title: Secretory phospholipase A(2)-IIA and cardiovascular disease: a mendelian randomization study.
abstract: OBJECTIVE
  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.
authors.affiliation: Faculty of Population Health Sciences, University College London, London, United Kingdom. Electronic address: mvholmes@gmail.com.
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mesh_terms: D000483:Alleles; D002318:Cardiovascular Diseases / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D004247:DNA / Q000235:genetics*; D005786:Gene Expression Regulation; D014943:Global Health; D006801:Humans; D015994:Incidence; D057182:Mendelian Randomization Analysis / Q000379:methods*; D054497:Phospholipases A2, Secretory / Q000235:genetics* / Q000378:metabolism
chemical_list: D004247:DNA; D054497:Phospholipases A2, Secretory
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
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