Journal article

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

  • Schmidt AF Institute of Cardiovascular Science, University College London, 222 Euston Road, London, NW1 2DA, UK. amand.schmidt@ucl.ac.uk.
  • Holmes MV 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.
  • Preiss D 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.
  • Swerdlow DI Institute of Cardiovascular Science, University College London, 222 Euston Road, London, NW1 2DA, UK.
  • Denaxas S UCL's BHF Research Accelerator Centre, London, UK.
  • Fatemifar G UCL's BHF Research Accelerator Centre, London, UK.
  • Faraway R Institute of Cardiovascular Science, University College London, 222 Euston Road, London, NW1 2DA, UK.
  • Finan C Institute of Cardiovascular Science, University College London, 222 Euston Road, London, NW1 2DA, UK.
  • Valentine D UCL's BHF Research Accelerator Centre, London, UK.
  • Fairhurst-Hunter Z 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.
  • Hartwig FP Postgraduate Program in Epidemiology, Federal University of Pelotas, Pelotas, Brazil.
  • Horta BL Postgraduate Program in Epidemiology, Federal University of Pelotas, Pelotas, Brazil.
  • Hypponen E Centre for Population Health Research, Sansom Institute for Health Research, University of South Australia, Adelaide, Australia.
  • Power C Population, Policy and Practice, UCL GOS Institute of Child Health, London, UK.
  • Moldovan M South Australian Health and Medical Research Institute, Adelaide, Australia.
  • van Iperen E Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, The Netherlands.
  • Hovingh K Department of vascular medicine, Academic Medical Center Amsterdam, Amsterdam, the Netherlands.
  • Demuth I 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.
  • Norman K Institute of Nutritional Science, University of Potsdam, 14558, Nuthetal, Germany.
  • Steinhagen-Thiessen E 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.
  • Demuth J E.CA Economics GmbH, Berlin, Germany.
  • Bertram L Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics & Cardiogenetics, University of Lübeck, Lübeck, Germany.
  • Lill CM Genetic and Molecular Epidemiology Group, Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics & Cardiogenetics, University of Lübeck, Lübeck, Germany.
  • Coassin S Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, 6020, Innsbruck, Austria.
  • Willeit J Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
  • Kiechl S Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
  • Willeit K Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
  • Mason D Bradford Institute for Health Research, Bradford Royal Infirmary, Bradford, UK.
  • Wright J Bradford Institute for Health Research, Bradford Royal Infirmary, Bradford, UK.
  • Morris R Department Primary Care & Population Health, University College London, London, UK.
  • Wanamethee G Department Primary Care & Population Health, University College London, London, UK.
  • Whincup P Population Health Research Institute, St George's, University of London, London, UK.
  • Ben-Shlomo Y Population Health Sciences, University of Bristol, Bristol, UK.
  • McLachlan S Centre for Population Health Sciences, The Usher Institute, University of Edinburgh, Edinburgh, UK.
  • Price JF Centre for Population Health Sciences, The Usher Institute, University of Edinburgh, Edinburgh, UK.
  • Kivimaki M Department of Epidemiology and Public Health, UCL Institute of Epidemiology and Health Care, University College London, London, UK.
  • Welch C Department of Epidemiology and Public Health, UCL Institute of Epidemiology and Health Care, University College London, London, UK.
  • Sanchez-Galvez A Department of Epidemiology and Public Health, UCL Institute of Epidemiology and Health Care, University College London, London, UK.
  • Marques-Vidal P Department of Medicine, Internal Medicine, Lausanne University Hospital, Lausanne, Switzerland.
  • Nicolaides A Department of Vascular Surgery, Imperial College, London, United Kingdom.
  • Panayiotou AG Cyprus International Institute for Environmental and Public Health, Cyprus University of Technology, Limassol, Cyprus.
  • Onland-Moret NC Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
  • van der Schouw YT Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
  • Matullo G Italian Institute for Genomic Medicine (IIGM), Turin, Italy.
  • Fiorito G Italian Institute for Genomic Medicine (IIGM), Turin, Italy.
  • Guarrera S Italian Institute for Genomic Medicine (IIGM), Turin, Italy.
