Secretory Phospholipase A(2)-IIA and Cardiovascular Disease
2013 (English)In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 62, no 21, 1966-1976 p.Article in journal (Refereed) Published
Objectives This study sought to investigate the role of secretory phospholipase A(2) (sPLA(2))-IIA in cardiovascular disease. less thanbrgreater than less thanbrgreater thanBackground Higher circulating levels of sPLA(2)-IIA mass or sPLA(2) 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 sPLA(2) inhibitor (varespladib) was stopped prematurely for lack of efficacy. less thanbrgreater than less thanbrgreater thanMethods 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 sPLA(2)-IIA isoenzyme, as an instrumental variable. less thanbrgreater than less thanbrgreater thanResults PLA2G2A rs11573156 C allele associated with lower circulating sPLA(2)-IIA mass (38% to 44%) and sPLA(2) 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 sPLA(2)-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. less thanbrgreater than less thanbrgreater thanConclusions Reducing sPLA(2)-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.
Place, publisher, year, edition, pages
Elsevier , 2013. Vol. 62, no 21, 1966-1976 p.
cardiovascular diseases, drug development, epidemiology, genetics, Mendelian randomization
Engineering and Technology
IdentifiersURN: urn:nbn:se:liu:diva-102496DOI: 10.1016/j.jacc.2013.06.044ISI: 000326939500010OAI: oai:DiVA.org:liu-102496DiVA: diva2:678602
Funding Agencies|BHG programme grant|RG/10/12/28456|UK Medical Research Council (Population Health Scientist Fellowship)|G0802432|British Heart Foundation|RG 10/12/28456RG008/014RG/10/001/27643PG07/133/24260FS 08/ 048/25628|National Institute of Health Research University College London Hospitals Biomedical Research Centre||Dutch Kidney Foundation|E033|Netherlands Organisation for Health Research and Development (NWO VENI)|916.761.70|Dutch Inter University Cardiology Institute Netherlands (ICIN)||Canada Research Chair in Genetic and Molecular Epidemiology||Europe Against Cancer Programme of the European Commission (SANCO), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch Cancer Society|||EU-LSHM-CT-2006037697|2013-12-122013-12-122014-02-14