PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study
Identifieur interne : 002719 ( Pmc/Corpus ); précédent : 002718; suivant : 002720PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study
Auteurs : 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 Paj K ; 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 ; 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 ; Naveed SattarSource :
- The Lancet. Diabetes & Endocrinology [ 2213-8587 ] ; 2017.
Abstract
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
In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of
Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent
British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.
Url:
DOI: 10.1016/S2213-8587(16)30396-5
PubMed: 27908689
PubMed Central: 5266795
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PMC:5266795Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en"><italic>PCSK9</italic> genetic variants and risk of type 2 diabetes: a mendelian randomisation study</title><author><name sortKey="Schmidt, Amand F" sort="Schmidt, Amand F" uniqKey="Schmidt A" first="Amand F" last="Schmidt">Amand F. Schmidt</name><affiliation><nlm:aff id="aff1">Institute of Cardiovascular Science, University College London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Farr Institute of Health Informatics Research, UCL Institute of Health Informatics, University College London, UK</nlm:aff></affiliation></author><author><name sortKey="Swerdlow, Daniel I" sort="Swerdlow, Daniel I" uniqKey="Swerdlow D" first="Daniel I" last="Swerdlow">Daniel I. Swerdlow</name><affiliation><nlm:aff id="aff1">Institute of Cardiovascular Science, University College London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Department of Medicine, Imperial College London, London, UK</nlm:aff></affiliation></author><author><name sortKey="Holmes, Michael V" sort="Holmes, Michael V" uniqKey="Holmes M" first="Michael V" last="Holmes">Michael V. Holmes</name><affiliation><nlm:aff id="aff11">Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff12">Medical Research Council Population Health Research Unit at the University of Oxford, University of Oxford, Oxford, UK</nlm:aff></affiliation></author><author><name sortKey="Patel, Riyaz S" sort="Patel, Riyaz S" uniqKey="Patel R" first="Riyaz S" last="Patel">Riyaz S. Patel</name><affiliation><nlm:aff id="aff1">Institute of Cardiovascular Science, University College London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Farr Institute of Health Informatics Research, UCL Institute of Health Informatics, University College London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff14">The Barts Heart Centre, St Bartholomew's Hospital, London, UK</nlm:aff></affiliation></author><author><name sortKey="Fairhurst Hunter, Zammy" sort="Fairhurst Hunter, Zammy" uniqKey="Fairhurst Hunter Z" first="Zammy" last="Fairhurst-Hunter">Zammy Fairhurst-Hunter</name><affiliation><nlm:aff id="aff13">Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK</nlm:aff></affiliation></author><author><name sortKey="Lyall, Donald M" sort="Lyall, Donald M" uniqKey="Lyall D" first="Donald M" last="Lyall">Donald M. Lyall</name><affiliation><nlm:aff id="aff15">Institute of Health & Wellbeing, University of Glasgow, Glasgow, UK</nlm:aff></affiliation></author><author><name sortKey="Hartwig, Fernando Pires" sort="Hartwig, Fernando Pires" uniqKey="Hartwig F" first="Fernando Pires" last="Hartwig">Fernando Pires Hartwig</name><affiliation><nlm:aff id="aff18">Postgraduate Program in Epidemiology, Federal University of Pelotas, Pelotas, Brazil</nlm:aff></affiliation></author><author><name sortKey="Horta, Bernardo Lessa" sort="Horta, Bernardo Lessa" uniqKey="Horta B" first="Bernardo Lessa" last="Horta">Bernardo Lessa Horta</name><affiliation><nlm:aff id="aff18">Postgraduate Program in Epidemiology, Federal University of Pelotas, Pelotas, Brazil</nlm:aff></affiliation></author><author><name sortKey="Hypponen, Elina" sort="Hypponen, Elina" uniqKey="Hypponen E" first="Elina" last="Hyppönen">Elina Hyppönen</name><affiliation><nlm:aff id="aff19">Centre for Population Health Research, Sansom Institute for Health Research, University of South Australia, Adelaide, SA, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff21">Population, Policy and Practice, UCL Great Ormond Street Institute of Child Health, London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff22">South Australian Health and Medical Research Institute, Adelaide, SA, Australia</nlm:aff></affiliation></author><author><name sortKey="Power, Christine" sort="Power, Christine" uniqKey="Power C" first="Christine" last="Power">Christine Power</name><affiliation><nlm:aff id="aff21">Population, Policy and Practice, UCL Great Ormond Street Institute of Child Health, London, UK</nlm:aff></affiliation></author><author><name sortKey="Moldovan, Max" sort="Moldovan, Max" uniqKey="Moldovan M" first="Max" last="Moldovan">Max Moldovan</name><affiliation><nlm:aff id="aff20">School of Health Sciences, University of South Australia, Adelaide, SA, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff23">South Australian Health and Medical Research Institute–EMBL Australia, Adelaide, SA, Australia</nlm:aff></affiliation></author><author><name sortKey="Van Iperen, Erik" sort="Van Iperen, Erik" uniqKey="Van Iperen E" first="Erik" last="Van Iperen">Erik Van Iperen</name><affiliation><nlm:aff id="aff24">Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, Netherlands</nlm:aff></affiliation><affiliation><nlm:aff id="aff25">Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center Amsterdam, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Hovingh, G Kees" sort="Hovingh, G Kees" uniqKey="Hovingh G" first="G Kees" last="Hovingh">G Kees Hovingh</name><affiliation><nlm:aff id="aff26">Department of Vascular Medicine, Academic Medical Center Amsterdam, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Demuth, Ilja" sort="Demuth, Ilja" uniqKey="Demuth I" first="Ilja" last="Demuth">Ilja Demuth</name><affiliation><nlm:aff id="aff28">Charité Research Group on Geriatrics, Charité–Universitätsmedizin Berlin, Berlin, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff29">Institute of Medical and Human Genetics, Charité–Universitätsmedizin Berlin, Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Norman, Kristina" sort="Norman, Kristina" uniqKey="Norman K" first="Kristina" last="Norman">Kristina Norman</name><affiliation><nlm:aff id="aff28">Charité Research Group on Geriatrics, Charité–Universitätsmedizin Berlin, Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Steinhagen Thiessen, Elisabeth" sort="Steinhagen Thiessen, Elisabeth" uniqKey="Steinhagen Thiessen E" first="Elisabeth" last="Steinhagen-Thiessen">Elisabeth Steinhagen-Thiessen</name><affiliation><nlm:aff id="aff28">Charité Research Group on Geriatrics, Charité–Universitätsmedizin Berlin, Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Demuth, Juri" sort="Demuth, Juri" uniqKey="Demuth J" first="Juri" last="Demuth">Juri Demuth</name><affiliation><nlm:aff id="aff30">E.CA Economics GmbH, Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Bertram, Lars" sort="Bertram, Lars" uniqKey="Bertram L" first="Lars" last="Bertram">Lars Bertram</name><affiliation><nlm:aff id="aff7">Neuroepidemiology and Ageing Research Unit, Imperial College London, London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff31">Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics and Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany</nlm:aff></affiliation></author><author><name sortKey="Liu, Tian" sort="Liu, Tian" uniqKey="Liu T" first="Tian" last="Liu">Tian Liu</name><affiliation><nlm:aff id="aff32">Max Planck Institute for Human Development, Berlin, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff33">Max Planck Institute for Molecular Genetics, Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Coassin, Stefan" sort="Coassin, Stefan" uniqKey="Coassin S" first="Stefan" last="Coassin">Stefan Coassin</name><affiliation><nlm:aff id="aff34">Division of Genetic Epidemiology Innsbruck, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria</nlm:aff></affiliation></author><author><name sortKey="Willeit, Johann" sort="Willeit, Johann" uniqKey="Willeit J" first="Johann" last="Willeit">Johann Willeit</name><affiliation><nlm:aff id="aff35">Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria</nlm:aff></affiliation></author><author><name sortKey="Kiechl, Stefan" sort="Kiechl, Stefan" uniqKey="Kiechl S" first="Stefan" last="Kiechl">Stefan Kiechl</name><affiliation><nlm:aff id="aff35">Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria</nlm:aff></affiliation></author><author><name sortKey="Willeit, Karin" sort="Willeit, Karin" uniqKey="Willeit K" first="Karin" last="Willeit">Karin Willeit</name><affiliation><nlm:aff id="aff35">Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria</nlm:aff></affiliation></author><author><name sortKey="Mason, Dan" sort="Mason, Dan" uniqKey="Mason D" first="Dan" last="Mason">Dan Mason</name><affiliation><nlm:aff id="aff36">Bradford Institute for Health Research, Bradford Royal Infirmary, Bradford, UK</nlm:aff></affiliation></author><author><name sortKey="Wright, John" sort="Wright, John" uniqKey="Wright J" first="John" last="Wright">John Wright</name><affiliation><nlm:aff id="aff36">Bradford Institute for Health Research, Bradford Royal Infirmary, Bradford, UK</nlm:aff></affiliation></author><author><name sortKey="Morris, Richard" sort="Morris, Richard" uniqKey="Morris R" first="Richard" last="Morris">Richard Morris</name><affiliation><nlm:aff id="aff37">School of Social and Community Medicine, University of Bristol, Bristol, UK</nlm:aff></affiliation></author><author><name sortKey="Wanamethee, Goya" sort="Wanamethee, Goya" uniqKey="Wanamethee G" first="Goya" last="Wanamethee">Goya Wanamethee</name><affiliation><nlm:aff id="aff2">Department of Primary Care & Population Health, University College London, UK</nlm:aff></affiliation></author><author><name sortKey="Whincup, Peter" sort="Whincup, Peter" uniqKey="Whincup P" first="Peter" last="Whincup">Peter Whincup</name><affiliation><nlm:aff id="aff38">Population Health Research Institute, St George's, University of London, London, UK</nlm:aff></affiliation></author><author><name sortKey="Ben Shlomo, Yoav" sort="Ben Shlomo, Yoav" uniqKey="Ben Shlomo Y" first="Yoav" last="Ben-Shlomo">Yoav Ben-Shlomo</name><affiliation><nlm:aff id="aff37">School of Social and Community Medicine, University of Bristol, Bristol, UK</nlm:aff></affiliation></author><author><name sortKey="Mclachlan, Stela" sort="Mclachlan, Stela" uniqKey="Mclachlan S" first="Stela" last="Mclachlan">Stela Mclachlan</name><affiliation><nlm:aff id="aff39">Centre for Population Health Sciences, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK</nlm:aff></affiliation></author><author><name sortKey="Price, Jackie F" sort="Price, Jackie F" uniqKey="Price J" first="Jackie F" last="Price">Jackie F. Price</name><affiliation><nlm:aff id="aff39">Centre for Population Health Sciences, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK</nlm:aff></affiliation></author><author><name sortKey="Kivimaki, Mika" sort="Kivimaki, Mika" uniqKey="Kivimaki M" first="Mika" last="Kivimaki">Mika Kivimaki</name><affiliation><nlm:aff id="aff3">Department of Epidemiology and Public Health, UCL Institute of Epidemiology and Health Care, University College London, UK</nlm:aff></affiliation></author><author><name sortKey="Welch, Catherine" sort="Welch, Catherine" uniqKey="Welch C" first="Catherine" last="Welch">Catherine Welch</name><affiliation><nlm:aff id="aff3">Department of Epidemiology and Public Health, UCL Institute of Epidemiology and Health Care, University College London, UK</nlm:aff></affiliation></author><author><name sortKey="Sanchez Galvez, Adelaida" sort="Sanchez Galvez, Adelaida" uniqKey="Sanchez Galvez A" first="Adelaida" last="Sanchez-Galvez">Adelaida Sanchez-Galvez</name><affiliation><nlm:aff id="aff3">Department of Epidemiology and Public Health, UCL Institute of Epidemiology and Health Care, University College London, UK</nlm:aff></affiliation></author><author><name sortKey="Marques Vidal, Pedro" sort="Marques Vidal, Pedro" uniqKey="Marques Vidal P" first="Pedro" last="Marques-Vidal">Pedro Marques-Vidal</name><affiliation><nlm:aff id="aff41">Internal Medicine Unit, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Nicolaides, Andrew" sort="Nicolaides, Andrew" uniqKey="Nicolaides A" first="Andrew" last="Nicolaides">Andrew Nicolaides</name><affiliation><nlm:aff id="aff8">Department of Vascular Surgery, Imperial College London, London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff42">Department of Surgery, Nicosia Medical School, University of Nicosia, Nicosia, Cyprus</nlm:aff></affiliation></author><author><name sortKey="Panayiotou, Andrie G" sort="Panayiotou, Andrie G" uniqKey="Panayiotou A" first="Andrie G" last="Panayiotou">Andrie G. Panayiotou</name><affiliation><nlm:aff id="aff43">Cyprus International Institute for Environmental and Public Health, Cyprus University of Technology, Limassol, Cyprus</nlm:aff></affiliation></author><author><name sortKey="Onland Moret, N Charlotte" sort="Onland Moret, N Charlotte" uniqKey="Onland Moret N" first="N Charlotte" last="Onland-Moret">N Charlotte Onland-Moret</name><affiliation><nlm:aff id="aff44">Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Van Der Schouw, Yvonne T" sort="Van Der Schouw, Yvonne T" uniqKey="Van Der Schouw Y" first="Yvonne T" last="Van Der Schouw">Yvonne T. Van Der Schouw</name><affiliation><nlm:aff id="aff44">Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Matullo, Giuseppe" sort="Matullo, Giuseppe" uniqKey="Matullo G" first="Giuseppe" last="Matullo">Giuseppe Matullo</name><affiliation><nlm:aff id="aff46">Human Genetics Foundation, HuGeF, Turin, Italy</nlm:aff></affiliation><affiliation><nlm:aff id="aff47">Department of Medical Sciences, University of Turin, Turin, Italy</nlm:aff></affiliation></author><author><name sortKey="Fiorito, Giovanni" sort="Fiorito, Giovanni" uniqKey="Fiorito G" first="Giovanni" last="Fiorito">Giovanni Fiorito</name><affiliation><nlm:aff id="aff46">Human Genetics Foundation, HuGeF, Turin, Italy</nlm:aff></affiliation><affiliation><nlm:aff id="aff47">Department of Medical Sciences, University of Turin, Turin, Italy</nlm:aff></affiliation></author><author><name sortKey="Guarrera, Simonetta" sort="Guarrera, Simonetta" uniqKey="Guarrera S" first="Simonetta" last="Guarrera">Simonetta Guarrera</name><affiliation><nlm:aff id="aff46">Human Genetics Foundation, HuGeF, Turin, Italy</nlm:aff></affiliation><affiliation><nlm:aff id="aff47">Department of Medical Sciences, University of Turin, Turin, Italy</nlm:aff></affiliation></author><author><name sortKey="Sacerdote, Carlotta" sort="Sacerdote, Carlotta" uniqKey="Sacerdote C" first="Carlotta" last="Sacerdote">Carlotta Sacerdote</name><affiliation><nlm:aff id="aff48">Cancer Epidemiology Unit, San Giovanni Battista Hospital, Turin, Italy</nlm:aff></affiliation><affiliation><nlm:aff id="aff49">Centre for Oncology Prevention, CPO Piemonte, Turin, Italy</nlm:aff></affiliation></author><author><name sortKey="Wareham, Nicholas J" sort="Wareham, Nicholas J" uniqKey="Wareham N" first="Nicholas J" last="Wareham">Nicholas J. Wareham</name><affiliation><nlm:aff id="aff50">MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK</nlm:aff></affiliation></author><author><name sortKey="Langenberg, Claudia" sort="Langenberg, Claudia" uniqKey="Langenberg C" first="Claudia" last="Langenberg">Claudia Langenberg</name><affiliation><nlm:aff id="aff50">MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK</nlm:aff></affiliation></author><author><name sortKey="Scott, Robert" sort="Scott, Robert" uniqKey="Scott R" first="Robert" last="Scott">Robert Scott</name><affiliation><nlm:aff id="aff50">MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK</nlm:aff></affiliation></author><author><name sortKey="Luan, Jian An" sort="Luan, Jian An" uniqKey="Luan J" first="Jian'An" last="Luan">Jian'An Luan</name><affiliation><nlm:aff id="aff50">MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK</nlm:aff></affiliation></author><author><name sortKey="Bobak, Martin" sort="Bobak, Martin" uniqKey="Bobak M" first="Martin" last="Bobak">Martin Bobak</name><affiliation><nlm:aff id="aff3">Department of Epidemiology and Public Health, UCL Institute of Epidemiology and Health Care, University College London, UK</nlm:aff></affiliation></author><author><name sortKey="Malyutina, Sofia" sort="Malyutina, Sofia" uniqKey="Malyutina S" first="Sofia" last="Malyutina">Sofia Malyutina</name><affiliation><nlm:aff id="aff51">Novosibirsk State Medical University, Novosibirsk, Russia</nlm:aff></affiliation><affiliation><nlm:aff id="aff52">Institute of Internal and Preventive Medicine, Siberian Branch of the Russian Academy of Medical Sciences, Novosibirsk, Russia</nlm:aff></affiliation></author><author><name sortKey="Paj K, Andrzej" sort="Paj K, Andrzej" uniqKey="Paj K A" first="Andrzej" last="Paj K">Andrzej Paj K</name><affiliation><nlm:aff id="aff53">Jagiellonian University Collegium Medicum, Krakow, Poland</nlm:aff></affiliation></author><author><name sortKey="Kubinova, Ruzena" sort="Kubinova, Ruzena" uniqKey="Kubinova R" first="Ruzena" last="Kubinova">Ruzena Kubinova</name><affiliation><nlm:aff id="aff54">National Institute of Public Health, Prague, Czech Republic</nlm:aff></affiliation></author><author><name sortKey="Tamosiunas, Abdonas" sort="Tamosiunas, Abdonas" uniqKey="Tamosiunas A" first="Abdonas" last="Tamosiunas">Abdonas Tamosiunas</name><affiliation><nlm:aff id="aff55">Lithuanian University of Health Sciences, Kaunas, Lithuania</nlm:aff></affiliation></author><author><name sortKey="Pikhart, Hynek" sort="Pikhart, Hynek" uniqKey="Pikhart H" first="Hynek" last="Pikhart">Hynek Pikhart</name><affiliation><nlm:aff id="aff3">Department of Epidemiology and Public Health, UCL Institute of Epidemiology and Health Care, University College London, UK</nlm:aff></affiliation></author><author><name sortKey="Husemoen, Lise Lotte Nystrup" sort="Husemoen, Lise Lotte Nystrup" uniqKey="Husemoen L" first="Lise Lotte Nystrup" last="Husemoen">Lise Lotte Nystrup Husemoen</name><affiliation><nlm:aff id="aff56">Research Centre for Prevention and Health, Capital Region of Denmark, Denmark</nlm:aff></affiliation></author><author><name sortKey="Grarup, Niels" sort="Grarup, Niels" uniqKey="Grarup N" first="Niels" last="Grarup">Niels Grarup</name><affiliation><nlm:aff id="aff57">Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark</nlm:aff></affiliation></author><author><name sortKey="Pedersen, Oluf" sort="Pedersen, Oluf" uniqKey="Pedersen O" first="Oluf" last="Pedersen">Oluf Pedersen</name><affiliation><nlm:aff id="aff57">Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark</nlm:aff></affiliation></author><author><name sortKey="Hansen, Torben" sort="Hansen, Torben" uniqKey="Hansen T" first="Torben" last="Hansen">Torben Hansen</name><affiliation><nlm:aff id="aff57">Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark</nlm:aff></affiliation></author><author><name sortKey="Linneberg, Allan" sort="Linneberg, Allan" uniqKey="Linneberg A" first="Allan" last="Linneberg">Allan Linneberg</name><affiliation><nlm:aff id="aff56">Research Centre for Prevention and Health, Capital Region of Denmark, Denmark</nlm:aff></affiliation><affiliation><nlm:aff id="aff58">Department of Clinical Experimental Research, Rigshospitalet, Copenhagen, Denmark</nlm:aff></affiliation><affiliation><nlm:aff id="aff59">Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark</nlm:aff></affiliation></author><author><name sortKey="Simonsen, Kenneth Starup" sort="Simonsen, Kenneth Starup" uniqKey="Simonsen K" first="Kenneth