Secretory phospholipase A(2)-IIA and cardiovascular disease: a mendelian randomization study.
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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.
SUBMITTER: Holmes MV
PROVIDER: S-EPMC3826105 | biostudies-literature | 2013 Nov
REPOSITORIES: biostudies-literature
Publications
Secretory phospholipase A(2)-IIA and cardiovascular disease: a mendelian randomization study.
Holmes Michael V MV Simon Tabassome T Exeter Holly J HJ Folkersen Lasse L Asselbergs Folkert W FW Guardiola Montse M Cooper Jackie A JA Palmen Jutta J Hubacek Jaroslav A JA Carruthers Kathryn F KF Horne Benjamin D BD Brunisholz Kimberly D KD Mega Jessica L JL van Iperen Erik P A EPA Li Mingyao M Leusink Maarten M Trompet Stella S Verschuren Jeffrey J W JJW Hovingh G Kees GK Dehghan Abbas A Nelson Christopher P CP Kotti Salma S Danchin Nicolas N Scholz Markus M Haase Christiane L CL Rothenbacher Dietrich D Swerdlow Daniel I DI Kuchenbaecker Karoline B KB Staines-Urias Eleonora E Goel Anuj A van 't Hooft Ferdinand F Gertow Karl K de Faire Ulf U Panayiotou Andrie G AG Tremoli Elena E Baldassarre Damiano D Veglia Fabrizio F Holdt Lesca M LM Beutner Frank F Gansevoort Ron T RT Navis Gerjan J GJ Mateo Leach Irene I Breitling Lutz P LP Brenner Hermann H Thiery Joachim J Dallmeier Dhayana D Franco-Cereceda Anders A Boer Jolanda M A JMA Stephens Jeffrey W JW Hofker Marten H MH Tedgui Alain A Hofman Albert A Uitterlinden André G AG Adamkova Vera V Pitha Jan J Onland-Moret N Charlotte NC Cramer Maarten J MJ Nathoe Hendrik M HM Spiering Wilko W Klungel Olaf H OH Kumari Meena M Whincup Peter H PH Morrow David A DA Braund Peter S PS Hall Alistair S AS Olsson Anders G AG Doevendans Pieter A PA Trip Mieke D MD Tobin Martin D MD Hamsten Anders A Watkins Hugh H Koenig Wolfgang W Nicolaides Andrew N AN Teupser Daniel D Day Ian N M INM Carlquist John F JF Gaunt Tom R TR Ford Ian I Sattar Naveed N Tsimikas Sotirios S Schwartz Gregory G GG Lawlor Debbie A DA Morris Richard W RW Sandhu Manjinder S MS Poledne Rudolf R Maitland-van der Zee Anke H AH Khaw Kay-Tee KT Keating Brendan J BJ van der Harst Pim P Price Jackie F JF Mehta Shamir R SR Yusuf Salim S Witteman Jaqueline C M JCM Franco Oscar H OH Jukema J Wouter JW de Knijff Peter P Tybjaerg-Hansen Anne A Rader Daniel J DJ Farrall Martin M Samani Nilesh J NJ Kivimaki Mika M Fox Keith A A KAA Humphries Steve E SE Anderson Jeffrey L JL Boekholdt S Matthijs SM Palmer Tom M TM Eriksson Per P Paré Guillaume G Hingorani Aroon D AD Sabatine Marc S MS Mallat Ziad Z Casas Juan P JP Talmud Philippa J PJ
Journal of the American College of Cardiology 20130731 21
<h4>Objectives</h4>This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease.<h4>Background</h4>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.<h4>Methods</h4>We conducted a Mendelian rand ...[more]