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Title: Secretory phospholipase A2-IIA and cardiovascular disease: a mendelian randomization study
Authors: Holmes, Michael Vaclav 
Simon, Tabassome 
Exeter, Holly J. 
Folkersen, Lasse 
Asselbergs, Folkert W. 
Guardiola, Montse 
Cooper, Jackie A. 
Palmen, Jutta A. 
Hubacek, Jaroslav Alois 
Carruthers, Kathryn F. 
Horne, Benjamin D. 
Ford, Ian 
Klungel, Olaf H H 
Kumari, Meena 
Whincup, Peter H. 
Morrow, David A. 
Morris, Richard W. 
Braund, Peter S. 
Hall, Alistair S. 
Doevendans, Pieter A F M 
Trip, Mieke D. 
Price, Jackie F. 
Tobin, Martin D. 
Hamsten, Anders 
Koenig, Wolfgang 
Nicolaides, Andrew N. 
Teupser, Daniel 
Day, Ian N.M. 
Jukema, Johan Wouter Outer 
Carlquist, John F. 
Gaunt, Tom R. 
Sattar, Naveed A. 
Tsimikas, Sotirios 
Fox, Keith A.A. 
Schwartz, Gregory G. 
Lawlor, Debbie A. 
Sandhu, Manjinder S. 
Poledne, Rudolf 
Maitland-van Der Zee, Anke Hilse 
Khaw, Kay Tee T 
Eriksson, Per Olof 
Keating, Brendan J. 
Van Der Harst, Pim 
Mehta, Shamir R. 
Yusuf, Salim M. 
Brunisholz, Kimberly D. 
Witteman, Jacqueline C M 
Franco, Oscar H. 
De Knijff, Peter 
Tybjærg-Hansen, Anne 
Rader, Daniel J. 
Farrall, Martin J. 
Verschuren, Jeffrey J W 
Samani, Nilesh 
Kivimaki, Mika 
Humphries, Steve Eric 
Anderson, Jeffrey L. 
Danchin, N. 
Boekholdt, S. Matthijs 
Palmer, Tom M. 
Pare, Guillaume J. 
Hingorani, Aroon D. 
Sabatine, Marc S. 
Mallat, Ziad 
Goel, Anuj K. 
Casas, Juan Pablo 
Talmud, Philippa J. 
Mega, Jessica 
Van Iperen, Erik P A 
Tremoli, Elena 
Leusink, Maarten 
Trompet, Stella 
Hovingh, Gerald Kees 
Dehghan, Abbas Jan 
Nelson, Christopher P. 
Kotti, Salma 
Mateo Leach, Irene 
Scholz, Markus R. 
Haase, Christiane L. 
Rothenbacher, Dietrich 
Swerdlow, Daniel I. 
Franco-Cereceda, Anders 
Kuchenbaecker, Karoline B. 
Staines-Urias, Eleonora 
Van 'T Hooft, Ferdinand M. 
Gertow, Karl 
De Faire, Ulf H. 
Panayiotou, Andrie G. 
Adamkova, Vera 
Baldassarre, Damiano 
Veglia, Fabrizio 
Holdt, Lesca Miriam 
Beutner, Frank 
Spiering, Wilko 
Gansevoort, Ron T. 
Navis, Gerjan J. 
Breitling, Lutz Philipp H 
Brenner, Hermann Hermann 
Thiery, Joachim J. 
Dallmeier, Dhayana 
Olsson, Anders G. 
Boer, Jolanda Ma A 
Stephens, Jeffrey W. 
Hofker, Marten 
Tedgui, Alain S. 
Watkins, Hugh C. 
Hofman, Albert 
Uitterlinden, Andre Gerardus 
Piťha, Jan 
Onland-Moret, N. Charlotte 
Cramer, Maarten Jan M 
Nathoe, H. 
Major Field of Science: Medical and Health Sciences
Field Category: Clinical Medicine
Keywords: Cardiovascular diseases;Drug development;Epidemiology;Genetics;Mendelian randomization
Issue Date: 19-Nov-2013
Source: Journal of the American College of Cardiology, 2013, vol. 62, no. 21, pp. 1966-1976
Volume: 62
Issue: 21
Start page: 1966
End page: 1976
Journal: Journal of the American College of Cardiology 
Abstract: Objectives This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease. Background Higher circulating levels of sPLA2-IIA mass or sPLA 2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy. Methods We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable. Results PLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA 2 enzyme activity and MVE. Conclusions Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.
ISSN: 1558-3597
DOI: 10.1016/j.jacc.2013.06.044
Collaboration : University College London
Hôpital Saint-Antoine
Université Pierre et Marie Curie
Karolinska Institutet
Karolinska University Hospital
University Medical Center Utrecht
Durrer Center for Cardiogenetic Research
Universitat Rovira i Virgili
Institute for Clinical and Experimental Medicine
University of Edinburgh
Intermountain Medical Center
University of Utah School of Medicine
Harvard Medical School
University of Amsterdam
University of Pennsylvania
Utrecht University
Leiden University
Erasmus University Rotterdam
Netherlands Consortium for Healthy Aging
University of Leicester
Glenfield Hospital
Hôpital Européen Georges Pompidou
Universite Paris
University of Leipzig
Copenhagen University Hospital
Ulm University
German Cancer Research Center
University of Cambridge
London School of Hygiene and Tropical Medicine
University of Oxford
Cyprus University of Technology
Universitá di Milano
Centro Cardiologico Monzino
University Hospital Leipzig
University of Leipzig
University Medical Center Groningen
University of Ulm Medical Center
Swansea University
University of Groningen
Inserm Research Unit
St George's University of London
University of Leeds
Linköping University
Imperial College London
Ludwig Maximilians Universität
University of Bristol
University of Glasgow
University of California
University of Colorado
Childrens Hospital of Philadelphia
McMaster University
Interuniversity Cardiology Institute of the Netherlands
Leiden University
Penn Heart and Vascular Center
University of Warwick
Rights: © American College of Cardiology Foundation
Type: Article
Appears in Collections:Άρθρα/Articles

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