Abstract

Venous thromboembolism (VTE) is a common, multi-causal disease with potentially serious short- and long-term complications. In clinical practice, there is a need for improved plasma biomarker-based tools for VTE diagnosis and risk prediction. Here we show, using proteomics profiling to screen plasma from patients with suspected acute VTE, and several case-control studies for VTE, how Complement Factor H Related 5 protein (CFHR5), a regulator of the alternative pathway of complement activation, is a VTE-associated plasma biomarker. In plasma, higher CFHR5 levels are associated with increased thrombin generation potential and recombinant CFHR5 enhanced platelet activation in vitro. GWAS analysis of ~52,000 participants identifies six loci associated with CFHR5 plasma levels, but Mendelian randomization do not demonstrate causality between CFHR5 and VTE. Our results indicate an important role for the regulation of the alternative pathway of complement activation in VTE and that CFHR5 represents a potential diagnostic and/or risk predictive plasma biomarker.

Improved biomarker-based tools for diagnosis and risk prediction of venous thromboembolism (VTE) are needed. Here, the authors show that Complement Factor H Related 5 protein, a regulator of the alternative pathway of complement activation, is a VTE-associated plasma biomarker in 5 independent cohorts.

Details

Title
Elevated plasma complement factor H related 5 protein is associated with venous thromboembolism
Author
Iglesias, Maria Jesus 1 ; Sanchez-Rivera, Laura 2 ; Ibrahim-Kosta, Manal 3 ; Naudin, Clément 4   VIAFID ORCID Logo  ; Munsch, Gaëlle 5   VIAFID ORCID Logo  ; Goumidi, Louisa 3   VIAFID ORCID Logo  ; Farm, Maria 6 ; Smith, Philip M. 7 ; Thibord, Florian 8 ; Kral-Pointner, Julia Barbara 9 ; Hong, Mun-Gwan 2   VIAFID ORCID Logo  ; Suchon, Pierre 3 ; Germain, Marine 10 ; Schrottmaier, Waltraud 9   VIAFID ORCID Logo  ; Dusart, Philip 4   VIAFID ORCID Logo  ; Boland, Anne 11 ; Kotol, David 2   VIAFID ORCID Logo  ; Edfors, Fredrik 2   VIAFID ORCID Logo  ; Koprulu, Mine 12   VIAFID ORCID Logo  ; Pietzner, Maik 13   VIAFID ORCID Logo  ; Langenberg, Claudia 13   VIAFID ORCID Logo  ; Damrauer, Scott M. 14   VIAFID ORCID Logo  ; Johnson, Andrew D. 15   VIAFID ORCID Logo  ; Klarin, Derek M. 16   VIAFID ORCID Logo  ; Smith, Nicholas L. 17 ; Smadja, David M. 18 ; Holmström, Margareta 19 ; Magnusson, Maria 20 ; Silveira, Angela 21   VIAFID ORCID Logo  ; Uhlén, Mathias 2   VIAFID ORCID Logo  ; Renné, Thomas 22 ; Martinez-Perez, Angel 23   VIAFID ORCID Logo  ; Emmerich, Joseph 24 ; Deleuze, Jean-Francois 25   VIAFID ORCID Logo  ; Antovic, Jovan 6 ; Soria Fernandez, Jose Manuel 23 ; Assinger, Alice 9   VIAFID ORCID Logo  ; Schwenk, Jochen M. 2   VIAFID ORCID Logo  ; Souto Andres, Joan Carles 26   VIAFID ORCID Logo  ; Morange, Pierre-Emmanuel 3   VIAFID ORCID Logo  ; Butler, Lynn Marie 27   VIAFID ORCID Logo  ; Trégouët, David-Alexandre 10   VIAFID ORCID Logo  ; Odeberg, Jacob 28   VIAFID ORCID Logo 

1  CBH, KTH Royal Institute of Technology, Science for Life Laboratory, Department of Protein Science, Stockholm, Sweden (GRID:grid.5037.1) (ISNI:0000000121581746); University Hospital of North Norway (UNN), PB100, Division of Internal Medicine, Tromsø, Norway (GRID:grid.412244.5) (ISNI:0000 0004 4689 5540); UiT The Arctic University of Norway, Translational Vascular Research, Department of Clinical Medicine, Tromsø, Norway (GRID:grid.10919.30) (ISNI:0000 0001 2259 5234) 
2  CBH, KTH Royal Institute of Technology, Science for Life Laboratory, Department of Protein Science, Stockholm, Sweden (GRID:grid.5037.1) (ISNI:0000000121581746) 
3  INSERM, INRAE, C2VN, Laboratory of Haematology, CRB Assistance Publique—Hôpitaux de Marseille, Aix-Marseille Univ, Marseille, France (GRID:grid.457381.c) (ISNI:0000 0004 0638 6194) 
4  CBH, KTH Royal Institute of Technology, Science for Life Laboratory, Department of Protein Science, Stockholm, Sweden (GRID:grid.5037.1) (ISNI:0000000121581746); UiT The Arctic University of Norway, Translational Vascular Research, Department of Clinical Medicine, Tromsø, Norway (GRID:grid.10919.30) (ISNI:0000 0001 2259 5234) 
5  INSERM, Bordeaux Population Health Research Center, University of Bordeaux, Bordeaux, France (GRID:grid.457371.3) 
6  Karolinska Institute, Department of Molecular Medicine and Surgery, Stockholm, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626); Karolinska University Hospital, Department of Clinical Chemistry, Stockholm, Sweden (GRID:grid.24381.3c) (ISNI:0000 0000 9241 5705) 
7  Karolinska Institute and Karolinska University Hospital, Department of Medicine Solna, Stockholm, Sweden (GRID:grid.24381.3c) (ISNI:0000 0000 9241 5705); Karolinska University Hospital, Theme of Emergency and Reparative Medicine, Stockholm, Sweden (GRID:grid.24381.3c) (ISNI:0000 0000 9241 5705) 
8  Division of Intramural Research, National Heart, Lung and Blood Institute, Population Sciences Branch, Framingham, USA (GRID:grid.24381.3c); The Framingham Heart Study, Boston University, Framingham, USA (GRID:grid.510954.c) (ISNI:0000 0004 0444 3861) 
9  Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Vascular Biology and Thrombosis Research, Vienna, Austria (GRID:grid.22937.3d) (ISNI:0000 0000 9259 8492) 
10  INSERM, Bordeaux Population Health Research Center, University of Bordeaux, Bordeaux, France (GRID:grid.457371.3); Laboratory of Excellence GENMED (Medical Genomics), Bordeaux, France (GRID:grid.457371.3) 
11  Centre National de Recherche en Génomique Humaine (CNRGH), Université Paris-Saclay, CEA, Evry, France (GRID:grid.418135.a) (ISNI:0000 0004 0641 3404); Laboratory of Excellence GENMED (Medical Genomics), Evry, France (GRID:grid.418135.a) 
12  University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, MRC Epidemiology Unit, Cambridge, UK (GRID:grid.470900.a) (ISNI:0000 0004 0369 9638) 
13  University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, MRC Epidemiology Unit, Cambridge, UK (GRID:grid.470900.a) (ISNI:0000 0004 0369 9638); Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Computational Medicine, Berlin, Germany (GRID:grid.484013.a); Queen Mary University of London, Precision Healthcare University Research Institute, London, UK (GRID:grid.4868.2) (ISNI:0000 0001 2171 1133) 
14  Corporal Michael Crescenz VA Medical Center, Philadelphia, USA (GRID:grid.410355.6) (ISNI:0000 0004 0420 350X); University of Pennsylvania, Department of Surgery and Department of Genetics, Perelman School of Medicine, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972) 
15  Division of Intramural Research, National Heart, Lung and Blood Institute, Population Sciences Branch, Framingham, USA (GRID:grid.25879.31); The Framingham Heart Study, Boston University, Framingham, USA (GRID:grid.510954.c) (ISNI:0000 0004 0444 3861) 
16  VA Palo Alto Healthcare System, Palo Alto, USA (GRID:grid.280747.e) (ISNI:0000 0004 0419 2556); Stanford University School of Medicine, Department of Vascular Surgery, Palo Alto, USA (GRID:grid.168010.e) (ISNI:0000000419368956) 
17  University of Washington, Department of Epidemiology, Seattle, USA (GRID:grid.34477.33) (ISNI:0000 0001 2298 6657); Kaiser Permanente Washington Health Research Institute, Seattle, USA (GRID:grid.488833.c) (ISNI:0000 0004 0615 7519); Department of Veterans Affairs Office of Research and Development, Seattle Epidemiologic Research and Information Center, Seattle, USA (GRID:grid.511389.7) 
