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

Amand F Schmidt; Daniel I Swerdlow; Michael V Holmes; Riyaz S Patel; Zammy Fairhurst-Hunter; Donald M Lyall; Fernando Pires Hartwig; Bernardo Lessa Horta; Elina Hyppönen; Christine Power; Max Moldovan; Erik van Iperen; G Kees Hovingh; Ilja Demuth; Kristina Norman; Elisabeth Steinhagen-Thiessen; Juri Demuth; Lars Bertram; Tian Liu; Stefan Coassin; Johann Willeit; Stefan Kiechl; Karin Willeit; Dan Mason; John Wright; Richard Morris; Goya Wanamethee; Peter Whincup; Yoav Ben-Shlomo; Stela McLachlan; Jackie F Price; Mika Kivimaki; Catherine Welch; Adelaida Sanchez-Galvez; Pedro Marques-Vidal; Andrew Nicolaides; Andrie G Panayiotou; N Charlotte Onland-Moret; Yvonne T van der Schouw; Giuseppe Matullo; Giovanni Fiorito; Simonetta Guarrera; Carlotta Sacerdote; Nicholas J Wareham; Claudia Langenberg; Robert Scott; Jian'an Luan; Martin Bobak; Sofia Malyutina; Andrzej Pająk; Ruzena Kubinova; Abdonas Tamosiunas; Hynek Pikhart; Lise Lotte Nystrup Husemoen; Niels Grarup; Oluf Pedersen; Torben Hansen; Allan Linneberg; Kenneth Starup Simonsen; Jackie Cooper; Steve E Humphries; Murray Brilliant; Terrie Kitchner; Hakon Hakonarson; David S Carrell; Catherine A McCarty; H Lester Kirchner; Eric B Larson; David R Crosslin; Mariza de Andrade; Dan M Roden; Joshua C Denny; Cara Carty; Stephen Hancock; John Attia; Elizabeth Holliday; Martin O'Donnell; Salim Yusuf; Michael Chong; Guillaume Pare; Pim van der Harst; M Abdullah Said; Ruben N Eppinga; Niek Verweij; Harold Snieder; LifeLines Cohort study group; Tim Christen; Dennis O Mook-Kanamori; Stefan Gustafsson; Lars Lind; Erik Ingelsson; Raha Pazoki; Oscar Franco; Albert Hofman; Andre Uitterlinden; Abbas Dehghan; Alexander Teumer; Sebastian Baumeister; Marcus Dörr; Markus M Lerch; Uwe Völker; Henry Völzke; Joey Ward; Jill P Pell; Daniel J Smith; Tom Meade; Anke H Maitland-van der Zee; Ekaterina V Baranova; Robin Young; Ian Ford; Archie Campbell; Sandosh Padmanabhan; Michiel L Bots; Diederick E Grobbee; Philippe Froguel; Dorothée Thuillier; Beverley Balkau; Amélie Bonnefond; Bertrand Cariou; Melissa Smart; Yanchun Bao; Meena Kumari; Anubha Mahajan; Paul M Ridker; Daniel I Chasman; Alex P Reiner; Leslie A Lange; Marylyn D Ritchie; Folkert W Asselbergs; Juan-Pablo Casas; Brendan J Keating; David Preiss; Aroon D Hingorani; UCLEB consortium; Naveed Sattar

