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Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

By Amand F Schmidt, Michael V Holmes, David Preiss, Daniel Swerdlow, Spiros Denaxas, Ghazaleh Fatemifar, Rupert Faraway, Chris Finan, Tom Lumbers, Albert Henry, Dennis Valentine, Zammy Fairhurst-Hunter, Fernando Pires Hartwig, Bernardo Lessa Horta, Elina Hypponen, Christine Power, Max Moldovan, Erik van Iperen, Kees Hovingh, Ilja Demuth, Kristina Norman, Elisabeth Steinhagen-Thiessen, Juri Demuth, Lars Bertram, Christina M. Lill, 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, Nick Wareham, Claudia Langenberg, Robert A Scott, Jian’an Luan, Martin Bobak, Sofia Malyutina, Andrzej Pajak, Ruzena Kubinova, Abdonas Tamosiunas, Hynek Pikhart, Niels Grarup, Oluf Pedersen, Torben Hansen, Allan Linneberg, Tine Jess, Jackie Cooper, Steve E Humphries, Murray Brilliant, Terrie Kitchner, Hakon Hakonarson, David S Carrell, Catherine A. McCarty, Kirchner H Lester, Eric B Larson, David R. Crosslin, Mariza de Andrade, Dan M. Roden, Joshua C. Denny, Cara Carty, Stephen Hancock, John Attia, Elizabeth Holliday, Rodney Scott, Peter Schofield, 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, D.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, Tom Meade, Ingrid E. Christophersen, 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, Ronan Roussel, Amelie Bonnefond, Bertrand Cariou, Melissa Smart, Yanchun Bao, Meena Kumari, Anubha Mahajan, Jemma C. Hopewell, Sudha Seshadri, Caroline Dale, Rui Providencia E Costa, Paul M Ridker, Daniel I Chasman, Alex P Reiner, Marylyn D Ritchie, Leslie A Lange, Alex J. Cornish, Sara E. Dobbins, Kari Hemminki, Ben Kinnersley, Marc Sanson, Karim Labreche, Matthias Simon, Melissa Bondy, Philip Law, Helen Speedy, James Allan, Ni Li, Molly Went, Niels Weinhold, Gareth Morgan, Pieter Sonneveld, Björn Nilsson, Hartmut Goldschmidt, Amit Sud, Andreas Engert, Markus Hansson, Harry Hemingway, Folkert W Asselbergs, Riyaz S Patel, Brendan J Keating, Naveed Sattar, Richard Houlston, Juan P Casas, Aroon D. Hingorani

Posted 25 May 2018
bioRxiv DOI: 10.1101/329052 (published DOI: 10.1186/s12872-019-1187-z)

Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Fourteen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95%CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95%CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95%CI 0.57; 1.22) for the GS, compared to 0.85 (95%CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95%CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. Apparent discordance between genetic associations and trial outcome for T2DM might be explained lack by a of statistical precision, or differences in the nature and duration of genetic versus pharmacological perturbation of PCSK9.

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