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Semin Thromb Hemost 2025; 51(03): 272-278
DOI: 10.1055/s-0044-1790259
Review Article

Causal Relationships of Circulating Inflammatory Proteins and Portal Vein Thrombosis: A Mendelian Randomization Study

Bihui Zhang   *
1   Department of Interventional Radiology and Vascular Surgery, Peking University First Hospital, Beijing, China
,
Ziping Yao   *
1   Department of Interventional Radiology and Vascular Surgery, Peking University First Hospital, Beijing, China
,
Pengyu Li
1   Department of Interventional Radiology and Vascular Surgery, Peking University First Hospital, Beijing, China
,
Guochen Niu
1   Department of Interventional Radiology and Vascular Surgery, Peking University First Hospital, Beijing, China
,
Ziguang Yan
1   Department of Interventional Radiology and Vascular Surgery, Peking University First Hospital, Beijing, China
,
Kang She
1   Department of Interventional Radiology and Vascular Surgery, Peking University First Hospital, Beijing, China
,
Gong Cheng
1   Department of Interventional Radiology and Vascular Surgery, Peking University First Hospital, Beijing, China
,
Min Yang
1   Department of Interventional Radiology and Vascular Surgery, Peking University First Hospital, Beijing, China
› Institutsangaben Funding This research was funded by the National High Level Hospital Clinical Research Funding (grant number 2022CR44) and the National Natural Science Foundation of China (82200537).
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Abstract

Portal vein thrombosis (PVT) is commonly encountered in patients with cirrhosis, challenging our understanding of its development, particularly the ambiguous contribution of inflammation. This study utilized Mendelian randomization (MR) to explore the causal impact of circulating inflammatory markers on PVT.

Employing a two-sample MR framework, we merged genome-wide association study (GWAS) meta-analysis findings of 91 inflammation-associated proteins with independent PVT data from the FinnGen consortium's R10 release. A replication analysis was performed using a distinct GWAS dataset from the UK Biobank. Inverse variance weighting, MR-Egger regression, weighted median estimator, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier were used for analysis, supplemented by multivariable MR (MVMR) to adjust for cirrhosis effects.

Findings indicate a significant inverse association between the genetically inferred concentration of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and PVT risk, evidenced by an odds ratio (OR) of 0.37 (95% confidence interval [CI]: 0.21–0.67; p = 9.2 × 10−4; adjusted for multiple testing p = 0.084). This association was corroborated in the replication phase (OR = 0.39, 95% CI: 0.17–0.93; p = 0.03) and through MVMR analysis (OR = 0.34, 95% CI: 0.15–0.79; p = 0.012). Sensitivity analyses disclosed no evidence of heterogeneity or pleiotropy.

Our investigation emphasizes the 4E-BP1 as a protective factor against PVT, underscoring its potential relevance in understanding PVT pathogenesis and its implications for diagnosis and therapy.

Keywords

portal vein thrombosis - Mendelian randomization - inflammatory proteins - biomarker - FinnGen

Ethical Approval

This research has been conducted using published studies and consortia, which provide publicly available summary statistics. All original studies have been approved by the corresponding ethical review board, and the participants have provided informed consent. In addition, no individual-level data were used in this study. Therefore, no new ethical review board approval was required.


Availability of Data and Materials

The datasets analyzed during the current study are available in the EBI GWAS Catalog (accession numbers GCST90274758–GCST90274848 for inflammation-related proteins, GCST90044027 for PVT, and GCST90044186 for liver cirrhosis; https://www.ebi.ac.uk/gwas/), and the FinnGen repository (finngen_R10_I9_PVT; https://www.finngen.fi/en/access_results).


* These authors contributed equally to this article and thus share co-first authorship.


