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 CoassinJohann 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 Pajak, 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 Sattar

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

186 Citations (Scopus)
250 Downloads (Pure)

Abstract

Background Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of low-density lipoprotein cholesterol (LDL-C) and the risk of coronary heart disease, but also with modest hyperglycemia, higher weight and risk of type 2 diabetes mellitus (T2DM). We sought to clarify the associations of LDL-C-lowering PCSK9 variants with T2DM and related biomarkers to gauge likely effects of PCSK9 inhibitors.
Methods Associations of PCSK9 variants with LDL-C, fasting blood glucose, HbA1c, fasting insulin, weight and T2DM risk, available for over 550,000 individuals and 51,623 T2DM cases, were estimated using a standardised analysis plan, meta-analyses and weighted gene-centric scores (GS).
Findings Combined analysis of four independent PCSK9 variants scaled to 1 mmol/L lower LDL-C resulted in the following associations: fasting glucose (0·09 mmol/L; 95%CI 0·02; 0·15), HbA1c (0·03%; 95%CI -0·01; 0·08), fasting insulin (0·00% 95%CI -0·06; 0·07), body weight (1·03 kg; 95%CI 0·24; 1·82), waist-to-hip ratio (0·006; 95%CI 0·003; 0·010), body mass index (0·11 kg/m2; 95%CI -0·09; 0·30), and an odds ratio of 1·29 for T2DM (95%CI 1·11; 1·50).
Interpretation PCSK9 variants associated with lower LDL-C were also associated with higher levels of glucose, weight, waist-to-hip ratio and increased T2DM risk. Trials of PCSK9 inhibitor drugs should carefully evaluate these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment as previously done for statins.
Original languageEnglish
Pages (from-to)97-105
Number of pages9
JournalLancet Diabetes and Endocrinology
Volume5
Issue number2
Early online date29 Nov 2016
DOIs
Publication statusPublished - 1 Feb 2017

Keywords

  • Diabetes Mellitus
  • Genetic Association Studies
  • Mendelian randomisation
  • LDL-cholesterol
  • PCSK9 inhibition

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