department of Medicine, Internal Medicine, Lausanne University Hospital, Lausanne, Switzerland.
⁴¹ Department of Vascular Surgery, Imperial College, London, United Kingdom.
⁴² Department of Surgery, Nicosia Medical School, University of Nicosia, Nicosia, Cyprus.
⁴³ Cyprus International Institute for Environmental and Public Health, Cyprus University of Technology, Limassol, Cyprus.
⁴⁴ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
⁴⁵ Italian Institute for Genomic Medicine (IIGM), Turin, Italy.
⁴⁶ Department of Medical Sciences, University of Turin, Turin, Italy.
⁴⁷ Unit of Cancer Epidemiology, Città della Salute e della Scienza University-Hospital and Center for Cancer Prevention (CPO), Turin, Italy.
⁴⁸ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Addenbrooke's Hospital, Cambridge, UK.
⁴⁹ Novosibirsk State Medical University, Novosibirsk, Russian Federation.
⁵⁰ Institute of Internal and Preventive Medicine, Siberian Branch of the Russian Academy of Medical Sciences, Novosibirsk, Russian Federation.
⁵¹ Department of Epidemiology and Population Studies, Faculty of Health Sciences, Jagiellonian University Medical College, Kraków, Poland.
⁵² National Institute of Public Health, Prague, Czech Republic.
⁵³ Lithuanian University of Health Sciences, Kaunas, Lithuania.
⁵⁴ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁵⁵ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁵⁶ Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Copenhagen, The Capital Region of Denmark, Denmark.
⁵⁷ Centre for Cardiovascular Genetics, Department of Medicine, University College London, London, UK.
⁵⁸ Center for Human Genetics, Marshfield Clinic Research Institute, Marshfield, USA.
⁵⁹ Children's Hospital of Philadelphia, Philadelphia, USA.
⁶⁰ Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
⁶¹ University of Minnesota, Minneapolis, USA.
⁶² Geisinger, Danville, USA.
⁶³ Department of Biomedical Informatics and Medical Education University of Washington Seattle, Seattle, WA, USA.
⁶⁴ Mayo Clinic, Rochester, USA.
⁶⁵ Department of Medicine, Department of Pharmacology, Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, USA.
⁶⁶ Vanderbilt University, Nashville, USA.
⁶⁷ WHI, Seattle, USA.
⁶⁸ University of Newcastle, Newcastle, NSW, Australia.
⁶⁹ Public Health Program, Hunter Medical Research Institute, Newcastle, NSW, Australia.
⁷⁰ Hunter New England Local Health District, Newcastle, NSW, Australia.
⁷¹ Population Health Research Institute, Hamilton, Ontario, Canada.
⁷² Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁷³ Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁷⁴ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
⁷⁵ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
⁷⁶ Department of Medical Sciences, Molecular Epidemiology, Uppsala University, Uppsala, Sweden.
⁷⁷ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
⁷⁸ Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
⁷⁹ Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
⁸⁰ Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
⁸¹ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
⁸² DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
⁸³ Chair of Epidemiology, Ludwig-Maximilians-Universität München, UNIKA-T Augsburg, Augsburg, Germany.
⁸⁴ Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.
⁸⁵ Department of Internal Medicine A, University Medicine Greifswald, Greifswald, Germany.
⁸⁶ Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
⁸⁷ Institute of Health and Wellbeing, University of Glasgow, Glasgow, G12 8RZ, Scotland, UK.
⁸⁸ Department of Non-Communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK.
⁸⁹ The Department of Medical Research, Bærum Hospital, Vestre Viken Hospital Trust, Gjettum, Norway.
⁹⁰ Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
⁹¹ Department of Respiratory Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
⁹² Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK.
⁹³ Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
⁹⁴ Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, G12 8TA, UK.
⁹⁵ CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, 59000, Lille, France.
⁹⁶ Department of Genomics of Common Disease, Imperial College London, W12 0NN, London, United Kingdom.
⁹⁷ INSERM, U-1138, Centre de Recherche des Cordeliers, Paris, France.
⁹⁸ UFR de Médecine, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
⁹⁹ Départment de Diabétologie, Endocrinologie et Nutrition, Assistance Publique Hôpitaux de Paris, Hôpital Bicha, Paris, France.
¹⁰⁰ l'institut du Thorax, INSERM, CNRS, UNIV Nantes, CHU Nantes, Nantes, France.
¹⁰¹ Institute for Social and Economic Research, University of Essex, Essex, UK.
¹⁰² Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, England.
¹⁰³ Boston University School of Medicine, Boston, MA, USA.
¹⁰⁴ Harvard Medical School Center for Cardiovascular Disease Prevention Brigham and Women's Hospital, Boston, USA.
¹⁰⁵ UWash, Seattle, USA.
¹⁰⁶ Penn State, State College, USA.
¹⁰⁷ University of Colorado Denver, Denver, USA.
¹⁰⁸ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
¹⁰⁹ Div. Molecular Genetic Epidemiology German Cancer Research Center, Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.
¹¹⁰ Deutsches Krebsforschungszentrum, Heidelberg, Germany.
¹¹¹ The Institut du Cerveau et de la Moelle épinière - ICM, Paris, France.
¹¹² Sorbonne Universités, UPMC Université Paris 06, UMR S 1127, F-75013, Paris, France.
¹¹³ Department of Neurosurgery, Bethel Clinic, Kantensiek 11, 33617, Bielefeld, Germany.
¹¹⁴ Division of Hematology-Oncology, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, 77030, USA.
¹¹⁵ Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
¹¹⁶ Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, USA.
¹¹⁷ Department of Hematology, Erasmus MC Cancer Institute, 3075 EA, Rotterdam, the Netherlands.
¹¹⁸ Hematology and Transfusion Medicine, Department of Laboratory Medicine, BMC B13, SE-221 84, Lund, Sweden.
¹¹⁹ University Clinic Heidelberg, Internal Medicine V and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
¹²⁰ Department of Internal Medicine, University Hospital of Cologne, Cologne, Germany.
¹²¹ Hematology Clinic, Skåne University Hospital, Skåne, Sweden.
¹²² Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden.
¹²³ The National Institute for Health Research University College London Hospitals Biomedical Research Centre, University College London, 222 Euston Road, London, NW1 2DA, UK.
¹²⁴ Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
¹²⁵ Health Data Research UK and Institute of Health Informatics, University College London, London, United Kingdom.
¹²⁶ The Barts Heart Centre, St Bartholomew's Hospital, London, UK.
¹²⁷ UPenn, Philadelphia, USA.
¹²⁸ Massachusetts Veterans Epidemiology and Research Information Center (MAVERIC) Veterans Affairs Boston Healthcare System, Boston, USA.