Supplementary Material



Publikationsverlauf

Artikel online veröffentlicht:
18. September 2024

© 2024. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Senzolo M, Garcia-Tsao G, García-Pagán JC. Current knowledge and management of portal vein thrombosis in cirrhosis. J Hepatol 2021; 75 (02) 442-453
    CrossrefPubMedSuche in Google Scholar
  • 2 Tsochatzis EA, Senzolo M, Germani G, Gatt A, Burroughs AK. Systematic review: portal vein thrombosis in cirrhosis. Aliment Pharmacol Ther 2010; 31 (03) 366-374
    CrossrefPubMedSuche in Google Scholar
  • 3 Violi F, Corazza GR, Caldwell SH. et al; PRO-LIVER Collaborative Group. Incidence and recurrence of portal vein thrombosis in cirrhotic patients. Thromb Haemost 2019; 119 (03) 496-499
    Thieme ConnectPubMedSuche in Google Scholar
  • 4 Ponziani FR, Zocco MA, Senzolo M, Pompili M, Gasbarrini A, Avolio AW. Portal vein thrombosis and liver transplantation: implications for waiting list period, surgical approach, early and late follow-up. Transplant Rev (Orlando) 2014; 28 (02) 92-101
    CrossrefPubMedSuche in Google Scholar
  • 5 Intagliata NM, Caldwell SH, Tripodi A. Diagnosis, development, and treatment of portal vein thrombosis in patients with and without cirrhosis. Gastroenterology 2019; 156 (06) 1582-1599.e1
    CrossrefPubMedSuche in Google Scholar
  • 6 Stine JG, Shah PM, Cornella SL. et al. Portal vein thrombosis, mortality and hepatic decompensation in patients with cirrhosis: a meta-analysis. World J Hepatol 2015; 7 (27) 2774-2780
    CrossrefPubMedSuche in Google Scholar
  • 7 Prakash S, Bies J, Hassan M, Mares A, Didia SC. Portal vein thrombosis in cirrhosis: a literature review. Front Med (Lausanne) 2023; 10: 1134801
    CrossrefPubMedSuche in Google Scholar
  • 8 Nicolai L, Leunig A, Brambs S. et al. Immunothrombotic dysregulation in COVID-19 pneumonia is associated with respiratory failure and coagulopathy. Circulation 2020; 142 (12) 1176-1189
    CrossrefPubMedSuche in Google Scholar
  • 9 Bonaventura A, Vecchié A, Dagna L. et al. Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19. Nat Rev Immunol 2021; 21 (05) 319-329
    CrossrefPubMedSuche in Google Scholar
  • 10 Praktiknjo M, Trebicka J, Carnevale R. et al. von Willebrand and Factor VIII portosystemic circulation gradient in cirrhosis: implications for portal vein thrombosis. Clin Transl Gastroenterol 2020; 11 (02) e00123
    CrossrefPubMedSuche in Google Scholar
  • 11 Driever EG, Magaz M, Adelmeijer J. et al. The portal vein in patients with cirrhosis is not an excessively inflammatory or hypercoagulable vascular bed, a prospective cohort study. J Thromb Haemost 2022; 20 (09) 2075-2082
    CrossrefPubMedSuche in Google Scholar
  • 12 Davey Smith G, Hemani G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet 2014; 23 (R1): R89-R98
    CrossrefPubMedSuche in Google Scholar
  • 13 Emdin CA, Khera AV, Kathiresan S. Mendelian randomization. JAMA 2017; 318 (19) 1925-1926
    CrossrefPubMedSuche in Google Scholar
  • 14 Larsson SC, Butterworth AS, Burgess S. Mendelian randomization for cardiovascular diseases: principles and applications. Eur Heart J 2023; 44 (47) 4913-4924
    CrossrefPubMedSuche in Google Scholar
  • 15 Skrivankova VW, Richmond RC, Woolf BAR. et al. Strengthening the reporting of observational studies in epidemiology using Mendelian randomisation (STROBE-MR): explanation and elaboration. BMJ 2021; 375 (2233): n2233
    CrossrefPubMedSuche in Google Scholar
