Secretory phospholipase A(2)-IIA and cardiovascular disease:a mendelian randomization study

Holmes, Michael V. and Simon, Tabassome and Exeter, Holly J. and Folkersen, Lasse and Asselbergs, Folkert W. and Guardiola, Montse and Cooper, Jackie A. and Palmen, Jutta and Hubacek, Jaroslav A. and Carruthers, Kathryn F. and Horne, Benjamin D. and Brunisholz, Kimberly D. and Mega, Jessica L. and van Iperen, Erik P. A. and Li, Mingyao and Leusink, Maarten and Trompet, Stella and Verschuren, Jeffrey J. W. and Hovingh, G. Kees and Dehghan, Abbas and Nelson, Christopher P. and Kotti, Salma and Danchin, Nicolas and Scholz, Markus and Haase, Christiane L. and Rothenbacher, Dietrich and Swerdlow, Daniel I. and Kuchenbaecker, Karoline B. and Staines-Urias, Eleonora and Goel, Anuj and van 't Hooft, Ferdinand and Gertow, Karl and de Faire, Ulf and Panayiotou, Andrie G. and Tremoli, Elena and Baldassarre, Damiano and Veglia, Fabrizio and Holdt, Lesca M. and Beutner, Frank and Gansevoort, Ron T. and Navis, Gerjan J. and Mateo Leach, Irene and Breitling, Lutz P. and Brenner, Hermann and Thiery, Joachim and Dallmeier, Dhayana and Franco-Cereceda, Anders and Boer, Jolanda M. A. and Stephens, Jeffrey W. and Hofker, Marten H. and Tedgui, Alain and Hofman, Albert and Uitterlinden, André G. and Adamkova, Vera and Pitha, Jan and Onland-Moret, N. Charlotte and Cramer, Maarten J. and Nathoe, Hendrik M. and Spiering, Wilko and Klungel, Olaf H. and Kumari, Meena and Whincup, Peter H. and Morrow, David A. and Braund, Peter S. and Hall, Alistair S. and Olsson, Anders G. and Doevendans, Pieter A. and Trip, Mieke D. and Tobin, Martin D. and Hamsten, Anders and Watkins, Hugh and Koenig, Wolfgang and Nicolaides, Andrew N. and Teupser, Daniel and Day, Ian N. M. and Carlquist, John F. and Gaunt, Tom R. and Ford, Ian and Sattar, Naveed and Tsimikas, Sotirios and Schwartz, Gregory G. and Lawlor, Debbie A. and Morris, Richard W. and Sandhu, Manjinder S. and Poledne, Rudolf and Maitland-van der Zee, Anke H. and Khaw, Kay-Tee and Keating, Brendan J. and van der Harst, Pim and Price, Jackie F. and Mehta, Shamir R. and Yusuf, Salim and Witteman, Jaqueline C. M. and Franco, Oscar H. and Jukema, J. Wouter and de Knijff, Peter and Tybjaerg-Hansen, Anne and Rader, Daniel J. and Farrall, Martin and Samani, Nilesh J. and Kivimaki, Mika and Fox, Keith A. A. and Humphries, Steve E. and Anderson, Jeffrey L. and Boekholdt, S. Matthijs and Palmer, Tom M. and Eriksson, Per and Paré, Guillaume and Hingorani, Aroon D. and Sabatine, Marc S. and Mallat, Ziad and Casas, Juan P. and Talmud, Philippa J. (2013) Secretory phospholipase A(2)-IIA and cardiovascular disease:a mendelian randomization study. Journal of the American College of Cardiology, 62 (21). pp. 1966-1976. ISSN 1558-3597

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 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 null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE. CONCLUSIONS: Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.