  • Sacerdote C Unit of Cancer Epidemiology, Città della Salute e della Scienza University-Hospital and Center for Cancer Prevention (CPO), Turin, Italy.
  • Wareham NJ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Addenbrooke's Hospital, Cambridge, UK.
  • Langenberg C MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Addenbrooke's Hospital, Cambridge, UK.
  • Scott RA MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Addenbrooke's Hospital, Cambridge, UK.
  • Luan J MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Addenbrooke's Hospital, Cambridge, UK.
  • Bobak M Department of Epidemiology and Public Health, UCL Institute of Epidemiology and Health Care, University College London, London, UK.
  • Malyutina S Novosibirsk State Medical University, Novosibirsk, Russian Federation.
  • Pająk A Department of Epidemiology and Population Studies, Faculty of Health Sciences, Jagiellonian University Medical College, Kraków, Poland.
  • Kubinova R National Institute of Public Health, Prague, Czech Republic.
  • Tamosiunas A Lithuanian University of Health Sciences, Kaunas, Lithuania.
  • Pikhart H Department of Epidemiology and Public Health, UCL Institute of Epidemiology and Health Care, University College London, London, UK.
  • Grarup N Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Pedersen O Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Hansen T Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Linneberg A Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Jess T Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Copenhagen, The Capital Region of Denmark, Denmark.
  • Cooper J Centre for Cardiovascular Genetics, Department of Medicine, University College London, London, UK.
  • Humphries SE Centre for Cardiovascular Genetics, Department of Medicine, University College London, London, UK.
  • Brilliant M Center for Human Genetics, Marshfield Clinic Research Institute, Marshfield, USA.
  • Kitchner T Center for Human Genetics, Marshfield Clinic Research Institute, Marshfield, USA.
  • Hakonarson H Children's Hospital of Philadelphia, Philadelphia, USA.
  • Carrell DS Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
  • McCarty CA University of Minnesota, Minneapolis, USA.
  • Lester KH Geisinger, Danville, USA.
  • Larson EB Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
  • Crosslin DR Department of Biomedical Informatics and Medical Education University of Washington Seattle, Seattle, WA, USA.
  • de Andrade M Mayo Clinic, Rochester, USA.
  • Roden DM Department of Medicine, Department of Pharmacology, Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, USA.
  • Denny JC Vanderbilt University, Nashville, USA.
  • Carty C WHI, Seattle, USA.
  • Hancock S University of Newcastle, Newcastle, NSW, Australia.
  • Attia J University of Newcastle, Newcastle, NSW, Australia.
  • Holliday E University of Newcastle, Newcastle, NSW, Australia.
  • Scott R University of Newcastle, Newcastle, NSW, Australia.
  • Schofield P Hunter New England Local Health District, Newcastle, NSW, Australia.
  • O'Donnell M Population Health Research Institute, Hamilton, Ontario, Canada.
  • Yusuf S Population Health Research Institute, Hamilton, Ontario, Canada.
  • Chong M Population Health Research Institute, Hamilton, Ontario, Canada.
  • Pare G Population Health Research Institute, Hamilton, Ontario, Canada.
  • van der Harst P Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, The Netherlands.
  • Said MA Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
  • Eppinga RN Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
  • Verweij N Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
  • Snieder H Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
  • Christen T Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
  • Mook-Kanamori DO Department of Medical Sciences, Molecular Epidemiology, Uppsala University, Uppsala, Sweden.
  • Gustafsson S Department of Medical Sciences, Molecular Epidemiology, Uppsala University, Uppsala, Sweden.
  • Lind L Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
  • Ingelsson E Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
  • Pazoki R Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
  • Franco O Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
  • Hofman A Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
  • Uitterlinden A Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
  • Dehghan A Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
  • Teumer A DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
  • Baumeister S Department of Internal Medicine A, University Medicine Greifswald, Greifswald, Germany.
  • Dörr M DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
  • Lerch MM Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
  • Völker U Institute of Health and Wellbeing, University of Glasgow, Glasgow, G12 8RZ, Scotland, UK.
  • Völzke H Institute of Health and Wellbeing, University of Glasgow, Glasgow, G12 8RZ, Scotland, UK.
