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BMC Cardiovasc Disord. 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.

Schmidt AF1,2,3, Holmes MV4, Preiss D4, Swerdlow DI5,6, Denaxas S7,8,9,10, Fatemifar G7,8,9, Faraway R5, Finan C5,7, Valentine D7,11, Fairhurst-Hunter Z12, Hartwig FP13, Horta BL13, Hypponen E14,15,16, Power C15, Moldovan M16, van Iperen E17,18, Hovingh K19, Demuth I20,21, Norman K22,23,24, Steinhagen-Thiessen E20, Demuth J25, Bertram L26,27, Lill CM28,29,30, Coassin S31, Willeit J32, Kiechl S32, Willeit K32,33, Mason D34, Wright J34, Morris R35, Wanamethee G35, Whincup P36, Ben-Shlomo Y37, McLachlan S38, Price JF38, Kivimaki M39, Welch C39, Sanchez-Galvez A39, Marques-Vidal P40, Nicolaides A41,42, Panayiotou AG43, Onland-Moret NC44, van der Schouw YT44, Matullo G45,46, Fiorito G45,46, Guarrera S45,46, Sacerdote C47, Wareham NJ48, Langenberg C48, Scott RA48, Luan J48, Bobak M39, Malyutina S49,50, Pająk A51, Kubinova R52, Tamosiunas A53, Pikhart H39, Grarup N54, Pedersen O54, Hansen T54, Linneberg A55,56, Jess T56, Cooper J57, Humphries SE57, Brilliant M58, Kitchner T58, Hakonarson H59, Carrell DS60, McCarty CA61, Lester KH62, Larson EB60, Crosslin DR63, de Andrade M64, Roden DM65, Denny JC66, Carty C67, Hancock S68, Attia J68,69, Holliday E68,69, Scott R68, Schofield P70, O'Donnell M71, Yusuf S71, Chong M71, Pare G71, van der Harst P17,18,72,73, Said MA73, Eppinga RN73, Verweij N73, Snieder H74; Lifelines Cohort authors, Christen T75, Mook-Kanamori DO75; ICBP Consortium, Gustafsson S76, Lind L77,78, Ingelsson E76,77, Pazoki R79,80, Franco O79, Hofman A79, Uitterlinden A79, Dehghan A79, Teumer A81,82, Baumeister S81,83, Dörr M82,84, Lerch MM85, Völker U82,86, Völzke H81,82, Ward J87, Pell JP87, Meade T88, Christophersen IE89, Maitland-van der Zee AH90,91, Baranova EV92, Young R92, Ford I92, Campbell A93, Padmanabhan S94, Bots ML43, Grobbee DE43, Froguel P95,96, Thuillier D95, Roussel R97,98,99, Bonnefond A95, Cariou B100, Smart M101, Bao Y102, Kumari M103, Mahajan A102, Hopewell JC12, Seshadri S103; METASTROKE Consortium of the ISGC, Dale C11, Costa RPE11, Ridker PM104, Chasman DI104, Reiner AP105, Ritchie MD106, Lange LA107, Cornish AJ108, Dobbins SE108, Hemminki K109,110, Kinnersley B108, Sanson M111,112, Labreche K111,112, Simon M113, Bondy M114, Law P108, Speedy H108, Allan J115, Li N108, Went M108, Weinhold N116, Morgan G116, Sonneveld P117, Nilsson B118, Goldschmidt H119, Sud A108, Engert A120, Hansson M121,122, Hemingway H7,8,9,123, Asselbergs FW5,124,7,125, Patel RS5,7,126, Keating BJ127, Sattar N94, Houlston R108, Casas JP128, Hingorani AD5,7.

Author information

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.

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

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