Starup" last="Simonsen">Kenneth Starup Simonsen</name><affiliation><nlm:aff id="aff56">Research Centre for Prevention and Health, Capital Region of Denmark, Denmark</nlm:aff></affiliation></author><author><name sortKey="Cooper, Jackie" sort="Cooper, Jackie" uniqKey="Cooper J" first="Jackie" last="Cooper">Jackie Cooper</name><affiliation><nlm:aff id="aff4">Centre for Cardiovascular Genetics, University College London, UK</nlm:aff></affiliation></author><author><name sortKey="Humphries, Steve E" sort="Humphries, Steve E" uniqKey="Humphries S" first="Steve E" last="Humphries">Steve E. Humphries</name><affiliation><nlm:aff id="aff4">Centre for Cardiovascular Genetics, University College London, UK</nlm:aff></affiliation></author><author><name sortKey="Brilliant, Murray" sort="Brilliant, Murray" uniqKey="Brilliant M" first="Murray" last="Brilliant">Murray Brilliant</name><affiliation><nlm:aff id="aff60">Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI, USA</nlm:aff></affiliation></author><author><name sortKey="Kitchner, Terrie" sort="Kitchner, Terrie" uniqKey="Kitchner T" first="Terrie" last="Kitchner">Terrie Kitchner</name><affiliation><nlm:aff id="aff60">Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI, USA</nlm:aff></affiliation></author><author><name sortKey="Hakonarson, Hakon" sort="Hakonarson, Hakon" uniqKey="Hakonarson H" first="Hakon" last="Hakonarson">Hakon Hakonarson</name><affiliation><nlm:aff id="aff61">Children's Hospital of Philadelphia, Philadelphia, PA, USA</nlm:aff></affiliation></author><author><name sortKey="Carrell, David S" sort="Carrell, David S" uniqKey="Carrell D" first="David S" last="Carrell">David S. Carrell</name><affiliation><nlm:aff id="aff62">Group Health Research Institute in Seattle, WA, USA</nlm:aff></affiliation></author><author><name sortKey="Mccarty, Catherine A" sort="Mccarty, Catherine A" uniqKey="Mccarty C" first="Catherine A" last="Mccarty">Catherine A. Mccarty</name><affiliation><nlm:aff id="aff63">Essentia Institute of Rural Health, Duluth, MN, USA</nlm:aff></affiliation></author><author><name sortKey="Kirchner, H Lester" sort="Kirchner, H Lester" uniqKey="Kirchner H" first="H Lester" last="Kirchner">H Lester Kirchner</name><affiliation><nlm:aff id="aff64">Center for Health Research, Geisinger Clinic, Danville, PA, USA</nlm:aff></affiliation></author><author><name sortKey="Larson, Eric B" sort="Larson, Eric B" uniqKey="Larson E" first="Eric B" last="Larson">Eric B. Larson</name><affiliation><nlm:aff id="aff65">Group Health Research Institute, Seattle, WA, USA</nlm:aff></affiliation></author><author><name sortKey="Crosslin, David R" sort="Crosslin, David R" uniqKey="Crosslin D" first="David R" last="Crosslin">David R. Crosslin</name><affiliation><nlm:aff id="aff65">Group Health Research Institute, Seattle, WA, USA</nlm:aff></affiliation></author><author><name sortKey="De Andrade, Mariza" sort="De Andrade, Mariza" uniqKey="De Andrade M" first="Mariza" last="De Andrade">Mariza De Andrade</name><affiliation><nlm:aff id="aff66">Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA</nlm:aff></affiliation></author><author><name sortKey="Roden, Dan M" sort="Roden, Dan M" uniqKey="Roden D" first="Dan M" last="Roden">Dan M. Roden</name><affiliation><nlm:aff id="aff67">Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA</nlm:aff></affiliation></author><author><name sortKey="Denny, Joshua C" sort="Denny, Joshua C" uniqKey="Denny J" first="Joshua C" last="Denny">Joshua C. Denny</name><affiliation><nlm:aff id="aff68">Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, USA</nlm:aff></affiliation></author><author><name sortKey="Carty, Cara" sort="Carty, Cara" uniqKey="Carty C" first="Cara" last="Carty">Cara Carty</name><affiliation><nlm:aff id="aff69">George Washington University, Washington, DC, USA</nlm:aff></affiliation></author><author><name sortKey="Hancock, Stephen" sort="Hancock, Stephen" uniqKey="Hancock S" first="Stephen" last="Hancock">Stephen Hancock</name><affiliation><nlm:aff id="aff70">University of Newcastle, Newcastle, NSW, Australia</nlm:aff></affiliation></author><author><name sortKey="Attia, John" sort="Attia, John" uniqKey="Attia J" first="John" last="Attia">John Attia</name><affiliation><nlm:aff id="aff70">University of Newcastle, Newcastle, NSW, Australia</nlm:aff></affiliation></author><author><name sortKey="Holliday, Elizabeth" sort="Holliday, Elizabeth" uniqKey="Holliday E" first="Elizabeth" last="Holliday">Elizabeth Holliday</name><affiliation><nlm:aff id="aff70">University of Newcastle, Newcastle, NSW, Australia</nlm:aff></affiliation></author><author><name sortKey="O Donnell, Martin" sort="O Donnell, Martin" uniqKey="O Donnell M" first="Martin" last="O'Donnell">Martin O'Donnell</name><affiliation><nlm:aff id="aff71">Population Health Research Institute, Hamilton, ON, Canada</nlm:aff></affiliation></author><author><name sortKey="Yusuf, Salim" sort="Yusuf, Salim" uniqKey="Yusuf S" first="Salim" last="Yusuf">Salim Yusuf</name><affiliation><nlm:aff id="aff71">Population Health Research Institute, Hamilton, ON, Canada</nlm:aff></affiliation></author><author><name sortKey="Chong, Michael" sort="Chong, Michael" uniqKey="Chong M" first="Michael" last="Chong">Michael Chong</name><affiliation><nlm:aff id="aff71">Population Health Research Institute, Hamilton, ON, Canada</nlm:aff></affiliation></author><author><name sortKey="Pare, Guillaume" sort="Pare, Guillaume" uniqKey="Pare G" first="Guillaume" last="Pare">Guillaume Pare</name><affiliation><nlm:aff id="aff71">Population Health Research Institute, Hamilton, ON, Canada</nlm:aff></affiliation></author><author><name sortKey="Van Der Harst, Pim" sort="Van Der Harst, Pim" uniqKey="Van Der Harst P" first="Pim" last="Van Der Harst">Pim Van Der Harst</name><affiliation><nlm:aff id="aff24">Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, Netherlands</nlm:aff></affiliation><affiliation><nlm:aff id="aff72">Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands</nlm:aff></affiliation><affiliation><nlm:aff id="aff73">Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Said, M Abdullah" sort="Said, M Abdullah" uniqKey="Said M" first="M Abdullah" last="Said">M Abdullah Said</name><affiliation><nlm:aff id="aff72">Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Eppinga, Ruben N" sort="Eppinga, Ruben N" uniqKey="Eppinga R" first="Ruben N" last="Eppinga">Ruben N. Eppinga</name><affiliation><nlm:aff id="aff72">Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Verweij, Niek" sort="Verweij, Niek" uniqKey="Verweij N" first="Niek" last="Verweij">Niek Verweij</name><affiliation><nlm:aff id="aff72">Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Snieder, Harold" sort="Snieder, Harold" uniqKey="Snieder H" first="Harold" last="Snieder">Harold Snieder</name><affiliation><nlm:aff id="aff74">Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Christen, Tim" sort="Christen, Tim" uniqKey="Christen T" first="Tim" last="Christen">Tim Christen</name><affiliation><nlm:aff id="aff75">Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Mook Kanamori, Dennis O" sort="Mook Kanamori, Dennis O" uniqKey="Mook Kanamori D" first="Dennis O" last="Mook-Kanamori">Dennis O. Mook-Kanamori</name><affiliation><nlm:aff id="aff75">Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Gustafsson, Stefan" sort="Gustafsson, Stefan" uniqKey="Gustafsson S" first="Stefan" last="Gustafsson">Stefan Gustafsson</name><affiliation><nlm:aff id="aff76">Molecular Epidemiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden</nlm:aff></affiliation></author><author><name sortKey="Lind, Lars" sort="Lind, Lars" uniqKey="Lind L" first="Lars" last="Lind">Lars Lind</name><affiliation><nlm:aff id="aff76">Molecular Epidemiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden</nlm:aff></affiliation></author><author><name sortKey="Ingelsson, Erik" sort="Ingelsson, Erik" uniqKey="Ingelsson E" first="Erik" last="Ingelsson">Erik Ingelsson</name><affiliation><nlm:aff id="aff76">Molecular Epidemiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden</nlm:aff></affiliation><affiliation><nlm:aff id="aff77">Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden</nlm:aff></affiliation><affiliation><nlm:aff id="aff78">Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA</nlm:aff></affiliation></author><author><name sortKey="Pazoki, Raha" sort="Pazoki, Raha" uniqKey="Pazoki R" first="Raha" last="Pazoki">Raha Pazoki</name><affiliation><nlm:aff id="aff79">Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Franco, Oscar" sort="Franco, Oscar" uniqKey="Franco O" first="Oscar" last="Franco">Oscar Franco</name><affiliation><nlm:aff id="aff79">Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Hofman, Albert" sort="Hofman, Albert" uniqKey="Hofman A" first="Albert" last="Hofman">Albert Hofman</name><affiliation><nlm:aff id="aff79">Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Uitterlinden, Andre" sort="Uitterlinden, Andre" uniqKey="Uitterlinden A" first="Andre" last="Uitterlinden">Andre Uitterlinden</name><affiliation><nlm:aff id="aff80">Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Dehghan, Abbas" sort="Dehghan, Abbas" uniqKey="Dehghan A" first="Abbas" last="Dehghan">Abbas Dehghan</name><affiliation><nlm:aff id="aff10">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</nlm:aff></affiliation><affiliation><nlm:aff id="aff79">Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Teumer, Alexander" sort="Teumer, Alexander" uniqKey="Teumer A" first="Alexander" last="Teumer">Alexander Teumer</name><affiliation><nlm:aff id="aff81">Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff85">German Centre for Cardiovascular Research (DZHK), Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Baumeister, Sebastian" sort="Baumeister, Sebastian" uniqKey="Baumeister S" first="Sebastian" last="Baumeister">Sebastian Baumeister</name><affiliation><nlm:aff id="aff81">Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff86">Department of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany</nlm:aff></affiliation></author><author><name sortKey="Dorr, Marcus" sort="Dorr, Marcus" uniqKey="Dorr M" first="Marcus" last="Dörr">Marcus Dörr</name><affiliation><nlm:aff id="aff82">Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff85">German Centre for Cardiovascular Research (DZHK), Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Lerch, Markus M" sort="Lerch, Markus M" uniqKey="Lerch M" first="Markus M" last="Lerch">Markus M. Lerch</name><affiliation><nlm:aff id="aff83">Department of Medicine A, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Volker, Uwe" sort="Volker, Uwe" uniqKey="Volker U" first="Uwe" last="Völker">Uwe Völker</name><affiliation><nlm:aff id="aff84">Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff85">German Centre for Cardiovascular Research (DZHK), Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Volzke, Henry" sort="Volzke, Henry" uniqKey="Volzke H" first="Henry" last="Völzke">Henry Völzke</name><affiliation><nlm:aff id="aff81">Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff85">German Centre for Cardiovascular Research (DZHK), Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Ward, Joey" sort="Ward, Joey" uniqKey="Ward J" first="Joey" last="Ward">Joey Ward</name><affiliation><nlm:aff id="aff15">Institute of Health & Wellbeing, University of Glasgow, Glasgow, UK</nlm:aff></affiliation></author><author><name sortKey="Pell, Jill P" sort="Pell, Jill P" uniqKey="Pell J" first="Jill P" last="Pell">Jill P. Pell</name><affiliation><nlm:aff id="aff15">Institute of Health & Wellbeing, University of Glasgow, Glasgow, UK</nlm:aff></affiliation></author><author><name sortKey="Smith, Daniel J" sort="Smith, Daniel J" uniqKey="Smith D" first="Daniel J" last="Smith">Daniel J. Smith</name><affiliation><nlm:aff id="aff15">Institute of Health & Wellbeing, University of Glasgow, Glasgow, UK</nlm:aff></affiliation></author><author><name sortKey="Meade, Tom" sort="Meade, Tom" uniqKey="Meade T" first="Tom" last="Meade">Tom Meade</name><affiliation><nlm:aff id="aff87">Department of Non-Communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK</nlm:aff></affiliation></author><author><name sortKey="Maitland Van Der Zee, Anke H" sort="Maitland Van Der Zee, Anke H" uniqKey="Maitland Van Der Zee A" first="Anke H" last="Maitland-Van Der Zee">Anke H. Maitland-Van Der Zee</name><affiliation><nlm:aff id="aff27">Department of Respiratory Medicine, Academic Medical Center Amsterdam, Netherlands</nlm:aff></affiliation><affiliation><nlm:aff id="aff88">Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Baranova, Ekaterina V" sort="Baranova, Ekaterina V" uniqKey="Baranova E" first="Ekaterina V" last="Baranova">Ekaterina V. Baranova</name><affiliation><nlm:aff id="aff88">Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Young, Robin" sort="Young, Robin" uniqKey="Young R" first="Robin" last="Young">Robin Young</name><affiliation><nlm:aff id="aff16">Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK</nlm:aff></affiliation></author><author><name sortKey="Ford, Ian" sort="Ford, Ian" uniqKey="Ford I" first="Ian" last="Ford">Ian Ford</name><affiliation><nlm:aff id="aff16">Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK</nlm:aff></affiliation></author><author><name sortKey="Campbell, Archie" sort="Campbell, Archie" uniqKey="Campbell A" first="Archie" last="Campbell">Archie Campbell</name><affiliation><nlm:aff id="aff40">Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK</nlm:aff></affiliation></author><author><name sortKey="Padmanabhan, Sandosh" sort="Padmanabhan, Sandosh" uniqKey="Padmanabhan S" first="Sandosh" last="Padmanabhan">Sandosh Padmanabhan</name><affiliation><nlm:aff id="aff17">Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK</nlm:aff></affiliation></author><author><name sortKey="Bots, Michiel L" sort="Bots, Michiel L" uniqKey="Bots M" first="Michiel L" last="Bots">Michiel L. Bots</name><affiliation><nlm:aff id="aff44">Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Grobbee, Diederick E" sort="Grobbee, Diederick E" uniqKey="Grobbee D" first="Diederick E" last="Grobbee">Diederick E. Grobbee</name><affiliation><nlm:aff id="aff44">Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Froguel, Philippe" sort="Froguel, Philippe" uniqKey="Froguel P" first="Philippe" last="Froguel">Philippe Froguel</name><affiliation><nlm:aff id="aff9">Department of Genomics of Common Disease, Imperial College London, London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff89">CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille, France</nlm:aff></affiliation></author><author><name sortKey="Thuillier, Dorothee" sort="Thuillier, Dorothee" uniqKey="Thuillier D" first="Dorothée" last="Thuillier">Dorothée Thuillier</name><affiliation><nlm:aff id="aff89">CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille, France</nlm:aff></affiliation></author><author><name sortKey="Balkau, Beverley" sort="Balkau, Beverley" uniqKey="Balkau B" first="Beverley" last="Balkau">Beverley Balkau</name><affiliation><nlm:aff id="aff90">Renal and Cardiovascular Epidemiology, Centre de Recherche en Epidémiologie et Santé des Populations (CESP), INSERM U1018, Villejuif, France</nlm:aff></affiliation></author><author><name sortKey="Bonnefond, Amelie" sort="Bonnefond, Amelie" uniqKey="Bonnefond A" first="Amélie" last="Bonnefond">Amélie Bonnefond</name><affiliation><nlm:aff id="aff9">Department of Genomics of Common Disease, Imperial College London, London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff89">CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille, France</nlm:aff></affiliation></author><author><name sortKey="Cariou, Bertrand" sort="Cariou, Bertrand" uniqKey="Cariou B" first="Bertrand" last="Cariou">Bertrand Cariou</name><affiliation><nlm:aff id="aff91">I'institut du Thorax, INSERM, CNRS, University of Nantes, CHU de Nantes, Nantes, France</nlm:aff></affiliation></author><author><name sortKey="Smart, Melissa" sort="Smart, Melissa" uniqKey="Smart M" first="Melissa" last="Smart">Melissa Smart</name><affiliation><nlm:aff id="aff92">Institute for Social and Economic Research, University of Essex, Colchester, Essex, UK</nlm:aff></affiliation></author><author><name sortKey="Bao, Yanchun" sort="Bao, Yanchun" uniqKey="Bao Y" first="Yanchun" last="Bao">Yanchun Bao</name><affiliation><nlm:aff id="aff92">Institute for Social and Economic Research, University of Essex, Colchester, Essex, UK</nlm:aff></affiliation></author><author><name sortKey="Kumari, Meena" sort="Kumari, Meena" uniqKey="Kumari M" first="Meena" last="Kumari">Meena Kumari</name><affiliation><nlm:aff id="aff92">Institute for Social and Economic Research, University of Essex, Colchester, Essex, UK</nlm:aff></affiliation></author><author><name sortKey="Mahajan, Anubha" sort="Mahajan, Anubha" uniqKey="Mahajan A" first="Anubha" last="Mahajan">Anubha Mahajan</name><affiliation><nlm:aff id="aff13">Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK</nlm:aff></affiliation></author><author><name sortKey="Ridker, Paul M" sort="Ridker, Paul M" uniqKey="Ridker P" first="Paul M" last="Ridker">Paul M. Ridker</name><affiliation><nlm:aff id="aff93">Harvard Medical School Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Boston, MA, USA</nlm:aff></affiliation></author><author><name sortKey="Chasman, Daniel I" sort="Chasman, Daniel I" uniqKey="Chasman D" first="Daniel I" last="Chasman">Daniel I. Chasman</name><affiliation><nlm:aff id="aff93">Harvard Medical School Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Boston, MA, USA</nlm:aff></affiliation></author><author><name sortKey="Reiner, Alex P" sort="Reiner, Alex P" uniqKey="Reiner A" first="Alex P" last="Reiner">Alex P. Reiner</name><affiliation><nlm:aff id="aff94">Department of Epidemiology, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA</nlm:aff></affiliation></author><author><name sortKey="Lange, Leslie A" sort="Lange, Leslie A" uniqKey="Lange L" first="Leslie A" last="Lange">Leslie A. Lange</name><affiliation><nlm:aff id="aff95">Anschutz Medical Campus, University of Colorado Denver, Denver, CO, USA</nlm:aff></affiliation></author><author><name sortKey="Ritchie, Marylyn D" sort="Ritchie, Marylyn D" uniqKey="Ritchie M" first="Marylyn D" last="Ritchie">Marylyn D. Ritchie</name><affiliation><nlm:aff id="aff96">Biomedical and Translational Informatics, Geisinger Health System, Danville, PA, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff97">Department of Biochemistry and Molecular Biology, Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, USA</nlm:aff></affiliation></author><author><name sortKey="Asselbergs, Folkert W" sort="Asselbergs, Folkert W" uniqKey="Asselbergs F" first="Folkert W" last="Asselbergs">Folkert W. Asselbergs</name><affiliation><nlm:aff id="aff1">Institute of Cardiovascular Science, University College London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Farr Institute of Health Informatics Research, UCL Institute of Health Informatics, University College London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff24">Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, Netherlands</nlm:aff></affiliation><affiliation><nlm:aff id="aff44">Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands</nlm:aff></affiliation><affiliation><nlm:aff id="aff45">Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Casas, Juan Pablo" sort="Casas, Juan Pablo" uniqKey="Casas J" first="Juan-Pablo" last="Casas">Juan-Pablo Casas</name><affiliation><nlm:aff id="aff5">Farr Institute of Health Informatics Research, UCL Institute of Health Informatics, University College London, UK</nlm:aff></affiliation></author><author><name sortKey="Keating, Brendan J" sort="Keating, Brendan J" uniqKey="Keating B" first="Brendan J" last="Keating">Brendan J. Keating</name><affiliation><nlm:aff