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Lancet Diabetes Endocrinol. 2017 Feb;5(2):97-105. doi: 10.1016/S2213-8587(16)30396-5. Epub 2016 Nov 29.

PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study.

Schmidt AF1, Swerdlow DI2, Holmes MV3, Patel RS4, Fairhurst-Hunter Z5, Lyall DM6, Hartwig FP7, Horta BL7, Hyppönen E8, Power C9, Moldovan M10, van Iperen E11, Hovingh GK12, Demuth I13, Norman K14, Steinhagen-Thiessen E14, Demuth J15, Bertram L16, Liu T17, Coassin S18, Willeit J19, Kiechl S19, Willeit K19, Mason D20, Wright J20, Morris R21, Wanamethee G22, Whincup P23, Ben-Shlomo Y21, McLachlan S24, Price JF24, Kivimaki M25, Welch C25, Sanchez-Galvez A25, Marques-Vidal P26, Nicolaides A27, Panayiotou AG28, Onland-Moret NC29, van der Schouw YT29, Matullo G30, Fiorito G30, Guarrera S30, Sacerdote C31, Wareham NJ32, Langenberg C32, Scott R32, Luan J32, Bobak M25, Malyutina S33, Pająk A34, Kubinova R35, Tamosiunas A36, Pikhart H25, Husemoen LL37, Grarup N38, Pedersen O38, Hansen T38, Linneberg A39, Simonsen KS37, Cooper J40, Humphries SE40, Brilliant M41, Kitchner T41, Hakonarson H42, Carrell DS43, McCarty CA44, Kirchner HL45, Larson EB46, Crosslin DR46, de Andrade M47, Roden DM48, Denny JC49, Carty C50, Hancock S51, Attia J51, Holliday E51, O'Donnell M52, Yusuf S52, Chong M52, Pare G52, van der Harst P53, Said MA54, Eppinga RN54, Verweij N54, Snieder H55; LifeLines Cohort study group, Christen T56, Mook-Kanamori DO56, Gustafsson S57, Lind L57, Ingelsson E58, Pazoki R59, Franco O59, Hofman A59, Uitterlinden A60, Dehghan A61, Teumer A62, Baumeister S63, Dörr M64, Lerch MM65, Völker U66, Völzke H62, Ward J6, Pell JP6, Smith DJ6, Meade T67, Maitland-van der Zee AH68, Baranova EV69, Young R70, Ford I70, Campbell A71, Padmanabhan S72, Bots ML29, Grobbee DE29, Froguel P73, Thuillier D74, Balkau B75, Bonnefond A73, Cariou B76, Smart M77, Bao Y77, Kumari M77, Mahajan A5, Ridker PM78, Chasman DI78, Reiner AP79, Lange LA80, Ritchie MD81, Asselbergs FW82, Casas JP83, Keating BJ84, Preiss D3, Hingorani AD85; UCLEB consortium, Sattar N86.

