Secretory Phospholipase A2-IIA and Cardiovascular Disease

作者：Michael V. Holmes, Tabassome Simon, Holly Exeter, Lasse Folkersen, Folkert W. Asselbergs, Montse Guardiola, Jackie A. Cooper, Jutta Palmen, Jaroslav A. Hubáček, Kathryn Carruthers, Benjamin D. Horne, Kimberly D. Brunisholz, Jessica L. Mega, Erik P.A. van Iperen, Mingyao Li, Maarten Leusink, Stella Trompet, Jeffrey J. W. Verschuren, G. Kees Hovingh, Abbas Dehghan, Christopher P. Nelson, Salma Kotti, Nicolas Danchin, Markus Scholz, Christiane L. Haase, Dietrich Rothenbacher, Daniel I. Swerdlow, Karoline Kuchenbaecker, Eleonora Staines-Urias, Anuj Goel, Ferdinand van 't Hooft, Karl Gertow, Ulf dé Fairé, Andrie G. Panayiotou, Elena Tremoli, Damiano Baldassarre, Fabrizio Veglia, Lesca M. Holdt, Frank Beutner, Ron T. Gansevoort, Gerjan Navis, Irene Mateo Leach, Lutz P. Breitling, Hermann Brenner, Joachim Thiery, Dhayana Dallmeier, Anders Franco‐Cereceda, Jolanda M.A. Boer, Jeffrey W. Stephens, Marten H. Hofker, Alain Tedgui, Albert Hofman, André G. Uitterlinden, Věra Adámková, Jan Piťha, N. Charlotte Onland‐Moret, Maarten J. Cramer, Hendrik M. Nathoe, Wilko Spiering, Olaf H. Klungel, Meena Kumari, Peter H. Whincup, David A. Morrow, Peter S. Braund, Alistair S. Hall, Anders Olsson, Pieter A. Doevendans, Mieke D. Trip, Martin D. Tobin, Anders Hamsten, Hugh Watkins, Wolfgang Köenig, Andrew Nicolaides, Daniel Teupser, Ian N.M. Day, John F. Carlquist, Tom R. Gaunt, Ian Ford, Naveed Sattar, Sotirios Tsimikas, Gregory G. Schwartz, Debbie A. Lawlor, Richard Morris, Manjinder S. Sandhu, R. Poledne, Anke H. Maitland‐van der Zee, Kay‐Tee Khaw, Brendan J. Keating, Pim van der Harst, Jackie F. Price, Shamir R. Mehta, Salim Yusuf, J. C. M. Witteman, Oscar H. Franco, J. Wouter Jukema, Peter de Knijff, Anne Tybjærg‐Hansen, Daniel J. Rader, Martin Farrall, Nilesh J. Samani, Mika Kivimäki, Keith A.A. Fox, Steve E. Humphries, J. L. Ross Anderson, S. Matthijs Boekholdt, Tom Palmer, Per Eriksson, Guillaume Paré, Aroon D. Hingorani, Marc S. Sabatine, Ziad Mallat, Juan P. Casas, Philippa J. Talmud · 发表于：Journal of the American College of Cardiology · 年份：2013 · DOI：10.1016/j.jacc.2013.06.044 · 被引用次数：128 · 研究领域：Protein Kinase Regulation and GTPase Signaling、Protease and Inhibitor Mechanisms、Renin-Angiotensin System Studies

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 sPLA2 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 n...