Secretory phospholipase A(2)-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 ; +103 more... Benjamin D Horne ; Kimberly D Brunisholz ; Jessica L Mega ; Erik PA van Iperen ; Mingyao Li ; Maarten Leusink ; Stella Trompet ; Jeffrey JW Verschuren ; G Kees Hovingh ; Abbas Dehghan ; Christopher 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 MA Boer ; Jeffrey W Stephens ; Marten H Hofker ; Alain Tedgui ; Albert Hofman ; André 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 NM 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 CM Witteman ; Oscar H Franco ; J Wouter Jukema ; Peter de Knijff ; Anne Tybjaerg-Hansen ; Daniel J Rader ; Martin Farrall ; Nilesh J Samani ; Mika Kivimaki ; Keith AA Fox ; Steve E Humphries ; Jeffrey L Anderson ; S Matthijs Boekholdt ; Tom M Palmer ; Per Eriksson ; Guillaume Paré ; Aroon D Hingorani ; Marc S Sabatine ; Ziad Mallat ; Juan P Casas ; Philippa J Talmud ; (2013) Secretory phospholipase A(2)-IIA and cardiovascular disease: a mendelian randomization study. Journal of the American College of Cardiology, 62 (21). pp. 1966-1976. ISSN 0735-1097 DOI: 10.1016/j.jacc.2013.06.044

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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.