Secretory Phospholipase A2-IIA and Cardiovascular Disease: A Mendelian Randomization Study

Michael V. Holmes*, Tabassome Simon, Holly J. Exeter, Lasse Folkersen, Folkert W. Asselbergs, Montse Guardiola, Jackie A. Cooper, Jutta Palmen, Jaroslav A. Hubacek, Kathryn F. 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 DehghanChristopher P. Nelson, Salma Kotti, Nicolas Danchin, Markus Scholz, Christiane L. Haase, Dietrich Rothenbacher, Daniel I. Swerdlow, Karoline B. Kuchenbaecker, Eleonora Staines-Urias, Anuj Goel, Ferdinand van 't Hooft, Karl Gertow, Ulf de Faire, Andrie G. Panayiotou, Elena Tremoli, Damiano Baldassarre, Fabrizio Veglia, Lesca M. Holdt, Frank Beutner, Ron T. Gansevoort, Gerjan J. 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, Andre G. Uitterlinden, Vera Adamkova, Jan Pitha, 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 G. Olsson, Pieter A. Doevendans, Mieke D. Trip, Martin D. Tobin, Anders Hamsten, Hugh Watkins, Wolfgang Koenig, Andrew N. 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 W. Morris, Manjinder S. Sandhu, Rudolf 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, Jaqueline C. M. Witteman, Oscar H. Franco, J. Wouter Jukema, Peter de Knijff, Anne Tybjaerg-Hansen, Daniel J. Rader, Martin Farrall, Nilesh J. Samani, Mika Kivimaki, Keith A. A. Fox, Steve E. Humphries, Jeffrey L. Anderson, S. Matthijs Boekholdt, Tom M. Palmer, Per Eriksson, Guillaume Pare, Aroon D. Hingorani, Marc S. Sabatine, Ziad Mallat, Juan P. Casas, Philippa J. Talmud

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)1966-1976
Number of pages11
JournalJournal of the American College of Cardiology
Volume62
Issue number21
DOIs
Publication statusPublished - 19 Nov 2013

Keywords

  • cardiovascular diseases
  • drug development
  • epidemiology
  • genetics
  • Mendelian randomization
  • ACUTE CORONARY SYNDROMES
  • MENDELIAN RANDOMIZATION
  • ARTERY-DISEASE
  • EPIC-NORFOLK
  • SERUM-LEVELS
  • HEALTHY-MEN
  • EVENTS
  • TRIAL
  • INHIBITOR
  • RISK

Fingerprint Dive into the research topics of 'Secretory Phospholipase A2-IIA and Cardiovascular Disease: A Mendelian Randomization Study'. Together they form a unique fingerprint.

Cite this