Secretory Phospholipase A2 -IIA and Cardiovascular Disease

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 t...

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Veröffentlicht in:	Journal of the American College of Cardiology 2013-11, Vol.62 (21), p.1966-1976
Hauptverfasser:	Holmes, Michael V., MSc, Simon, Tabassome, MD, PhD, Exeter, Holly J., PhD, Folkersen, Lasse, PhD, Guardiola, Montse, PhD, Cooper, Jackie A., MSc, Hubacek, Jaroslav A., DSc, PhD, Carruthers, Kathryn F., MPhil, Horne, Benjamin D., PhD, MPH, Brunisholz, Kimberly D., MST, Mega, Jessica L., MD, MPH, van Iperen, Erik P.A., MSc, Li, Mingyao, PhD, Leusink, Maarten, MSc, Trompet, Stella, PhD, Verschuren, Jeffrey J.W., MD, MSc, Hovingh, G. Kees, MD, PhD, Dehghan, Abbas, MD, PhD, Nelson, Christopher P., PhD, Kotti, Salma, PharmD, PhD, Danchin, Nicolas, MD, PhD, Haase, Christiane L., PhD, Rothenbacher, Dietrich, MD, Swerdlow, Daniel I., MBBS, PhD, Kuchenbaecker, Karoline B., Dipl Psych, MSc, Staines-Urias, Eleonora, MD, MSc, Goel, Anuj, MSc, van 't Hooft, Ferdinand, MD, PhD, Gertow, Karl, PhD, de Faire, Ulf, MD, PhD, Tremoli, Elena, PhD, Baldassarre, Damiano, PhD, Veglia, Fabrizio, PhD, Beutner, Frank, MD, PhD, Gansevoort, Ron T., MD, PhD, Navis, Gerjan J., MD, PhD, Mateo Leach, Irene, PhD, Brenner, Hermann, MD, MPH, Thiery, Joachim, MD, MBA, Dallmeier, Dhayana, MD, Franco-Cereceda, Anders, MD, PhD, Boer, Jolanda M.A., PhD, Stephens, Jeffrey W., PhD, Hofker, Marten H., PhD, Hofman, Albert, MD, PhD, Uitterlinden, André G., PhD, Adamkova, Vera, MD, PhD, Pitha, Jan, MD, PhD, Onland-Moret, N. Charlotte, PhD, Nathoe, Hendrik M., MD, PhD, Spiering, Wilko, MD, PhD, Klungel, Olaf H., PharmD, PhD, Kumari, Meena, PhD, Whincup, Peter H, Morrow, David A., MD, Braund, Peter S., MSc, Hall, Alistair S., PhD, Olsson, Anders G., MD, PhD, Doevendans, Pieter A., MD, PhD, Trip, Mieke D., MD, PhD, Tobin, Martin D., PhD, Hamsten, Anders, PhD, Watkins, Hugh, PhD, Koenig, Wolfgang, MD, Teupser, Daniel, MD, PhD, Day, Ian N.M, Carlquist, John F., PhD, Ford, Ian, PhD, Sattar, Naveed, Tsimikas, Sotirios, MD, Schwartz, Gregory G., MD PhD, Lawlor, Debbie A., PhD, Morris, Richard W., PhD, Sandhu, Manjinder S., PhD, Poledne, Rudolf, PhD, Maitland-van der Zee, Anke H., PhD, Khaw, Kay-Tee, MBBChir, Keating, Brendan J., PhD, van der Harst, Pim, MD, PhD, Price, Jackie F., MD, Mehta, Shamir R., MD, MSc, Yusuf, Salim, MBBS, DPhil, Witteman, Jaqueline C.M., PhD, de Knijff, Peter, PhD, Tybjaerg-Hansen, Anne, MD, DMSc, Rader, Daniel J., MD, Samani, Nilesh J., MD, Kivimaki, Mika, PhD, Fox, Keith A.A., MB, ChB, Humphries, Steve E., PhD, Anderson, Jeffrey L., MD, Boekholdt, S. Matthijs, MD, PhD, Palmer, Tom M., PhD, Eriksson, Per, PhD, Paré, Guillaume, MD, Hingorani, Aroon D., PhD, Sabatine, Marc S., MD, PhD, Mallat, Ziad, MD, PhD, Casas, Juan P., MD, PhD, Talmud, Philippa J., DSc
Format:	Artikel
Sprache:	eng
Schlagworte:	Cardiology Cardiovascular Cardiovascular disease cardiovascular diseases Cholesterol drug development Drug therapy epidemiology genetics Heart attacks Internal Medicine Mendelian randomization Mortality Studies
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Beschreibung
Zusammenfassung:	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.
ISSN:	0735-1097 1558-3597
DOI:	10.1016/j.jacc.2013.06.044