Secretory Phospholipase A 2 -IIA and Cardiovascular Disease Academic Article uri icon

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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.

authors

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

publication date

  • November 2013