Please use this identifier to cite or link to this item: https://ktisis.cut.ac.cy/handle/10488/19111
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 
Horta, Bernardo Lessa 
Hyppönen, Elina 
Power, Christine 
Moldovan, Max V. 
Van Iperen, Erik P.A 
Hovingh, Kees 
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 
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. 
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 
Roussel, Ronan 
Bonnefond, Amélie 
Cariou, Bertrand 
Smart, Melissa C. 
Bao, Yanchun 
Kumari, Meena 
Mahajan, Anubha 
Hopewell, Jemma C. 
Seshadri, Sudha 
Dale, Caroline E. 
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 
Sanson, Marc 
Labreche, Karim 
Simon, Matthias 
Bondy, Melissa 
Law, Philip 
Speedy, Helen 
Allan, James 
Li, Ni 
Went, Molly 
Weinhold, Niels 
Morgan, Gareth 
Sonneveld, Pieter 
Nilsson, Björn 
Goldschmidt, Hartmut 
Sud, Amit 
Engert, Andreas 
Hansson, Markus 
Hemingway, Harry 
Asselbergs, Folkert W. 
Patel, Riyaz S. 
Keating, Brendan J. 
Sattar, Naveed A. 
Houlston, Richard 
Casas, Juan Pablo 
Hingorani, Aroon D. 
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://ktisis.cut.ac.cy/handle/10488/19111
ISSN: 1471-2261
DOI: 10.1186/s12872-019-1187-z
Rights: © 2019 The Author(s).
Attribution-NonCommercial-NoDerivatives 4.0 International
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 Center Amsterdam 
Charité-Universitätsmedizin Berlin 
Freie Universität Berlin 
Humboldt-Universitat zu Berlin 
Berlin Institute of Health 
University of Potsdam 
German Institute of Human Nutrition Potsdam-Rehbruecke 
E.CA Economics GmbH 
University of Lübeck 
University of Oslo 
Institute of Human Genetics 
Imperial College 
Innsbruck Medical University 
University of Bern 
Bradford Institute for Health Research 
University of London 
University of Bristol 
University of Lille 
Lausanne University Hospital 
Imperial College 
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 
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 
University of Newcastle 
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 
Imperial College London 
University of Glasgow 
German Centre for Cardiovascular Research 
Ludwig-Maximilians-Universität München 
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 School of Medicine 
Harvard Medical School 
UWash 
Penn State College 
University of Colorado Denver 
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 
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