id="aff98">Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA</nlm:aff></affiliation></author><author><name sortKey="Preiss, David" sort="Preiss, David" uniqKey="Preiss D" first="David" last="Preiss">David Preiss</name><affiliation><nlm:aff id="aff11">Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff12">Medical Research Council Population Health Research Unit at the University of Oxford, University of Oxford, Oxford, UK</nlm:aff></affiliation></author><author><name sortKey="Hingorani, Aroon D" sort="Hingorani, Aroon D" uniqKey="Hingorani A" first="Aroon D" last="Hingorani">Aroon D. Hingorani</name><affiliation><nlm:aff id="aff1">Institute of Cardiovascular Science, University College London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Farr Institute of Health Informatics Research, UCL Institute of Health Informatics, University College London, UK</nlm:aff></affiliation></author><author><name sortKey="Sattar, Naveed" sort="Sattar, Naveed" uniqKey="Sattar N" first="Naveed" last="Sattar">Naveed Sattar</name><affiliation><nlm:aff id="aff17">Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">27908689</idno><idno type="pmc">5266795</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5266795</idno><idno type="RBID">PMC:5266795</idno><idno type="doi">10.1016/S2213-8587(16)30396-5</idno><date when="2017">2017</date><idno type="wicri:Area/Pmc/Corpus">002719</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002719</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main"><italic>PCSK9</italic> genetic variants and risk of type 2 diabetes: a mendelian randomisation study</title><author><name sortKey="Schmidt, Amand F" sort="Schmidt, Amand F" uniqKey="Schmidt A" first="Amand F" last="Schmidt">Amand F. Schmidt</name><affiliation><nlm:aff id="aff1">Institute of Cardiovascular Science, University College London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Farr Institute of Health Informatics Research, UCL Institute of Health Informatics, University College London, UK</nlm:aff></affiliation></author><author><name sortKey="Swerdlow, Daniel I" sort="Swerdlow, Daniel I" uniqKey="Swerdlow D" first="Daniel I" last="Swerdlow">Daniel I. Swerdlow</name><affiliation><nlm:aff id="aff1">Institute of Cardiovascular Science, University College London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Department of Medicine, Imperial College London, London, UK</nlm:aff></affiliation></author><author><name sortKey="Holmes, Michael V" sort="Holmes, Michael V" uniqKey="Holmes M" first="Michael V" last="Holmes">Michael V. Holmes</name><affiliation><nlm:aff id="aff11">Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff12">Medical Research Council Population Health Research Unit at the University of Oxford, University of Oxford, Oxford, UK</nlm:aff></affiliation></author><author><name sortKey="Patel, Riyaz S" sort="Patel, Riyaz S" uniqKey="Patel R" first="Riyaz S" last="Patel">Riyaz S. Patel</name><affiliation><nlm:aff id="aff1">Institute of Cardiovascular Science, University College London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Farr Institute of Health Informatics Research, UCL Institute of Health Informatics, University College London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff14">The Barts Heart Centre, St Bartholomew's Hospital, London, UK</nlm:aff></affiliation></author><author><name sortKey="Fairhurst Hunter, Zammy" sort="Fairhurst Hunter, Zammy" uniqKey="Fairhurst Hunter Z" first="Zammy" last="Fairhurst-Hunter">Zammy Fairhurst-Hunter</name><affiliation><nlm:aff id="aff13">Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK</nlm:aff></affiliation></author><author><name sortKey="Lyall, Donald M" sort="Lyall, Donald M" uniqKey="Lyall D" first="Donald M" last="Lyall">Donald M. Lyall</name><affiliation><nlm:aff id="aff15">Institute of Health & Wellbeing, University of Glasgow, Glasgow, UK</nlm:aff></affiliation></author><author><name sortKey="Hartwig, Fernando Pires" sort="Hartwig, Fernando Pires" uniqKey="Hartwig F" first="Fernando Pires" last="Hartwig">Fernando Pires Hartwig</name><affiliation><nlm:aff id="aff18">Postgraduate Program in Epidemiology, Federal University of Pelotas, Pelotas, Brazil</nlm:aff></affiliation></author><author><name sortKey="Horta, Bernardo Lessa" sort="Horta, Bernardo Lessa" uniqKey="Horta B" first="Bernardo Lessa" last="Horta">Bernardo Lessa Horta</name><affiliation><nlm:aff id="aff18">Postgraduate Program in Epidemiology, Federal University of Pelotas, Pelotas, Brazil</nlm:aff></affiliation></author><author><name sortKey="Hypponen, Elina" sort="Hypponen, Elina" uniqKey="Hypponen E" first="Elina" last="Hyppönen">Elina Hyppönen</name><affiliation><nlm:aff id="aff19">Centre for Population Health Research, Sansom Institute for Health Research, University of South Australia, Adelaide, SA, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff21">Population, Policy and Practice, UCL Great Ormond Street Institute of Child Health, London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff22">South Australian Health and Medical Research Institute, Adelaide, SA, Australia</nlm:aff></affiliation></author><author><name sortKey="Power, Christine" sort="Power, Christine" uniqKey="Power C" first="Christine" last="Power">Christine Power</name><affiliation><nlm:aff id="aff21">Population, Policy and Practice, UCL Great Ormond Street Institute of Child Health, London, UK</nlm:aff></affiliation></author><author><name sortKey="Moldovan, Max" sort="Moldovan, Max" uniqKey="Moldovan M" first="Max" last="Moldovan">Max Moldovan</name><affiliation><nlm:aff id="aff20">School of Health Sciences, University of South Australia, Adelaide, SA, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff23">South Australian Health and Medical Research Institute–EMBL Australia, Adelaide, SA, Australia</nlm:aff></affiliation></author><author><name sortKey="Van Iperen, Erik" sort="Van Iperen, Erik" uniqKey="Van Iperen E" first="Erik" last="Van Iperen">Erik Van Iperen</name><affiliation><nlm:aff id="aff24">Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, Netherlands</nlm:aff></affiliation><affiliation><nlm:aff id="aff25">Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center Amsterdam, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Hovingh, G Kees" sort="Hovingh, G Kees" uniqKey="Hovingh G" first="G Kees" last="Hovingh">G Kees Hovingh</name><affiliation><nlm:aff id="aff26">Department of Vascular Medicine, Academic Medical Center Amsterdam, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Demuth, Ilja" sort="Demuth, Ilja" uniqKey="Demuth I" first="Ilja" last="Demuth">Ilja Demuth</name><affiliation><nlm:aff id="aff28">Charité Research Group on Geriatrics, Charité–Universitätsmedizin Berlin, Berlin, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff29">Institute of Medical and Human Genetics, Charité–Universitätsmedizin Berlin, Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Norman, Kristina" sort="Norman, Kristina" uniqKey="Norman K" first="Kristina" last="Norman">Kristina Norman</name><affiliation><nlm:aff id="aff28">Charité Research Group on Geriatrics, Charité–Universitätsmedizin Berlin, Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Steinhagen Thiessen, Elisabeth" sort="Steinhagen Thiessen, Elisabeth" uniqKey="Steinhagen Thiessen E" first="Elisabeth" last="Steinhagen-Thiessen">Elisabeth Steinhagen-Thiessen</name><affiliation><nlm:aff id="aff28">Charité Research Group on Geriatrics, Charité–Universitätsmedizin Berlin, Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Demuth, Juri" sort="Demuth, Juri" uniqKey="Demuth J" first="Juri" last="Demuth">Juri Demuth</name><affiliation><nlm:aff id="aff30">E.CA Economics GmbH, Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Bertram, Lars" sort="Bertram, Lars" uniqKey="Bertram L" first="Lars" last="Bertram">Lars Bertram</name><affiliation><nlm:aff id="aff7">Neuroepidemiology and Ageing Research Unit, Imperial College London, London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff31">Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics and Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany</nlm:aff></affiliation></author><author><name sortKey="Liu, Tian" sort="Liu, Tian" uniqKey="Liu T" first="Tian" last="Liu">Tian Liu</name><affiliation><nlm:aff id="aff32">Max Planck Institute for Human Development, Berlin, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff33">Max Planck Institute for Molecular Genetics, Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Coassin, Stefan" sort="Coassin, Stefan" uniqKey="Coassin S" first="Stefan" last="Coassin">Stefan Coassin</name><affiliation><nlm:aff id="aff34">Division of Genetic Epidemiology Innsbruck, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria</nlm:aff></affiliation></author><author><name sortKey="Willeit, Johann" sort="Willeit, Johann" uniqKey="Willeit J" first="Johann" last="Willeit">Johann Willeit</name><affiliation><nlm:aff id="aff35">Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria</nlm:aff></affiliation></author><author><name sortKey="Kiechl, Stefan" sort="Kiechl, Stefan" uniqKey="Kiechl S" first="Stefan" last="Kiechl">Stefan Kiechl</name><affiliation><nlm:aff id="aff35">Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria</nlm:aff></affiliation></author><author><name sortKey="Willeit, Karin" sort="Willeit, Karin" uniqKey="Willeit K" first="Karin" last="Willeit">Karin Willeit</name><affiliation><nlm:aff id="aff35">Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria</nlm:aff></affiliation></author><author><name sortKey="Mason, Dan" sort="Mason, Dan" uniqKey="Mason D" first="Dan" last="Mason">Dan Mason</name><affiliation><nlm:aff id="aff36">Bradford Institute for Health Research, Bradford Royal Infirmary, Bradford, UK</nlm:aff></affiliation></author><author><name sortKey="Wright, John" sort="Wright, John" uniqKey="Wright J" first="John" last="Wright">John Wright</name><affiliation><nlm:aff id="aff36">Bradford Institute for Health Research, Bradford Royal Infirmary, Bradford, UK</nlm:aff></affiliation></author><author><name sortKey="Morris, Richard" sort="Morris, Richard" uniqKey="Morris R" first="Richard" last="Morris">Richard Morris</name><affiliation><nlm:aff id="aff37">School of Social and Community Medicine, University of Bristol, Bristol, UK</nlm:aff></affiliation></author><author><name sortKey="Wanamethee, Goya" sort="Wanamethee, Goya" uniqKey="Wanamethee G" first="Goya" last="Wanamethee">Goya Wanamethee</name><affiliation><nlm:aff id="aff2">Department of Primary Care & Population Health, University College London, UK</nlm:aff></affiliation></author><author><name sortKey="Whincup, Peter" sort="Whincup, Peter" uniqKey="Whincup P" first="Peter" last="Whincup">Peter Whincup</name><affiliation><nlm:aff id="aff38">Population Health Research Institute, St George's, University of London, London, UK</nlm:aff></affiliation></author><author><name sortKey="Ben Shlomo, Yoav" sort="Ben Shlomo, Yoav" uniqKey="Ben Shlomo Y" first="Yoav" last="Ben-Shlomo">Yoav Ben-Shlomo</name><affiliation><nlm:aff id="aff37">School of Social and Community Medicine, University of Bristol, Bristol, UK</nlm:aff></affiliation></author><author><name sortKey="Mclachlan, Stela" sort="Mclachlan, Stela" uniqKey="Mclachlan S" first="Stela" last="Mclachlan">Stela Mclachlan</name><affiliation><nlm:aff id="aff39">Centre for Population Health Sciences, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK</nlm:aff></affiliation></author><author><name sortKey="Price, Jackie F" sort="Price, Jackie F" uniqKey="Price J" first="Jackie F" last="Price">Jackie F. Price</name><affiliation><nlm:aff id="aff39">Centre for Population Health Sciences, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK</nlm:aff></affiliation></author><author><name sortKey="Kivimaki, Mika" sort="Kivimaki, Mika" uniqKey="Kivimaki M" first="Mika" last="Kivimaki">Mika Kivimaki</name><affiliation><nlm:aff id="aff3">Department of Epidemiology and Public Health, UCL Institute of Epidemiology and Health Care, University College London, UK</nlm:aff></affiliation></author><author><name sortKey="Welch, Catherine" sort="Welch, Catherine" uniqKey="Welch C" first="Catherine" last="Welch">Catherine Welch</name><affiliation><nlm:aff id="aff3">Department of Epidemiology and Public Health, UCL Institute of Epidemiology and Health Care, University College London, UK</nlm:aff></affiliation></author><author><name sortKey="Sanchez Galvez, Adelaida" sort="Sanchez Galvez, Adelaida" uniqKey="Sanchez Galvez A" first="Adelaida" last="Sanchez-Galvez">Adelaida Sanchez-Galvez</name><affiliation><nlm:aff id="aff3">Department of Epidemiology and Public Health, UCL Institute of Epidemiology and Health Care, University College London, UK</nlm:aff></affiliation></author><author><name sortKey="Marques Vidal, Pedro" sort="Marques Vidal, Pedro" uniqKey="Marques Vidal P" first="Pedro" last="Marques-Vidal">Pedro Marques-Vidal</name><affiliation><nlm:aff id="aff41">Internal Medicine Unit, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Nicolaides, Andrew" sort="Nicolaides, Andrew" uniqKey="Nicolaides A" first="Andrew" last="Nicolaides">Andrew Nicolaides</name><affiliation><nlm:aff id="aff8">Department of Vascular Surgery, Imperial College London, London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff42">Department of Surgery, Nicosia Medical School, University of Nicosia, Nicosia, Cyprus</nlm:aff></affiliation></author><author><name sortKey="Panayiotou, Andrie G" sort="Panayiotou, Andrie G" uniqKey="Panayiotou A" first="Andrie G" last="Panayiotou">Andrie G. Panayiotou</name><affiliation><nlm:aff id="aff43">Cyprus International Institute for Environmental and Public Health, Cyprus University of Technology, Limassol, Cyprus</nlm:aff></affiliation></author><author><name sortKey="Onland Moret, N Charlotte" sort="Onland Moret, N Charlotte" uniqKey="Onland Moret N" first="N Charlotte" last="Onland-Moret">N Charlotte Onland-Moret</name><affiliation><nlm:aff id="aff44">Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Van Der Schouw, Yvonne T" sort="Van Der Schouw, Yvonne T" uniqKey="Van Der Schouw Y" first="Yvonne T" last="Van Der Schouw">Yvonne T. Van Der Schouw</name><affiliation><nlm:aff id="aff44">Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Matullo, Giuseppe" sort="Matullo, Giuseppe" uniqKey="Matullo G" first="Giuseppe" last="Matullo">Giuseppe Matullo</name><affiliation><nlm:aff id="aff46">Human Genetics Foundation, HuGeF, Turin, Italy</nlm:aff></affiliation><affiliation><nlm:aff id="aff47">Department of Medical Sciences, University of Turin, Turin, Italy</nlm:aff></affiliation></author><author><name sortKey="Fiorito, Giovanni" sort="Fiorito, Giovanni" uniqKey="Fiorito G" first="Giovanni" last="Fiorito">Giovanni Fiorito</name><affiliation><nlm:aff id="aff46">Human Genetics Foundation, HuGeF, Turin, Italy</nlm:aff></affiliation><affiliation><nlm:aff id="aff47">Department of Medical Sciences, University of Turin, Turin, Italy</nlm:aff></affiliation></author><author><name sortKey="Guarrera, Simonetta" sort="Guarrera, Simonetta" uniqKey="Guarrera S" first="Simonetta" last="Guarrera">Simonetta Guarrera</name><affiliation><nlm:aff id="aff46">Human Genetics Foundation, HuGeF, Turin, Italy</nlm:aff></affiliation><affiliation><nlm:aff id="aff47">Department of Medical Sciences, University of Turin, Turin, Italy</nlm:aff></affiliation></author><author><name sortKey="Sacerdote, Carlotta" sort="Sacerdote, Carlotta" uniqKey="Sacerdote C" first="Carlotta" last="Sacerdote">Carlotta Sacerdote</name><affiliation><nlm:aff id="aff48">Cancer Epidemiology Unit, San Giovanni Battista Hospital, Turin, Italy</nlm:aff></affiliation><affiliation><nlm:aff id="aff49">Centre for Oncology Prevention, CPO Piemonte, Turin, Italy</nlm:aff></affiliation></author><author><name sortKey="Wareham, Nicholas J" sort="Wareham, Nicholas J" uniqKey="Wareham N" first="Nicholas J" last="Wareham">Nicholas J. Wareham</name><affiliation><nlm:aff id="aff50">MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK</nlm:aff></affiliation></author><author><name sortKey="Langenberg, Claudia" sort="Langenberg, Claudia" uniqKey="Langenberg C" first="Claudia" last="Langenberg">Claudia Langenberg</name><affiliation><nlm:aff id="aff50">MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK</nlm:aff></affiliation></author><author><name sortKey="Scott, Robert" sort="Scott, Robert" uniqKey="Scott R" first="Robert" last="Scott">Robert Scott</name><affiliation><nlm:aff id="aff50">MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK</nlm:aff></affiliation></author><author><name sortKey="Luan, Jian An" sort="Luan, Jian An" uniqKey="Luan J" first="Jian'An" last="Luan">Jian'An Luan</name><affiliation><nlm:aff id="aff50">MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK</nlm:aff></affiliation></author><author><name sortKey="Bobak, Martin" sort="Bobak, Martin" uniqKey="Bobak M" first="Martin" last="Bobak">Martin Bobak</name><affiliation><nlm:aff id="aff3">Department of Epidemiology and Public Health, UCL Institute of Epidemiology and Health Care, University College London, UK</nlm:aff></affiliation></author><author><name sortKey="Malyutina, Sofia" sort="Malyutina, Sofia" uniqKey="Malyutina S" first="Sofia" last="Malyutina">Sofia Malyutina</name><affiliation><nlm:aff id="aff51">Novosibirsk State Medical University, Novosibirsk, Russia</nlm:aff></affiliation><affiliation><nlm:aff id="aff52">Institute of Internal and Preventive Medicine, Siberian Branch of the Russian Academy of Medical Sciences, Novosibirsk, Russia</nlm:aff></affiliation></author><author><name sortKey="Paj K, Andrzej" sort="Paj K, Andrzej" uniqKey="Paj K A" first="Andrzej" last="Paj K">Andrzej Paj K</name><affiliation><nlm:aff id="aff53">Jagiellonian University Collegium Medicum, Krakow, Poland</nlm:aff></affiliation></author><author><name sortKey="Kubinova, Ruzena" sort="Kubinova, Ruzena" uniqKey="Kubinova R" first="Ruzena" last="Kubinova">Ruzena Kubinova</name><affiliation><nlm:aff id="aff54">National Institute of Public Health, Prague, Czech Republic</nlm:aff></affiliation></author><author><name sortKey="Tamosiunas, Abdonas" sort="Tamosiunas, Abdonas" uniqKey="Tamosiunas A" first="Abdonas" last="Tamosiunas">Abdonas Tamosiunas</name><affiliation><nlm:aff id="aff55">Lithuanian University of Health Sciences, Kaunas, Lithuania</nlm:aff></affiliation></author><author><name sortKey="Pikhart, Hynek" sort="Pikhart, Hynek" uniqKey="Pikhart H" first="Hynek" last="Pikhart">Hynek Pikhart</name><affiliation><nlm:aff id="aff3">Department of Epidemiology and Public Health, UCL Institute of Epidemiology and Health Care, University College London, UK</nlm:aff></affiliation></author><author><name sortKey="Husemoen, Lise Lotte Nystrup" sort="Husemoen, Lise Lotte Nystrup" uniqKey="Husemoen L" first="Lise Lotte Nystrup" last="Husemoen">Lise Lotte Nystrup Husemoen</name><affiliation><nlm:aff id="aff56">Research Centre for Prevention and Health, Capital Region of Denmark, Denmark</nlm:aff></affiliation></author><author><name sortKey="Grarup, Niels" sort="Grarup, Niels" uniqKey="Grarup N" first="Niels" last="Grarup">Niels Grarup</name><affiliation><nlm:aff id="aff57">Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark</nlm:aff></affiliation></author><author><name sortKey="Pedersen, Oluf" sort="Pedersen, Oluf" uniqKey="Pedersen O" first="Oluf" last="Pedersen">Oluf Pedersen</name><affiliation><nlm:aff id="aff57">Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark</nlm:aff></affiliation></author><author><name sortKey="Hansen, Torben" sort="Hansen, Torben" uniqKey="Hansen T" first="Torben" last="Hansen">Torben Hansen</name><affiliation><nlm:aff id="aff57">Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark</nlm:aff></affiliation></author><author><name sortKey="Linneberg, Allan" sort="Linneberg, Allan" uniqKey="Linneberg