PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study
Amand F. Schmidt(Farr Institute), Daniel I. Swerdlow(NIHR Imperial Biomedical Research Centre), Michael V. Holmes(University of Oxford), Riyaz Patel(St Bartholomew's Hospital), Zammy Fairhurst-Hunter(Centre for Human Genetics), Donald M. Lyall(University of Glasgow), Fernando Pires Hartwig(Universidade Federal de Pelotas), Bernardo Lessa Horta(Universidade Federal de Pelotas), Elina Hyppönen(University of South Australia), Christine Power(Great Ormond Street Hospital), Max Moldovan(University of South Australia), Erik Van Iperen(Amsterdam UMC Location University of Amsterdam), G. Kees Hovingh(Amsterdam UMC Location University of Amsterdam), Ilja Demuth(Charité - Universitätsmedizin Berlin), Kristina Norman(Charité - Universitätsmedizin Berlin), Elisabeth Steinhagen‐Thiessen(Charité - Universitätsmedizin Berlin), Juri Demuth, Lars Bertram(Institute for Integrative and Experimental Genomics), Tian Liu(Max Planck Institute for Human Development), Stefan Coassin(Innsbruck Medical University), Johann Willeit(Innsbruck Medical University), Stefan Kiechl(Innsbruck Medical University), Karin Willeit(Innsbruck Medical University), Dan Mason(Bradford Royal Infirmary), John Wright(Bradford Royal Infirmary), Richard Morris(University of Bristol), Goya Wanamethee(University College London), Peter H. Whincup(St George's, University of London), Yoav Ben‐Shlomo(University of Bristol), Stela McLachlan(Glasgow Centre for Population Health), Jackie F. Price(Glasgow Centre for Population Health), Mika Kivimäki(University College London), Catherine Welch(University College London), Adelaida Sánchez-Gálvez(University College London), Pedro Marques‐Vidal(University of Lausanne), Andrew Nicolaides(University of Nicosia), Andrie G. Panayiotou(Cyprus University of Technology), N. Charlotte Onland‐Moret(University Medical Center Utrecht), Yvonne T. van der Schouw(University Medical Center Utrecht), Giuseppe Matullo(Italian institute for Genomic Medicine), Giovanni Fiorito(Italian institute for Genomic Medicine), Simonetta Guarrera(Italian institute for Genomic Medicine), Carlotta Sacerdote(Azienda Ospedaliero Universitaria San Giovanni Battista), Nicholas J. Wareham(University of Cambridge), Claudia Langenberg(University of Cambridge), Robert A. Scott(University of Cambridge), Jian’an Luan(University of Cambridge), Martin Bobák(University College London), Sofia Malyutina(Novosibirsk State Medical University), Andrzej Pająk(Jagiellonian University), Růžena Kubínová(National Institute of Public Health), Abdonas Tamošiūnas(Lithuanian University of Health Sciences), Hynek Pikhart(University College London), Lise Lotte N. Husemoen(Capital Region of Denmark), Niels Grarup(University of Copenhagen), Oluf Pedersen(University of Copenhagen), Torben Hansen(University of Copenhagen), Allan Linneberg(University of Copenhagen), Kenneth Starup Simonsen(Capital Region of Denmark), Jackie A. Cooper(University College London), Steve E. Humphries(University College London), Murray H. Brilliant(Marshfield Clinic), Terrie Kitchner(Marshfield Clinic), Håkon Håkonarson(Children's Hospital of Philadelphia), David Carrell(Kaiser Permanente Washington Health Research Institute), Catherine A. McCarty(Essentia Health), H. Lester Kirchner(Geisinger Medical Center), Eric B. Larson(Kaiser Permanente Washington Health Research Institute), David R. Crosslin(Kaiser Permanente Washington Health Research Institute), Mariza de Andrade(Mayo Clinic), Dan M. Roden(Vanderbilt University), Joshua C. Denny(Vanderbilt University), Cara L. Carty(George Washington University), Stephen Hancock(University of Newcastle Australia), John Attia(University of Newcastle Australia), Elizabeth Holliday(University of Newcastle Australia), Martin O’Donnell(Population Health Research Institute), Salim Yusuf(Population Health Research Institute), Michael Chong(Population Health Research Institute), Guillaume Paré(Population Health Research Institute), Pim van der Harst(University Medical Center Groningen), M. Abdullah Said(University Medical Center Groningen), Ruben N. Eppinga(University Medical Center Groningen), Niek Verweij(University Medical Center Groningen), Harold Snieder(University Medical Center Groningen), Tim Christen(Leiden University Medical Center), Dennis O. Mook‐Kanamori(Leiden University Medical Center), Stefan Gustafsson(Uppsala University), Lars Lind(Uppsala University), Erik Ingelsson(Uppsala University), Raha Pazoki(Erasmus MC), Oscar H. Franco(Erasmus MC), Albert Hofman(Erasmus MC), André G. Uitterlinden(Erasmus MC), Abbas Dehghan(Erasmus MC), Alexander Teumer(Universitätsmedizin Greifswald), Sebastian E. Baumeister(Universitätsmedizin Greifswald), Marcus Dörr(Universitätsmedizin Greifswald), Markus M. Lerch(Universitätsmedizin Greifswald), Uwe Völker(Universitätsmedizin Greifswald), Henry Völzke(Universitätsmedizin Greifswald), Joey Ward(University of Glasgow), Jill P. Pell(University of Glasgow), Daniel J. Smıth(University of Glasgow), Tom Meade(London School of Hygiene & Tropical Medicine), Anke H. Maitland‐van der Zee(Utrecht University), E.V. Baranova(Utrecht University), Robin Young(University of Glasgow), Ian Ford(University of Glasgow), Archie Campbell(Institute of Genetics and Cancer), Sandosh Padmanabhan(University of Glasgow), Michiel L. Bots(University Medical Center Utrecht), Diederick E. Grobbee(University Medical Center Utrecht), Philippe Froguel(Centre National de la Recherche Scientifique), Dorothée Thuillier(Centre National de la Recherche Scientifique), Beverley Balkau(Inserm), Amélie Bonnefond(Centre National de la Recherche Scientifique), Bertrand Cariou(Centre National de la Recherche Scientifique), Melissa Smart(University of Essex), Yanchun Bao(University of Essex), Meena Kumari(University of Essex), Anubha Mahajan(Centre for Human Genetics), Paul M. Ridker(Brigham and Women's Hospital), Daniel I. Chasman(Brigham and Women's Hospital), Alex P. Reiner(University of Washington), Leslie A. Lange(University of Colorado Anschutz Medical Campus), Marylyn D. Ritchie(Pennsylvania State University), Folkert W. Asselbergs(University Medical Center Utrecht), Juan-Pablo Casas(Farr Institute), Brendan J. Keating(University of Pennsylvania), David Preiss(University of Oxford), Aroon D. Hingorani(Farr Institute), Naveed Sattar(University of Glasgow)
Cited by 388Open Access
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: , 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: , -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.
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