Secretory phospholipase A2-IIA and cardiovascular disease

Holmes, M.V. et al. (2013) Secretory phospholipase A2-IIA and cardiovascular disease. Journal of the American College of Cardiology, 62(21), pp. 1966-1976. (doi:10.1016/j.jacc.2013.06.044)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Ford, Professor Ian and Sattar, Professor Naveed
Authors: Holmes, M.V., Simon, T., Exeter, H.J., Folkersen, L., Asselbergs, F.W., Guardiola, M., Cooper, J.A., Palmen, J., Hubacek, J.A., Carruthers, K.F., Horne, B.D., Brunisholz, K.D., Mega, J.L., van Iperen, E.P.A., Li, M., Leusink, M., Trompet, S., Verschuren, J.J.W., Hovingh, G.K., Dehghan, A., Nelson, C.P., Kotti, S., Danchin, N., Scholz, M., Haase, C.L., Rothenbacher, D., Swerdlow, D.I., Kuchenbaecker, K.B., Staines-Urias, E., Goel, A., van 't Hooft, F., Gertow, K., de Faire, U., Panayiotou, A.G., Tremoli, E., Baldassarre, D., Veglia, F., Holdt, L.M., Beutner, F., Gansevoort, R.T., Navis, G.J., Mateo Leach, I., Breitling, L.P., Brenner, H., Thiery, J., Dallmeier, D., Franco-Cereceda, A., Boer, J.M.A., Stephens, J.W., Hofker, M.H., Tedgui, A., Hofman, A., Uitterlinden, A.G., Adamkova, V., Pitha, J., Onland-Moret, N.C., Cramer, M.J., Nathoe, H.M., Spiering, W., Klungel, O.H., Kumari, M., Whincup, P.H., Morrow, D.A., Braund, P.S., Hall, A.S., Olsson, A.G., Doevendans, P.A., Trip, M.D., Tobin, M.D., Hamsten, A., Watkins, H., Koenig, W., Nicolaides, A.N., Teupser, D., Day, I.N.M., Carlquist, J.F., Gaunt, T.R., Ford, I., Sattar, N., Tsimikas, S., Schwartz, G.G., Lawlor, D.A., Morris, R.W., Sandhu, M.S., Poledne, R., Maitland-van der Zee, A.H., Khaw, K., Keating, B.J., van der Harst, P., Price, J.F., Mehta, S.R., Yusuf, S., Witteman, J.C.M., Franco, O.H., Jukema, J.W., de Knijff, P.r., Tybjaerg-Hansen, A., Rader, D.J., Farrall, M., Samani, N.J., Kivimaki, M., Fox, K.A.A., Humphries, S.E., Anderson, J.L., Boekholdt, S.M., Palmer, T.M., Eriksson, P., Paré, G., Hingorani, A.D., Sabatine, M.S., Mallat, Z., Casas, J.P., and Talmud, P.J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Robertson Centre
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Journal of the American College of Cardiology
Publisher:Elsevier Inc.
ISSN:0735-1097
ISSN (Online):1558-3597
Copyright Holders:Copyright © 2013 American College of Cardiology Foundation
First Published:First published in the Journal of the American College of Cardiology 62(21):1966-1976
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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