A" first="Allan" last="Linneberg">Allan Linneberg</name><affiliation><nlm:aff id="aff56">Research Centre for Prevention and Health, Capital Region of Denmark, Denmark</nlm:aff></affiliation><affiliation><nlm:aff id="aff58">Department of Clinical Experimental Research, Rigshospitalet, Copenhagen, Denmark</nlm:aff></affiliation><affiliation><nlm:aff id="aff59">Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark</nlm:aff></affiliation></author><author><name sortKey="Simonsen, Kenneth Starup" sort="Simonsen, Kenneth Starup" uniqKey="Simonsen K" first="Kenneth Starup" last="Simonsen">Kenneth Starup Simonsen</name><affiliation><nlm:aff id="aff56">Research Centre for Prevention and Health, Capital Region of Denmark, Denmark</nlm:aff></affiliation></author><author><name sortKey="Cooper, Jackie" sort="Cooper, Jackie" uniqKey="Cooper J" first="Jackie" last="Cooper">Jackie Cooper</name><affiliation><nlm:aff id="aff4">Centre for Cardiovascular Genetics, University College London, UK</nlm:aff></affiliation></author><author><name sortKey="Humphries, Steve E" sort="Humphries, Steve E" uniqKey="Humphries S" first="Steve E" last="Humphries">Steve E. Humphries</name><affiliation><nlm:aff id="aff4">Centre for Cardiovascular Genetics, University College London, UK</nlm:aff></affiliation></author><author><name sortKey="Brilliant, Murray" sort="Brilliant, Murray" uniqKey="Brilliant M" first="Murray" last="Brilliant">Murray Brilliant</name><affiliation><nlm:aff id="aff60">Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI, USA</nlm:aff></affiliation></author><author><name sortKey="Kitchner, Terrie" sort="Kitchner, Terrie" uniqKey="Kitchner T" first="Terrie" last="Kitchner">Terrie Kitchner</name><affiliation><nlm:aff id="aff60">Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI, USA</nlm:aff></affiliation></author><author><name sortKey="Hakonarson, Hakon" sort="Hakonarson, Hakon" uniqKey="Hakonarson H" first="Hakon" last="Hakonarson">Hakon Hakonarson</name><affiliation><nlm:aff id="aff61">Children's Hospital of Philadelphia, Philadelphia, PA, USA</nlm:aff></affiliation></author><author><name sortKey="Carrell, David S" sort="Carrell, David S" uniqKey="Carrell D" first="David S" last="Carrell">David S. Carrell</name><affiliation><nlm:aff id="aff62">Group Health Research Institute in Seattle, WA, USA</nlm:aff></affiliation></author><author><name sortKey="Mccarty, Catherine A" sort="Mccarty, Catherine A" uniqKey="Mccarty C" first="Catherine A" last="Mccarty">Catherine A. Mccarty</name><affiliation><nlm:aff id="aff63">Essentia Institute of Rural Health, Duluth, MN, USA</nlm:aff></affiliation></author><author><name sortKey="Kirchner, H Lester" sort="Kirchner, H Lester" uniqKey="Kirchner H" first="H Lester" last="Kirchner">H Lester Kirchner</name><affiliation><nlm:aff id="aff64">Center for Health Research, Geisinger Clinic, Danville, PA, USA</nlm:aff></affiliation></author><author><name sortKey="Larson, Eric B" sort="Larson, Eric B" uniqKey="Larson E" first="Eric B" last="Larson">Eric B. Larson</name><affiliation><nlm:aff id="aff65">Group Health Research Institute, Seattle, WA, USA</nlm:aff></affiliation></author><author><name sortKey="Crosslin, David R" sort="Crosslin, David R" uniqKey="Crosslin D" first="David R" last="Crosslin">David R. Crosslin</name><affiliation><nlm:aff id="aff65">Group Health Research Institute, Seattle, WA, USA</nlm:aff></affiliation></author><author><name sortKey="De Andrade, Mariza" sort="De Andrade, Mariza" uniqKey="De Andrade M" first="Mariza" last="De Andrade">Mariza De Andrade</name><affiliation><nlm:aff id="aff66">Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA</nlm:aff></affiliation></author><author><name sortKey="Roden, Dan M" sort="Roden, Dan M" uniqKey="Roden D" first="Dan M" last="Roden">Dan M. Roden</name><affiliation><nlm:aff id="aff67">Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA</nlm:aff></affiliation></author><author><name sortKey="Denny, Joshua C" sort="Denny, Joshua C" uniqKey="Denny J" first="Joshua C" last="Denny">Joshua C. Denny</name><affiliation><nlm:aff id="aff68">Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, USA</nlm:aff></affiliation></author><author><name sortKey="Carty, Cara" sort="Carty, Cara" uniqKey="Carty C" first="Cara" last="Carty">Cara Carty</name><affiliation><nlm:aff id="aff69">George Washington University, Washington, DC, USA</nlm:aff></affiliation></author><author><name sortKey="Hancock, Stephen" sort="Hancock, Stephen" uniqKey="Hancock S" first="Stephen" last="Hancock">Stephen Hancock</name><affiliation><nlm:aff id="aff70">University of Newcastle, Newcastle, NSW, Australia</nlm:aff></affiliation></author><author><name sortKey="Attia, John" sort="Attia, John" uniqKey="Attia J" first="John" last="Attia">John Attia</name><affiliation><nlm:aff id="aff70">University of Newcastle, Newcastle, NSW, Australia</nlm:aff></affiliation></author><author><name sortKey="Holliday, Elizabeth" sort="Holliday, Elizabeth" uniqKey="Holliday E" first="Elizabeth" last="Holliday">Elizabeth Holliday</name><affiliation><nlm:aff id="aff70">University of Newcastle, Newcastle, NSW, Australia</nlm:aff></affiliation></author><author><name sortKey="O Donnell, Martin" sort="O Donnell, Martin" uniqKey="O Donnell M" first="Martin" last="O'Donnell">Martin O'Donnell</name><affiliation><nlm:aff id="aff71">Population Health Research Institute, Hamilton, ON, Canada</nlm:aff></affiliation></author><author><name sortKey="Yusuf, Salim" sort="Yusuf, Salim" uniqKey="Yusuf S" first="Salim" last="Yusuf">Salim Yusuf</name><affiliation><nlm:aff id="aff71">Population Health Research Institute, Hamilton, ON, Canada</nlm:aff></affiliation></author><author><name sortKey="Chong, Michael" sort="Chong, Michael" uniqKey="Chong M" first="Michael" last="Chong">Michael Chong</name><affiliation><nlm:aff id="aff71">Population Health Research Institute, Hamilton, ON, Canada</nlm:aff></affiliation></author><author><name sortKey="Pare, Guillaume" sort="Pare, Guillaume" uniqKey="Pare G" first="Guillaume" last="Pare">Guillaume Pare</name><affiliation><nlm:aff id="aff71">Population Health Research Institute, Hamilton, ON, Canada</nlm:aff></affiliation></author><author><name sortKey="Van Der Harst, Pim" sort="Van Der Harst, Pim" uniqKey="Van Der Harst P" first="Pim" last="Van Der Harst">Pim Van Der Harst</name><affiliation><nlm:aff id="aff24">Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, Netherlands</nlm:aff></affiliation><affiliation><nlm:aff id="aff72">Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands</nlm:aff></affiliation><affiliation><nlm:aff id="aff73">Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Said, M Abdullah" sort="Said, M Abdullah" uniqKey="Said M" first="M Abdullah" last="Said">M Abdullah Said</name><affiliation><nlm:aff id="aff72">Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Eppinga, Ruben N" sort="Eppinga, Ruben N" uniqKey="Eppinga R" first="Ruben N" last="Eppinga">Ruben N. Eppinga</name><affiliation><nlm:aff id="aff72">Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Verweij, Niek" sort="Verweij, Niek" uniqKey="Verweij N" first="Niek" last="Verweij">Niek Verweij</name><affiliation><nlm:aff id="aff72">Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Snieder, Harold" sort="Snieder, Harold" uniqKey="Snieder H" first="Harold" last="Snieder">Harold Snieder</name><affiliation><nlm:aff id="aff74">Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Christen, Tim" sort="Christen, Tim" uniqKey="Christen T" first="Tim" last="Christen">Tim Christen</name><affiliation><nlm:aff id="aff75">Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Mook Kanamori, Dennis O" sort="Mook Kanamori, Dennis O" uniqKey="Mook Kanamori D" first="Dennis O" last="Mook-Kanamori">Dennis O. Mook-Kanamori</name><affiliation><nlm:aff id="aff75">Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Gustafsson, Stefan" sort="Gustafsson, Stefan" uniqKey="Gustafsson S" first="Stefan" last="Gustafsson">Stefan Gustafsson</name><affiliation><nlm:aff id="aff76">Molecular Epidemiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden</nlm:aff></affiliation></author><author><name sortKey="Lind, Lars" sort="Lind, Lars" uniqKey="Lind L" first="Lars" last="Lind">Lars Lind</name><affiliation><nlm:aff id="aff76">Molecular Epidemiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden</nlm:aff></affiliation></author><author><name sortKey="Ingelsson, Erik" sort="Ingelsson, Erik" uniqKey="Ingelsson E" first="Erik" last="Ingelsson">Erik Ingelsson</name><affiliation><nlm:aff id="aff76">Molecular Epidemiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden</nlm:aff></affiliation><affiliation><nlm:aff id="aff77">Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden</nlm:aff></affiliation><affiliation><nlm:aff id="aff78">Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA</nlm:aff></affiliation></author><author><name sortKey="Pazoki, Raha" sort="Pazoki, Raha" uniqKey="Pazoki R" first="Raha" last="Pazoki">Raha Pazoki</name><affiliation><nlm:aff id="aff79">Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Franco, Oscar" sort="Franco, Oscar" uniqKey="Franco O" first="Oscar" last="Franco">Oscar Franco</name><affiliation><nlm:aff id="aff79">Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Hofman, Albert" sort="Hofman, Albert" uniqKey="Hofman A" first="Albert" last="Hofman">Albert Hofman</name><affiliation><nlm:aff id="aff79">Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Uitterlinden, Andre" sort="Uitterlinden, Andre" uniqKey="Uitterlinden A" first="Andre" last="Uitterlinden">Andre Uitterlinden</name><affiliation><nlm:aff id="aff80">Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Dehghan, Abbas" sort="Dehghan, Abbas" uniqKey="Dehghan A" first="Abbas" last="Dehghan">Abbas Dehghan</name><affiliation><nlm:aff id="aff10">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</nlm:aff></affiliation><affiliation><nlm:aff id="aff79">Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Teumer, Alexander" sort="Teumer, Alexander" uniqKey="Teumer A" first="Alexander" last="Teumer">Alexander Teumer</name><affiliation><nlm:aff id="aff81">Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff85">German Centre for Cardiovascular Research (DZHK), Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Baumeister, Sebastian" sort="Baumeister, Sebastian" uniqKey="Baumeister S" first="Sebastian" last="Baumeister">Sebastian Baumeister</name><affiliation><nlm:aff id="aff81">Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff86">Department of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany</nlm:aff></affiliation></author><author><name sortKey="Dorr, Marcus" sort="Dorr, Marcus" uniqKey="Dorr M" first="Marcus" last="Dörr">Marcus Dörr</name><affiliation><nlm:aff id="aff82">Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff85">German Centre for Cardiovascular Research (DZHK), Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Lerch, Markus M" sort="Lerch, Markus M" uniqKey="Lerch M" first="Markus M" last="Lerch">Markus M. Lerch</name><affiliation><nlm:aff id="aff83">Department of Medicine A, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Volker, Uwe" sort="Volker, Uwe" uniqKey="Volker U" first="Uwe" last="Völker">Uwe Völker</name><affiliation><nlm:aff id="aff84">Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff85">German Centre for Cardiovascular Research (DZHK), Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Volzke, Henry" sort="Volzke, Henry" uniqKey="Volzke H" first="Henry" last="Völzke">Henry Völzke</name><affiliation><nlm:aff id="aff81">Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff85">German Centre for Cardiovascular Research (DZHK), Greifswald, Germany</nlm:aff></affiliation></author><author><name sortKey="Ward, Joey" sort="Ward, Joey" uniqKey="Ward J" first="Joey" last="Ward">Joey Ward</name><affiliation><nlm:aff id="aff15">Institute of Health & Wellbeing, University of Glasgow, Glasgow, UK</nlm:aff></affiliation></author><author><name sortKey="Pell, Jill P" sort="Pell, Jill P" uniqKey="Pell J" first="Jill P" last="Pell">Jill P. Pell</name><affiliation><nlm:aff id="aff15">Institute of Health & Wellbeing, University of Glasgow, Glasgow, UK</nlm:aff></affiliation></author><author><name sortKey="Smith, Daniel J" sort="Smith, Daniel J" uniqKey="Smith D" first="Daniel J" last="Smith">Daniel J. Smith</name><affiliation><nlm:aff id="aff15">Institute of Health & Wellbeing, University of Glasgow, Glasgow, UK</nlm:aff></affiliation></author><author><name sortKey="Meade, Tom" sort="Meade, Tom" uniqKey="Meade T" first="Tom" last="Meade">Tom Meade</name><affiliation><nlm:aff id="aff87">Department of Non-Communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK</nlm:aff></affiliation></author><author><name sortKey="Maitland Van Der Zee, Anke H" sort="Maitland Van Der Zee, Anke H" uniqKey="Maitland Van Der Zee A" first="Anke H" last="Maitland-Van Der Zee">Anke H. Maitland-Van Der Zee</name><affiliation><nlm:aff id="aff27">Department of Respiratory Medicine, Academic Medical Center Amsterdam, Netherlands</nlm:aff></affiliation><affiliation><nlm:aff id="aff88">Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Baranova, Ekaterina V" sort="Baranova, Ekaterina V" uniqKey="Baranova E" first="Ekaterina V" last="Baranova">Ekaterina V. Baranova</name><affiliation><nlm:aff id="aff88">Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Young, Robin" sort="Young, Robin" uniqKey="Young R" first="Robin" last="Young">Robin Young</name><affiliation><nlm:aff id="aff16">Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK</nlm:aff></affiliation></author><author><name sortKey="Ford, Ian" sort="Ford, Ian" uniqKey="Ford I" first="Ian" last="Ford">Ian Ford</name><affiliation><nlm:aff id="aff16">Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK</nlm:aff></affiliation></author><author><name sortKey="Campbell, Archie" sort="Campbell, Archie" uniqKey="Campbell A" first="Archie" last="Campbell">Archie Campbell</name><affiliation><nlm:aff id="aff40">Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK</nlm:aff></affiliation></author><author><name sortKey="Padmanabhan, Sandosh" sort="Padmanabhan, Sandosh" uniqKey="Padmanabhan S" first="Sandosh" last="Padmanabhan">Sandosh Padmanabhan</name><affiliation><nlm:aff id="aff17">Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK</nlm:aff></affiliation></author><author><name sortKey="Bots, Michiel L" sort="Bots, Michiel L" uniqKey="Bots M" first="Michiel L" last="Bots">Michiel L. Bots</name><affiliation><nlm:aff id="aff44">Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Grobbee, Diederick E" sort="Grobbee, Diederick E" uniqKey="Grobbee D" first="Diederick E" last="Grobbee">Diederick E. Grobbee</name><affiliation><nlm:aff id="aff44">Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Froguel, Philippe" sort="Froguel, Philippe" uniqKey="Froguel P" first="Philippe" last="Froguel">Philippe Froguel</name><affiliation><nlm:aff id="aff9">Department of Genomics of Common Disease, Imperial College London, London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff89">CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille, France</nlm:aff></affiliation></author><author><name sortKey="Thuillier, Dorothee" sort="Thuillier, Dorothee" uniqKey="Thuillier D" first="Dorothée" last="Thuillier">Dorothée Thuillier</name><affiliation><nlm:aff id="aff89">CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille, France</nlm:aff></affiliation></author><author><name sortKey="Balkau, Beverley" sort="Balkau, Beverley" uniqKey="Balkau B" first="Beverley" last="Balkau">Beverley Balkau</name><affiliation><nlm:aff id="aff90">Renal and Cardiovascular Epidemiology, Centre de Recherche en Epidémiologie et Santé des Populations (CESP), INSERM U1018, Villejuif, France</nlm:aff></affiliation></author><author><name sortKey="Bonnefond, Amelie" sort="Bonnefond, Amelie" uniqKey="Bonnefond A" first="Amélie" last="Bonnefond">Amélie Bonnefond</name><affiliation><nlm:aff id="aff9">Department of Genomics of Common Disease, Imperial College London, London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff89">CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille, France</nlm:aff></affiliation></author><author><name sortKey="Cariou, Bertrand" sort="Cariou, Bertrand" uniqKey="Cariou B" first="Bertrand" last="Cariou">Bertrand Cariou</name><affiliation><nlm:aff id="aff91">I'institut du Thorax, INSERM, CNRS, University of Nantes, CHU de Nantes, Nantes, France</nlm:aff></affiliation></author><author><name sortKey="Smart, Melissa" sort="Smart, Melissa" uniqKey="Smart M" first="Melissa" last="Smart">Melissa Smart</name><affiliation><nlm:aff id="aff92">Institute for Social and Economic Research, University of Essex, Colchester, Essex, UK</nlm:aff></affiliation></author><author><name sortKey="Bao, Yanchun" sort="Bao, Yanchun" uniqKey="Bao Y" first="Yanchun" last="Bao">Yanchun Bao</name><affiliation><nlm:aff id="aff92">Institute for Social and Economic Research, University of Essex, Colchester, Essex, UK</nlm:aff></affiliation></author><author><name sortKey="Kumari, Meena" sort="Kumari, Meena" uniqKey="Kumari M" first="Meena" last="Kumari">Meena Kumari</name><affiliation><nlm:aff id="aff92">Institute for Social and Economic Research, University of Essex, Colchester, Essex, UK</nlm:aff></affiliation></author><author><name sortKey="Mahajan, Anubha" sort="Mahajan, Anubha" uniqKey="Mahajan A" first="Anubha" last="Mahajan">Anubha Mahajan</name><affiliation><nlm:aff id="aff13">Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK</nlm:aff></affiliation></author><author><name sortKey="Ridker, Paul M" sort="Ridker, Paul M" uniqKey="Ridker P" first="Paul M" last="Ridker">Paul M. Ridker</name><affiliation><nlm:aff id="aff93">Harvard Medical School Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Boston, MA, USA</nlm:aff></affiliation></author><author><name sortKey="Chasman, Daniel I" sort="Chasman, Daniel I" uniqKey="Chasman D" first="Daniel I" last="Chasman">Daniel I. Chasman</name><affiliation><nlm:aff id="aff93">Harvard Medical School Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Boston, MA, USA</nlm:aff></affiliation></author><author><name sortKey="Reiner, Alex P" sort="Reiner, Alex P" uniqKey="Reiner A" first="Alex P" last="Reiner">Alex P. Reiner</name><affiliation><nlm:aff id="aff94">Department of Epidemiology, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA</nlm:aff></affiliation></author><author><name sortKey="Lange, Leslie A" sort="Lange, Leslie A" uniqKey="Lange L" first="Leslie A" last="Lange">Leslie A. Lange</name><affiliation><nlm:aff id="aff95">Anschutz Medical Campus, University of Colorado Denver, Denver, CO, USA</nlm:aff></affiliation></author><author><name sortKey="Ritchie, Marylyn D" sort="Ritchie, Marylyn D" uniqKey="Ritchie M" first="Marylyn D" last="Ritchie">Marylyn D. Ritchie</name><affiliation><nlm:aff id="aff96">Biomedical and Translational Informatics, Geisinger Health System, Danville, PA, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff97">Department of Biochemistry and Molecular Biology, Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, USA</nlm:aff></affiliation></author><author><name sortKey="Asselbergs, Folkert W" sort="Asselbergs, Folkert W" uniqKey="Asselbergs F" first="Folkert W" last="Asselbergs">Folkert W. Asselbergs</name><affiliation><nlm:aff id="aff1">Institute of Cardiovascular Science, University College London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Farr Institute of Health Informatics Research, UCL Institute of Health Informatics, University College London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff24">Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, Netherlands</nlm:aff></affiliation><affiliation><nlm:aff id="aff44">Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands</nlm:aff></affiliation><affiliation><nlm:aff id="aff45">Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Casas, Juan Pablo" sort="Casas, Juan Pablo" uniqKey="Casas J" first="Juan-Pablo" last="Casas">Juan-Pablo Casas</name><affiliation><nlm:aff id="aff5">Farr Institute of Health Informatics Research, UCL Institute of Health Informatics, University College London, UK</nlm:aff></affiliation></author><author><name sortKey="Keating, Brendan J" sort="Keating, Brendan J" uniqKey="Keating B" first="Brendan J" last="Keating">Brendan J. Keating</name><affiliation><nlm:aff id="aff98">Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA</nlm:aff></affiliation></author><author><name sortKey="Preiss, David" sort="Preiss, David" uniqKey="Preiss D" first="David" last="Preiss">David Preiss</name><affiliation><nlm:aff id="aff11">Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff12">Medical Research Council Population Health Research Unit at the University of Oxford, University of Oxford, Oxford, UK</nlm:aff></affiliation></author><author><name sortKey="Hingorani, Aroon D" sort="Hingorani, Aroon D" uniqKey="Hingorani A" first="Aroon D" last="Hingorani">Aroon D. Hingorani</name><affiliation><nlm:aff id="aff1">Institute of Cardiovascular Science, University College London, UK</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Farr Institute of Health Informatics Research, UCL Institute of Health Informatics, University College London, UK</nlm:aff></affiliation></author><author><name sortKey="Sattar, Naveed" sort="Sattar, Naveed" uniqKey="Sattar N" first="Naveed" last="Sattar">Naveed Sattar</name><affiliation><nlm:aff id="aff17">Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK</nlm:aff></affiliation></author></analytic><series><title level="j">The Lancet. Diabetes & Endocrinology</title><idno type="ISSN">2213-8587</idno><idno type="eISSN">2213-8595</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Summary</title><sec><title>Background</title><p>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 <italic>PCSK9</italic> variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk.</p></sec><sec><title>Methods</title><p>In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of <italic>PCSK9</italic> genetic variants with LDL cholesterol, fasting blood glucose, HbA<sub>1c</sub>, 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.</p></sec><sec><title>Findings</title><p>Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent <italic>PCSK9</italic> 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<sub>1c</sub> (0·03%, −0·01 to 0·08), fasting insulin (0·00%, −0·06 to 0·07), and BMI (0·11 kg/m<sup>2</sup>, −0·09 to 0·30).</p></sec><sec><title>Interpretation</title><p><italic>PCSK9</italic> 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.</p></sec><sec><title>Funding</title><p>British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Sattar, N" uniqKey="Sattar N">N Sattar</name></author><author><name sortKey="Preiss, D" uniqKey="Preiss D">D Preiss</name></author><author><name sortKey="Murray, Hm" uniqKey="Murray H">HM Murray</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Preiss, D" uniqKey="Preiss D">D Preiss</name></author><author><name sortKey="Seshasai, Sr" uniqKey="Seshasai S">SR Seshasai</name></author><author><name sortKey="Welsh, P" uniqKey="Welsh P">P 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Lancet Diabetes Endocrinol</journal-id><journal-id journal-id-type="iso-abbrev">Lancet Diabetes Endocrinol</journal-id><journal-title-group><journal-title>The Lancet. Diabetes & Endocrinology</journal-title></journal-title-group><issn pub-type="ppub">2213-8587</issn><issn pub-type="epub">2213-8595</issn><publisher><publisher-name>The Lancet, Diabetes & Endocrinology</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">27908689</article-id><article-id pub-id-type="pmc">5266795</article-id><article-id pub-id-type="publisher-id">S2213-8587(16)30396-5</article-id><article-id pub-id-type="doi">10.1016/S2213-8587(16)30396-5</article-id><article-categories><subj-group subj-group-type="heading"><subject>Articles</subject></subj-group></article-categories><title-group><article-title><italic>PCSK9</italic> genetic variants and risk of type 2 diabetes: a mendelian randomisation study</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Schmidt</surname><given-names>Amand F</given-names></name><degrees>Dr</degrees><degrees>PhD</degrees><email>amand.schmidt@ucl.ac.uk</email><xref rid="aff1" ref-type="aff">a</xref><xref rid="aff5" ref-type="aff">e</xref><xref rid="cor1" ref-type="corresp">*</xref><xref rid="fn1" ref-type="fn">*</xref></contrib><contrib contrib-type="author"><name><surname>Swerdlow</surname><given-names>Daniel I</given-names></name><degrees>PhD</degrees><xref rid="aff1" ref-type="aff">a</xref><xref rid="aff6" ref-type="aff">f</xref><xref rid="fn1" ref-type="fn">*</xref></contrib><contrib contrib-type="author"><name><surname>Holmes</surname><given-names>Michael V</given-names></name><degrees>PhD</degrees><xref rid="aff11" ref-type="aff">k</xref><xref rid="aff12" ref-type="aff">l</xref><xref rid="fn1" ref-type="fn">*</xref></contrib><contrib contrib-type="author"><name><surname>Patel</surname><given-names>Riyaz S</given-names></name><degrees>MD</degrees><xref rid="aff1" ref-type="aff">a</xref><xref rid="aff5" ref-type="aff">e</xref><xref rid="aff14" ref-type="aff">n</xref></contrib><contrib contrib-type="author"><name><surname>Fairhurst-Hunter</surname><given-names>Zammy</given-names></name><degrees>MSc</degrees><xref rid="aff13" ref-type="aff">m</xref></contrib><contrib contrib-type="author"><name><surname>Lyall</surname><given-names>Donald M</given-names></name><degrees>PhD</degrees><xref rid="aff15" ref-type="aff">o</xref></contrib><contrib contrib-type="author"><name><surname>Hartwig</surname><given-names>Fernando Pires</given-names></name><degrees>MSc</degrees><xref rid="aff18" ref-type="aff">r</xref></contrib><contrib contrib-type="author"><name><surname>Horta</surname><given-names>Bernardo Lessa</given-names></name><degrees>Prof</degrees><degrees>PhD</degrees><xref rid="aff18" ref-type="aff">r</xref></contrib><contrib contrib-type="author"><name><surname>Hyppönen</surname><given-names>Elina</given-names></name><degrees>Prof</degrees><degrees>PhD</degrees><xref rid="aff19" ref-type="aff">s</xref><xref rid="aff21" ref-type="aff">u</xref><xref rid="aff22" ref-type="aff">v</xref></contrib><contrib contrib-type="author"><name><surname>Power</surname><given-names>Christine</given-names></name><degrees>Prof</degrees><degrees>PhD</degrees><xref rid="aff21" ref-type="aff">u</xref></contrib><contrib contrib-type="author"><name><surname>Moldovan</surname><given-names>Max</given-names></name><degrees>PhD</degrees><xref rid="aff20" ref-type="aff">t</xref><xref rid="aff23" ref-type="aff">w</xref></contrib><contrib contrib-type="author"><name><surname>van Iperen</surname><given-names>Erik</given-names></name><degrees>MSc</degrees><xref rid="aff24" ref-type="aff">x</xref><xref rid="aff25" ref-type="aff">y</xref></contrib><contrib contrib-type="author"><name><surname>Hovingh</surname><given-names>G Kees</given-names></name><degrees>Prof</degrees><degrees>PhD</degrees><xref rid="aff26" ref-type="aff">z</xref></contrib><contrib contrib-type="author"><name><surname>Demuth</surname><given-names>Ilja</given-names></name><degrees>PhD</degrees><xref rid="aff28" ref-type="aff">ab</xref><xref rid="aff29" ref-type="aff">ac</xref></contrib><contrib contrib-type="author"><name><surname>Norman</surname><given-names>Kristina</given-names></name><degrees>PhD</degrees><xref rid="aff28" ref-type="aff">ab</xref></contrib><contrib contrib-type="author"><name><surname>Steinhagen-Thiessen</surname><given-names>Elisabeth</given-names></name><degrees>Prof</degrees><degrees>MD</degrees><xref rid="aff28" ref-type="aff">ab</xref></contrib><contrib contrib-type="author"><name><surname>Demuth</surname><given-names>Juri</given-names></name><degrees>PhD</degrees><xref rid="aff30" ref-type="aff">ad</xref></contrib><contrib contrib-type="author"><name><surname>Bertram</surname><given-names>Lars</given-names></name><degrees>Prof</degrees><degrees>MD</degrees><xref rid="aff7" ref-type="aff">g</xref><xref rid="aff31" ref-type="aff">ae</xref></contrib><contrib contrib-type="author"><name><surname>Liu</surname><given-names>Tian</given-names></name><degrees>PhD</degrees><xref rid="aff32" ref-type="aff">af</xref><xref rid="aff33" ref-type="aff">ag</xref></contrib><contrib contrib-type="author"><name><surname>Coassin</surname><given-names>Stefan</given-names></name><degrees>PhD</degrees><xref rid="aff34" ref-type="aff">ah</xref></contrib><contrib contrib-type="author"><name><surname>Willeit</surname><given-names>Johann</given-names></name><degrees>Prof</degrees><degrees>PhD</degrees><xref rid="aff35" ref-type="aff">ai</xref></contrib><contrib contrib-type="author"><name><surname>Kiechl</surname><given-names>Stefan</given-names></name><degrees>MD</degrees><xref rid="aff35" ref-type="aff">ai</xref></contrib><contrib contrib-type="author"><name><surname>Willeit</surname><given-names>Karin</given-names></name><degrees>MD</degrees><xref rid="aff35" ref-type="aff">ai</xref></contrib><contrib contrib-type="author"><name><surname>Mason</surname><given-names>Dan</given-names></name><degrees>PhD</degrees><xref rid="aff36" ref-type="aff">aj</xref></contrib><contrib contrib-type="author"><name><surname>Wright</surname><given-names>John</given-names></name><degrees>Prof</degrees><degrees>FRCP</degrees><xref rid="aff36" ref-type="aff">aj</xref></contrib><contrib contrib-type="author"><name><surname>Morris</surname><given-names>Richard</given-names></name><degrees>Prof</degrees><degrees>PhD</degrees><xref rid="aff37" ref-type="aff">ak</xref></contrib><contrib contrib-type="author"><name><surname>Wanamethee</surname><given-names>Goya</given-names></name><degrees>Prof</degrees><degrees>PhD</degrees><xref rid="aff2" ref-type="aff">b</xref></contrib><contrib contrib-type="author"><name><surname>Whincup</surname><given-names>Peter</given-names></name><degrees>Prof</degrees><degrees>FRCP</degrees><xref rid="aff38" ref-type="aff">al</xref></contrib><contrib contrib-type="author"><name><surname>Ben-Shlomo</surname><given-names>Yoav</given-names></name><degrees>Prof</degrees><degrees>PhD</degrees><xref rid="aff37" ref-type="aff">ak</xref></contrib><contrib contrib-type="author"><name><surname>McLachlan</surname><given-names>Stela</given-names></name><degrees>PhD</degrees><xref rid="aff39" ref-type="aff">am</xref></contrib><contrib contrib-type="author"><name><surname>Price</surname><given-names>Jackie F</given-names></name><degrees>Prof</degrees><degrees>MD</degrees><xref rid="aff39" ref-type="aff">am</xref></contrib><contrib contrib-type="author"><name><surname>Kivimaki</surname><given-names>Mika</given-names></name><degrees>Prof</degrees><degrees>PhD</degrees><xref rid="aff3" ref-type="aff">c</xref></contrib><contrib contrib-type="author"><name><surname>Welch</surname><given-names>Catherine</given-names></name><degrees>PhD</degrees><xref rid="aff3" ref-type="aff">c</xref></contrib><contrib contrib-type="author"><name><surname>Sanchez-Galvez</surname><given-names>Adelaida</given-names></name><degrees>PhD</degrees><xref rid="aff3" ref-type="aff">c</xref></contrib><contrib contrib-type="author"><name><surname>Marques-Vidal</surname><given-names>Pedro</given-names></name><degrees>PhD</degrees><xref rid="aff41" ref-type="aff">ao</xref></contrib><contrib contrib-type="author"><name><surname>Nicolaides</surname><given-names>Andrew</given-names></name><degrees>PhD</degrees><xref rid="aff8" ref-type="aff">h</xref><xref rid="aff42" ref-type="aff">ap</xref></contrib><contrib contrib-type="author"><name><surname>Panayiotou</surname><given-names>Andrie G</given-names></name><degrees>PhD</degrees><xref rid="aff43" ref-type="aff">aq</xref></contrib><contrib contrib-type="author"><name><surname>Onland-Moret</surname><given-names>N Charlotte</given-names></name><degrees>PhD</degrees><xref rid="aff44" ref-type="aff">ar</xref></contrib><contrib contrib-type="author"><name><surname>van der Schouw</surname><given-names>Yvonne T</given-names></name><degrees>Prof</degrees><degrees>PhD</degrees><xref rid="aff44" ref-type="aff">ar</xref></contrib><contrib contrib-type="author"><name><surname>Matullo</surname><given-names>Giuseppe</given-names></name><degrees>PhD</degrees><xref rid="aff46" ref-type="aff">at</xref><xref rid="aff47" ref-type="aff">au</xref></contrib><contrib contrib-type="author"><name><surname>Fiorito</surname><given-names>Giovanni</given-names></name><degrees>PhD</degrees><xref rid="aff46" ref-type="aff">at</xref><xref rid="aff47" ref-type="aff">au</xref></contrib><contrib contrib-type="author"><name><surname>Guarrera</surname><given-names>Simonetta</given-names></name><degrees>MSc</degrees><xref rid="aff46" ref-type="aff">at</xref><xref rid="aff47" ref-type="aff">au</xref></contrib><contrib contrib-type="author"><name><surname>Sacerdote</surname><given-names>Carlotta</given-names></name><degrees>PhD</degrees><xref rid="aff48" ref-type="aff">av</xref><xref rid="aff49" ref-type="aff">aw</xref></contrib><contrib contrib-type="author"><name><surname>Wareham</surname><given-names>Nicholas J</given-names></name><degrees>Prof</degrees><degrees>PhD</degrees><xref rid="aff50" ref-type="aff">ax</xref></contrib><contrib contrib-type="author"><name><surname>Langenberg</surname><given-names>Claudia</given-names></name><degrees>PhD</degrees><xref rid="aff50" ref-type="aff">ax</xref></contrib><contrib contrib-type="author"><name><surname>Scott</surname><given-names>Robert</given-names></name><degrees>PhD</degrees><xref rid="aff50" ref-type="aff">ax</xref></contrib><contrib contrib-type="author"><name><surname>Luan</surname><given-names>Jian'an</given-names></name><degrees>PhD</degrees><xref rid="aff50" ref-type="aff">ax</xref></contrib><contrib contrib-type="author"><name><surname>Bobak</surname><given-names>Martin</given-names></name><degrees>Prof</degrees><degrees>PhD</degrees><xref rid="aff3" ref-type="aff">c</xref></contrib><contrib contrib-type="author"><name><surname>Malyutina</surname><given-names>Sofia</given-names></name><degrees>Prof</degrees><degrees>PhD</degrees><xref rid="aff51" ref-type="aff">ay</xref><xref rid="aff52" ref-type="aff">az</xref></contrib><contrib contrib-type="author"><name><surname>Pająk</surname><given-names>Andrzej</given-names></name><degrees>PhD</degrees><xref rid="aff53" ref-type="aff">ba</xref></contrib><contrib contrib-type="author"><name><surname>Kubinova</surname><given-names>Ruzena</given-names></name><degrees>PhD</degrees><xref rid="aff54" ref-type="aff">bb</xref></contrib><contrib contrib-type="author"><name><surname>Tamosiunas</surname><given-names>Abdonas</given-names></name><degrees>Prof</degrees><degrees>PhD</degrees><xref rid="aff55" ref-type="aff">bc</xref></contrib><contrib contrib-type="author"><name><surname>Pikhart</surname><given-names>Hynek</given-names></name><degrees>PhD</degrees><xref rid="aff3" ref-type="aff">c</xref></contrib><contrib contrib-type="author"><name><surname>Husemoen</surname><given-names>Lise Lotte Nystrup</given-names></name><degrees>PhD</degrees><xref rid="aff56" ref-type="aff">bd</xref></contrib><contrib contrib-type="author"><name><surname>Grarup</surname><given-names>Niels</given-names></name><degrees>PhD</degrees><xref rid="aff57" ref-type="aff">be</xref></contrib><contrib contrib-type="author"><name><surname>Pedersen</surname><given-names>Oluf</given-names></name><degrees>PhD</degrees><xref rid="aff57" ref-type="aff">be</xref></contrib><contrib contrib-type="author"><name><surname>Hansen</surname><given-names>Torben</given-names></name><degrees>PhD</degrees><xref rid="aff57" ref-type="aff">be</xref></contrib><contrib contrib-type="author"><name><surname>Linneberg</surname><given-names>Allan</given-names></name><degrees>Prof</degrees><degrees>PhD</degrees><xref rid="aff56" ref-type="aff">bd</xref><xref rid="aff58" ref-type="aff">bf</xref><xref rid="aff59" ref-type="aff">bg</xref></contrib><contrib contrib-type="author"><name><surname>Simonsen</surname><given-names>Kenneth Starup</given-names></name><degrees>PhD</degrees><xref rid="aff56" ref-type="aff">bd</xref></contrib><contrib contrib-type="author"><name><surname>Cooper</surname><given-names>Jackie</given-names></name><degrees>MSc</degrees><xref rid="aff4" ref-type="aff">d</xref></contrib><contrib contrib-type="author"><name><surname>Humphries</surname><given-names>Steve E</given-names></name><degrees>Prof</degrees><degrees>PhD</degrees><xref rid="aff4" ref-type="aff">d</xref></contrib><contrib contrib-type="author"><name><surname>Brilliant</surname><given-names>Murray</given-names></name><degrees>PhD</degrees><xref rid="aff60" ref-type="aff">bh</xref></contrib><contrib contrib-type="author"><name><surname>Kitchner</surname><given-names>Terrie</given-names></name><degrees>CCRP</degrees><xref rid="aff60" ref-type="aff">bh</xref></contrib><contrib contrib-type="author"><name><surname>Hakonarson</surname><given-names>Hakon</given-names></name><degrees>PhD</degrees><xref rid="aff61" ref-type="aff">bi</xref></contrib><contrib contrib-type="author"><name><surname>Carrell</surname><given-names>David S</given-names></name><degrees>PhD</degrees><xref rid="aff62" ref-type="aff">bj</xref></contrib><contrib contrib-type="author"><name><surname>McCarty</surname><given-names>Catherine A</given-names></name><degrees>PhD</degrees><xref rid="aff63" ref-type="aff">bk</xref></contrib><contrib contrib-type="author"><name><surname>Kirchner</surname><given-names>H Lester</given-names></name><degrees>PhD</degrees><xref rid="aff64" ref-type="aff">bl</xref></contrib><contrib contrib-type="author"><name><surname>Larson</surname><given-names>Eric B</given-names></name><degrees>MD</degrees><xref rid="aff65" ref-type="aff">bm</xref></contrib><contrib contrib-type="author"><name><surname>Crosslin</surname><given-names>David R</given-names></name><degrees>PhD</degrees><xref rid="aff65" ref-type="aff">bm</xref></contrib><contrib contrib-type="author"><name><surname>de Andrade</surname><given-names>Mariza</given-names></name><degrees>Prof</degrees><degrees>PhD</degrees><xref rid="aff66" ref-type="aff">bn</xref></contrib><contrib contrib-type="author"><name><surname>Roden</surname><given-names>Dan M</given-names></name><degrees>Prof</degrees><degrees>MD</degrees><xref rid="aff67" ref-type="aff">bo</xref></contrib><contrib contrib-type="author"><name><surname>Denny</surname><given-names>Joshua C</given-names></name><degrees>MD</degrees><xref rid="aff68" ref-type="aff">bp</xref></contrib><contrib contrib-type="author"><name><surname>Carty</surname><given-names>Cara</given-names></name><degrees>PhD</degrees><xref rid="aff69" ref-type="aff">bq</xref></contrib><contrib contrib-type="author"><name><surname>Hancock</surname><given-names>Stephen</given-names></name><degrees>MSciStud</degrees><xref rid="aff70" ref-type="aff">br</xref></contrib><contrib contrib-type="author"><name><surname>Attia</surname><given-names>John</given-names></name><degrees>PhD</degrees><xref rid="aff70" ref-type="aff">br</xref></contrib><contrib contrib-type="author"><name><surname>Holliday</surname><given-names>Elizabeth</given-names></name><degrees>PhD</degrees><xref rid="aff70" ref-type="aff">br</xref></contrib><contrib contrib-type="author"><name><surname>O'Donnell</surname><given-names>Martin</given-names></name><degrees>PhD</degrees><xref rid="aff71" ref-type="aff">bs</xref></contrib><contrib contrib-type="author"><name><surname>Yusuf</surname><given-names>Salim</given-names></name><degrees>Prof</degrees><degrees>DPhil</degrees><xref rid="aff71" ref-type="aff">bs</xref></contrib><contrib contrib-type="author"><name><surname>Chong</surname><given-names>Michael</given-names></name><degrees>MSc</degrees><xref