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

J Am Coll Cardiol. 2013 Nov 19;62(21):1966-1976. doi: 10.1016/j.jacc.2013.06.044. Epub 2013 Jul 31.


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.

Keywords: ACS; CI; LDL-C; MI; MVE; Mendelian randomization; OR; RCT; SNP; acute coronary syndrome(s); cardiovascular diseases; confidence interval; drug development; epidemiology; genetics; low-density lipoprotein cholesterol; major vascular events; myocardial infarction; odds ratio; randomized clinical trial; sPLA(2); secretory phospholipase A(2); single-nucleotide polymorphism.

Publication types

  • Meta-Analysis

MeSH terms

  • Alleles
  • Cardiovascular Diseases / enzymology
  • Cardiovascular Diseases / epidemiology
  • Cardiovascular Diseases / genetics*
  • DNA / genetics*
  • Gene Expression Regulation*
  • Global Health
  • Humans
  • Incidence
  • Mendelian Randomization Analysis / methods*
  • Phospholipases A2, Secretory / genetics*
  • Phospholipases A2, Secretory / metabolism


  • DNA
  • Phospholipases A2, Secretory