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

LifeLines Cohort study group; UCLEB consortium

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

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

LifeLines Cohort study group
, UCLEB consortium

University College London
Imperial College London
University of Oxford Medical Sciences Division
University of Oxford
St Bartholomew's Hospital
Wellcome Trust Centre for Human Genetics
University of Glasgow
Hospital Escola da Universidade Federal de Pelotas
University of South Australia
UCL Great Ormond Street Institute of Child Health
South Australian Health and Medical Research Institute
Interuniv. Cardiol. Inst. N.
Academic Medical Center
Charité – Universitätsmedizin Berlin
E.CA Economics
Universitaet Luebeck
Max Planck Institute for Human Development
Max Planck Institute for Molecular Genetics
Medical University Innsbruck
Bradford Institute for Health Research
University of Bristol
St. Georges Hospital
University of Edinburgh
University Hospital Center
University of Nicosia
Cyprus University of Technology
University Medical Centre Utrecht
Human Genetics Foundation
University of Turin
San Giovanni Hospital
CPO Piemonte
University of Cambridge School of Clinical Medicine
Novosibirsk State Medical University
Siberian Branch of the Russian Academy of Medical Sciences
Jagiellonian University Medical College
National Institute of Public Health Prague
Lithuanian University of Health Sciences
Research Centre for Prevention and Health
Novo Nordisk Foundation Center for Basic Metabolic Research
University Hospital of Copenhagen - Rigshospitalet
University of Copenhagen
Marshfield Clinic
Research Institute
Group Health Research Institute
Essentia Institute of Rural Health
Weis Center for Research
Mayo Clinic
Vanderbilt University School of Medicine
George Washington University
University of Newcastle
Population Health Research Institute, Ontario
University Medical Center Groningen
Leiden University Medical Center
Uppsala University
Stanford University School of Medicine
Erasmus MC
University Medicine Greifswald
Partner site Berlin
University of Regensburg
London School of Hygiene and Tropical Medicine
Utrecht University
University of Edinburgh
University Lille
Hormones and Women's Health Team
Université de Nantes
Institute for Social and Economic Research, University of Essex
Brigham and Women's Hospital
University of Washington
University of Colorado Anschutz Medical Campus
Geisinger Health System
Huck Institutes of the Life Sciences
University of Pennsylvania

Research output: Contribution to a Journal (Peer & Non Peer) › Article › peer-review

334 Citations (Scopus)

Abstract

Background Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk. Methods In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA_1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores. Findings Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50). Based on the collected data, we did not identify associations with HbA_1c (0·03%, −0·01 to 0·08), fasting insulin (0·00%, −0·06 to 0·07), and BMI (0·11 kg/m², −0·09 to 0·30). Interpretation PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins. Funding British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.

Original language	English
Pages (from-to)	97-105
Number of pages	9
Journal	The Lancet Diabetes and Endocrinology
Volume	5
Issue number	2
DOIs	https://doi.org/10.1016/S2213-8587(16)30396-5
Publication status	Published - 1 Feb 2017
Externally published	Yes

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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10.1016/S2213-8587(16)30396-5

Cite this

@article{1338064c8ef5460e96d65799e7a1401c,

title = "PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study",

abstract = "Background Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk. Methods In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores. Findings Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95\% CI 0·02 to 0·15), bodyweight (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50). Based on the collected data, we did not identify associations with HbA1c (0·03\%, −0·01 to 0·08), fasting insulin (0·00\%, −0·06 to 0·07), and BMI (0·11 kg/m2, −0·09 to 0·30). Interpretation PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins. Funding British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.",