PMID: 31664920
PMCID: PMC6820948
DOI: 10.1186/s12872-019-1187-z

Multicenter Study

Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

Amand F Schmidt et al. BMC Cardiovasc Disord. 2019.

. 2019 Oct 29;19(1):240.

doi: 10.1186/s12872-019-1187-z.

Authors

Affiliations

¹ Institute of Cardiovascular Science, University College London, 222 Euston Road, London, NW1 2DA, UK. amand.schmidt@ucl.ac.uk.
² Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. amand.schmidt@ucl.ac.uk.
³ UCL's BHF Research Accelerator Centre, London, UK. amand.schmidt@ucl.ac.uk.
⁴ Medical Research Council Population Health Research Unit, Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁵ Institute of Cardiovascular Science, University College London, 222 Euston Road, London, NW1 2DA, UK.
⁶ Department of Medicine, Imperial College London, London, UK.
⁷ UCL's BHF Research Accelerator Centre, London, UK.
⁸ Health Data Research UK, University College London, 222 Euston Road, London, NW1 2DA, UK.
⁹ Institute of Health Informatics, University College London, 222 Euston Road, London, NW1 2DA, UK.
¹⁰ The Alan Turing Institute, British Library, 96 Euston Rd, London, NW1 2DB, UK.
¹¹ University College London, Farr Institute of Health Informatics, London, UK.
¹² Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford, OX3 7LF, UK.
¹³ Postgraduate Program in Epidemiology, Federal University of Pelotas, Pelotas, Brazil.
¹⁴ Centre for Population Health Research, Sansom Institute for Health Research, University of South Australia, Adelaide, Australia.
¹⁵ Population, Policy and Practice, UCL GOS Institute of Child Health, London, UK.
¹⁶ South Australian Health and Medical Research Institute, Adelaide, Australia.
¹⁷ Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, The Netherlands.
¹⁸ Department of Clinical Epidemiology, Biostatistics And Bioinformatics, Academic Medical Center Amsterdam, Amsterdam, the Netherlands.
¹⁹ Department of vascular medicine, Academic Medical Center Amsterdam, Amsterdam, the Netherlands.
²⁰ Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Lipid Clinic at the Interdisciplinary Metabolism Center, Berlin, Germany.
²¹ Charité - Universitätsmedizin Berlin, BCRT - Berlin Institute of Health Center for Regenerative Therapies, Berlin, Germany.
²² Institute of Nutritional Science, University of Potsdam, 14558, Nuthetal, Germany.
²³ Geriatrics Research Group, Charité - Universitätsmedizin Berlin, 13347, Berlin, Germany.
²⁴ Department of Nutrition and Gerontology, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558, Nuthetal, Germany.
²⁵ E.CA Economics GmbH, Berlin, Germany.
²⁶ Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics & Cardiogenetics, University of Lübeck, Lübeck, Germany.
²⁷ Center for Lifespan Changes in Brain and Cognition (LCBC), Dept. Psychology, University of Oslo, Oslo, Norway.
²⁸ Genetic and Molecular Epidemiology Group, Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics & Cardiogenetics, University of Lübeck, Lübeck, Germany.
²⁹ Institute of Human Genetics, Lübeck, Germany.
³⁰ Ageing Epidemiology Research Unit, School of Public Health, Imperial College, London, UK.
³¹ Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, 6020, Innsbruck, Austria.
³² Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
³³ Department of Neurology, Inselspital, University Hospital Bern, University of Bern, Bern, Switzerland.
³⁴ Bradford Institute for Health Research, Bradford Royal Infirmary, Bradford, UK.
³⁵ Department Primary Care & Population Health, University College London, London, UK.
³⁶ Population Health Research Institute, St George's, University of London, London, UK.