  • Ward J Department of Non-Communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK.
  • Pell JP The Department of Medical Research, Bærum Hospital, Vestre Viken Hospital Trust, Gjettum, Norway.
  • Meade T Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
  • Christophersen IE Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK.
  • Maitland-van der Zee AH Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK.
  • Baranova EV Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK.
  • Young R Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
  • Ford I Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, G12 8TA, UK.
  • Campbell A Cyprus International Institute for Environmental and Public Health, Cyprus University of Technology, Limassol, Cyprus.
  • Padmanabhan S Cyprus International Institute for Environmental and Public Health, Cyprus University of Technology, Limassol, Cyprus.
  • Bots ML CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, 59000, Lille, France.
  • Grobbee DE CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, 59000, Lille, France.
  • Froguel P INSERM, U-1138, Centre de Recherche des Cordeliers, Paris, France.
  • Thuillier D CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, 59000, Lille, France.
  • Roussel R l'institut du Thorax, INSERM, CNRS, UNIV Nantes, CHU Nantes, Nantes, France.
  • Bonnefond A Institute for Social and Economic Research, University of Essex, Essex, UK.
  • Cariou B Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, England.
  • Smart M Boston University School of Medicine, Boston, MA, USA.
  • Bao Y Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, England.
  • Kumari M 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.
  • Mahajan A Boston University School of Medicine, Boston, MA, USA.
  • Hopewell JC University College London, Farr Institute of Health Informatics, London, UK.
  • Seshadri S University College London, Farr Institute of Health Informatics, London, UK.
  • Dale C Harvard Medical School Center for Cardiovascular Disease Prevention Brigham and Women's Hospital, Boston, USA.
  • Costa RPE UWash, Seattle, USA.
  • Ridker PM Penn State, State College, USA.
  • Chasman DI University of Colorado Denver, Denver, USA.
  • Reiner AP Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
  • Ritchie MD Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
  • Lange LA Div. Molecular Genetic Epidemiology German Cancer Research Center, Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.
  • Cornish AJ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
  • Dobbins SE The Institut du Cerveau et de la Moelle épinière - ICM, Paris, France.
  • Hemminki K The Institut du Cerveau et de la Moelle épinière - ICM, Paris, France.
  • Kinnersley B Department of Neurosurgery, Bethel Clinic, Kantensiek 11, 33617, Bielefeld, Germany.
  • Sanson M Division of Hematology-Oncology, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, 77030, USA.
  • Labreche K Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
  • Simon M Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
  • Bondy M Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
  • Law P Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
  • Speedy H Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
  • Allan J Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, USA.
  • Li N Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, USA.
  • Went M Department of Hematology, Erasmus MC Cancer Institute, 3075 EA, Rotterdam, the Netherlands.
  • Weinhold N Hematology and Transfusion Medicine, Department of Laboratory Medicine, BMC B13, SE-221 84, Lund, Sweden.
  • Morgan G University Clinic Heidelberg, Internal Medicine V and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
  • Sonneveld P Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
  • Nilsson B Department of Internal Medicine, University Hospital of Cologne, Cologne, Germany.
  • Goldschmidt H Hematology Clinic, Skåne University Hospital, Skåne, Sweden.
  • Sud A UCL's BHF Research Accelerator Centre, London, UK.
  • Engert A Institute of Cardiovascular Science, University College London, 222 Euston Road, London, NW1 2DA, UK.
  • Hansson M Institute of Cardiovascular Science, University College London, 222 Euston Road, London, NW1 2DA, UK.
  • Hemingway H UPenn, Philadelphia, USA.
  • Asselbergs FW Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, G12 8TA, UK.
  • Patel RS Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
  • Keating BJ Massachusetts Veterans Epidemiology and Research Information Center (MAVERIC) Veterans Affairs Boston Healthcare System, Boston, USA.
  • Sattar N Institute of Cardiovascular Science, University College London, 222 Euston Road, London, NW1 2DA, UK.
  • Houlston R
  • Casas JP
  • Hingorani AD
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  • 2019-10-31
Published in:
  • BMC cardiovascular disorders. - 2019
English 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.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/68470
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