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

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

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

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

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

Amand F. Schmidt, Daniel I. Swerdlow, Michael V. Holmes, Riyaz S. Patel, Zammy Fairhurst-Hunter, Donald M. Lyall, Fernando Pires Hartwig, Bernardo Lessa Horta, Elina Hyppönen, Christine Power, …

The Lancet. Diabetes & Endocrinology , Vol.5(2), pp.97--105

Equipe IV

02/2017

DOI: https://doi.org/10.1016/S2213-8587(16)30396-5

PMCID: PMC5266795

PMID: 27908689

Abstract

BACKGROUND: Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk. METHODS: In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores. FINDINGS: Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50). Based on the collected data, we did not identify associations with HbA1c (0·03%, -0·01 to 0·08), fasting insulin (0·00%, -0·06 to 0·07), and BMI (0·11 kg/m(2), -0·09 to 0·30). INTERPRETATION: PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins. FUNDING: British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.

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Title: PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study
Creators - without role: Amand F. Schmidt - University College London
Daniel I. Swerdlow - University College London
Michael V. Holmes - University of Oxford
Riyaz S. Patel - Farr Institute
Zammy Fairhurst-Hunter - Centre for Human Genetics
Donald M. Lyall - University of Glasgow
Fernando Pires Hartwig - Universidade Federal de Pelotas
Bernardo Lessa Horta - Universidade Federal de Pelotas
Elina Hyppönen - Great Ormond Street Hospital
Christine Power - Great Ormond Street Hospital
Max Moldovan - South Australian Health and Medical Research Institute
Erik Van Iperen
G. Kees Hovingh - Academic Medical Center
Ilja Demuth - Charité - Universitätsmedizin Berlin
Kristina Norman - Charité - Universitätsmedizin Berlin
Elisabeth Steinhagen-Thiessen - Charité - Universitätsmedizin Berlin
Juri Demuth
Lars Bertram - Institute for Integrative and Experimental Genomics
Tian Liu - Max Planck Institute for Human Development
Stefan Coassin - Universität Innsbruck
Johann Willeit - Universität Innsbruck
Stefan Kiechl - Innsbruck Medical University
Karin Willeit - Innsbruck Medical University
Dan Mason - Bradford Royal Infirmary
John Wright - Bradford Royal Infirmary
Richard Morris - University of Bristol
Goya Wanamethee - University College London
Peter Whincup - St George's, University of London
Yoav Ben-Shlomo - University of Bristol
Stela Mclachlan - Glasgow Centre for Population Health
Jackie F. Price - Glasgow Centre for Population Health
Mika Kivimaki - University College London
Catherine Welch - University College London
Adelaida Sanchez-Galvez - University College London
Pedro Marques-Vidal - University of Lausanne
Andrew Nicolaides - Imperial College London
Andrie G. Panayiotou - Cyprus University of Technology
N. Charlotte Onland-Moret - University Medical Center Utrecht
Yvonne T. van Der Schouw - University Medical Center [Utrecht]
Giuseppe Matullo - Italian institute for Genomic Medicine
Giovanni Fiorito - University of Turin
Simonetta Guarrera - Italian institute for Genomic Medicine
Carlotta Sacerdote - Piedmont Reference Center for Epidemiology and Cancer Prevention
Nicholas J. Wareham - MRC Epidemiology Unit
Claudia Langenberg - MRC Epidemiology Unit
Robert Scott - MRC Epidemiology Unit
Jian'An Luan - Serono Genetics Institute S.A.[Evry]
Martin Bobak - University College London
Sofia Malyutina - Novosibirsk State Medical University
Andrzej Pająk - Jagiellonian University
Ruzena Kubinova - National Institute of Public Health
Abdonas Tamosiunas - Lithuanian University of Health Sciences
Hynek Pikhart - University College London
Lise Lotte Nystrup Husemoen - Capital Region of Denmark