doi:10.1016/S2213-8587(16)30396-5

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

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

Authors

Amand F Schmidt¹, Daniel I Swerdlow², Michael V Holmes³, Riyaz S Patel⁴, Zammy Fairhurst-Hunter⁵, Donald M Lyall⁶, Fernando Pires Hartwig⁷, Bernardo Lessa Horta⁷, Elina Hyppönen⁸, Christine Power⁹, Max Moldovan¹⁰, Erik van Iperen¹¹, G Kees Hovingh¹², Ilja Demuth¹³, Kristina Norman¹⁴, Elisabeth Steinhagen-Thiessen¹⁴, Juri Demuth¹⁵, Lars Bertram¹⁶, Tian Liu¹⁷, Stefan Coassin¹⁸, Johann Willeit¹⁹, Stefan Kiechl¹⁹, Karin Willeit¹⁹, Dan Mason²⁰, John Wright²⁰, Richard Morris²¹, Goya Wanamethee²², Peter Whincup²³, Yoav Ben-Shlomo²¹, Stela McLachlan²⁴, Jackie F Price²⁴, Mika Kivimaki²⁵, Catherine Welch²⁵, Adelaida Sanchez-Galvez²⁵, Pedro Marques-Vidal²⁶, Andrew Nicolaides²⁷, Andrie G Panayiotou²⁸, N Charlotte Onland-Moret²⁹, Yvonne T van der Schouw²⁹, Giuseppe Matullo³⁰, Giovanni Fiorito³⁰, Simonetta Guarrera³⁰, Carlotta Sacerdote³¹, Nicholas J Wareham³², Claudia Langenberg³², Robert Scott³², Jian'an Luan³², Martin Bobak²⁵, Sofia Malyutina³³, Andrzej Pająk³⁴, Ruzena Kubinova³⁵, Abdonas Tamosiunas³⁶, Hynek Pikhart²⁵, Lise Lotte Nystrup Husemoen³⁷, Niels Grarup³⁸, Oluf Pedersen³⁸, Torben Hansen³⁸, Allan Linneberg³⁹, Kenneth Starup Simonsen³⁷, Jackie Cooper⁴⁰, Steve E Humphries⁴⁰, Murray Brilliant⁴¹, Terrie Kitchner⁴¹, Hakon Hakonarson⁴², David S Carrell⁴³, Catherine A McCarty⁴⁴, H Lester Kirchner⁴⁵, Eric B Larson⁴⁶, David R Crosslin⁴⁶, Mariza de Andrade⁴⁷, Dan M Roden⁴⁸, Joshua C Denny⁴⁹, Cara Carty⁵⁰, Stephen Hancock⁵¹, John Attia⁵¹, Elizabeth Holliday⁵¹, Martin O'Donnell⁵², Salim Yusuf⁵², Michael Chong⁵², Guillaume Pare⁵², Pim van der Harst⁵³, M Abdullah Said⁵⁴, Ruben N Eppinga⁵⁴, Niek Verweij⁵⁴, Harold Snieder⁵⁵; LifeLines Cohort study group; Tim Christen⁵⁶, Dennis O Mook-Kanamori⁵⁶, Stefan Gustafsson⁵⁷, Lars Lind⁵⁷, Erik Ingelsson⁵⁸, Raha Pazoki⁵⁹, Oscar Franco⁵⁹, Albert Hofman⁵⁹, Andre Uitterlinden⁶⁰, Abbas Dehghan⁶¹, Alexander Teumer⁶², Sebastian Baumeister⁶³, Marcus Dörr⁶⁴, Markus M Lerch⁶⁵, Uwe Völker⁶⁶, Henry Völzke⁶², Joey Ward⁶, Jill P Pell⁶, Daniel J Smith⁶, Tom Meade⁶⁷, Anke H Maitland-van der Zee⁶⁸, Ekaterina V Baranova⁶⁹, Robin Young⁷⁰, Ian Ford⁷⁰, Archie Campbell⁷¹, Sandosh Padmanabhan⁷², Michiel L Bots²⁹, Diederick E Grobbee²⁹, Philippe Froguel⁷³, Dorothée Thuillier⁷⁴, Beverley Balkau⁷⁵, Amélie Bonnefond⁷³, Bertrand Cariou⁷⁶, Melissa Smart⁷⁷, Yanchun Bao⁷⁷, Meena Kumari⁷⁷, Anubha Mahajan⁵, Paul M Ridker⁷⁸, Daniel I Chasman⁷⁸, Alex P Reiner⁷⁹, Leslie A Lange⁸⁰, Marylyn D Ritchie⁸¹, Folkert W Asselbergs⁸², Juan-Pablo Casas⁸³, Brendan J Keating⁸⁴, David Preiss³, Aroon D Hingorani⁸⁵; UCLEB consortium; Naveed Sattar⁸⁶

Affiliations

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: [email protected].
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: [email protected].

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, HbA_1c, 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 HbA_1c (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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Blood Glucose / metabolism
Case-Control Studies
Cholesterol, LDL / blood
Cholesterol, LDL / genetics
Cohort Studies
Diabetes Mellitus, Type 2 / blood*
Diabetes Mellitus, Type 2 / diagnosis
Diabetes Mellitus, Type 2 / genetics*
Genetic Predisposition to Disease / genetics*
Genetic Variation / genetics*
Humans
Mendelian Randomization Analysis / methods*
Proprotein Convertase 9 / genetics*
Randomized Controlled Trials as Topic / methods

Substances

Blood Glucose
Cholesterol, LDL
PCSK9 protein, human
Proprotein Convertase 9

Abstract

Publication types

MeSH terms

Substances

Grants and funding