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

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

Holmes MV1, Simon T2, Exeter HJ3, Folkersen L4, Asselbergs FW5, Guardiola M6, Cooper JA3, Palmen J3, Hubacek JA7, Carruthers KF8, Horne BD9, Brunisholz KD10, Mega JL11, van Iperen EPA12, Li M13, Leusink M14, Trompet S15, Verschuren JJW16, Hovingh GK17, Dehghan A18, Nelson CP19, Kotti S20, Danchin N21, Scholz M22, Haase CL23, Rothenbacher D24, Swerdlow DI25, Kuchenbaecker KB26, Staines-Urias E27, Goel A28, van 't Hooft F4, Gertow K4, de Faire U29, Panayiotou AG30, Tremoli E31, Baldassarre D31, Veglia F32, Holdt LM33, Beutner F34, Gansevoort RT35, Navis GJ35, Mateo Leach I36, Breitling LP37, Brenner H37, Thiery J38, Dallmeier D39, Franco-Cereceda A40, Boer JMA41, Stephens JW42, Hofker MH43, Tedgui A44, Hofman A18, Uitterlinden AG45, Adamkova V7, Pitha J7, Onland-Moret NC46, Cramer MJ47, Nathoe HM47, Spiering W48, Klungel OH14, Kumari M25, Whincup PH49, Morrow DA11, Braund PS50, Hall AS51, Olsson AG52, Doevendans PA47, Trip MD53, Tobin MD54, Hamsten A4, Watkins H28, Koenig W39, Nicolaides AN55, Teupser D33, Day INM20, Carlquist JF9, Gaunt TR56, Ford I57, Sattar N58, Tsimikas S59, Schwartz GG60, Lawlor DA56, Morris RW61, Sandhu MS60, Poledne R7, Maitland-van der Zee AH14, Khaw KT62, Keating BJ63, van der Harst P36, Price JF64, Mehta SR65, Yusuf S66, Witteman JCM18, Franco OH18, Jukema JW67, de Knijff P68, Tybjaerg-Hansen A23, Rader DJ69, Farrall M28, Samani NJ19, Kivimaki M25, Fox KAA8, Humphries SE3, Anderson JL9, Boekholdt SM53, Palmer TM70, Eriksson P4, Paré G71, Hingorani AD72, Sabatine MS11, Mallat Z73, Casas JP74, Talmud PJ3.

Author information

1
Faculty of Population Health Sciences, University College London, London, United Kingdom. Electronic address: mvholmes@gmail.com.
2
Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Antoine, Department of Clinical Pharmacology, URC-EST, Paris, France; Université Pierre et Marie Curie, Paris, France; INSERM, U 698, Paris, France.
3
Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, United Kingdom.
4
Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska University Hospital Solna, Stockholm, Sweden.
5
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.
6
Unitat de Recerca en Lípids i Arteriosclerosi, IISPV, Universitat Rovira i Virgili, CIBERDEM, Reus, Spain.
7
Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
8
Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
9
Intermountain Heart Institute, Intermountain Medical Center, Salt Lake City, Utah; Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah.
10
Intermountain Heart Institute, Intermountain Medical Center, Salt Lake City, Utah.
11
TIMI Study Group, Divison of Cardiovascular Medicine, Brigham and Women's Hospital & Harvard Medical School, Boston, Massachusetts.
12
Durrer Center for Cardiogenetic Research, Amsterdam, the Netherlands; Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
13
Department of Biostatistics & Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
14
Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.
15
Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands; Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
16
Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
17
Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
18
Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Member of the Netherlands Consortium on Healthy Aging (NCHA), Leiden, the Netherlands.
19
Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, United Kingdom.
20
Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Antoine, Department of Clinical Pharmacology, URC-EST, Paris, France.
21
Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Department of Cardiology, Paris, France; Université Paris Descartes, Paris V, Paris, France.
22
Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany; LIFE: Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany.
23
Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
24
Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany; Division of Clinical Epidemiology & Aging Research, German Cancer Research Center, Heidelberg, Germany.
25
Faculty of Population Health Sciences, University College London, London, United Kingdom.
26
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
27
Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, United Kingdom.
28
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Department of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom.
29
Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
30
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.
31
Dipartimento di Scienze Farmacologiche e Biomolecolari, Universitá di Milano, Milan, Italy; Centro Cardiologico Monzino, IRCCS, Milan, Italy.
32
Centro Cardiologico Monzino, IRCCS, Milan, Italy.
33
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 (LMU), Ludwig-Maximilians-University Munich, Munich, Germany.
34
LIFE: Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany; Department of Internal Medicine/Cardiology, Heart Center, University of Leipzig, Leipzig, Germany.
35
University Medical Center Groningen, University of Groningen, Department of Internal Medicine, Groningen, the Netherlands.
36
University Medical Center Groningen, University of Groningen, Department of Cardiology, Groningen, the Netherlands.
37
Division of Clinical Epidemiology & Aging Research, German Cancer Research Center, Heidelberg, Germany.
38
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.
39
Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, Ulm, Germany.
40
Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
41
Department for Nutrition and Health, National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
42
Diabetes Research Group, Institute of Life Sciences, College of Medicine, Swansea University, Swansea, Wales, United Kingdom.
43
Department of Pathology and Medical Biology, Medical Biology Section, Molecular Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
44
Inserm U970, Paris-Cardiovascular Research Center, Paris, France.
45
Member of the Netherlands Consortium on Healthy Aging (NCHA), Leiden, the Netherlands; Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
46
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, the Netherlands.
47
Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands.
48
Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
49
Division of Population Health Sciences and Education, St George's, University of London, London, United Kingdom.
50
Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom.
51
Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, United Kingdom.
52
Stockholm Heart Center, Stockholm, and Linköping University, Linkőping, Sweden.
53
Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
54
Departments of Health Sciences & Genetics, University of Leicester, Leicester, United Kingdom.
55
Department of Vascular Surgery, Imperial College, London, United Kingdom; Cyprus Cardiovascular Educational and Research Trust, Nicosia, Cyprus.
56
MRC Centre for Causal Analyses in Translational Epidemiology (CAiTE), and Bristol Genetic Epidemiology Laboratories (BGEL), School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
57
Robertson Centre for Biostatistics, University of Glasgow, Glasgow, Scotland, United Kingdom.
58
British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, Scotland, United Kingdom.
59
Division of Cardiovascular Diseases, Department of Medicine, University of California San Diego, La Jolla, California.
60
VA Medical Center and University of Colorado School of Medicine, Denver, Colorado.
61
Department of Primary Care & Population Health, University College London, Royal Free Campus, London, United Kingdom.
62
Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
63
Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
64
Centre for Population Health Sciences, University of Edinburgh, United Kingdom.
65
Department of Clinical Epidemiology & 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.
66
Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada.
67
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.
68
Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
69
Preventive Cardiovascular Medicine, Penn Heart and Vascular Center, Philadelphia, Pennsylvania.
70
Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, United Kingdom.
71
Department of Clinical Epidemiology & 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.
72
Faculty of Population Health Sciences, University College London, London, United Kingdom; Centre for Clinical Pharmacology, Division of Medicine, University College London, London, United Kingdom.
73
Inserm U970, Paris-Cardiovascular Research Center, Paris, France; Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
74
Faculty of Population Health Sciences, University College London, London, United Kingdom; Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, United Kingdom. Electronic address: Juan.Pablo-Casas@lshtm.ac.uk.

Abstract

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

PMID:
23916927
PMCID:
PMC3826105
DOI:
10.1016/j.jacc.2013.06.044
[Indexed for MEDLINE]
Free PMC Article

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