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Title: PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study
Authors: Schmidt, Amand F. 
Swerdlow, Daniel I. 
Holmes, Michael Vaclav 
Patel, Riyaz Suleman 
Fairhurst-Hunter, Zammy 
Lyall, Donald M. 
Hartwig, Fernando Pires 
Horta, Bernardo Lessa 
Hyppönen, Elina 
Power, Chris 
Moldovan, Max V. 
Larson, Eric B. 
Crosslin, David R. 
De Andrade, Mariza De 
Roden, Dan M. 
Denny, Joshua C. 
Carty, Cara L. 
Hancock, Stephen John 
Attia, John 
Holliday, Elizabeth G. 
O'Donnell, Martin 
Völzke, Henry 
Yusuf, Salim 
Chong, Michael 
Pare, Guillaume 
Van Der Harst, Pim 
Said, Michael Abdullah 
Eppinga, Ruben N. 
Verweij, Niek 
Snieder, Harold 
Christen, Tim 
Mook-Kanamori, Dennis Owen 
Ward, Joey 
Gustafsson, Stefan 
Lind, Lars 
Ingelsson, Erik 
Pazoki, Raha 
Franco, Oscar H. 
Hofman, Albert 
Uitterlinden, André G. 
Dehghan, Abbas 
Teumer, Alexander 
Baumeister, Sebastian Edgar 
Pell, Jill P. 
Dörr, Marcus 
Lerch, Markus M. 
Völker, Uwe U. 
Smith, Daniel J. 
Meade, Tom W. 
Maitland-van Der Zee, Anke Hilse 
Baranova, Ekaterina V. 
Young, Robin 
Ford, Ian 
Campbell, Archie 
Van Iperen, Erik P.A 
Padmanabhan, Sandosh 
Bots, Michiel L. 
Grobbee, Diederick E. 
Froguel, Philippe H. 
Thuillier, Dorothée 
Balkau, Beverley J. 
Bonnefond, Amélie 
Cariou, Bertrand 
Smart, Melissa C. 
Bao, Yanchun 
Hovingh, Gerald Kees 
Kumari, Meena 
Mahajan, Anubha 
Ridker, Paul M. 
Chasman, Daniel I. 
Reiner, Alexander Paul 
Lange, Leslie A. 
Ritchie, Marylyn D. 
Asselbergs, Folkert W. 
Casas, Juan Pablo 
Keating, Brendan J. 
Demuth, Ilja 
Preiss, David J. 
Hingorani, Aroon D. 
Sattar, Naveed A. 
Norman, Kristina 
Steinhagen-Thiessen, Elisabeth 
Demuth, Juri 
Bertram, Lars 
Liu, Tian 
Coassin, Stefan 
Willeit, Johann 
Kiechl, Stefan 
Willeit, Karin 
Mason, Dan 
Wright, John P. 
Morris, Richard W. 
Wanamethee, Goya 
Whincup, Peter Hynes 
Ben-Shlomo, Yoav 
McLachlan, Stela 
Price, Jackie F. 
Kivimaki, Mika 
Welch, Catherine A. 
Sanchez-Galvez, Adelaida 
Marques-Vidal, Pedro 
Nicolaides, Andrew N. 
Panayiotou, Andrie 
Onland-Moret, N. Charlotte 
Van der Schouw, Y. T. 
Matullo, Giuseppe 
Fiorito, Giovanni 
Guarrera, Simonetta 
Sacerdote, Carlotta 
Wareham, Nicholas J.J. 
Langenberg, Claudia 
Scott, Robert A. 
Luan, Jian'an 
Bobak, Martin 
Malyutina, Sofia 
Pająk, Andrzej 
Kubinova, Růžena 
Tamosiunas, Abdonas 
Pikhart, Hynek 
Husemoen, Lise Lotte Nystrup 
Grarup, Niels 
Pedersen, Oluf Borbye Orbye 
Hansen, Torben Froestrup 
Linneberg, Allan 
Simonsen, Kenneth Starup 
Cooper, Jackie A. 
Humphries, Steve Eric 
Brilliant, Murray H. 
Kitchner, Terrie E. 
Hakonarson, Håkon H. 
Carrell, David S. 
McCarty, Catherine A. 
Kirchner, H. Lester 
Keywords: Heart disease;LDL cholesterol;Diabetes
Category: Health Sciences
Field: Medical and Health Sciences
Issue Date: 1-Feb-2017
Publisher: Lancet Publishing Group
Source: The Lancet Diabetes and Endocrinology, 2017, Volume 5, Issue 2, Pages 97-105
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 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.
ISSN: 22138587
Rights: © 2017 The Author(s).
Type: Article
Appears in Collections:Άρθρα/Articles

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