³⁷ Population Health Sciences, University of Bristol, Bristol, UK.
³⁸ Centre for Population Health Sciences, The Usher Institute, University of Edinburgh, Edinburgh, UK.
³⁹ Department of Epidemiology and Public Health, UCL Institute of Epidemiology and Health Care, University College London, London, UK.
⁴⁰ Department of Medicine, Internal Medicine, Lausanne University Hospital, Lausanne, Switzerland.
⁴¹ Department of Vascular Surgery, Imperial College, London, United Kingdom.
⁴² Department of Surgery, Nicosia Medical School, University of Nicosia, Nicosia, Cyprus.
⁴³ Cyprus International Institute for Environmental and Public Health, Cyprus University of Technology, Limassol, Cyprus.
⁴⁴ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
⁴⁵ Italian Institute for Genomic Medicine (IIGM), Turin, Italy.
⁴⁶ Department of Medical Sciences, University of Turin, Turin, Italy.
⁴⁷ Unit of Cancer Epidemiology, Città della Salute e della Scienza University-Hospital and Center for Cancer Prevention (CPO), Turin, Italy.
⁴⁸ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Addenbrooke's Hospital, Cambridge, UK.
⁴⁹ Novosibirsk State Medical University, Novosibirsk, Russian Federation.
⁵⁰ Institute of Internal and Preventive Medicine, Siberian Branch of the Russian Academy of Medical Sciences, Novosibirsk, Russian Federation.
⁵¹ Department of Epidemiology and Population Studies, Faculty of Health Sciences, Jagiellonian University Medical College, Kraków, Poland.
⁵² National Institute of Public Health, Prague, Czech Republic.
⁵³ Lithuanian University of Health Sciences, Kaunas, Lithuania.
⁵⁴ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁵⁵ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁵⁶ Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Copenhagen, The Capital Region of Denmark, Denmark.
⁵⁷ Centre for Cardiovascular Genetics, Department of Medicine, University College London, London, UK.
⁵⁸ Center for Human Genetics, Marshfield Clinic Research Institute, Marshfield, USA.
⁵⁹ Children's Hospital of Philadelphia, Philadelphia, USA.
⁶⁰ Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
⁶¹ University of Minnesota, Minneapolis, USA.
⁶² Geisinger, Danville, USA.
⁶³ Department of Biomedical Informatics and Medical Education University of Washington Seattle, Seattle, WA, USA.
⁶⁴ Mayo Clinic, Rochester, USA.
⁶⁵ Department of Medicine, Department of Pharmacology, Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, USA.
⁶⁶ Vanderbilt University, Nashville, USA.
⁶⁷ WHI, Seattle, USA.
⁶⁸ University of Newcastle, Newcastle, NSW, Australia.
⁶⁹ Public Health Program, Hunter Medical Research Institute, Newcastle, NSW, Australia.
⁷⁰ Hunter New England Local Health District, Newcastle, NSW, Australia.
⁷¹ Population Health Research Institute, Hamilton, Ontario, Canada.
⁷² Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁷³ Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁷⁴ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
⁷⁵ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
⁷⁶ Department of Medical Sciences, Molecular Epidemiology, Uppsala University, Uppsala, Sweden.
⁷⁷ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
⁷⁸ Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
⁷⁹ Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
⁸⁰ Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
⁸¹ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
⁸² DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
⁸³ Chair of Epidemiology, Ludwig-Maximilians-Universität München, UNIKA-T Augsburg, Augsburg, Germany.