rid="aff71" ref-type="aff">bs</xref></contrib><contrib contrib-type="author"><name><surname>Pare</surname><given-names>Guillaume</given-names></name><degrees>Prof</degrees><degrees>MD</degrees><xref rid="aff71" ref-type="aff">bs</xref></contrib><contrib contrib-type="author"><name><surname>van der Harst</surname><given-names>Pim</given-names></name><degrees>Prof</degrees><degrees>PhD</degrees><xref rid="aff24" ref-type="aff">x</xref><xref rid="aff72" ref-type="aff">bt</xref><xref rid="aff73" ref-type="aff">bu</xref></contrib><contrib contrib-type="author"><name><surname>Said</surname><given-names>M Abdullah</given-names></name><degrees>BSc</degrees><xref rid="aff72" ref-type="aff">bt</xref></contrib><contrib contrib-type="author"><name><surname>Eppinga</surname><given-names>Ruben N</given-names></name><degrees>PhD</degrees><xref rid="aff72" ref-type="aff">bt</xref></contrib><contrib contrib-type="author"><name><surname>Verweij</surname><given-names>Niek</given-names></name><degrees>PhD</degrees><xref rid="aff72" ref-type="aff">bt</xref></contrib><contrib contrib-type="author"><name><surname>Snieder</surname><given-names>Harold</given-names></name><degrees>Prof</degrees><degrees>PhD</degrees><xref rid="aff74" ref-type="aff">bv</xref></contrib><on-behalf-of>for the LifeLines Cohort study group<xref rid="fn2" ref-type="fn">†</xref></on-behalf-of><contrib contrib-type="author"><name><surname>Christen</surname><given-names>Tim</given-names></name><degrees>MSc</degrees><xref rid="aff75" ref-type="aff">bw</xref></contrib><contrib contrib-type="author"><name><surname>Mook-Kanamori</surname><given-names>Dennis O</given-names></name><degrees>PhD</degrees><xref rid="aff75" ref-type="aff">bw</xref></contrib><contrib contrib-type="author"><name><surname>Gustafsson</surname><given-names>Stefan</given-names></name><degrees>PhD</degrees><xref rid="aff76" ref-type="aff">bx</xref></contrib><contrib contrib-type="author"><name><surname>Lind</surname><given-names>Lars</given-names></name><degrees>Prof</degrees><degrees>PhD</degrees><xref rid="aff76" ref-type="aff">bx</xref></contrib><contrib contrib-type="author"><name><surname>Ingelsson</surname><given-names>Erik</given-names></name><degrees>Prof</degrees><degrees>PhD</degrees><xref rid="aff76" ref-type="aff">bx</xref><xref rid="aff77" ref-type="aff">by</xref><xref rid="aff78" ref-type="aff">bz</xref></contrib><contrib contrib-type="author"><name><surname>Pazoki</surname><given-names>Raha</given-names></name><degrees>PhD</degrees><xref rid="aff79" ref-type="aff">ca</xref></contrib><contrib contrib-type="author"><name><surname>Franco</surname><given-names>Oscar</given-names></name><degrees>PhD</degrees><xref rid="aff79" ref-type="aff">ca</xref></contrib><contrib contrib-type="author"><name><surname>Hofman</surname><given-names>Albert</given-names></name><degrees>Prof</degrees><degrees>PhD</degrees><xref rid="aff79" ref-type="aff">ca</xref></contrib><contrib contrib-type="author"><name><surname>Uitterlinden</surname><given-names>Andre</given-names></name><degrees>PhD</degrees><xref rid="aff80" ref-type="aff">cb</xref></contrib><contrib contrib-type="author"><name><surname>Dehghan</surname><given-names>Abbas</given-names></name><degrees>PhD</degrees><xref rid="aff10" ref-type="aff">j</xref><xref rid="aff79" ref-type="aff">ca</xref></contrib><contrib contrib-type="author"><name><surname>Teumer</surname><given-names>Alexander</given-names></name><degrees>PhD</degrees><xref rid="aff81" ref-type="aff">cc</xref><xref rid="aff85" ref-type="aff">cg</xref></contrib><contrib contrib-type="author"><name><surname>Baumeister</surname><given-names>Sebastian</given-names></name><degrees>PhD</degrees><xref rid="aff81" ref-type="aff">cc</xref><xref rid="aff86" ref-type="aff">ch</xref></contrib><contrib contrib-type="author"><name><surname>Dörr</surname><given-names>Marcus</given-names></name><degrees>Prof</degrees><degrees>MD</degrees><xref rid="aff82" ref-type="aff">cd</xref><xref rid="aff85" ref-type="aff">cg</xref></contrib><contrib contrib-type="author"><name><surname>Lerch</surname><given-names>Markus M</given-names></name><degrees>Prof</degrees><degrees>MD</degrees><xref rid="aff83" ref-type="aff">ce</xref></contrib><contrib contrib-type="author"><name><surname>Völker</surname><given-names>Uwe</given-names></name><degrees>Prof</degrees><degrees>PhD</degrees><xref rid="aff84" ref-type="aff">cf</xref><xref rid="aff85" ref-type="aff">cg</xref></contrib><contrib contrib-type="author"><name><surname>Völzke</surname><given-names>Henry</given-names></name><degrees>Prof</degrees><degrees>MD</degrees><xref rid="aff81" ref-type="aff">cc</xref><xref rid="aff85" ref-type="aff">cg</xref></contrib><contrib contrib-type="author"><name><surname>Ward</surname><given-names>Joey</given-names></name><degrees>PhD</degrees><xref rid="aff15" ref-type="aff">o</xref></contrib><contrib contrib-type="author"><name><surname>Pell</surname><given-names>Jill P</given-names></name><degrees>PhD</degrees><xref rid="aff15" ref-type="aff">o</xref></contrib><contrib contrib-type="author"><name><surname>Smith</surname><given-names>Daniel J</given-names></name><degrees>PhD</degrees><xref rid="aff15" ref-type="aff">o</xref></contrib><contrib contrib-type="author"><name><surname>Meade</surname><given-names>Tom</given-names></name><degrees>FRS</degrees><xref rid="aff87" ref-type="aff">ci</xref></contrib><contrib contrib-type="author"><name><surname>Maitland-van der Zee</surname><given-names>Anke H</given-names></name><degrees>Prof</degrees><degrees>PhD</degrees><xref rid="aff27" ref-type="aff">aa</xref><xref rid="aff88" ref-type="aff">cj</xref></contrib><contrib contrib-type="author"><name><surname>Baranova</surname><given-names>Ekaterina V</given-names></name><degrees>MSc</degrees><xref rid="aff88" ref-type="aff">cj</xref></contrib><contrib contrib-type="author"><name><surname>Young</surname><given-names>Robin</given-names></name><degrees>PhD</degrees><xref rid="aff16" ref-type="aff">p</xref></contrib><contrib contrib-type="author"><name><surname>Ford</surname><given-names>Ian</given-names></name><degrees>PhD</degrees><xref rid="aff16" ref-type="aff">p</xref></contrib><contrib contrib-type="author"><name><surname>Campbell</surname><given-names>Archie</given-names></name><degrees>MA</degrees><xref rid="aff40" ref-type="aff">an</xref></contrib><contrib contrib-type="author"><name><surname>Padmanabhan</surname><given-names>Sandosh</given-names></name><degrees>Prof</degrees><degrees>PhD</degrees><xref rid="aff17" ref-type="aff">q</xref></contrib><contrib contrib-type="author"><name><surname>Bots</surname><given-names>Michiel L</given-names></name><degrees>Prof</degrees><degrees>MD</degrees><xref rid="aff44" ref-type="aff">ar</xref></contrib><contrib contrib-type="author"><name><surname>Grobbee</surname><given-names>Diederick E</given-names></name><degrees>Prof</degrees><degrees>PhD</degrees><xref rid="aff44" ref-type="aff">ar</xref></contrib><contrib contrib-type="author"><name><surname>Froguel</surname><given-names>Philippe</given-names></name><degrees>Prof</degrees><degrees>PhD</degrees><xref rid="aff9" ref-type="aff">i</xref><xref rid="aff89" ref-type="aff">ck</xref></contrib><contrib contrib-type="author"><name><surname>Thuillier</surname><given-names>Dorothée</given-names></name><degrees>MSc</degrees><xref rid="aff89" ref-type="aff">ck</xref></contrib><contrib contrib-type="author"><name><surname>Balkau</surname><given-names>Beverley</given-names></name><degrees>PhD</degrees><xref rid="aff90" ref-type="aff">cl</xref></contrib><contrib contrib-type="author"><name><surname>Bonnefond</surname><given-names>Amélie</given-names></name><degrees>PhD</degrees><xref rid="aff9" ref-type="aff">i</xref><xref rid="aff89" ref-type="aff">ck</xref></contrib><contrib contrib-type="author"><name><surname>Cariou</surname><given-names>Bertrand</given-names></name><degrees>Prof</degrees><degrees>MD</degrees><xref rid="aff91" ref-type="aff">cm</xref></contrib><contrib contrib-type="author"><name><surname>Smart</surname><given-names>Melissa</given-names></name><degrees>PhD</degrees><xref rid="aff92" ref-type="aff">cn</xref></contrib><contrib contrib-type="author"><name><surname>Bao</surname><given-names>Yanchun</given-names></name><degrees>PhD</degrees><xref rid="aff92" ref-type="aff">cn</xref></contrib><contrib contrib-type="author"><name><surname>Kumari</surname><given-names>Meena</given-names></name><degrees>Prof</degrees><degrees>PhD</degrees><xref rid="aff92" ref-type="aff">cn</xref></contrib><contrib contrib-type="author"><name><surname>Mahajan</surname><given-names>Anubha</given-names></name><degrees>PhD</degrees><xref rid="aff13" ref-type="aff">m</xref></contrib><contrib contrib-type="author"><name><surname>Ridker</surname><given-names>Paul M</given-names></name><degrees>Prof</degrees><degrees>MD</degrees><xref rid="aff93" ref-type="aff">co</xref></contrib><contrib contrib-type="author"><name><surname>Chasman</surname><given-names>Daniel I</given-names></name><degrees>PhD</degrees><xref rid="aff93" ref-type="aff">co</xref></contrib><contrib contrib-type="author"><name><surname>Reiner</surname><given-names>Alex P</given-names></name><degrees>MD</degrees><xref rid="aff94" ref-type="aff">cp</xref></contrib><contrib contrib-type="author"><name><surname>Lange</surname><given-names>Leslie A</given-names></name><degrees>Prof</degrees><degrees>PhD</degrees><xref rid="aff95" ref-type="aff">cq</xref></contrib><contrib contrib-type="author"><name><surname>Ritchie</surname><given-names>Marylyn D</given-names></name><degrees>PhD</degrees><xref rid="aff96" ref-type="aff">cr</xref><xref rid="aff97" ref-type="aff">cs</xref></contrib><contrib contrib-type="author"><name><surname>Asselbergs</surname><given-names>Folkert W</given-names></name><degrees>Prof</degrees><degrees>MD</degrees><xref rid="aff1" ref-type="aff">a</xref><xref rid="aff5" ref-type="aff">e</xref><xref rid="aff24" ref-type="aff">x</xref><xref rid="aff44" ref-type="aff">ar</xref><xref rid="aff45" ref-type="aff">as</xref></contrib><contrib contrib-type="author"><name><surname>Casas</surname><given-names>Juan-Pablo</given-names></name><degrees>Prof</degrees><degrees>PhD</degrees><xref rid="aff5" ref-type="aff">e</xref></contrib><contrib contrib-type="author"><name><surname>Keating</surname><given-names>Brendan J</given-names></name><degrees>PhD</degrees><xref rid="aff98" ref-type="aff">ct</xref><xref rid="fn3" ref-type="fn">‡</xref></contrib><contrib contrib-type="author"><name><surname>Preiss</surname><given-names>David</given-names></name><degrees>MD</degrees><xref rid="aff11" ref-type="aff">k</xref><xref rid="aff12" ref-type="aff">l</xref><xref rid="fn3" ref-type="fn">‡</xref></contrib><contrib contrib-type="author"><name><surname>Hingorani</surname><given-names>Aroon D</given-names></name><degrees>Prof</degrees><degrees>PhD</degrees><xref rid="aff1" ref-type="aff">a</xref><xref rid="aff5" ref-type="aff">e</xref><xref rid="fn3" ref-type="fn">‡</xref></contrib><on-behalf-of>for the UCLEB consortium<xref rid="fn2" ref-type="fn">†</xref></on-behalf-of><contrib contrib-type="author"><name><surname>Sattar</surname><given-names>Naveed</given-names></name><degrees>Prof</degrees><degrees>FMedSci</degrees><email>naveed.sattar@glasgow.ac.uk</email><xref rid="aff17" ref-type="aff">q</xref><xref rid="cor2" ref-type="corresp">**</xref><xref rid="fn3" ref-type="fn">‡</xref></contrib></contrib-group><aff id="aff1"><label>a</label>Institute of Cardiovascular Science, University College London, UK</aff><aff id="aff2"><label>b</label>Department of Primary Care & Population Health, University College London, UK</aff><aff id="aff3"><label>c</label>Department of Epidemiology and Public Health, UCL Institute of Epidemiology and Health Care, University College London, UK</aff><aff id="aff4"><label>d</label>Centre for Cardiovascular Genetics, University College London, UK</aff><aff id="aff5"><label>e</label>Farr Institute of Health Informatics Research, UCL Institute of Health Informatics, University College London, UK</aff><aff id="aff6"><label>f</label>Department of Medicine, Imperial College London, London, UK</aff><aff id="aff7"><label>g</label>Neuroepidemiology and Ageing Research Unit, Imperial College London, London, UK</aff><aff id="aff8"><label>h</label>Department of Vascular Surgery, Imperial College London, London, UK</aff><aff id="aff9"><label>i</label>Department of Genomics of Common Disease, Imperial College London, London, UK</aff><aff id="aff10"><label>j</label>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</aff><aff id="aff11"><label>k</label>Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK</aff><aff id="aff12"><label>l</label>Medical Research Council Population Health Research Unit at the University of Oxford, University of Oxford, Oxford, UK</aff><aff id="aff13"><label>m</label>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK</aff><aff id="aff14"><label>n</label>The Barts Heart Centre, St Bartholomew's Hospital, London, UK</aff><aff id="aff15"><label>o</label>Institute of Health & Wellbeing, University of Glasgow, Glasgow, UK</aff><aff id="aff16"><label>p</label>Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK</aff><aff id="aff17"><label>q</label>Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK</aff><aff id="aff18"><label>r</label>Postgraduate Program in Epidemiology, Federal University of Pelotas, Pelotas, Brazil</aff><aff id="aff19"><label>s</label>Centre for Population Health Research, Sansom Institute for Health Research, University of South Australia, Adelaide, SA, Australia</aff><aff id="aff20"><label>t</label>School of Health Sciences, University of South Australia, Adelaide, SA, Australia</aff><aff id="aff21"><label>u</label>Population, Policy and Practice, UCL Great Ormond Street Institute of Child Health, London, UK</aff><aff id="aff22"><label>v</label>South Australian Health and Medical Research Institute, Adelaide, SA, Australia</aff><aff id="aff23"><label>w</label>South Australian Health and Medical Research Institute–EMBL Australia, Adelaide, SA, Australia</aff><aff id="aff24"><label>x</label>Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, Netherlands</aff><aff id="aff25"><label>y</label>Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center Amsterdam, Netherlands</aff><aff id="aff26"><label>z</label>Department of Vascular Medicine, Academic Medical Center Amsterdam, Netherlands</aff><aff id="aff27"><label>aa</label>Department of Respiratory Medicine, Academic Medical Center Amsterdam, Netherlands</aff><aff id="aff28"><label>ab</label>Charité Research Group on Geriatrics, Charité–Universitätsmedizin Berlin, Berlin, Germany</aff><aff id="aff29"><label>ac</label>Institute of Medical and Human Genetics, Charité–Universitätsmedizin Berlin, Berlin, Germany</aff><aff id="aff30"><label>ad</label>E.CA Economics GmbH, Berlin, Germany</aff><aff id="aff31"><label>ae</label>Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics and Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany</aff><aff id="aff32"><label>af</label>Max Planck Institute for Human Development, Berlin, Germany</aff><aff id="aff33"><label>ag</label>Max Planck Institute for Molecular Genetics, Berlin, Germany</aff><aff id="aff34"><label>ah</label>Division of Genetic Epidemiology Innsbruck, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria</aff><aff id="aff35"><label>ai</label>Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria</aff><aff id="aff36"><label>aj</label>Bradford Institute for Health Research, Bradford Royal Infirmary, Bradford, UK</aff><aff id="aff37"><label>ak</label>School of Social and Community Medicine, University of Bristol, Bristol, UK</aff><aff id="aff38"><label>al</label>Population Health Research Institute, St George's, University of London, London, UK</aff><aff id="aff39"><label>am</label>Centre for Population Health Sciences, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK</aff><aff id="aff40"><label>an</label>Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK</aff><aff id="aff41"><label>ao</label>Internal Medicine Unit, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland</aff><aff id="aff42"><label>ap</label>Department of Surgery, Nicosia Medical School, University of Nicosia, Nicosia, Cyprus</aff><aff id="aff43"><label>aq</label>Cyprus International Institute for Environmental and Public Health, Cyprus University of Technology, Limassol, Cyprus</aff><aff id="aff44"><label>ar</label>Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands</aff><aff id="aff45"><label>as</label>Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, Netherlands</aff><aff id="aff46"><label>at</label>Human Genetics Foundation, HuGeF, Turin, Italy</aff><aff id="aff47"><label>au</label>Department of Medical Sciences, University of Turin, Turin, Italy</aff><aff id="aff48"><label>av</label>Cancer Epidemiology Unit, San Giovanni Battista Hospital, Turin, Italy</aff><aff id="aff49"><label>aw</label>Centre for Oncology Prevention, CPO Piemonte, Turin, Italy</aff><aff id="aff50"><label>ax</label>MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK</aff><aff id="aff51"><label>ay</label>Novosibirsk State Medical University, Novosibirsk, Russia</aff><aff id="aff52"><label>az</label>Institute of Internal and Preventive Medicine, Siberian Branch of the Russian Academy of Medical Sciences, Novosibirsk, Russia</aff><aff id="aff53"><label>ba</label>Jagiellonian University Collegium Medicum, Krakow, Poland</aff><aff id="aff54"><label>bb</label>National Institute of Public Health, Prague, Czech Republic</aff><aff id="aff55"><label>bc</label>Lithuanian University of Health Sciences, Kaunas, Lithuania</aff><aff id="aff56"><label>bd</label>Research Centre for Prevention and Health, Capital Region of Denmark, Denmark</aff><aff id="aff57"><label>be</label>Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark</aff><aff id="aff58"><label>bf</label>Department of Clinical Experimental Research, Rigshospitalet, Copenhagen, Denmark</aff><aff id="aff59"><label>bg</label>Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark</aff><aff id="aff60"><label>bh</label>Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI, USA</aff><aff id="aff61"><label>bi</label>Children's Hospital of Philadelphia, Philadelphia, PA, USA</aff><aff id="aff62"><label>bj</label>Group Health Research Institute in Seattle, WA, USA</aff><aff id="aff63"><label>bk</label>Essentia Institute of Rural Health, Duluth, MN, USA</aff><aff id="aff64"><label>bl</label>Center for Health Research, Geisinger Clinic, Danville, PA, USA</aff><aff id="aff65"><label>bm</label>Group Health Research Institute, Seattle, WA, USA</aff><aff id="aff66"><label>bn</label>Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA</aff><aff id="aff67"><label>bo</label>Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA</aff><aff id="aff68"><label>bp</label>Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, USA</aff><aff id="aff69"><label>bq</label>George Washington University, Washington, DC, USA</aff><aff id="aff70"><label>br</label>University of Newcastle, Newcastle, NSW, Australia</aff><aff id="aff71"><label>bs</label>Population Health Research Institute, Hamilton, ON, Canada</aff><aff id="aff72"><label>bt</label>Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands</aff><aff id="aff73"><label>bu</label>Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands</aff><aff id="aff74"><label>bv</label>Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands</aff><aff id="aff75"><label>bw</label>Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands</aff><aff id="aff76"><label>bx</label>Molecular Epidemiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden</aff><aff id="aff77"><label>by</label>Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden</aff><aff