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.

Assistance Publique Hôpitaux de Paris Hôpital Européen Georges Pompidou Department of Cardiology Paris France; Université Paris Descartes Paris 5 Paris France

Assistance Publique Hôpitaux de Paris Hôpital Saint Antoine Department of Clinical Pharmacology URC EST Paris France

Assistance Publique Hôpitaux de Paris Hôpital Saint Antoine Department of Clinical Pharmacology URC EST Paris France; Université Pierre et Marie Curie Paris France; INSERM U 698 Paris France

Atherosclerosis Research Unit Department of Medicine Solna Karolinska Institutet Stockholm Sweden; Center for Molecular Medicine Karolinska University Hospital Solna Stockholm Sweden

British Heart Foundation Glasgow Cardiovascular Research Centre University of Glasgow Glasgow Scotland United Kingdom

Cardiothoracic Surgery Unit Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden

Center for Applied Genomics Children's Hospital of Philadelphia Philadelphia Pennsylvania

Center for Experimental Medicine Institute for Clinical and Experimental Medicine Prague Czech Republic

Centre for Cancer Genetic Epidemiology Department of Public Health and Primary Care University of Cambridge Cambridge United Kingdom

Centre for Cardiovascular Genetics Institute of Cardiovascular Science University College London London United Kingdom

Centre for Cardiovascular Science University of Edinburgh Edinburgh Scotland United Kingdom

Centre for Population Health Sciences University of Edinburgh United Kingdom

Centro Cardiologico Monzino IRCCS Milan Italy

Cyprus Cardiovascular Educational and Research Trust Nicosia Cyprus and Cyprus International Institute for Environmental and Public Health in association with the Harvard School of Public Health Cyprus University of Technology Limassol Cyprus

Department for Nutrition and Health National Institute for Public Health and the Environment Bilthoven the Netherlands

Department of Biostatistics and Epidemiology University of Pennsylvania School of Medicine Philadelphia Pennsylvania

Department of Cardiology Academic Medical Center University of Amsterdam Amsterdam the Netherlands

Department of Cardiology Division Heart and Lungs University Medical Center Utrecht Utrecht the Netherlands

Department of Cardiology Division Heart and Lungs University Medical Center Utrecht Utrecht the Netherlands; Julius Center for Health Sciences and Primary Care University Medical Center Utrecht the Netherlands; Durrer Center for Cardiogenetic Research Amsterdam the Netherlands

Department of Cardiology Leiden University Medical Center Leiden the Netherlands

Department of Cardiology Leiden University Medical Center Leiden the Netherlands; Department of Gerontology and Geriatrics Leiden University Medical Center Leiden the Netherlands

Department of Cardiovascular Sciences University of Leicester Leicester United Kingdom

Department of Cardiovascular Sciences University of Leicester Leicester United Kingdom; Leicester NIHR Biomedical Research Unit in Cardiovascular Disease Glenfield Hospital Leicester United Kingdom

Department of Clinical Biochemistry Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

Department of Clinical Epidemiology and Biostatistics McMaster University Hamilton Ontario Canada; Department of Medicine McMaster University Hamilton Ontario Canada; Interventional Cardiology McMaster University Hamilton Ontario Canada; Population Health Research Institute McMaster University and Hamilton Health Sciences Hamilton Ontario Canada

Department of Clinical Epidemiology and Biostatistics McMaster University Hamilton Ontario Canada; Population Health Research Institute McMaster University and Hamilton Health Sciences Hamilton Ontario Canada; Department of Pathology and Molecular Medicine McMaster University Hamilton Ontario Canada; Genetic and Molecular Epidemiology Laboratory McMaster University Hamilton Ontario Canada

Department of Epidemiology Erasmus Medical Center Rotterdam the Netherlands; Member of the Netherlands Consortium on Healthy Aging Leiden the Netherlands

Department of Human Genetics Leiden University Medical Center Leiden the Netherlands

Department of Internal Medicine 2 Cardiology University of Ulm Medical Center Ulm Germany

Department of Pathology and Medical Biology Medical Biology Section Molecular Genetics University of Groningen University Medical Center Groningen Groningen the Netherlands

Department of Primary Care and Population Health University College London Royal Free Campus London United Kingdom

Department of Public Health and Primary Care University of Cambridge Cambridge United Kingdom

Department of Vascular Medicine Academic Medical Center University of Amsterdam Amsterdam the Netherlands

Department of Vascular Medicine University Medical Center Utrecht Utrecht the Netherlands

Department of Vascular Surgery Imperial College London United Kingdom; Cyprus Cardiovascular Educational and Research Trust Nicosia Cyprus

Departments of Health Sciences and Genetics University of Leicester Leicester United Kingdom

Diabetes Research Group Institute of Life Sciences College of Medicine Swansea University Swansea Wales United Kingdom