author = "\{LifeLines Cohort study group\} and \{UCLEB consortium\} and Schmidt, \{Amand F.\} and Swerdlow, \{Daniel I.\} and Holmes, \{Michael V.\} and Patel, \{Riyaz S.\} and Zammy Fairhurst-Hunter and Lyall, \{Donald M.\} and Hartwig, \{Fernando Pires\} and Horta, \{Bernardo Lessa\} and Elina Hypp{\"o}nen and Christine Power and Max Moldovan and \{van Iperen\}, Erik and Hovingh, \{G. Kees\} and Ilja Demuth and Kristina Norman and Elisabeth Steinhagen-Thiessen and Juri Demuth and Lars Bertram and Tian Liu and Stefan Coassin and Johann Willeit and Stefan Kiechl and Karin Willeit and Dan Mason and John Wright and Richard Morris and Goya Wanamethee and Peter Whincup and Yoav Ben-Shlomo and Stela McLachlan and Price, \{Jackie F.\} and Mika Kivimaki and Catherine Welch and Adelaida Sanchez-Galvez and Pedro Marques-Vidal and Andrew Nicolaides and Panayiotou, \{Andrie G.\} and Onland-Moret, \{N. Charlotte\} and \{van der Schouw\}, \{Yvonne T.\} and Giuseppe Matullo and Giovanni Fiorito and Simonetta Guarrera and Carlotta Sacerdote and Wareham, \{Nicholas J.\} and Claudia Langenberg and Robert Scott and Jian'an Luan and Martin Bobak and Sofia Malyutina and Andrzej Paj{\c a}k and Ruzena Kubinova and Abdonas Tamosiunas and Hynek Pikhart and Husemoen, \{Lise Lotte Nystrup\} and Niels Grarup and Oluf Pedersen and Torben Hansen and Allan Linneberg and Simonsen, \{Kenneth Starup\} and Jackie Cooper and Humphries, \{Steve E.\} and Murray Brilliant and Terrie Kitchner and Hakon Hakonarson and Carrell, \{David S.\} and McCarty, \{Catherine A.\} and Kirchner, \{H. Lester\} and Larson, \{Eric B.\} and Crosslin, \{David R.\} and \{de Andrade\}, Mariza and Roden, \{Dan M.\} and Denny, \{Joshua C.\} and Cara Carty and Stephen Hancock and John Attia and Elizabeth Holliday and Martin O'Donnell and Salim Yusuf and Michael Chong and Guillaume Pare and \{van der Harst\}, Pim and Said, \{M. Abdullah\} and Eppinga, \{Ruben N.\} and Niek Verweij and Harold Snieder and Tim Christen and Mook-Kanamori, \{Dennis O.\} and Stefan Gustafsson and Lars Lind and Erik Ingelsson and Raha Pazoki and Oscar Franco and Albert Hofman and Andre Uitterlinden and Abbas Dehghan and Alexander Teumer and Sebastian Baumeister and Marcus D{\"o}rr and Lerch, \{Markus M.\} and Uwe V{\"o}lker",

note = "Publisher Copyright: {\textcopyright} 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license",

year = "2017",

month = feb,

day = "1",

doi = "10.1016/S2213-8587(16)30396-5",

language = "English",

volume = "5",

pages = "97--105",

journal = "The Lancet Diabetes and Endocrinology",

issn = "2213-8587",

publisher = "Elsevier Ltd",

number = "2",

}

TY - JOUR

T1 - PCSK9 genetic variants and risk of type 2 diabetes

T2 - a mendelian randomisation study

AU - LifeLines Cohort study group

AU - UCLEB consortium

AU - Schmidt, Amand F.

AU - Swerdlow, Daniel I.

AU - Holmes, Michael V.

AU - Patel, Riyaz S.

AU - Fairhurst-Hunter, Zammy

AU - Lyall, Donald M.

AU - Hartwig, Fernando Pires

AU - Horta, Bernardo Lessa

AU - Hyppönen, Elina

AU - Power, Christine

AU - Moldovan, Max

AU - van Iperen, Erik

AU - Hovingh, G. Kees

AU - Demuth, Ilja

AU - Norman, Kristina

AU - Steinhagen-Thiessen, Elisabeth

AU - Demuth, Juri

AU - Bertram, Lars

AU - Liu, Tian

AU - Coassin, Stefan

AU - Willeit, Johann

AU - Kiechl, Stefan

AU - Willeit, Karin

AU - Mason, Dan

AU - Wright, John

AU - Morris, Richard

AU - Wanamethee, Goya

AU - Whincup, Peter

AU - Ben-Shlomo, Yoav

AU - McLachlan, Stela

AU - Price, Jackie F.