⁸⁴ Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.
⁸⁵ Department of Internal Medicine A, University Medicine Greifswald, Greifswald, Germany.
⁸⁶ Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
⁸⁷ Institute of Health and Wellbeing, University of Glasgow, Glasgow, G12 8RZ, Scotland, UK.
⁸⁸ Department of Non-Communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK.
⁸⁹ The Department of Medical Research, Bærum Hospital, Vestre Viken Hospital Trust, Gjettum, Norway.
⁹⁰ Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
⁹¹ Department of Respiratory Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
⁹² Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK.
⁹³ Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
⁹⁴ Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, G12 8TA, UK.
⁹⁵ CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, 59000, Lille, France.
⁹⁶ Department of Genomics of Common Disease, Imperial College London, W12 0NN, London, United Kingdom.
⁹⁷ INSERM, U-1138, Centre de Recherche des Cordeliers, Paris, France.
⁹⁸ UFR de Médecine, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
⁹⁹ Départment de Diabétologie, Endocrinologie et Nutrition, Assistance Publique Hôpitaux de Paris, Hôpital Bicha, Paris, France.
¹⁰⁰ l'institut du Thorax, INSERM, CNRS, UNIV Nantes, CHU Nantes, Nantes, France.
¹⁰¹ Institute for Social and Economic Research, University of Essex, Essex, UK.
¹⁰² Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, England.
¹⁰³ Boston University School of Medicine, Boston, MA, USA.
¹⁰⁴ Harvard Medical School Center for Cardiovascular Disease Prevention Brigham and Women's Hospital, Boston, USA.
¹⁰⁵ UWash, Seattle, USA.
¹⁰⁶ Penn State, State College, USA.
¹⁰⁷ University of Colorado Denver, Denver, USA.
¹⁰⁸ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
¹⁰⁹ Div. Molecular Genetic Epidemiology German Cancer Research Center, Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.
¹¹⁰ Deutsches Krebsforschungszentrum, Heidelberg, Germany.
¹¹¹ The Institut du Cerveau et de la Moelle épinière - ICM, Paris, France.
¹¹² Sorbonne Universités, UPMC Université Paris 06, UMR S 1127, F-75013, Paris, France.
¹¹³ Department of Neurosurgery, Bethel Clinic, Kantensiek 11, 33617, Bielefeld, Germany.
¹¹⁴ Division of Hematology-Oncology, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, 77030, USA.
¹¹⁵ Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
¹¹⁶ Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, USA.
¹¹⁷ Department of Hematology, Erasmus MC Cancer Institute, 3075 EA, Rotterdam, the Netherlands.
¹¹⁸ Hematology and Transfusion Medicine, Department of Laboratory Medicine, BMC B13, SE-221 84, Lund, Sweden.
¹¹⁹ University Clinic Heidelberg, Internal Medicine V and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
¹²⁰ Department of Internal Medicine, University Hospital of Cologne, Cologne, Germany.
¹²¹ Hematology Clinic, Skåne University Hospital, Skåne, Sweden.
¹²² Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden.
¹²³ The National Institute for Health Research University College London Hospitals Biomedical Research Centre, University College London, 222 Euston Road, London, NW1 2DA, UK.
¹²⁴ Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
¹²⁵ Health Data Research UK and Institute of Health Informatics, University College London, London, United Kingdom.
¹²⁶ The Barts Heart Centre, St Bartholomew's Hospital, London, UK.
¹²⁷ UPenn, Philadelphia, USA.
¹²⁸ Massachusetts Veterans Epidemiology and Research Information Center (MAVERIC) Veterans Affairs Boston Healthcare System, Boston, USA.