id="aff78"><label>bz</label>Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA</aff><aff id="aff79"><label>ca</label>Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands</aff><aff id="aff80"><label>cb</label>Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, Netherlands</aff><aff id="aff81"><label>cc</label>Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany</aff><aff id="aff82"><label>cd</label>Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany</aff><aff id="aff83"><label>ce</label>Department of Medicine A, University Medicine Greifswald, Greifswald, Germany</aff><aff id="aff84"><label>cf</label>Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany</aff><aff id="aff85"><label>cg</label>German Centre for Cardiovascular Research (DZHK), Greifswald, Germany</aff><aff id="aff86"><label>ch</label>Department of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany</aff><aff id="aff87"><label>ci</label>Department of Non-Communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK</aff><aff id="aff88"><label>cj</label>Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands</aff><aff id="aff89"><label>ck</label>CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille, France</aff><aff id="aff90"><label>cl</label>Renal and Cardiovascular Epidemiology, Centre de Recherche en Epidémiologie et Santé des Populations (CESP), INSERM U1018, Villejuif, France</aff><aff id="aff91"><label>cm</label>I'institut du Thorax, INSERM, CNRS, University of Nantes, CHU de Nantes, Nantes, France</aff><aff id="aff92"><label>cn</label>Institute for Social and Economic Research, University of Essex, Colchester, Essex, UK</aff><aff id="aff93"><label>co</label>Harvard Medical School Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Boston, MA, USA</aff><aff id="aff94"><label>cp</label>Department of Epidemiology, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA</aff><aff id="aff95"><label>cq</label>Anschutz Medical Campus, University of Colorado Denver, Denver, CO, USA</aff><aff id="aff96"><label>cr</label>Biomedical and Translational Informatics, Geisinger Health System, Danville, PA, USA</aff><aff id="aff97"><label>cs</label>Department of Biochemistry and Molecular Biology, Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, USA</aff><aff id="aff98"><label>ct</label>Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA</aff><author-notes><corresp id="cor1"><label>*</label>Correspondence to: Dr Amand F Schmidt, Institute of Cardiovascular Science, University College London, London NW1 2DA, UKCorrespondence to: Dr Amand F SchmidtInstitute of Cardiovascular ScienceUniversity College LondonLondonNW1 2DAUK <email>amand.schmidt@ucl.ac.uk</email></corresp><corresp id="cor2"><label>**</label>Prof Naveed Sattar, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, G12 8TA, UKProf Naveed SattarInstitute of Cardiovascular and Medical SciencesUniversity of GlasgowGlasgowG12 8TAUK <email>naveed.sattar@glasgow.ac.uk</email></corresp><fn id="fn1"><label>*</label><p id="cenpara10">Joint first authors</p></fn><fn id="fn2"><label>†</label><p id="cenpara20">See <xref rid="sec1" ref-type="sec">appendix</xref></p></fn><fn id="fn3"><label>‡</label><p id="cenpara30">Joint senior authors</p></fn></author-notes><pub-date pub-type="pmc-release"><day>1</day><month>2</month><year>2017</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="ppub"><month>2</month><year>2017</year></pub-date><volume>5</volume><issue>2</issue><fpage>97</fpage><lpage>105</lpage><permissions><copyright-statement>© 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license</copyright-statement><copyright-year>2017</copyright-year><license license-type="CC BY" xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).</license-p></license></permissions><related-article related-article-type="article-reference" id="d32e12" ext-link-type="doi" xlink:href="10.1016/S2213-8587(16)30398-9"></related-article><abstract id="ceab10"><title>Summary</title><sec><title>Background</title><p>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 <italic>PCSK9</italic> variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk.</p></sec><sec><title>Methods</title><p>In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of <italic>PCSK9</italic> genetic variants with LDL cholesterol, fasting blood glucose, HbA<sub>1c</sub>, 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.</p></sec><sec><title>Findings</title><p>Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent <italic>PCSK9</italic> 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<sub>1c</sub> (0·03%, −0·01 to 0·08), fasting insulin (0·00%, −0·06 to 0·07), and BMI (0·11 kg/m<sup>2</sup>, −0·09 to 0·30).</p></sec><sec><title>Interpretation</title><p><italic>PCSK9</italic> 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.</p></sec><sec><title>Funding</title><p>British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.</p></sec></abstract></article-meta></front><body><sec id="cesec10"><title>Introduction</title><p>The benefit of statins in reducing LDL cholesterol and coronary heart disease (CHD) risk is well established. More recently, and only after completion of numerous randomised controlled trials, was it discovered that statins increase risk of type 2 diabetes,<xref rid="bib1" ref-type="bibr">1</xref>, <xref rid="bib2" ref-type="bibr">2</xref> although this effect is modest and greatly outweighed by the benefits of this drug class. Genetic studies based on common variants in the gene encoding the target of statins, HMG-CoA reductase (HMGCR), suggest the effect is mechanism-based (ie, on-target).<xref rid="bib3" ref-type="bibr"><sup>3</sup></xref> Genetic studies assessing the effects of variants in a broader range of genes suggest a more general link between lower LDL cholesterol and higher risk of type 2 diabetes.<xref rid="bib4" ref-type="bibr">4</xref>, <xref rid="bib5" ref-type="bibr">5</xref> Consistent with this finding, patients with autosomal dominant familial hypercholesterolaemia caused by mutations in the LDL receptor and apolipoprotein B genes are 50% less likely to be diagnosed with type 2 diabetes compared with their unaffected relatives.<xref rid="bib6" ref-type="bibr"><sup>6</sup></xref></p><p><boxed-text id="cetextbox10"><caption><title>Research in context</title></caption><p><bold>Evidence before this study</bold></p><p>We searched PubMed for “pcsk9[All Fields] AND (“antagonists and inhibitors”[Subheading] OR (“antagonists”[All Fields] AND “inhibitors”[All Fields]) OR “antagonists and inhibitors”[All Fields] OR “inhibitors”[All Fields]) AND (“diabetes mellitus”[MeSH Terms] OR (“diabetes”[All Fields] AND “mellitus”[All Fields]) OR “diabetes mellitus”[All Fields])” for articles published up to Oct 8, 2016, to identify studies that assessed treatment with PCSK9 inhibitors or carriage of genetic variants in <italic>PCSK9</italic> in relation to diabetes. This search identified 17 studies, two of which presented novel, yet contrasting findings in relation to genetic variants in <italic>PCSK9</italic> and glycaemic status.</p><p>Randomised trials of treatment with statins and carriage of corresponding genetic variants in <italic>HMGCR</italic> that lower LDL cholesterol both show and increase in the risk of type 2 diabetes. More recently, genetic predisposition to lower LDL cholesterol concentrations has been linked to an increased risk of diabetes, suggesting that dysglycaemia might be a consequence of lowering LDL cholesterol in general. Whether lowering of LDL cholesterol by PCSK9 inhibitors results in increased risk of diabetes is currently unknown. Clinical trials of PCSK9 inhibitors to assess their effect on cardiovascular outcomes are ongoing, but reliable evidence for a possible association between PCSK9 inhibition and risk of diabetes could take longer to accrue.</p><p><bold>Added value of this study</bold></p><p>Mendelian randomisation is an established approach that uses randomly allocated variants in the encoding gene to infer mechanism-based efficacy and safety outcomes from pharmacological perturbation of a drug target. We used four genetic variants in <italic>PCSK9</italic> in more than 550 000 individuals (including about 50 000 diabetes cases) and showed that <italic>PCSK9</italic> genetic variants associated with lower LDL cholesterol concentrations were associated with increased concentration of fasting glucose, bodyweight, and risk of diabetes. This finding adds robust new evidence to previous research that identified weak associations of <italic>PCSK9</italic> with risk of diabetes.</p><p><bold>Implications of all the available evidence</bold></p><p>Similar to statin therapy, treatment with PCSK9 inhibitors is likely to increase the risk of diabetes. Patients treated with PCSK9 inhibitors should be carefully monitored for dysglycaemia, including within ongoing and future clinical trials.</p></boxed-text></p><p>Gain-of-function mutations in <italic>PCSK9</italic>, the gene encoding proprotein convertase subtilisin/kexin type 9, also cause familial hypercholesterolaemia,<xref rid="bib7" ref-type="bibr"><sup>7</sup></xref> whereas loss-of-function mutations in the same gene lower LDL cholesterol and protect against CHD.<xref rid="bib8" ref-type="bibr"><sup>8</sup></xref> Consequently, monoclonal antibodies inhibiting PCSK9 have been developed<xref rid="bib9" ref-type="bibr"><sup>9</sup></xref> and are effective in lowering LDL cholesterol by 50–70%,<xref rid="bib10" ref-type="bibr"><sup>10</sup></xref> with preliminary evidence suggesting that this effect might be associated with reduced risk of myocardial infarction and all-cause mortality.<xref rid="bib9" ref-type="bibr"><sup>9</sup></xref> Although large phase 3 trials to assess the effects of PCSK9 monoclonal antibodies on cardiovascular events are underway, conclusive evidence for the specific effect of PCSK9 inhibition on risk of type 2 diabetes from individual randomised controlled trials or meta-analyses might not emerge for some time.</p><p>We used the principle of mendelian randomisation as a tool for drug target validation, whereby common variants in a gene that encodes a drug target, through effects on expression or activity, are used to predict the on-target effect of pharmacological modification of the same target.<xref rid="bib3" ref-type="bibr">3</xref>, <xref rid="bib11" ref-type="bibr">11</xref>, <xref rid="bib12" ref-type="bibr">12</xref> We investigated associations of common genetic variants in <italic>PCSK9</italic> with markers of glycaemia, bodyweight, and risk of type 2 diabetes to assess the potential on-target effects of PCSK9 inhibition on these traits. Although results of a recent study provided evidence of an association of a single nucleotide polymorphism (SNP) in <italic>PCSK9</italic> with type 2 diabetes risk,<xref rid="bib13" ref-type="bibr"><sup>13</sup></xref> our aim was to confirm the type 2 diabetes risk-increasing effect of <italic>PCSK9</italic> variation and explore potential biological mechanisms that might explain this effect. To do this we used four SNPs in the <italic>PCSK9</italic> locus collected in 50 studies supplemented with data from large genetic consortia.</p></sec><sec id="cesec20"><title>Methods</title><sec id="cesec30"><title>Genetic variant selection</title><p>We selected four SNPs in or near <italic>PCSK9</italic> on the basis of a strong association with LDL cholesterol, as reported by the Global Lipids Genetics Consortium (GLGC);<xref rid="bib14" ref-type="bibr"><sup>14</sup></xref> low pairwise linkage disequilibrium (r<sup>2</sup>≤0·30) with SNPs within the same and adjacent genes (1000 Genomes CEU data); high prior probability of being a functional variant based on the combined annotation dependent depletion (CADD) score, or the SNP being non-synonymous, or both;<xref rid="bib15" ref-type="bibr"><sup>15</sup></xref> or previous reported associations with CHD.<xref rid="bib16" ref-type="bibr"><sup>16</sup></xref> On the basis of these criteria, we selected the SNPs rs11583680 (minor allele frequency 0·14), rs11591147 (0·01), rs2479409 (0·36), and rs11206510 (0·17; <xref rid="sec1" ref-type="sec">appendix</xref>).</p></sec><sec id="cesec40"><title>Individual participant-level and summary-level data</title><p>Data were analysed from two sources. Participating studies executed a common analysis script on their own data, submitting summary estimates to a central analysis centre at University College London, London, UK. Main effect estimates from the participating studies were then meta-analysed with pooled summary estimates from the public domain data repositories of relevant genetic (genome-wide association study [GWAS]) consortia, but only if the study-level estimates had not previously contributed to consortia results, to prevent double counting. All studies contributing data to these analyses were approved by their local ethics committees.</p><p>Data were collected for LDL cholesterol, insulin (fasting and non-fasting), glucose (fasting and non-fasting), HbA<sub>1c</sub>, insulin resistance and secretion via basal homeostatic model assessments (HOMA-IR and HOMA-B), bodyweight, height, BMI, waist-to-hip ratio, and history or incidence of type 2 diabetes.</p><p>Publicly available summary-level data were available on blood lipids from the GLGC;<xref rid="bib14" ref-type="bibr"><sup>14</sup></xref> type 2 diabetes-related biomarkers (plasma insulin, glucose, HbA<sub>1c</sub>, HOMA-IR, and HOMA-B) from the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC);<xref rid="bib17" ref-type="bibr">17</xref>, <xref rid="bib18" ref-type="bibr">18</xref>, <xref rid="bib19" ref-type="bibr">19</xref> bodyweight, height, BMI, and waist-to-hip ratio from the Genetic Investigation of Anthropometric Traits consortium (GIANT);<xref rid="bib20" ref-type="bibr">20</xref>, <xref rid="bib21" ref-type="bibr">21</xref> and type 2 diabetes from the Diabetes Genetics Replication and Meta-analysis consortium (DIAGRAM)<xref rid="bib22" ref-type="bibr"><sup>22</sup></xref> and Exome chip 80K.<xref rid="bib23" ref-type="bibr"><sup>23</sup></xref> Additionally, cross-sectional data were obtained for adiposity traits and the prevalence of type 2 diabetes from UK Biobank.<xref rid="bib24" ref-type="bibr"><sup>24</sup></xref></p></sec><sec id="cesec50"><title>Statistical analyses</title><p>In all analyses we assumed an additive allele effect with genotypes coded as 0, 1, and 2, representing the number of minor alleles. We analysed continuous biomarkers using linear regression models; the composite endpoint of prevalent or incident type 2 diabetes was analysed with logistic regression. Study-specific associations were pooled for each SNP by use of the inverse-variance weighted method for fixed-effect and random-effects meta-analysis. We assessed between-study heterogeneity using the Q-test and the <italic>I</italic><sup>2</sup> statistic<xref rid="bib25" ref-type="bibr"><sup>25</sup></xref> with a one-sided upper 97·5% CI. Study-specific associations were excluded if the SNP was not in Hardy-Weinberg equilibrium (<xref rid="sec1" ref-type="sec">appendix</xref>).</p><p>Our approach to SNP selection was designed to prune the number of SNPs at <italic>PCSK9</italic> used in the analysis, without loss of information. We decided a priori to combine the four approximately independent SNPs in a weighted gene-centric score (GS) using the inverse-variance weighted method for fixed and random effects.<xref rid="bib26" ref-type="bibr"><sup>26</sup></xref> The GS provides a more precise estimate of the downstream effects of variation at <italic>PCSK9</italic> by incorporating maximum biological variation. Furthermore, if the four SNP effects are homogeneous (assessed by the heterogeneity measures Q-test and <italic>I</italic><sup>2</sup>), the GS estimates will be more powerful and precise compared with individual SNPs in isolation. If, however, the SNP effects are heterogeneous (meaning that the <italic>PCSK9</italic> effects are different according to which part of the gene is assessed), the GS method will be less powerful than the individual SNP tests (depending on the degree of heterogeneity). Our aim was to estimate the effect of the <italic>PCSK9</italic> locus as a whole, but SNP-specific estimates are also reported. Other important assumptions of the GS approach are (approximate) independence of the included SNPs (assessed by pairwise linkage disequilibrium (r<sup>2</sup>) and use of multivariable regression models) and the additivity of allele effects. We also investigated whether the association of individual SNPs with diabetes risk was in proportion to the association with LDL cholesterol lowering.</p><p>Estimates are presented as mean differences or odds ratios (ORs) with 95% CIs, presented either per LDL cholesterol-decreasing allele or, in the case of GS, per 1 mmol/L (38·67 mg/dL) lower LDL cholesterol. The per 1 mmol/L GS effect estimates were derived by multiplying point estimates and their variances by the multiplicative inverse of the estimated SNP-LDL cholesterol effects. Similar to most genetic studies, missing data were excluded in an available case manner, assuming a missing-completely-at-random mechanism.<xref rid="bib27" ref-type="bibr">27</xref>, <xref rid="bib28" ref-type="bibr">28</xref> To avoid potential bias due to population stratification and non-modelled ancestry interactions, analyses excluded individuals of non-European ancestry. Differences in ancestry can be a potential source of confounding bias (ie, population stratification bias) when environment is related to both the genes and the outcome of interest. Analyses were done with the statistical programme R (version 3.3.0).</p></sec><sec id="cesec60"><title>Sensitivity analyses</title><p>We assumed that the allele effects were additive, which we assessed in available individual participant data by comparing an additive model to a non-additive model (allowing for dominance or recessiveness) using a likelihood ratio test (meta-analysed by Fisher's method).<xref rid="bib29" ref-type="bibr"><sup>29</sup></xref> Because measurement error might be larger in prevalent cases (ascertained, for example, from hospital records) we did a further sensitivity analysis in which we separately analysed incident and prevalent type 2 diabetes. This sensitivity analysis was done not because we expect the true associations of <italic>PCSK9</italic> to be different with respect to prevalent and incident case status, but merely reflected a quality-control check. Although SNPs were selected to be independent, there was some degree of residual dependency (<xref rid="sec1" ref-type="sec">appendix</xref>; maximum r<sup>2</sup> 0·26). To explore the effect of this residual correlation between the four study SNPs (<xref rid="sec1" ref-type="sec">appendix</xref>), we compared results from a multivariable analysis (including the four SNPs in the same model) in studies with individual participant data (correcting for this correlation) to pairwise results (ignoring any between-SNP correlation) based on the same data.</p></sec><sec id="cesec70"><title>Role of the funding source</title><p>The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author (AFS) had full access to all the data in the study and shared final responsibility for the decision to submit for publication with all authors.