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Secretory phospholipase A(2)-IIA and cardiovascular disease: a mendelian randomization study

Research output: Contribution to Journal/MagazineJournal articlepeer-review

  • 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
  • Benjamin D. Horne
  • Kimberly D. Brunisholz
  • Jessica L. Mega
  • Erik P. A. van Iperen
  • Mingyao Li
  • Maarten Leusink
  • Stella Trompet
  • Jeffrey J. W. 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 M. A. 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 N. M. 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 C. M. Witteman
  • Oscar H. Franco
  • J. Wouter Jukema
  • Peter de Knijff
  • Anne Tybjaerg-Hansen
  • Daniel J. Rader
  • Martin Farrall
  • Nilesh J. Samani
  • Mika Kivimaki
  • Keith A. A. Fox
  • Steve E. Humphries
  • Jeffrey L. Anderson
  • S. Matthijs Boekholdt
  • Per Eriksson
  • Guillaume Paré
  • Aroon D. Hingorani
  • Marc S. Sabatine
  • Ziad Mallat
  • Juan P. Casas
  • Philippa J. Talmud
<mark>Journal publication date</mark>19/11/2013
<mark>Journal</mark>Journal of the American College of Cardiology
Issue number21
Number of pages11
Pages (from-to)1966-1976
Publication StatusPublished
<mark>Original language</mark>English


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.

Bibliographic note

Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.