18  European Georges Pompidou Hospital, Assistance Publique Hôpitaux de Paris, Hematology Department and Biosurgical Research Lab (Carpentier Foundation), Paris, France (GRID:grid.414093.b) (ISNI:0000 0001 2183 5849); Université de Paris, Innovative Therapies in Haemostasis, INSERM, Paris, France (GRID:grid.5842.b) (ISNI:0000 0001 2171 2558) 
19  Karolinska University Hospital, Coagulation Unit, Department of Haematology, Stockholm, Sweden (GRID:grid.24381.3c) (ISNI:0000 0000 9241 5705) 
20  Karolinska Institute, Department of Molecular Medicine and Surgery, Stockholm, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626); Karolinska University Hospital, Coagulation Unit, Department of Haematology, Stockholm, Sweden (GRID:grid.24381.3c) (ISNI:0000 0000 9241 5705); Intervention and Technology, Karolinska Institute, Department of Clinical Science, Stockholm, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626) 
21  Karolinska Institute and Karolinska University Hospital, Department of Medicine Solna, Stockholm, Sweden (GRID:grid.24381.3c) (ISNI:0000 0000 9241 5705) 
22  University Medical Centre Hamburg-Eppendorf, Institute for Clinical Chemistry and Laboratory Medicine, Hamburg, Germany (GRID:grid.13648.38) (ISNI:0000 0001 2180 3484); Johannes Gutenberg University Medical Center, D-, Center for Thrombosis and Hemostasis (CTH), Mainz, Germany (GRID:grid.5802.f) (ISNI:0000 0001 1941 7111); School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Irish Centre for Vascular Biology, Dublin 2, Ireland (GRID:grid.4912.e) (ISNI:0000 0004 0488 7120) 
23  Research Institute Hospital de la Santa Creu i Sant Pau. IIB Sant Pau, Genomics of Complex Diseases Group, Barcelona, Spain (GRID:grid.413396.a) (ISNI:0000 0004 1768 8905) 
24  University of Paris Cité, Department of vascular medicine, Paris Saint-Joseph Hospital Group, INSERM 1153-CRESS, Paris, France (GRID:grid.10988.38) (ISNI:0000 0001 2173 743X) 
25  Centre National de Recherche en Génomique Humaine (CNRGH), Université Paris-Saclay, CEA, Evry, France (GRID:grid.418135.a) (ISNI:0000 0004 0641 3404); Laboratory of Excellence GENMED (Medical Genomics), Evry, France (GRID:grid.418135.a); Fondation Jean Dausset, Centre D’Etude du Polymorphisme Humain, Paris, France (GRID:grid.417836.f) (ISNI:0000 0004 0639 125X) 
26  Unitat d’Hemostàsia i Trombosi. Hospital de la Santa Creu i Sant Pau and IIB-Sant Pau, Barcelona, Spain (GRID:grid.413396.a) (ISNI:0000 0004 1768 8905) 
27  CBH, KTH Royal Institute of Technology, Science for Life Laboratory, Department of Protein Science, Stockholm, Sweden (GRID:grid.5037.1) (ISNI:0000000121581746); UiT The Arctic University of Norway, Translational Vascular Research, Department of Clinical Medicine, Tromsø, Norway (GRID:grid.10919.30) (ISNI:0000 0001 2259 5234); Karolinska Institute, Department of Molecular Medicine and Surgery, Stockholm, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626); Karolinska University Hospital, Department of Clinical Chemistry, Stockholm, Sweden (GRID:grid.24381.3c) (ISNI:0000 0000 9241 5705) 
28  CBH, KTH Royal Institute of Technology, Science for Life Laboratory, Department of Protein Science, Stockholm, Sweden (GRID:grid.5037.1) (ISNI:0000000121581746); University Hospital of North Norway (UNN), PB100, Division of Internal Medicine, Tromsø, Norway (GRID:grid.412244.5) (ISNI:0000 0004 4689 5540); UiT The Arctic University of Norway, Translational Vascular Research, Department of Clinical Medicine, Tromsø, Norway (GRID:grid.10919.30) (ISNI:0000 0001 2259 5234); Karolinska Institute and Karolinska University Hospital, Department of Medicine Solna, Stockholm, Sweden (GRID:grid.24381.3c) (ISNI:0000 0000 9241 5705); Karolinska University Hospital, Coagulation Unit, Department of Haematology, Stockholm, Sweden (GRID:grid.24381.3c) (ISNI:0000 0000 9241 5705) 
Pages
3280
Publication year
2023
Publication date
2023
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-023-38383-y
ProQuest document ID
2826827883
Copyright
© The Author(s) 2023. corrected publication 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.