Dataset Information

Elevated plasma Complement Factor H Regulating Protein 5 is associated with venous thromboembolism

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. We use multiplex proteomics profiling to screen plasma from patients with suspected acute VTE, and several case-control studies for VTE, to identify Complement Factor H Related Protein 5 (CFHR5), a regulator of the alternative pathway of complement activation, as a novel 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.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Plasma

SUBMITTER: David Kotol

LAB HEAD: Jacob Odeberg

PROVIDER: PXD040913 | Pride | 2023-03-25

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	All_lists_20190625_20190709.fasta	Fasta
	HF_20200720_VEBIOS_DIA_350to1000mz_40min_1to32_10mz_A1.raw	Raw
	HF_20200720_VEBIOS_DIA_350to1000mz_40min_1to32_10mz_A10.raw	Raw
	HF_20200720_VEBIOS_DIA_350to1000mz_40min_1to32_10mz_A11.raw	Raw
	HF_20200720_VEBIOS_DIA_350to1000mz_40min_1to32_10mz_A12.raw	Raw

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

Iglesias Maria Jesus MJ Sanchez-Rivera Laura L Ibrahim-Kosta Manal M Naudin Clément C Munsch Gaëlle G Goumidi Louisa L Farm Maria M Smith Philip M PM Thibord Florian F Kral-Pointner Julia Barbara JB Hong Mun-Gwan MG Suchon Pierre P Germain Marine M Schrottmaier Waltraud W Dusart Philip P Boland Anne A Kotol David D Edfors Fredrik F Koprulu Mine M Pietzner Maik M Langenberg Claudia C Damrauer Scott M SM Johnson Andrew D AD Klarin Derek M DM Smith Nicholas L NL Smadja David M DM Holmström Margareta M Magnusson Maria M Silveira Angela A Uhlén Mathias M Renné Thomas T Martinez-Perez Angel A Emmerich Joseph J Deleuze Jean-Francois JF Antovic Jovan J Soria Fernandez Jose Manuel JM Assinger Alice A Schwenk Jochen M JM Souto Andres Joan Carles JC Morange Pierre-Emmanuel PE Butler Lynn Marie LM Trégouët David-Alexandre DA Odeberg Jacob J

Nature communications 20230607 1

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, i ...[more]

PMID: 37286573

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Project description:Recurrent venous thromboembolism (VTE) occurs infrequently following a provoked event but occurs in up to 30% of individuals following an initial unprovoked event. We studied 134 patients with VTE separated into 3 groups: (1) âlow-riskâ patients had â¥1 provoked VTE; (2) âmoderate-riskâ patients had no more than 1 unprovoked VTE; (3) âhigh-riskâ patients had â¥2 unprovoked VTE. 44 individuals with no history of VTE were enrolled as healthy controls. Consented individuals were enrolled at 4 medical centers in the US. Total RNA from whole blood was isolated and hybridized to Illumina HT-12 V4 Beadchips to assay whole genome expression. Using class prediction analysis, we distinguished high-risk patients from healthy controls with good receiver operating curve characteristics (AUC=0.88). We also distinguished high-risk from low-risk individuals, moderate-risk individuals from healthy controls, and low-risk individuals from healthy controls with AUCâs of 0.72, 0.77 and 0.72, respectively. Using differential expression analysis, we identified genes relevant to coagulation, immune response and vascular biology, such as SELP and CD46, which were differentially expressed in at least two comparisons. Neither approach distinguished the moderate-risk patients from the high-risk or low-risk groups. Gene expression profiles may provide insights into biological mechanisms associated with patients at risk for recurrent VTE. Prospective studies are needed to validate these findings. This study includes a total of 218 samples/individuals (in 5 groups; APS, high-risk VTE, moderate-risk VTE, low-risk VTE and healthy-controls). Samples in which the percent of probes present was 15% or less (n=51) were excluded leaving 167 samples. The data for these 167 samples were normalized together. However, this record represents the 132 individual samples in the following groups; high-risk (n=40); moderate-risk (n=33); low-risk (n=34); and healthy controls (n=25). The 35 samples in APS group are represented in GSE48001.

Project description:Background Hypertrophic cardiomyopathy (HCM) is defined clinically by pathological left ventricular hypertrophy (LVH). We have previously developed a plasma proteomics biomarker panel that correlates with clinical markers of disease severity and sudden cardiac death (SCD) risk in adult patients with HCM. The aim of this study was to validate the adult biomarkers and perform new discovery proteomics in childhood-onset HCM. Methods Fifty-nine protein biomarkers were identified from an exploratory plasma proteomics screen in children with HCM and augmented into our existing multiplexed targeted liquid chromatography-tandem/mass spectrometry-based assay. The association of these biomarkers with clinical phenotypes and outcomes was prospectively tested in plasma collected from 148 children with HCM and 50 healthy controls. Machine learning techniques were used to develop novel paediatric plasma proteomic biomarker panels.Results Four previously validated adult HCM markers (Aldolase Fructose-Bisphosphate A, Complement C3a, Talin-1 and Thrombospondin 1) and three new markers (Glycogen Phosphorylase B, Lipoprotein A and Profilin 1) were elevated in paediatric HCM. Using supervised machine learning applied to training (n=137) and validation cohorts (n=61), this 7-biomarker panel differentiated HCM from healthy controls with an area under the curve of 1.0 in the training dataset (sensitivity 100% [95% confidence interval: 95–100]; specificity 100% [96–100]) and 0.82 in the validation dataset (sensitivity 75% [59–86]; specificity 88% [75–94]). Reduced circulating levels of 4 other peptides (Apolipoprotein L1-, Complement 5b-, Immunoglobulin Heavy Constant Epsilon- and Serum Amyloid A4-peptide) found in children with high SCD risk provided complete separation from the low and intermediate risk groups, and predicted mortality and adverse cardiovascular outcomes (hazard ratio 1.53 [1.2 –2.0], p = 0.001). ConclusionIn children, a 7-biomarker proteomics panel can distinguish HCM from controls with high sensitivity and specificity, and a second 4-biomarker panel identifies those at high risk of adverse outcomes, including sudden cardiac death.

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