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Lipoprotein-associated phospholipase A2 activity, genetics and calcific aortic valve stenosis in humans
  1. Nicolas Perrot1,2,
  2. Sébastien Thériault1,3,
  3. Sidwell Rigade4,
  4. Hao Yu Chen5,
  5. Christian Dina4,
  6. Andreas Martinsson6,7,
  7. S Matthijs Boekholdt8,
  8. Romain Capoulade4,
  9. Thierry Le Tourneau9,
  10. David Messika-Zeitoun10,
  11. James C Engert5,
  12. Nicholas J Wareham11,
  13. Marie-Annick Clavel1,2,
  14. Philippe Pibarot1,2,
  15. J Gustav Smith6,12,
  16. Jean Jacques Schott4,
  17. Patrick Mathieu1,13,
  18. Yohan Bossé1,14,
  19. George Thanassoulis5,
  20. Benoit J Arsenault1,2
  1. 1Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Québec city, Québec, Canada
  2. 2Department of Medicine, Faculty of Medicine, Université Laval, Québec City, Québec, Canada
  3. 3Department of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Université Laval, Québec City, Québec, Canada
  4. 4l'institut du thorax, INSERM, CNRS, UNIV Nantes, CHU Nantes, Nantes, France
  5. 5McGill University Health Center Research Institute, Montreal, Quebec, Canada
  6. 6Department of Cardiology, Clinical Sciences, Lund University, Lund, Sweden
  7. 7Department of Cardiology, Sahlgrenska universitetssjukhuset, Goteborg, Sweden
  8. 8Department of Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
  9. 9Ultrasound and Cardiology Departments, University Hospital, Institut du Thorax, Nantes, France
  10. 10University of Ottawa Heart Institute, APHP, Bichat Hospital, Ottawa, Ontario, Canada
  11. 11Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
  12. 12Wallenberg Center for Molecular Medicine and Lund University Diabetes Center, Lund University, Lund, Sweden
  13. 13Department of Surgery, Faculty of Medicine, Université Laval, Québec City, Quebec, Canada
  14. 14Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec City, Quebec, Canada
  1. Correspondence to Dr Benoit J Arsenault, Universite Laval, Quebec, G1V 4G5, Canada; benoit.arsenault{at}criucpq.ulaval.ca

Abstract

Background Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity has been shown to predict calcific aortic valve stenosis (CAVS) outcomes. Our objective was to test the association between plasma Lp-PLA2 activity and genetically elevated Lp-PLA2 mass/activity with CAVS in humans.

Methods and results Lp-PLA2 activity was measured in 890 patients undergoing cardiac surgery, including 476 patients undergoing aortic valve replacement for CAVS and 414 control patients undergoing coronary artery bypass grafting. After multivariable adjustment, Lp-PLA2 activity was positively associated with the presence of CAVS (OR=1.21 (95% CI 1.04 to 1.41) per SD increment). We selected four single nucleotide polymorphisms (SNPs) at the PLA2G7 locus associated with either Lp-PLA2 mass or activity (rs7756935, rs1421368, rs1805017 and rs4498351). Genetic association studies were performed in eight cohorts: Quebec-CAVS (1009 cases/1017 controls), UK Biobank (1350 cases/349 043 controls), European Prospective Investigation into Cancer and Nutrition-Norfolk (504 cases/20 307 controls), Genetic Epidemiology Research on Aging (3469 cases/51 723 controls), Malmö Diet and Cancer Study (682 cases/5963 controls) and three French cohorts (3123 cases/6532 controls), totalling 10 137 CAVS cases and 434 585 controls. A fixed-effect meta-analysis using the inverse-variance weighted method revealed that none of the four SNPs was associated with CAVS (OR=0.99 (95% CI 0.96 to 1.02, p=0.55) for rs7756935, 0.97 (95% CI 0.93 to 1.01, p=0.11) for rs1421368, 1.00 (95% CI 1.00 to 1.01, p=0.29) for rs1805017, and 1.00 (95% CI 0.97 to 1.04, p=0.87) for rs4498351).

Conclusions Higher Lp-PLA2 activity is significantly associated with the presence of CAVS and might represent a biomarker of CAVS in patients with heart disease. Results of our genetic association study suggest that Lp-PLA2 is however unlikely to represent a causal risk factor or therapeutic target for CAVS.

  • aortic stenosis
  • coronary artery disease
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Footnotes

  • Twitter @none, @PPibarot, @ArsenaultBenoit

  • Contributors All authors have contributed to the manuscript with either substantial contributions to the conception or design of the work, or acquisition, analysis or interpretation of data. All authors have contributed to the first draft of the work or revising it critically for important intellectual content. They all gave final approval of the version published.

  • Funding This study was supported by grants from the Fondation de l’IUCPQ and the Canadian Institutes of Health Research (CIHR) (awarded to BA (FRN149068 and FRN155226) and YB (MOP102481 and MOP137058)) and by the Heart and Stroke Foundation of Canada (awarded to YB (PJT153396)). The COFRASA (NCT00338676) and GENERAC (NCT00647088) studies are supported by grants from the Assistance Publique - Hôpitaux de Paris (PHRC National 2005 and 2010 and PHRC Régional 2007). BA, ST and M-AC hold junior scholar awards from the Fonds de recherche du Québec: Santé (FRQS). PM holds an FRQS Research Chair on the Pathobiology of Calcific Aortic Valve Disease. His research programme is supported by the Canadian Institutes of Health Research grants (FRN148778, FRN159697). PP holds the Canada Research Chair in Valvular Heart Disease, and his research programme is supported by a Foundation Scheme Grant from CIHR. YB holds a Canada Research Chair in Genomics of Heart and Lung Diseases. JJS is supported by an ANR and FRM grant (13-BSV6-0011, DCV20070409278). TLT is supported by the Fédération Française de Cardiologie, a Fondation Coeur et Recherche and an Inserm Translational Research grant. RC is supported by a 'Connect Talent' research chair from Région Pays de la Loire and Nantes Métropole. JGS was supported by grants from the Swedish Heart-Lung Foundation (2016-0134 and 2016-0315), the Swedish Research Council (2017-02554), the European Research Council (ERC-STG-2015-679242), the Crafoord Foundation, Skåne University Hospital, the Scania County, governmental funding of clinical research within the Swedish National Health Service, a generous donation from the Knut and Alice Wallenberg Foundation to the Wallenberg Centre for Molecular Medicine in Lund, and funding from the Swedish Research Council (Linnaeus grant Dnr 349-2006-237, Strategic Research Area Exodiab Dnr 2009-1039) and the Swedish Foundation for Strategic Research (Dnr IRC15-0067) to the Lund University Diabetes Centre. GT is supported by R01 HL128550 from the NIH/NHLBI.

  • Competing interests BA has received research funding from Pfizer, Merck and Ionis Pharmaceuticals and is a consultant for Novartis. PM is a consultant for Casebia Therapeutics.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Patient consent for publication Not required.

  • Ethics approval For the biomarker study, the study protocol was approved by the Ethics Committee of the IUCPQ. For the genetic association study, all study protocols were approved by the local ethics committees.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement No data are available.

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