Secretory Phospholipase A(2)-IIA and Cardiovascular Disease

MV Holmes, T Simon, HJ Exeter, L Folkersen, FW Asselbergs, M Guardiola, JA Cooper, J Palmen, JA Hubacek, KF Carruthers, BD Horne, KD Brunisholz, JL Mega, EPA Van Iperen, MY Li, M Leusink, S Trompet, JJW Verschuren, GK Hovingh, Abbas DehghanCP Nelson, S Kotti, N Danchin, Markus Scholz, CL Haase, D Rothenbacher, DI Swerdlow, KB Kuchenbaecker, E Staines-Urias, A Goel, F van 't Hooft, K Gertow, U de Faire, AG Panayiotou, E Tremoli, D Baldassarre, F Veglia, LM Holdt, F Beutner, RT Gansevoort, GJ Navis, IM Leach, LP Breitling, H Brenner, J Thiery, D Dallmeier, A Franco-Cereceda, JMA Boer, JW Stephens, MH Hofker, A Tedgui, Bert Hofman, André Uitterlinden, V Adamkova, J Pitha, NC Onland-Moret, MJ Cramer, HM Nathoe, W Spiering, OH Klungel, M Kumari, PH Whincup, DA Morrow, PS Braund, AS Hall, AG Olsson, PA Doevendans, MD Trip, MD Tobin, A Hamsten, H Watkins, W Koenig, AN Nicolaides, D Teupser, INM Day, JF Carlquist, TR Gaunt, I Ford, N Sattar, S Tsimikas, GG Schwartz, DA Lawlor, RW Morris, MS Sandhu, R Poledne, AH Zee, KT Khaw, BJ Keating, P van der Harst, JF Price, SR Mehta, S Yusuf, JCM Witteman, OH Franco Duran, JW Jukema, P de Knijff, A Tybjaerg-Hansen, DJ Rader, M Farrall, NJ Samani, M Kivimaki, KAA Fox, SE Humphries, JL Anderson, SM Boekholdt, TM Palmer, P Eriksson, G Pare, AD Hingorani, MS Sabatine, Z Mallat, JP Casas, PJ Talmud

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Abstract

Objectives This study sought to investigate the role of secretory phospholipase A(2) (sPLA(2))-IIA in cardiovascular disease. Background Higher circulating levels of sPLA(2)-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 sPLA(2) 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 sPLA(2)-IIA isoenzyme, as an instrumental variable. Results PLA2G2A rs11573156 C allele associated with lower circulating sPLA(2)-IIA mass (38% to 44%) and sPLA(2) 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 sPLA(2)-IIA mass was 1.04 (95% CI: 0.96 Conclusions Reducing sPLA(2)-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events. (C) 2013 by the American College of Cardiology Foundation
Original languageEnglish
Pages (from-to)1966-1976
Number of pages11
JournalJournal of the American College of Cardiology
Volume62
Issue number21
DOIs
Publication statusPublished - 2013

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