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Thromb Haemost 2025; 125(06): 574-584
DOI: 10.1055/a-2484-0836
Stroke, Systemic or Venous Thromboembolism

The Plasma Proteome and Risk of Future Venous Thromboembolism—Results from the HUNT Study

Sigrid K. Brækkan
1   Thrombosis Research Center (TREC), Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway
2   Thrombosis Research group (TREC), Department of Clinical Medicine, UiT – The Arctic University of Norway, Tromsø, Norway
,
Asbjørn L. Onsaker
2   Thrombosis Research group (TREC), Department of Clinical Medicine, UiT – The Arctic University of Norway, Tromsø, Norway
,
Therese H. Nøst
3   HUNT Center for Molecular and Clinical Epidemiology, Norwegian University of Science and Technology, Trondheim, Norway
4   Department of Community Medicine, UiT – The Arctic University of Norway, Tromsø, Norway
,
Weihong Tang
5   Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, Minnesota, United States
,
Kristian D. Hindberg
1   Thrombosis Research Center (TREC), Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway
,
Vania M. Morelli
1   Thrombosis Research Center (TREC), Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway
2   Thrombosis Research group (TREC), Department of Clinical Medicine, UiT – The Arctic University of Norway, Tromsø, Norway
,
Weihua Guan
6   Division of Biostatistics, University of Minnesota School of Public Health, Minneapolis, Minnesota, United States
,
Christian Jonasson
7   HUNT Research Center, Norwegian University of Science and Technology, Levanger, Norway
,
Aaron R. Folsom 
5   Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, Minnesota, United States
,
Kristian Hveem
3   HUNT Center for Molecular and Clinical Epidemiology, Norwegian University of Science and Technology, Trondheim, Norway
7   HUNT Research Center, Norwegian University of Science and Technology, Levanger, Norway
,
John-Bjarne Hansen
1   Thrombosis Research Center (TREC), Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway
2   Thrombosis Research group (TREC), Department of Clinical Medicine, UiT – The Arctic University of Norway, Tromsø, Norway
› Author Affiliations
Funding The Thrombosis Research Center (TREC) was supported by an independent grant from Stiftelsen Kristian Gerhard Jebsen (SKGJ-MED-012) during the establishment of this project. The SOMAscan lab work was partly supported by the grant R01HL059367 and R01HL155209 from the National Heart, Lung, and Blood Institute.
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Abstract

Background

This study aimed to identify novel plasma proteins associated with first-lifetime venous thromboembolism (VTE) and molecular pathways involved in VTE pathogenesis.

Methods

A case–cohort comprising incident VTE cases (n = 294) and a randomly sampled age- and sex-weighted subcohort (n = 1,066) was derived from the Trøndelag Health Study (HUNT3, n = 50,800). Blood samples were collected and stored at cohort inclusion (2006–2008), and participants were followed up to 5 years. Proteome-wide analyses was performed using the 7k SomaScan® proteomics platform, and weighted Cox-regression models adjusted for age, sex, and sample batch were conducted, with the Bonferroni method applied to account for multiple testing. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were applied on the top-ranked 200 proteins associated with VTE.

Results

Out of 7,288 human proteins, 7 proteins were significantly associated with higher VTE risk with p-value <6.9 × 10−6 (hazard ratios per 1 standard deviation increase in protein levels ranging from 1.39 to 1.86). Except for coagulation factor VIII and tumor necrosis factor soluble receptor II, these proteins were novel associations and included collagen alpha-3(VI):BPTI/Kunitz inhibitor, histo-blood group ABO system transferase, peroxidasin, human epididymis protein 4, and regulator of G protein signaling 3. KEGG analyses of the top-ranked 200 proteins revealed significant pathway enrichment of nine proteins in the complement (mainly lectin pathway) and coagulation (mainly intrinsic pathway) cascades.

Conclusion

Our proteome-wide analysis led to discovery of five novel protein candidates associated with 5-year risk of future VTE. KEGG analyses supported an interplay between the complement and coagulation pathways in the pathogenesis of VTE.

Keywords

proteomics - plasma - aptamer - venous thromboembolism - deep vein thrombosis - pulmonary embolism

Data Availability Statement

Access to HUNT data can be obtained by application to the HUNT administration at https://www.ntnu.edu/hunt/research.


Authors' Contribution

Conception and design: J.B.H. Data collection: J.B.H., K.H., C.J., A.R.F., and W.T. Statistical analysis: T.H.N. Interpretation of data: J.B.H., S.K.B., K.H., A.R.F., C.J., T.H.N., W.T., W.G., A.L.O., K.D.H., and V.M.M. Draft of manuscript: S.K.B. Critical revision of manuscript: J.B.H., K.H., A.R.F., C.J., T.H.N., W.T., W.G., A.L.O., K.D.H., and V.M.M. Review and approval of final version: All co-authors.


Supplementary Material



Publication History

Received: 26 September 2024

Accepted: 23 November 2024

Accepted Manuscript online:
25 November 2024

Article published online:
18 December 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

Comment to this article:

The Plasma Proteome and Risk of Future Venous Thromboembolism—Results from the HUNT Study in Thrombosis and HaemostasisThromb Haemost 2025; 125(06): 585-588
DOI: 10.1055/a-2575-3388

 

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