AU - Kivimaki, Mika

AU - Welch, Catherine

AU - Sanchez-Galvez, Adelaida

AU - Marques-Vidal, Pedro

AU - Nicolaides, Andrew

AU - Panayiotou, Andrie G.

AU - Onland-Moret, N. Charlotte

AU - van der Schouw, Yvonne T.

AU - Matullo, Giuseppe

AU - Fiorito, Giovanni

AU - Guarrera, Simonetta

AU - Sacerdote, Carlotta

AU - Wareham, Nicholas J.

AU - Langenberg, Claudia

AU - Scott, Robert

AU - Luan, Jian'an

AU - Bobak, Martin

AU - Malyutina, Sofia

AU - Pająk, Andrzej

AU - Kubinova, Ruzena

AU - Tamosiunas, Abdonas

AU - Pikhart, Hynek

AU - Husemoen, Lise Lotte Nystrup

AU - Grarup, Niels

AU - Pedersen, Oluf

AU - Hansen, Torben

AU - Linneberg, Allan

AU - Simonsen, Kenneth Starup

AU - Cooper, Jackie

AU - Humphries, Steve E.

AU - Brilliant, Murray

AU - Kitchner, Terrie

AU - Hakonarson, Hakon

AU - Carrell, David S.

AU - McCarty, Catherine A.

AU - Kirchner, H. Lester

AU - Larson, Eric B.

AU - Crosslin, David R.

AU - de Andrade, Mariza

AU - Roden, Dan M.

AU - Denny, Joshua C.

AU - Carty, Cara

AU - Hancock, Stephen

AU - Attia, John

AU - Holliday, Elizabeth

AU - O'Donnell, Martin

AU - Yusuf, Salim

AU - Chong, Michael

AU - Pare, Guillaume

AU - van der Harst, Pim

AU - Said, M. Abdullah

AU - Eppinga, Ruben N.

AU - Verweij, Niek

AU - Snieder, Harold

AU - Christen, Tim

AU - Mook-Kanamori, Dennis O.

AU - Gustafsson, Stefan

AU - Lind, Lars

AU - Ingelsson, Erik

AU - Pazoki, Raha

AU - Franco, Oscar

AU - Hofman, Albert

AU - Uitterlinden, Andre

AU - Dehghan, Abbas

AU - Teumer, Alexander

AU - Baumeister, Sebastian

AU - Dörr, Marcus

AU - Lerch, Markus M.

AU - Völker, Uwe

PY - 2017/2/1

Y1 - 2017/2/1

N2 - Background Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk. Methods In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores. Findings Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50). Based on the collected data, we did not identify associations with HbA1c (0·03%, −0·01 to 0·08), fasting insulin (0·00%, −0·06 to 0·07), and BMI (0·11 kg/m2, −0·09 to 0·30). Interpretation PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins. Funding British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.

AB - Background Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk. Methods In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores. Findings Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50). Based on the collected data, we did not identify associations with HbA1c (0·03%, −0·01 to 0·08), fasting insulin (0·00%, −0·06 to 0·07), and BMI (0·11 kg/m2, −0·09 to 0·30). Interpretation PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins. Funding British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.

UR - https://www.scopus.com/pages/publications/85007330927

U2 - 10.1016/S2213-8587(16)30396-5

DO - 10.1016/S2213-8587(16)30396-5

M3 - Article

C2 - 27908689

AN - SCOPUS:85007330927

SN - 2213-8587

VL - 5

SP - 97

EP - 105

JO - The Lancet Diabetes and Endocrinology

JF - The Lancet Diabetes and Endocrinology

IS - 2

ER -

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

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