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CC BY-NC-ND 4.0 · Thromb Haemost 2025; 125(08): 791-801
DOI: 10.1055/a-2461-3349
Stroke, Systemic or Venous Thromboembolism

Brisk Walking Pace Offsets Venous Thromboembolism Risk Equivalent to Established Monogenic Mutations

Authors

  • Wenyan Xian

    1   School of Public Health and Emergency Management, Southern University of Science and Technology, Shenzhen, China

  • Yifan Tao

    2   School of Engineering, Johns Hopkins University, Baltimore, Maryland, United States

  • Chong You

    3   Shanghai Institute for Mathematics and Interdisciplinary Sciences, Fudan University, Shanghai, China

  • Ruinan Sun

    4   Department of Public and Ecosystem Health, Cornell University College of Veterinary Medicine, Ithaca, New York, United States

  • Janice M. Ranson

    5   University of Exeter Medical School, Exeter, United Kingdom

  • Valerio Napolioni

    6   School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy

  • Patrick W.C. Lau

    7   Department of Sport, Physical Education and Health, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China

  • Jie Huang

    1   School of Public Health and Emergency Management, Southern University of Science and Technology, Shenzhen, China

Funding J.H. was supported by the National Key Research and Development Program of China [2022YFC3600800]. J.M.R. is supported by the Alzheimer's Research UK.
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Abstract

Background

Mendelian mutations in the Prothrombin gene (F2) and the factor V Leiden gene (F5) genes are established risk factors for venous thromboembolism (VTE). Walking pace is associated with the risk of coronary artery diseases, but no study has investigated its association with VTE. This study aimed to investigate the association and causality between walking pace and VTE, compare its population risk with established Mendelian mutations, and determine if blood biomarkers mediate its effect.

Methods

We followed up 445,261 UK Biobank participants free of VTE at baseline. Self-reported walking pace was collected via touchscreen questionnaire at baseline. The carrier status of two Mendelian mutations in F2 and F5 genes was determined by the genotypes of rs1799963 (G20210A, c.*97 G > A) and rs6025 (p.R534Q), respectively. Cox proportional hazard model was used to estimate the effect of walking pace on incident VTE. We conducted a bidirectional Mendelian randomization (MR) analysis, by using 70 single-nucleotide polymorphisms (SNPs) from a walking pace genome-wide association studies (GWAS) and 93 SNPs from a VTE GWAS as instrumental variables. We used both individual-level data and GWAS summary statistics for mediation analysis.

Results

Over a median follow-up period of 12.8 years, 11,155 incident VTE cases were identified. The 10-year incidence rates for brisk and slow walking pace were 1.32% (confidence interval [CI]: 1.27–1.37%) and 3.90% (CI: 3.71–4.09%), respectively. For noncarriers, F2 and F5 carriers, the 10-year incidence rates were 1.70% (CI: 1.66–1.73%), 2.94% (CI: 2.66–3.22%), and 3.62% (CI: 3.39–3.84%), respectively. The overall risk of VTE for F5 mutation carriers with a brisk walking pace (2.65%) was smaller than that for noncarriers with a slow walking pace (3.66%). For F5 mutation carriers, brisk pace (but not steady pace) reduces the risk of VTE (p interaction < 0.05). MR analyses displayed a causal relationship (inverse variance weighted: p = 3.21 × 10−5) from walking pace to VTE incidence. Mediation analysis showed that serum albumin (ALB) and cystatin C (CYS) levels partially mediated the effect of brisk walking pace on the risk of VTE incidence, with mediation proportions of 8.7 to 11.7%, respectively.

Conclusion

On the population scale, the protective effect of brisk walking pace offsets the risk of VTE caused by Mendelian mutations. We provided preliminary evidence that a brisk walking pace causally reduces the risk of VTE. Serum ALB and CYS partially mediate this effect.

Keywords

walking pace - venous thromboembolism - prospective cohort - Mendelian randomization - mediation

Ethical Approval Statement

All participants provided written informed consent at their baseline visit. Ethical approval of the UK Biobank study was obtained from the National Information Governance Board for Health and Social Care and the National Health Service North West Multi-Centre Research Ethics Committee (Ref. 11/NW/0382). This research was conducted using the UK Biobank resources under application 66137.


Authors' Contribution

All authors meet authorship criteria by contributing to components of research conception, design, interpretation of results, and manuscript revisions. J.H. and W.X. conceptualized and designed the study, conducted formal data analyses, and drafted the initial manuscript. C.Y. and A.S.P. contributed to data analysis and manuscript writing. Y.Q., R.S., J.M.R., and V.N. provided input into the study design and revised the manuscript. T.W. and P.W.C.L. interpreted the results and revised the manuscript. All authors reviewed the final manuscript as submitted.




Publikationsverlauf

Eingereicht: 09. August 2024

Angenommen: 23. Oktober 2024

Accepted Manuscript online:
05. November 2024

Artikel online veröffentlicht:
16. Januar 2025

© 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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