Niels Grarup - University of Copenhagen
Oluf Pedersen - Novo Nordisk Foundation
Torben Hansen - Novo Nordisk Foundation
Allan Linneberg - University of Copenhagen
Kenneth Starup Simonsen - Capital Region of Denmark
Jackie Cooper - University College London
Steve E. Humphries - University College London
Murray Brilliant - Marshfield Clinic
Terrie Kitchner - Marshfield Clinic
Hakon Hakonarson - Children's Hospital of Philadelphia
David S. Carrell - Kaiser Permanente Washington Health Research Institute
Catherine A. Mccarty - Essentia Health
H. Lester Kirchner - Geisinger Medical Center
Eric B. Larson - Kaiser Permanente Washington Health Research Institute
David R. Crosslin - Kaiser Permanente Washington Health Research Institute
Mariza De Andrade
Dan M. Roden - Vanderbilt University
Joshua C. Denny - Vanderbilt University
Cara Carty - George Washington University
Stephen Hancock - University of Newcastle Australia
John Attia - University of Newcastle Australia
Elizabeth Holliday - University of Newcastle Australia
Martin O'Donnell
Salim Yusuf - Population Health Research Institute
Michael Chong - Population Health Research Institute
Guillaume Pare - Population Health Research Institute
Pim van Der Harst
M. Abdullah Said - University Medical Center Groningen
Ruben N. Eppinga - University of Groningen
Niek Verweij - University Medical Center Groningen
Harold Snieder - University Medical Center Groningen
Lifelines Cohort Study Group
Tim Christen - Leiden University Medical Center
Dennis O. Mook-Kanamori - Leiden University Medical Center
Stefan Gustafsson - Uppsala University
Lars Lind - Uppsala University
Erik Ingelsson - Stanford University
Raha Pazoki - Erasmus MC
Oscar Franco - Erasmus MC
Albert Hofman - Erasmus MC
Andre Uitterlinden - Erasmus MC
Abbas Dehghan - Imperial College London
Alexander Teumer - German Centre for Cardiovascular Research
Sebastian Baumeister - University of Regensburg
Marcus Dörr - German Centre for Cardiovascular Research
Markus M. Lerch - Universitätsmedizin Greifswald
Uwe Völker - German Centre for Cardiovascular Research
Henry Völzke - German Centre for Cardiovascular Research
Joey Ward - University of Glasgow
Jill P. Pell - University of Glasgow
Daniel J. Smith
Tom Meade - London School of Hygiene & Tropical Medicine
Anke H. Maitland-van Der Zee
Ekaterina V. Baranova - Utrecht University
Robin Young - University of Glasgow
Ian Ford - University of Glasgow
Archie Campbell - MRC Institute of Genetics and Molecular Medicine
Sandosh Padmanabhan - University of Glasgow
Michiel L. Bots - University Medical Center Utrecht
Diederick E. Grobbee - University Medical Center Utrecht
Philippe Froguel - Genomics England
Dorothée Thuillier - Institut Pasteur de Lille
Beverley Balkau - Centre de recherche en Epidémiologie et Santé des Populations
Amélie Bonnefond - Université de Montpellier, Cell souches plasticité cellul régénérat tissulaire immuno des maladies inflamm - IRMB
Bertrand Cariou - Institut du Thorax
Melissa Smart - University of Essex
Yanchun Bao - University of Essex
Meena Kumari - University of Essex
Anubha Mahajan - University of Oxford
Paul M. Ridker - Brigham and Women's Hospital
Daniel I. Chasman - Brigham and Women's Hospital
Alex P. Reiner - University of Washington
Leslie A. Lange - University of Colorado Anschutz Medical Campus
Marylyn D. Ritchie - Pennsylvania State University
Folkert W. Asselbergs - University Medical Center Utrecht
Juan-Pablo Casas - Farr Institute
Brendan J. Keating - University of Pennsylvania
David Preiss - University of Oxford
Aroon D. Hingorani - University College London
Ucleb Consortium
Naveed Sattar - University of Glasgow
Publication Details: The Lancet. Diabetes & Endocrinology , Vol.5(2), pp.97--105
Series: Equipe IV
Identifiers: 9934133809311
Academic Unit: Cell souches plasticité cellul régénérat tissulaire immuno des maladies inflamm - IRMB
Language: English
Resource Type: Journal article
Local Fields: hal-01833114