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https://hdl.handle.net/20.500.14279/19111
Title: | Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9 | Authors: | Schmidt, Amand F. Holmes, Michael Vaclav Preiss, David J. Swerdlow, Daniel I. Denaxas, Spiros Fatemifar, Ghazaleh Faraway, Rupert Finan, Chris I. Valentine, Dennis Fairhurst-Hunter, Zammy Hartwig, Fernando Pires Teumer, Alexander Baumeister, Sebastian Edgar Dörr, Marcus Lerch, Markus M. Völker, Uwe Völzke, Henry Ward, Joey Pell, Jill P. Meade, Tom W. Christophersen, Ingrid E. Horta, Bernardo Lessa Maitland-van Der Zee, Anke Hilse Baranova, Ekaterina V. Young, Robin Ford, Ian Campbell, Archie Padmanabhan, Sandosh Bots, Michiel L. Grobbee, Diederick E. Froguel, Philippe Thuillier, Dorothée Hyppönen, Elina Roussel, Ronan Bonnefond, Amélie Cariou, Bertrand Smart, Melissa C. Bao, Yanchun Kumari, Meena Mahajan, Anubha Hopewell, Jemma C. Seshadri, Sudha Dale, Caroline E. Power, Chris Costa, Rui Providencia E. Ridker, Paul M. Chasman, Daniel I. Reiner, Alex P. Ritchie, Marylyn D. Lange, Leslie A. Cornish, Alex J. Dobbins, Sara E. Hemminki, Kari Kinnersley, Ben Moldovan, Max V. Sanson, Marc Labreche, Karim Simon, Matthias Bondy, Melissa Law, Philip Speedy, Helen Allan, James Li, Ni Went, Molly Weinhold, Niels Van Iperen, Erik P.A Morgan, Gareth Sonneveld, Pieter Nilsson, Björn Goldschmidt, Hartmut Sud, Amit Engert, Andreas Hansson, Markus Hemingway, Harry Asselbergs, Folkert W. Patel, Riyaz S. Hovingh, Kees Keating, Brendan J. Sattar, Naveed A. Houlston, Richard Casas, Juan Pablo Hingorani, Aroon D. Demuth, Ilja Norman, Kristina Steinhagen-Thiessen, Elisabeth Demuth, Juri Bertram, Lars Lill, Christina M. Coassin, Stefan Willeit, Johann Kiechl, Stefan Willeit, Karin Mason, Dan Wright, John J. 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 G. Onland-Moret, N. Charlotte Van Der Schouw, Yvonne T. Matullo, Giuseppe Fiorito, Giovanni Guarrera, Simonetta Sacerdote, Carlotta Wareham, Nicholas J. Langenberg, Claudia Scott, Robert A. Luan, Jian'an Bobak, Martin Malyutina, Sofia K. Pająk, Andrzej Kubinova, Růžena Tamosiunas, Abdonas Pikhart, Hynek Grarup, Niels Pedersen, Oluf Borbye Orbye Hansen, Torben H. Linneberg, Allan Jess, Tine Cooper, Jackie A. Humphries, Steve Eric Brilliant, Murray H. Kitchner, Terrie E. Hakonarson, Håkon H. Carrell, David S. McCarty, Catherine A. Kirchner, H. Lester Larson, Eric B. Crosslin, David R. De Andrade, Mariza Roden, Dan M. Denny, Joshua C. Carty, Cara L. Hancock, Stephen John Attia, John Holliday, Elizabeth G. Scott, Rodney Schofield, Peter O'Donnell, Martin Yusuf, Salim Chong, Michael Pare, Guillaume Van Der Harst, Pim Said, Mir Abdullah Eppinga, Ruben N. Verweij, Niek Snieder, Harold Christen, Tim Mook-Kanamori, Dennis Owen Gustafsson, Stefan A. Lind, Lars Ingelsson, Erik Pazoki, Raha Franco, Oscar H. Hofman, Albert Uitterlinden, André G. Dehghan, Abbas |
Major Field of Science: | Medical and Health Sciences | Field Category: | Clinical Medicine | Keywords: | Genetic association studies;LDL-cholesterol;Mendelian randomisation;Phenome-wide association scan | Issue Date: | 2019 | Source: | BMC Cardiovascular Disorders, 2019, vol. 19, no. 1, articl. no. 240 | Volume: | 19 | Issue: | 1 | Journal: | BMC Cardiovascular Disorders | Abstract: | 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). Seventeen 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. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate. | URI: | https://hdl.handle.net/20.500.14279/19111 | ISSN: | 14712261 | DOI: | 10.1186/s12872-019-1187-z | Rights: | © 2019 The Author(s). | Type: | Article | Affiliation : | University College London UCL's BHF Research Accelerator Centre University of Oxford British Library Federal University of Pelotas University of South Australia UCL GOS Institute of Child Health South Australian Health and Medical Research Institute Netherlands Heart Institute Academic Medical Centre Charité-Universitätsmedizin Berlin Free University of Berlin Humboldt-Universitat zu Berlin Berlin Institute of Health University of Potsdam German Institute of Human Nutrition Potsdam-Rehbrücke E.CA Economics GmbH University of Lübeck University of Oslo Institute of Human Genetics Imperial College London Innsbruck Medical University University of Bern Bradford Institute for Health Research University of London University of Bristol University of Lille Lausanne University Hospital University of Nicosia Cyprus University of Technology Utrecht University Italian Institute for Genomic Medicine University of Turin Città della Salute e della Scienza University University of Cambridge Novosibirsk State Medical University Russian Academy of Medical Sciences National Institute of Public Health Prague Lithuanian University of Health Sciences University of Copenhagen Bispebjerg and Frederiksberg Hospital Marshfield Clinic Research Institute Childrens Hospital of Philadelphia University of Minnesota Kaiser Permanente Washington Health Research Institute University of Washington Seattle Mayo Clinic Vanderbilt University Newcastle University Hunter Medical Research Institute Hunter New England Local Health District Population Health Research Institute University of Groningen Leiden University Medical Center Uppsala University Stanford University Erasmus University Medical Center University of Glasgow German Center for Cardiovascular Research Ludwig Maximilians University University Medicine Greifswald London School of Hygiene and Tropical Medicine Vestre Viken Hospital Trust University of Amsterdam Centre de Recherche des Cordeliers Université Paris Diderot Assistance Publique Hôpitaux de Paris UNIV Nantes University of Essex Boston University Harvard University UWash Penn State College University of Colorado Institute of Cancer Research German Cancer Research Center Deutsches Krebsforschungszentrum Institut du Cerveau et de la Moelle Épinière UPMC Université Paris 06 Bethel Clinic Baylor College of Medicine Newcastle University University of Arkansas for Medical Sciences Erasmus MC Cancer Institute University Hospital of Cologne Skåne University Hospital Lund University St Bartholomew's Hospital UPenn Veterans Affairs Boston Healthcare System |
Publication Type: | Peer Reviewed |
Appears in Collections: | Άρθρα/Articles |
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