PMID: 31664920
PMCID: PMC6820948
DOI: 10.1186/s12872-019-1187-z

Abstract

Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9.

Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration.

Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable.

Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

Keywords: Genetic association studies; LDL-cholesterol; Mendelian randomisation; Phenome-wide association scan.

PubMed Disclaimer

Conflict of interest statement

Dr. Holmes has collaborated with Boehringer Ingelheim in research, and in accordance with the policy of the The Clinical Trial Service Unit and Epidemiological Studies Unit (University of Oxford), did not accept any personal payment. David Preiss consulted for Amgen on a single occasion but, in accordance with the policy of the Clinical Trial Service Unit (University of Oxford), did not accept any personal payment. He is an investigator on a clinical trial of the PCSK9 synthesis inhibitor, inclisiran, funded by a grant to the University of Oxford by the Medicines Company, but he receives no personal fees from this grant. Daniel I Swerdlow is an employee of BenevolentAI Ltd. Aroon Hingorani and Harry Hemingway are National Institute for Health Research Senior Investigators. Naveed Sattar consulted for Amgen and Sanofi related to PCSK9 inhibitors; and was an investigator on clinical trials of PCSK9 inhibition funded by Amgen. Naveed Sattar has also consulted for Boehringer Ingelheim, Janssen, Eli-Lilly and NovoNordisk. Daniel Swerdlow has consulted to Pfizer for work unrelated to this paper. Folkert W. Asselbergs is supported by UCL Hospitals NIHR Biomedical Research Centre. Dr. Patel has received honoraria and speaker fees from Sanofi, Amgen and Bayer. Kees Hovingh or his institution (AMC) received honoraria for consultancy, ad boards, and/or conduct of clinical trials from: AMGEN, Aegerion, Pfizer, Astra Zeneca, Sanofi, Regeneron, KOWA, Ionis pharmaceuticals and Cerenis. Bertrand Cariou has received research funding from Pfizer and Sanofi, received honoraria from AstraZeneca, Pierre Fabre, Janssen, Eli-Lilly, MSD Merck & Co., Novo-Nordisk, Sanofi, and Takeda, and has acted as a consultant/advisory panel member for Amgen, Eli Lilly, Novo-Nordisk, Sanofi, and Regeneron. Andrzej Pająk acted as a consultant/advisory pannel member for Amgen. Erik Ingelsson is a scientific advisor for Precision Wellness and Olink Proteomics for work unrelated to this paper. JCH is a scientific advisor to a clinical trial of PCSK9 inhibition. AE Honoraria: Takeda, BMS, Amgen; Consulting: Takeda, BMS, Amgen. SEH acknowledges BHF funding (PG008/08) and support from the UCL BRC. All other authors declare no competing interests.