  • 16 Zhao JH, Stacey D, Eriksson N. et al; Estonian Biobank Research Team. Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets. Nat Immunol 2023; 24 (09) 1540-1551
    CrossrefPubMedSuche in Google Scholar
  • 17 Kurki MI, Karjalainen J, Palta P. et al; FinnGen. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature 2023; 613 (7944): 508-518
    CrossrefPubMedSuche in Google Scholar
  • 18 Jiang L, Zheng Z, Fang H, Yang J. A generalized linear mixed model association tool for biobank-scale data. Nat Genet 2021; 53 (11) 1616-1621
    CrossrefPubMedSuche in Google Scholar
  • 19 Burgess S, Dudbridge F, Thompson SG. Combining information on multiple instrumental variables in Mendelian randomization: comparison of allele score and summarized data methods. Stat Med 2016; 35 (11) 1880-1906
    CrossrefPubMedSuche in Google Scholar
  • 20 Yavorska OO, Burgess S. Mendelian Randomization: an R package for performing Mendelian randomization analyses using summarized data. Int J Epidemiol 2017; 46 (06) 1734-1739
    CrossrefPubMedSuche in Google Scholar
  • 21 Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol 2015; 44 (02) 512-525
    CrossrefPubMedSuche in Google Scholar
  • 22 Bowden J, Davey Smith G, Haycock PC, Burgess S. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol 2016; 40 (04) 304-314
    CrossrefPubMedSuche in Google Scholar
  • 23 Verbanck M, Chen CY, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet 2018; 50 (05) 693-698
    CrossrefPubMedSuche in Google Scholar
  • 24 Staiger D, Stock JH. Instrumental variables with weak instruments. Econometrica 1997; 65 (03) 557-586
    CrossrefPubMedSuche in Google Scholar
  • 25 Bouras E, Karhunen V, Gill D. et al; PRACTICAL Consortium. Circulating inflammatory cytokines and risk of five cancers: a Mendelian randomization analysis. BMC Med 2022; 20 (01) 3
    CrossrefPubMedSuche in Google Scholar
  • 26 Stark K, Massberg S. Interplay between inflammation and thrombosis in cardiovascular pathology. Nat Rev Cardiol 2021; 18 (09) 666-682
    CrossrefPubMedSuche in Google Scholar
  • 27 McManus DD, Beaulieu LM, Mick E. et al. Relationship among circulating inflammatory proteins, platelet gene expression, and cardiovascular risk. Arterioscler Thromb Vasc Biol 2013; 33 (11) 2666-2673
    CrossrefPubMedSuche in Google Scholar
  • 28 Zakai NA, Katz R, Jenny NS. et al. Inflammation and hemostasis biomarkers and cardiovascular risk in the elderly: the Cardiovascular Health Study. J Thromb Haemost 2007; 5 (06) 1128-1135
    CrossrefPubMedSuche in Google Scholar
  • 29 von Brühl ML, Stark K, Steinhart A. et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 2012; 209 (04) 819-835
    CrossrefPubMedSuche in Google Scholar
  • 30 Brill A, Fuchs TA, Savchenko AS. et al. Neutrophil extracellular traps promote deep vein thrombosis in mice. J Thromb Haemost 2012; 10 (01) 136-144
    CrossrefPubMedSuche in Google Scholar
  • 31 Qin X, Jiang B, Zhang Y. 4E-BP1, a multifactor regulated multifunctional protein. Cell Cycle 2016; 15 (06) 781-786
    CrossrefPubMedSuche in Google Scholar
  • 32 Du K, Zou J, Liu C. et al. A multi-omics pan-cancer analysis of 4EBP1 in cancer prognosis and cancer-associated fibroblasts infiltration. Front Genet 2022; 13: 845751
    CrossrefPubMedSuche in Google Scholar
  • 33 Manne BK, Bhatlekar S, Middleton EA, Weyrich AS, Borst O, Rondina MT. Phospho-inositide-dependent kinase 1 regulates signal dependent translation in megakaryocytes and platelets. J Thromb Haemost 2020; 18 (05) 1183-1196
    CrossrefPubMedSuche in Google Scholar