Secretory Phospholipase A(2)-IIA and Cardiovascular Disease: A Mendelian Randomization Study

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 cl...

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Detalles Bibliográficos
Autores principales: 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 P.A., Li, Mingyao, Leusink, Maarten, Trompet, Stella, Verschuren, Jeffrey J.W., 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 M.A., 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 N.M., 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 R., Yusuf, Salim, Witteman, Jaqueline C.M., Franco, Oscar H., Jukema, J. Wouter, de Knijff, Peter, Tybjaerg-Hansen, Anne, Rader, Daniel J., Farrall, Martin, Samani, Nilesh J., Kivimaki, Mika, Fox, Keith A.A., Humphries, Steve E., Anderson, Jeffrey L., Boekholdt, S. Matthijs, Palmer, Tom M., Eriksson, Per, Paré, Guillaume, Hingorani, Aroon D., Sabatine, Marc S., Mallat, Ziad, Casas, Juan P., Talmud, Philippa J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Biomedical 2013
Materias:
Clinical Research
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3826105/
https://www.ncbi.nlm.nih.gov/pubmed/23916927
http://dx.doi.org/10.1016/j.jacc.2013.06.044
Descripción
Sumario: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 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 sPLA(2) enzyme activity and MVE. CONCLUSIONS: Reducing sPLA(2)-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.

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