Figures

**Fig. 1**
Lipid and lipoprotein associations of a *PCSK9* gene-centric score (GS) compared to placebo-controlled randomized trials of therapeutic inhibition of PCSK9. Footnote: Effect estimates are presented as mean differences, with 95% confidence interval (CI). Trial estimates are presented as percentage change from baseline (during 6 months of follow-up), and GS estimates scaled to a 1 mmol/L lower LDL-C (mmol/L). Results are pooled using a fixed effect model. Trial estimates are based on the systematic review by Schmidt et al 2017 [6, 17]

**Fig. 2**
Associations of a *PCSK9* gene-centric score with ischemic and non-ischemic cardiovascular endpoints. Footnote: Effect estimates are presented as odds ratios (OR), with 95% confidence interval (CI) scaled to a 1 mmol/L lower LDL-C (mmol/L). Results are pooled using a fixed effect model. The size of the squares are proportional to the inverse of the variance

**Fig. 3**
Clinical endpoint associations of the *PCSK9* gene-centric score (GS) as compared to placebo-controlled randomized trials of therapeutic inhibition of PCSK9. Footnote: Effect estimates are presented as odds ratios (OR), with 95% confidence interval (CI), for the GS scaled to a 1 mmol/L lower LDL-C (mmol/L). Results are pooled using a fixed effect model. Trial estimates are based on the systematic review by Schmidt et al 2017 [6], with the estimates on ischemic stroke and revascularization solely based on the FOURIER and ODYSSEY OUTCOMES trials

**Fig. 4**
Associations of a *PCSK9* gene-centric score (GS) with non-cardiovascular events. Footnote: Effect estimates are presented as odds ratios (OR), with 95% confidence interval (CI) scaled to a 1 mmol/L lower LDL-C (mmol/L). Results are pooled using a fixed effect model. The size of the squares are proportional to the inverse of the variance. Note, that all GS estimates are based on 4 SNPs, except for the Alzheimer’s disease estimate which excluded the SNP rs11591147 due to lack of data

See this image and copyright information in PMC

References

1. Collaborators CTT (CTT) Efficacy and safety of cholesterol-lowering treatment: Prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267–1278. doi: 10.1016/S0140-6736(05)67394-1. - DOI - PubMed
1. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al. Ezetimibe sed to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387–2397. doi: 10.1056/NEJMoa1410489. - DOI - PubMed
1. Bohula EA, Wiviott SD, Giugliano RP, Blazing MA, Park J-G, Murphy SA, et al. Prevention of stroke with the addition of ezetimibe to statin therapy in patients with acute coronary syndrome in IMPROVE-IT. Circulation. 2017. 10.1161/CIRCULATIONAHA.117.029095. - PubMed
1. Cohen JC, Boerwinkle E, Mosley TH, Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354:1264–1272. doi: 10.1056/NEJMoa054013. - DOI - PubMed
1. Benn M, Nordestgaard BG, Grande P, Schnohr P, Tybjaerg-Hansen A. PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses. J Am Coll Cardiol. 2010;55:2833–2842. doi: 10.1016/j.jacc.2010.02.044. - DOI - PubMed

Publication types

Actions
Actions
Actions

MeSH terms

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

Substances

Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Medical
- MedlinePlus Health Information
Miscellaneous
- NCI CPTAC Assay Portal

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

Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

Affiliations

Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous