Elevated plasma complement factor H related 5 protein is associated with venous thromboembolism

Maria Jesus Iglesias, Laura Sanchez-Rivera, Manal Ibrahim-Kosta, Clément Naudin, Gaëlle Munsch, Louisa Goumidi, Maria Farm, Philip M. Smith, Florian Thibord, Julia Barbara Kral-Pointner, Mun-Gwan Hong, Pierre Suchon, Marine Germain, Waltraud Schrottmaier, Philip Dusart, Anne Boland, David Kotol, Fredrik Edfors, Mine Koprulu, Maik Pietzner, Claudia Langenberg, Scott M. Damrauer, Andrew D. Johnson, Derek M. Klarin, Nicholas L. Smith, David M. Smadja, Margareta Holmström, Maria Magnusson, Angela Silveira, Mathias Uhlén, Thomas Renné, Angel Martinez-Perez, Joseph Emmerich, Jean-Francois Deleuze, Jovan Antovic, Jose Manuel Soria Fernandez, Alice Assinger, Jochen M. Schwenk, Joan Carles Souto Andres, Pierre-Emmanuel Morange, Lynn Marie Butler, David-Alexandre Trégouët () and Jacob Odeberg ()
Additional contact information
Maria Jesus Iglesias: CBH, KTH Royal Institute of Technology
Laura Sanchez-Rivera: CBH, KTH Royal Institute of Technology
Manal Ibrahim-Kosta: INSERM, INRAE, C2VN, Laboratory of Haematology, CRB Assistance Publique—Hôpitaux de Marseille
Clément Naudin: CBH, KTH Royal Institute of Technology
Gaëlle Munsch: INSERM, Bordeaux Population Health Research Center
Louisa Goumidi: INSERM, INRAE, C2VN, Laboratory of Haematology, CRB Assistance Publique—Hôpitaux de Marseille
Maria Farm: Karolinska Institute
Philip M. Smith: Karolinska Institute and Karolinska University Hospital
Florian Thibord: Division of Intramural Research, National Heart, Lung and Blood Institute
Julia Barbara Kral-Pointner: Medical University of Vienna
Mun-Gwan Hong: CBH, KTH Royal Institute of Technology
Pierre Suchon: INSERM, INRAE, C2VN, Laboratory of Haematology, CRB Assistance Publique—Hôpitaux de Marseille
Marine Germain: INSERM, Bordeaux Population Health Research Center
Waltraud Schrottmaier: Medical University of Vienna
Philip Dusart: CBH, KTH Royal Institute of Technology
Anne Boland: Centre National de Recherche en Génomique Humaine (CNRGH)
David Kotol: CBH, KTH Royal Institute of Technology
Fredrik Edfors: CBH, KTH Royal Institute of Technology
Mine Koprulu: University of Cambridge School of Clinical Medicine, Institute of Metabolic Science
Maik Pietzner: University of Cambridge School of Clinical Medicine, Institute of Metabolic Science
Claudia Langenberg: University of Cambridge School of Clinical Medicine, Institute of Metabolic Science
Scott M. Damrauer: Corporal Michael Crescenz VA Medical Center
Andrew D. Johnson: Division of Intramural Research, National Heart, Lung and Blood Institute
Derek M. Klarin: VA Palo Alto Healthcare System
Nicholas L. Smith: University of Washington
David M. Smadja: European Georges Pompidou Hospital, Assistance Publique Hôpitaux de Paris
Margareta Holmström: Karolinska University Hospital
Maria Magnusson: Karolinska Institute
Angela Silveira: Karolinska Institute and Karolinska University Hospital
Mathias Uhlén: CBH, KTH Royal Institute of Technology
Thomas Renné: University Medical Centre Hamburg-Eppendorf
Angel Martinez-Perez: Research Institute Hospital de la Santa Creu i Sant Pau. IIB Sant Pau
Joseph Emmerich: University of Paris Cité
Jean-Francois Deleuze: Centre National de Recherche en Génomique Humaine (CNRGH)
Jovan Antovic: Karolinska Institute
Jose Manuel Soria Fernandez: Research Institute Hospital de la Santa Creu i Sant Pau. IIB Sant Pau
Alice Assinger: Medical University of Vienna
Jochen M. Schwenk: CBH, KTH Royal Institute of Technology
Joan Carles Souto Andres: Unitat d’Hemostàsia i Trombosi. Hospital de la Santa Creu i Sant Pau and IIB-Sant Pau
Pierre-Emmanuel Morange: INSERM, INRAE, C2VN, Laboratory of Haematology, CRB Assistance Publique—Hôpitaux de Marseille
Lynn Marie Butler: CBH, KTH Royal Institute of Technology
David-Alexandre Trégouët: INSERM, Bordeaux Population Health Research Center
Jacob Odeberg: CBH, KTH Royal Institute of Technology

Nature Communications, 2023, vol. 14, issue 1, 1-23

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-38383-y

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