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 ; +125 more... 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 ; (2016) PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study. The lancet Diabetes & endocrinology, 5 (2). pp. 97-105. ISSN 2213-8587 DOI: 10.1016/S2213-8587(16)30396-5

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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.