Dipartimento di Scienze Farmacologiche e Biomolecolari Universitá di Milano Milan Italy; Centro Cardiologico Monzino IRCCS Milan Italy

Division of Cardiovascular Diseases Department of Medicine University of California San Diego La Jolla California

Division of Cardiovascular Epidemiology Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden

Division of Clinical Epidemiology and Aging Research German Cancer Research Center Heidelberg Germany

Division of Health Sciences Warwick Medical School University of Warwick Coventry United Kingdom

Division of Pharmacoepidemiology and Clinical Pharmacology Utrecht Institute for Pharmaceutical Sciences Utrecht University Utrecht the Netherlands

Division of Population Health Sciences and Education St George's University of London London United Kingdom

Durrer Center for Cardiogenetic Research Amsterdam the Netherlands; Department of Cardiology Leiden University Medical Center Leiden the Netherlands; Interuniversity Cardiology Institute of the Netherlands Utrecht the Netherlands

Durrer Center for Cardiogenetic Research Amsterdam the Netherlands; Department of Clinical Epidemiology Biostatistics and Bioinformatics Academic Medical Center University of Amsterdam Amsterdam the Netherlands

Faculty of Epidemiology and Population Health London School of Hygiene and Tropical Medicine London United Kingdom

Faculty of Population Health Sciences University College London London United Kingdom

Faculty of Population Health Sciences University College London London United Kingdom; Centre for Clinical Pharmacology Division of Medicine University College London London United Kingdom

Faculty of Population Health Sciences University College London London United Kingdom; Faculty of Epidemiology and Population Health London School of Hygiene and Tropical Medicine London United Kingdom

Inserm U970 Paris Cardiovascular Research Center Paris France

Inserm U970 Paris Cardiovascular Research Center Paris France; Division of Cardiovascular Medicine University of Cambridge Addenbrooke's Hospital Cambridge United Kingdom

Institute for Medical Informatics Statistics and Epidemiology University of Leipzig Leipzig Germany; LIFE Leipzig Research Center for Civilization Diseases University of Leipzig Leipzig Germany

Institute of Epidemiology and Medical Biometry Ulm University Ulm Germany; Division of Clinical Epidemiology and Aging Research German Cancer Research Center Heidelberg Germany

Intermountain Heart Institute Intermountain Medical Center Salt Lake City Utah

Intermountain Heart Institute Intermountain Medical Center Salt Lake City Utah; Department of Medicine University of Utah School of Medicine Salt Lake City Utah

Julius Center for Health Sciences and Primary Care University Medical Center Utrecht the Netherlands

Leeds Institute of Genetics Health and Therapeutics University of Leeds Leeds United Kingdom

LIFE Leipzig Research Center for Civilization Diseases University of Leipzig Leipzig Germany; Department of Internal Medicine Cardiology Heart Center University of Leipzig Leipzig Germany

LIFE Leipzig Research Center for Civilization Diseases University of Leipzig Leipzig Germany; Institute of Laboratory Medicine Clinical Chemistry and Molecular Diagnostics University Hospital Leipzig Leipzig Germany

LIFE Leipzig Research Center for Civilization Diseases University of Leipzig Leipzig Germany; Institute of Laboratory Medicine Clinical Chemistry and Molecular Diagnostics University Hospital Leipzig Leipzig Germany; Institute of Laboratory Medicine University Hospital Munich Ludwig Maximilians University Munich Munich Germany

Member of the Netherlands Consortium on Healthy Aging Leiden the Netherlands; Department of Internal Medicine Erasmus Medical Center Rotterdam the Netherlands

MRC Centre for Causal Analyses in Translational Epidemiology School of Social and Community Medicine University of Bristol Bristol United Kingdom

Population Health Research Institute McMaster University and Hamilton Health Sciences Hamilton Ontario Canada

Preventive Cardiovascular Medicine Penn Heart and Vascular Center Philadelphia Pennsylvania

Robertson Centre for Biostatistics University of Glasgow Glasgow Scotland United Kingdom

Stockholm Heart Center Stockholm and Linköping University Linkőping Sweden

TIMI Study Group Divison of Cardiovascular Medicine Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts

Unitat de Recerca en Lípids i Arteriosclerosi IISPV Universitat Rovira i Virgili CIBERDEM Reus Spain

University Medical Center Groningen University of Groningen Department of Cardiology Groningen the Netherlands

University Medical Center Groningen University of Groningen Department of Internal Medicine Groningen the Netherlands

VA Medical Center and University of Colorado School of Medicine Denver Colorado

Wellcome Trust Centre for Human Genetics University of Oxford Oxford United Kingdom; Department of Cardiovascular Medicine University of Oxford Oxford United Kingdom

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J Am Coll Cardiol. 2014 Mar 11;63(9):942-3. doi: 10.1016/j.jacc.2013.09.074. PubMed

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