</p></sec></sec><sec id="cesec80"><title>Results</title><p>50 studies shared participant-level data from up to 245 942 individuals, which was supplemented by summary effect estimates from data repositories, resulting in a maximum available sample size of 568 448 individuals, including 51 623 cases of incident or prevalent type 2 diabetes. Individual studies were similar with respect to the distribution of biochemical measures (assessed by the median of study-specific means): LDL cholesterol 3·41 mmol/L (IQR 0·39), fasting glucose 5·38 mmol/L (0·58), and HbA<sub>1c</sub> 5·50% (<xref rid="sec1" ref-type="sec">appendix</xref>). Pooled pairwise linkage disequilibrium estimates for the four <italic>PCSK9</italic> SNPs all had r<sup>2</sup> values less than 0·30 (<xref rid="sec1" ref-type="sec">appendix</xref>), confirming that the selected SNPs were in low correlation in the collected data.</p><p>The four <italic>PCSK9</italic> SNPs were associated with reductions in LDL cholesterol ranging from −0·02 mmol/L (95% CI −0·03 to −0·02) for rs11583680 to −0·34 mmol/L (−0·36 to −0·32) for rs11591147 per LDL cholesterol-decreasing allele (<xref rid="fig1" ref-type="fig">figure 1</xref>).</p><p><xref rid="fig2" ref-type="fig">Figure 2</xref> depicts the associations of the four <italic>PCSK9</italic> SNPs after scaling the SNP effect to 1 mmol/L lower LDL cholesterol. Results of the <italic>PCSK9</italic> GS analysis show that a 1 mmol/L lower LDL cholesterol was associated with an increase in bodyweight of 1·03 kg (95% CI 0·24 to 1·82; and an increase of 0·006 (0·003 to 0·010) in waist-to-hip ratio, but we observed a potentially neutral association with BMI (0·11 kg/m<sup>2</sup>, −0·09 to 0·30). Associations of the <italic>PCSK9</italic> GS with glycaemia measures were 0·09 mmol/L (0·02 to 0·15) higher fasting plasma glucose, HbA<sub>1c</sub> of 0·03% (−0·01 to 0·08; and for fasting insulin 0·00%, −0·06 to 0·07). SNP-specific forest plots are presented in the <xref rid="sec1" ref-type="sec">appendix</xref>. The estimates were similar when corrected for linkage disequilibrium (<xref rid="sec1" ref-type="sec">appendix</xref>), and no systematic deviations from an additive model were identified (<xref rid="sec1" ref-type="sec">appendix</xref>). Finally, we noted an unanticipated effect on height (mean difference 0·008 m, 0·0008 to 0·015; <xref rid="sec1" ref-type="sec">appendix</xref>).</p><p><xref rid="fig3" ref-type="fig">Figure 3</xref> shows the associations of individual <italic>PCSK9</italic> variants and the GS with risk of type 2 diabetes. Using the <italic>PCSK9</italic> GS, 1 mmol/L lower LDL cholesterol was associated with an increased risk of type 2 diabetes (OR 1·29, 95% CI 1·11 to 1·50). Exploring the <italic>PCSK9</italic> associations with incident (<xref rid="sec1" ref-type="sec">appendix</xref>) or prevalent (<xref rid="sec1" ref-type="sec">appendix</xref>) type 2 diabetes separately showed directional concordance of this effect (incident type 2 diabetes OR 1·15, 0·76 to 1·72; prevalent type 2 diabetes OR 1·26, 0·88 to 1·80). Associations of individual SNPs with LDL cholesterol and risk of type 2 diabetes showed a dose-response relation (<xref rid="fig4" ref-type="fig">figure 4</xref>).</p></sec><sec id="cesec90"><title>Discussion</title><p>In this mendelian randomisation study, genetic variants in <italic>PCSK9,</italic> used as a proxy for pharmacological inhibition of PCSK9, were associated with lower LDL cholesterol concentration and increased risk of type 2 diabetes. The same variants were also associated with higher fasting glucose, bodyweight, and waist-to-hip ratio, and with directionally concordant but non-significant associations for BMI and HbA<sub>1c</sub> and a seemingly neutral association for fasting insulin. These results are in agreement with previous findings for variants in the <italic>HMGCR</italic> gene encoding the target of statin drugs, with statins modestly increasing bodyweight and the risk of type 2 diabetes.<xref rid="bib3" ref-type="bibr"><sup>3</sup></xref></p><p>When scaled to 1 mmol/L lower LDL cholesterol, the risk for type 2 diabetes based on <italic>HMGCR</italic> variants<xref rid="bib13" ref-type="bibr"><sup>13</sup></xref> was an OR of 1·39 (95% CI 1·12 to 1·73), similar to the corresponding scaled estimate for this <italic>PCSK9</italic> GS (1·29, 1·11 to 1·50), and similar to an estimate based on SNPs affecting LDL cholesterol selected from throughout the genome (1·27, 1·14 to 1·41).<xref rid="bib5" ref-type="bibr"><sup>5</sup></xref> However, effect estimates obtained from mendelian randomisation studies proxy lifetime exposure to natural genetic variation, and might therefore not directly translate to the size of effect of any corresponding pharmacological treatment introduced much later in life and thus for a shorter duration of time.<xref rid="bib30" ref-type="bibr"><sup>30</sup></xref> For example, in a meta-analysis of randomised controlled trials of statin treatment,<xref rid="bib31" ref-type="bibr"><sup>31</sup></xref> the OR for type 2 diabetes was 1·12 (95% CI 1·06 to 1·18).</p><p>In the case of statins, the treatment benefit in terms of CHD risk reduction greatly outweighs any potential adverse effect on risk of type 2 diabetes, partly because the size of the risk reduction in CHD is greater than the risk increase in type 2 diabetes, and partly because the absolute risk of CHD in primary prevention populations eligible for statin treatment is greater than the absolute risk of type 2 diabetes.<xref rid="bib32" ref-type="bibr"><sup>32</sup></xref> A similarly precise risk assessment for PCSK9 inhibitors awaits results from larger and longer-term randomised trials. In a recent pooled analysis,<xref rid="bib33" ref-type="bibr"><sup>33</sup></xref> researchers reported that treatment with alirocumab was associated with an OR for type 2 diabetes of 0·89 (95% CI 0·62 to 1·28) compared with placebo, based on 133 type 2 diabetes events.</p><p>Variants that affect circulating LDL cholesterol have been reported previously to affect the probability of being prescribed a lipid-lowering drug.<xref rid="bib34" ref-type="bibr"><sup>34</sup></xref> We were unable to account for this effect in the analysis because prescription data for these treatments were often not available, and when they were recorded they were only available for a single follow-up point. For lipid-lowering treatments, one record of treatment does not properly reflect the time-varying therapy received, and adjusting for only a single record when in fact treatment varies over follow-up might increase bias.<xref rid="bib35" ref-type="bibr"><sup>35</sup></xref> Typically, diabetes drug treatments are much less variable over time and correction for this treatment might seem advisable; however, because of the strong correlation between history of type 2 diabetes and use of type 2 diabetes-related drugs, any correction for the latter would essentially correct for prevalent type 2 diabetes as well. Importantly, any effect of lipid-lowering drug therapy would attenuate rather than inflate any associations.</p><p>We have previously reported examples of common variants in genes encoding a protein drug target mimicking the on-target effects of pharmacological interventions on biomarkers and disease outcomes in type, direction, and relative size.<xref rid="bib3" ref-type="bibr">3</xref>, <xref rid="bib36" ref-type="bibr">36</xref>, <xref rid="bib37" ref-type="bibr">37</xref> However, such analyses cannot predict off-target effects of treatments. We refer to on-target effects as those that are due to a drug effect on the intended target (in this case PCSK9) and off-target effects as those that might occur because of the drug also binding to an unintended target (in this case, any target other than PCSK9). Although monoclonal antibody therapeutics are often highly specific, perhaps more so than small molecule therapeutics, they retain the potential for off-target effects. Hence, in the presence of off-target effects, results from ongoing randomised controlled trials could differ from the genetic associations reported here.</p><p>Our main findings are based on four <italic>PCSK9</italic> SNPs in combination and scaled to 1 mmol/L lower LDL cholesterol. This approach assumes additive effects across the SNPs, an assumption that held well in sensitivity analyses. A potentially unobserved non-additive effect might explain why we identified a genetic association with fasting glucose and a concordant (although non-significant) association with HbA<sub>1c</sub>, whereas fasting insulin seemed unaffected. Conflicting evidence exists about a possible role of <italic>PCSK9</italic> and PCSK9 monoclonal antibodies in disruption of pancreatic islet function.<xref rid="bib38" ref-type="bibr">38</xref>, <xref rid="bib39" ref-type="bibr">39</xref> Although concordant with fasting glucose, the HbA<sub>1c</sub> association was non-significant in the collected data, which might be related to the large amount of heterogeneity between the four SNPs (upper-bound <italic>I</italic><sup>2</sup> 72%). Interestingly, the association of the <italic>PCSK9</italic> GS with BMI was smaller than that with bodyweight, which might be (partially) explained by a slightly greater average height among individuals with <italic>PCSK9</italic> variants associated with lower LDL cholesterol concentrations. A further potential reason for the slight discrepancy between the BMI and bodyweight associations could be the greater heterogeneity in the associations of <italic>PCSK9</italic> SNPs with BMI than with weight. Notably, the GS effect estimates were often driven by a large effect of SNP rs11591147; as our dose-response analysis shows (<xref rid="fig4" ref-type="fig">figure 4</xref>), the larger influence of this SNP appropriately reflects the proportionally larger LDL cholesterol effect of this SNP. Finally, we did not have access to measures of PCSK9 concentration in this analysis, but others<xref rid="bib40" ref-type="bibr"><sup>40</sup></xref> have shown associations between common and rare <italic>PCSK9</italic> alleles (including some of the same SNPs used here) and circulating PCSK9 concentrations.</p><p>Setting aside associations with glycaemia and weight, risk of type 2 diabetes could also be increased because lifelong exposure to genetic variation in <italic>PCSK9</italic> might reduce mortality, making it conceivable that individuals with these variants survive longer and hence have more time to develop type 2 diabetes. However, whether <italic>PCSK9</italic> genotype reduces mortality has not be conclusively shown.<xref rid="bib8" ref-type="bibr">8</xref>, <xref rid="bib41" ref-type="bibr">41</xref> Irrespective of the nature of the <italic>PCSK9</italic> association with type 2 diabetes, large randomised trials should determine whether this relation also holds for PCSK9 monoclonal antibodies.</p><p>In a recent study,<xref rid="bib13" ref-type="bibr"><sup>13</sup></xref> investigators used a single SNP in <italic>PCSK9</italic> and also reported evidence of an association with type 2 diabetes (OR 1·19, 95% CI 1·02 to 1·38; per 1 mmol/L reduction in LDL cholesterol). In the present study, we incorporated data from four SNPs, instead of a single SNP, in a <italic>PCSK9</italic> gene score with participant data from 50 studies supplemented by large genetic consortia and are able to confirm their results, and also show this increase in type 2 diabetes risk is likely to be related to <italic>PCSK9</italic>-related increases in bodyweight and glucose. Previous studies of LDL cholesterol lowering <italic>HMGCR</italic><xref rid="bib3" ref-type="bibr"><sup>3</sup></xref> and <italic>NPC1L1</italic><xref rid="bib13" ref-type="bibr"><sup>13</sup></xref> variants (encoding pharmacological targets of statins and ezetimibe, respectively) and more widely on LDL cholesterol-lowering variants from multiple GWAS-associated loci,<xref rid="bib5" ref-type="bibr"><sup>5</sup></xref> as well as analyses of patients with monogenic hypercholesterolaemia,<xref rid="bib6" ref-type="bibr"><sup>6</sup></xref> have provided evidence of a link between LDL cholesterol and type 2 diabetes, compatible with the findings from the present study. However, it is far from certain that all LDL cholesterol-lowering interventions will increase risk of type 2 diabetes, as not all share the same mechanism of action. The major site of both statins and PCSK9 inhibitors is thought to be the liver, through increased cellular membrane expression of the LDL receptor. The liver is also the site of action of the investigational apolipoprotein B antisense oligonucleotide mipomersen, whereas ezetimibe, the other licensed LDL cholesterol lowering drug, acts in the intestine to limit LDL cholesterol absorption. A potential unifying mechanism might be pancreatic β cell LDL receptor upregulation, increased lipid accumulation, and β cell dysfunction,<xref rid="bib6" ref-type="bibr"><sup>6</sup></xref> but this suggestion will need to be tested experimentally.</p><p>In conclusion, genetic variants in <italic>PCSK9</italic> that associate with lower concentrations of LDL cholesterol are also associated with a modestly higher risk of type 2 diabetes and with associated differences in measures of glycaemia and bodyweight. Investigators of ongoing and future randomised controlled trials of PCSK9 inhibitors should carefully monitor changes in metabolic markers, including bodyweight and glycaemia, and the incidence of type 2 diabetes in study participants. 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AFS is funded by University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre (BRC10200) and by a UCL springboard population science fellowship. FWA is supported by a Dekker scholarship-Junior Staff Member 2014T001–Netherlands Heart Foundation and UCL Hospitals NIHR Biomedical Research Centre. ADH is an NIHR Senior Investigator. Funding information and acknowledgments for studies contributing data are reported in the <xref rid="sec1" ref-type="sec">appendix</xref>.</p></sec></ack><ack><title>Contributors</title><p>AFS, DIS, MVH, RSP, FWA, J-PC, BJK, ADH, DP, and NS contributed to the conception and design of the study. AFS, DIS, and MVH designed the analysis scripts shared with individual centres. AFS did the meta-analysis and had access to all the data. AFS, DIS, and MVH drafted the report. RSP, ZF-H, DML, FPH, BLH, EHy, CP, MM, EvI, GKH, ID, KN, ES-T, JD, LB, TL, SC, JWi, SK, KW, DM, JWr, RM, GW, PW, YB-S, SMc, JFP, MKi, CW, AS-G, PM-V, AN, AGP, NCO-M, YTvdS, GM, GF, SGua, CS, NJW, CL, RS, JL, MBo, SMa, AP, RK, ATa, HP, LLNH, NG, OP, TH, AL, KSS, JC, SEH, MBr, TK, HH, DSC, CAM, HLK, EBL, DRC, MdA, DMR, JCD, CC, SH, JA, EHo, MO'D, SY, MC, GP, PvdH, MAS, RNE, NV, HS (for the LifeLines Cohort study group), TC, DOM-K, SGus, LL, EI, RP, OF, AH, AU, AD, ATe, SB, MD, MML, UV, HV, JWa, JPP, DJS, TM, AHM-vdZ, EVB, RY, IF, AC, SP, MLB, DEG, PF, DT, BB, AB, BC, MS, YB, MKu, AM, PMR, DIC, APR, LAL, MDR, FWA, BJK, J-PC, ADH, DP, and NS were responsible for study-specific analyses and critically revised the report.</p></ack><ack><title>Declaration of interests</title><p>KH or his institution have received honoraria for consultancy, advisory board participation, or conduct of clinical trials from AMGEN, Aegerion, Pfizer, AstraZeneca, Sanofi, Regeneron, KOWA, Ionis pharmaceuticals, and Cerenis. GKH has received research support from Aegerion, AMGEN, Sanofi, AstraZeneca, and Synageva. BC has received research funding from Pfizer and Sanofi, has received personal fees for lectures from AstraZeneca, Pierre Fabre, Janssen, Eli Lilly, MSD Merck & Co, Novo Nordisk, Sanofi, and Takeda, and has acted as a consultant or advisory panel member for Amgen, Eli Lilly, Novo Nordisk, Sanofi, and Regeneron. DP has consulted for Sanofi on two occasions in previous employment (related to PCSK9 inhibitors) and was an investigator on clinical trials of PCSK9 inhibition funded by Amgen. NS has consulted for Amgen and Sanofi (related to PCSK9 inhibitors) and was an investigator on clinical trials of PCSK9 inhibition funded by Amgen. He has also consulted for MSD, Boehringer Ingelheim, Janssen, and Novo Nordisk. DIS has consulted for Pfizer for work unrelated to this report. AP has been a consultant and a member of an advisory panel for Amgen. EI is a scientific advisor and consultant for Precision Wellness Inc and a scientific advisor for Cellink, for work unrelated to this paper. All other authors declare no competing interests.</p></ack></back><floats-group><fig id="fig1"><label>Figure 1</label><caption><p>Association of genetic variants in <italic>PCSK9</italic> with circulating LDL cholesterol concentration</p><p>Effect estimates are presented as mean difference in LDL cholesterol (mmol/L) per LDL cholesterol-lowering allele, with 95% CIs. Results are pooled by use of a fixed-effect model. The size of the black dots representing the point estimates is proportional to the inverse of the variance. Note that results from individual participant data are supplemented by repository data from the Global Lipids Genetics Consortium.</p></caption><graphic xlink:href="gr1"></graphic></fig><fig id="fig2"><label>Figure 2</label><caption><p>Association of genetic variants in <italic>PCSK9</italic> with glycaemic and anthropometric biomarkers</p><p>Effect estimates are presented as mean difference with 95% CIs. Associations were scaled to a 1 mmol/L reduction in LDL cholesterol. SNP-specific results are pooled by use of a fixed-effect model; weighted gene-centric score (GS) models combining all four SNP-specific estimates are presented as fixed-effect and random-effects estimates. The size of the black dots representing the point estimates is proportional to the inverse of the variance. Between-SNP heterogeneity was measured as a two-sided Q-test (χ<sup>2</sup>) and an <italic>I</italic><sup>2</sup> with one-sided 97·5% CI. Note that results from individual participant data are supplemented by repository data from the Global Lipids Genetics Consortium, the Meta-Analyses of Glucose and Insulin-related traits Consortium, and the Genetic Investigation of Anthropometric Traits consortium.</p></caption><graphic xlink:href="gr2"></graphic></fig><fig id="fig3"><label>Figure 3</label><caption><p>Association of genetic variants in <italic>PCSK9</italic> with risk of type 2 diabetes, individually (A) and as weighted gene-centric score (B)</p><p>Effect estimates are presented as odds ratios (ORs) for the incidence or prevalence of type 2 diabetes, with 95% CIs. Associations were scaled to a 1 mmol/L reduction in LDL cholesterol. SNP-specific results are pooled by use of a fixed-effect model; weighted gene-centric score (GS) models combining all four SNP-specific estimates are presented as fixed-effect and random-effects estimates. The size of the black dots representing the point estimates is proportional to the inverse of the variance. Between-SNP heterogeneity was measured as a two-sided Q-test (χ<sup>2</sup>) and an <italic>I</italic><sup>2</sup> with one-sided 97·5% CI. Results from individual participant data are supplemented by repository data from the Diabetes Genetics Replication and Meta-analysis consortium.</p></caption><graphic xlink:href="gr3"></graphic></fig><fig id="fig4"><label>Figure 4</label><caption><p>Correlation between <italic>PCSK9</italic> associations with LDL cholesterol concentration and type 2 diabetes</p><p>Effect estimates are presented as mean difference in LDL cholesterol concentration (mmol/L) and odds ratios (ORs) for the incidence or prevalence of type 2 diabetes, with 95% CIs. Associations are presented per LDL cholesterol-decreasing allele. The Pearson correlation coefficient, regression line (grey), and its 95% CI (red) were calculated by weighting the SNPs for the inverse of the variance in the type 2 diabetes association. Excluding the SNP with the largest effect on LDL cholesterol (rs11591147) resulted in a correlation coefficient of 0·993 and a p value of 0·437.</p></caption><graphic xlink:href="gr4"></graphic></fig></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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