Author information

1
Institute of Cardiovascular Science, University College London, UK; Farr Institute of Health Informatics Research, UCL Institute of Health Informatics, University College London, UK. Electronic address: amand.schmidt@ucl.ac.uk.
2
Institute of Cardiovascular Science, University College London, UK; Department of Medicine, Imperial College London, London, UK.
3
Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK; Medical Research Council Population Health Research Unit at the University of Oxford, University of Oxford, Oxford, UK.
4
Institute of Cardiovascular Science, University College London, UK; Farr Institute of Health Informatics Research, UCL Institute of Health Informatics, University College London, UK; The Barts Heart Centre, St Bartholomew's Hospital, London, UK.
5
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
6
Institute of Health & Wellbeing, University of Glasgow, Glasgow, UK.
7
Postgraduate Program in Epidemiology, Federal University of Pelotas, Pelotas, Brazil.
8
Centre for Population Health Research, Sansom Institute for Health Research, University of South Australia, Adelaide, SA, Australia; Population, Policy and Practice, UCL Great Ormond Street Institute of Child Health, London, UK; South Australian Health and Medical Research Institute, Adelaide, SA, Australia.
9
Population, Policy and Practice, UCL Great Ormond Street Institute of Child Health, London, UK.
10
School of Health Sciences, University of South Australia, Adelaide, SA, Australia; South Australian Health and Medical Research Institute-EMBL Australia, Adelaide, SA, Australia.
11
Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, Netherlands; Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center Amsterdam, Netherlands.
12
Department of Vascular Medicine, Academic Medical Center Amsterdam, Netherlands.
13
Charité Research Group on Geriatrics, Charité-Universitätsmedizin Berlin, Berlin, Germany; Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
14
Charité Research Group on Geriatrics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
15
E.CA Economics GmbH, Berlin, Germany.
16
Neuroepidemiology and Ageing Research Unit, Imperial College London, London, UK; Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics and Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany.
17
Max Planck Institute for Human Development, Berlin, Germany; Max Planck Institute for Molecular Genetics, Berlin, Germany.
18
Division of Genetic Epidemiology Innsbruck, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
19
Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
20
Bradford Institute for Health Research, Bradford Royal Infirmary, Bradford, UK.
21
School of Social and Community Medicine, University of Bristol, Bristol, UK.
22
Department of Primary Care & Population Health, University College London, UK.
23
Population Health Research Institute, St George's, University of London, London, UK.
24
Centre for Population Health Sciences, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
25
Department of Epidemiology and Public Health, UCL Institute of Epidemiology and Health Care, University College London, UK.
26
Internal Medicine Unit, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland.
27
Department of Vascular Surgery, Imperial College London, London, UK; Department of Surgery, Nicosia Medical School, University of Nicosia, Nicosia, Cyprus.
28
Cyprus International Institute for Environmental and Public Health, Cyprus University of Technology, Limassol, Cyprus.
29
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands.
30
Human Genetics Foundation, HuGeF, Turin, Italy; Department of Medical Sciences, University of Turin, Turin, Italy.
31
Cancer Epidemiology Unit, San Giovanni Battista Hospital, Turin, Italy; Centre for Oncology Prevention, CPO Piemonte, Turin, Italy.
32
MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.
33
Novosibirsk State Medical University, Novosibirsk, Russia; Institute of Internal and Preventive Medicine, Siberian Branch of the Russian Academy of Medical Sciences, Novosibirsk, Russia.
34
Jagiellonian University Collegium Medicum, Krakow, Poland.
35
National Institute of Public Health, Prague, Czech Republic.
36
Lithuanian University of Health Sciences, Kaunas, Lithuania.
37
Research Centre for Prevention and Health, Capital Region of Denmark, Denmark.
38
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
39
Research Centre for Prevention and Health, Capital Region of Denmark, Denmark; Department of Clinical Experimental Research, Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
40
Centre for Cardiovascular Genetics, University College London, UK.
41
Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI, USA.
42
Children's Hospital of Philadelphia, Philadelphia, PA, USA.
43
Group Health Research Institute in Seattle, WA, USA.
44
Essentia Institute of Rural Health, Duluth, MN, USA.
45
Center for Health Research, Geisinger Clinic, Danville, PA, USA.
46
Group Health Research Institute, Seattle, WA, USA.
47
Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA.
48
Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA.
49
Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, USA.
50
George Washington University, Washington, DC, USA.
51
University of Newcastle, Newcastle, NSW, Australia.
52
Population Health Research Institute, Hamilton, ON, Canada.
53
Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, Netherlands; Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands; Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
54
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
55
Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
56
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands.
57
Molecular Epidemiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
58
Molecular Epidemiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden; Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden; Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
59
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands.
60
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, Netherlands.
61
Faculty of Medicine, and Department of Biostatistics and Epidemiology, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands.
62
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany; German Centre for Cardiovascular Research (DZHK), Greifswald, Germany.
63
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany; Department of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany.
64
Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany; German Centre for Cardiovascular Research (DZHK), Greifswald, Germany.
65
Department of Medicine A, University Medicine Greifswald, Greifswald, Germany.
66
Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany; German Centre for Cardiovascular Research (DZHK), Greifswald, Germany.
67
Department of Non-Communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK.
68
Department of Respiratory Medicine, Academic Medical Center Amsterdam, Netherlands; Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands.
69
Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands.
70
Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK.
71
Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
72
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
73
Department of Genomics of Common Disease, Imperial College London, London, UK; CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille, France.
74
CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille, France.
75
Renal and Cardiovascular Epidemiology, Centre de Recherche en Epidémiologie et Santé des Populations (CESP), INSERM U1018, Villejuif, France.
76
I'institut du Thorax, INSERM, CNRS, University of Nantes, CHU de Nantes, Nantes, France.
77
Institute for Social and Economic Research, University of Essex, Colchester, Essex, UK.
78
Harvard Medical School Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Boston, MA, USA.
79
Department of Epidemiology, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA.
80
Anschutz Medical Campus, University of Colorado Denver, Denver, CO, USA.
81
Biomedical and Translational Informatics, Geisinger Health System, Danville, PA, USA; Department of Biochemistry and Molecular Biology, Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, USA.
82
Institute of Cardiovascular Science, University College London, UK; Farr Institute of Health Informatics Research, UCL Institute of Health Informatics, University College London, UK; Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands; Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, Netherlands.
83
Farr Institute of Health Informatics Research, UCL Institute of Health Informatics, University College London, UK.
84
Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA.
85
Institute of Cardiovascular Science, University College London, UK; Farr Institute of Health Informatics Research, UCL Institute of Health Informatics, University College London, UK.
86
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK. Electronic address: naveed.sattar@glasgow.ac.uk.

Abstract

BACKGROUND:

Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk.

METHODS:

In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores.

FINDINGS:

Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50). Based on the collected data, we did not identify associations with HbA1c (0·03%, -0·01 to 0·08), fasting insulin (0·00%, -0·06 to 0·07), and BMI (0·11 kg/m2, -0·09 to 0·30).

INTERPRETATION:

PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins.

FUNDING:

British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.

PMID:
27908689
PMCID:
PMC5266795
DOI:
10.1016/S2213-8587(16)30396-5
[Indexed for MEDLINE]
Free PMC Article

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