Secretory Phospholipase A2-IIA and Cardiovascular Disease:A Mendelian Randomization Study

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Holmes, Michael V. ; Simon, Tabassome ; Exeter, Holly J. ; Folkersen, Lasse ; Asselbergs, Folkert W. ; Guardiola, Montse ; Cooper, Jackie A. ; Palmen, Jutta ; Hubacek, Jaroslav A. ; Carruthers, Kathryn F. ; Horne, Benjamin D. ; Brunisholz, Kimberly D. ; Mega, Jessica L. ; Van Iperen, Erik P. A. ; Li, Mingyao ; Leusink, Maarten ; Trompet, Stella ; Verschuren, Jeffrey J. W. ; Hovingh, G. Kees ; Dehghan, Abbas ; Nelson, Christopher P. ; Kotti, Salma ; Danchin, Nicolas ; Scholz, Markus ; Haase, Christiane L. ; Rothenbacher, Dietrich ; Swerdlow, Daniel I. ; Kuchenbaecker, Karoline B. ; Staines-Urias, Eleonora ; Goel, Anuj ... view all 113 authors (2013)
  • Publisher: ELSEVIER SCIENCE INC
  • Journal: volume 62, issue 21, pages 1,966-1,976 (issn: 0735-1097, eissn: 1558-3597)
  • Related identifiers: pmc: PMC3826105, doi: 10.1016/j.jacc.2013.06.044
  • Subject: MI, myocardial infarction | OR, odds ratio | LDL-C, low-density lipoprotein cholesterol | ARTERY-DISEASE | RCT, randomized clinical trial | Cardiology and Cardiovascular Medicine | SERUM-LEVELS | EPIC-NORFOLK | ACUTE CORONARY SYNDROMES | TRIAL | epidemiology | genetics | INHIBITOR | MVE, major vascular events | EVENTS | Cardiometabolic Risk | SNP, single-nucleotide polymorphism | drug development | sPLA2, secretory phospholipase A2 | cardiovascular diseases | CI, confidence interval | ACS, acute coronary syndrome(s) | Clinical Research | RISK | MENDELIAN RANDOMIZATION | HEALTHY-MEN

Objectives:\ud This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease.<p></p>\ud \ud Background:\ud 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.<p></p>\ud \ud Methods:\ud 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.<p></p>\ud \ud Results:\ud 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.<p></p>\ud \ud Conclusions:\ud Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.<p></p>
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