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

Funder: Familjen Erling Personssons StiftelseFunder: EPIDEMIOM-VT Senior Chair from the University of Bordeaux initiative of excellence IdEX EUR DPH within the framework of the PIA3 (Project reference 17-EURE-0019)Funder: Martin Rinds stiftelse VenforskningsstiftelsenFunder: Gates Cambridge Trust HDRUK Multi-Omics (G107794) grants and the UKRI/NIHR Strategic Priorities Award in Multimorbidity Research for the Multimorbidity Mechanism and Therapeutics Research Collaborative (MR/V033867/1).Funder: Cancer Research UK (C864/A14136) HDRUK Multi-Omics (G107794) grants and the UKRI/NIHR Strategic Priorities Award in Multimorbidity Research for the Multimorbidity Mechanism and Therapeutics Research Collaborative (MR/V033867/1).Funder: IK2-CX001780Funder: Department of Veterans Affairs Office of Research and Development, Million Veteran Program Grant MVP000 IK2BX005759-01Funder: grant PT17/0019, of the PE I+D+i 2013-2016, funded by ISCIII and ERDFFunder: EPIDEMIOM-VT Senior Chair from the University of Bordeaux initiative of excellence IdEX.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