Circulating Cytokines and Venous Thromboembolism: A Bidirectional Two-Sample Mendelian Randomization Study

 

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Abstract

Background Epidemiological evidence has linked circulating cytokines to venous thromboembolism (VTE). However, it remains uncertain whether these associations are causal due to confounding factors or reverse causality. We aim to explore the causality between circulating cytokines and VTE, encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE).

Methods In the current bidirectional Mendelian randomization (MR) study, instrumental variables of 41 circulating cytokines were obtained from the genome-wide association study meta-analyses (8,293 individuals). Summary statistics for the association of VTE (17,048 cases and 325,451 controls), DVT (8,077 cases and 295,014 controls), and PE (8,170 cases and 333,487 controls) were extracted from the FinnGen Study. A multivariable MR study was conducted to adjust for potential confounders. The inverse-variance weighted method was employed as the main analysis, and comprehensive sensitivity analyses were conducted in the supplementary analyses.

Results The MR analysis indicated stromal cell-derived factor-1α was suggestively associated with a reduced risk of VTE (odds ratio [OR]: 0.90; 95% confidence interval [CI]: 0.81–0.99; p = 0.033) and DVT (OR: 0.85; 95% CI: 0.75–0.97; p = 0.015). In addition, suggestive association of granulocyte colony-stimulating factor with PE (OR: 1.20; 95% CI: 1.06-1.37; p = 0.005) was observed. Multivariable MR analysis showed that the effect of cytokines on VTE was partly mediated through hemoglobin A1c and systolic blood pressure. Reverse MR analysis revealed that VTE was linked to decreased levels of several cytokines.

Conclusion We provide suggestive genetic evidence supporting the bidirectional causal effect between circulating cytokines and VTE, highlighting the importance of targeting circulating cytokines to reduce the incidence of VTE.

Data Availability Statement

All the data used in the present study had been publicly available. The original contributions presented in the study are included in the article/[Supplementary Material] (available in the online version), and further inquiries can be directed to the corresponding author/s.

Authors' Contribution

T.H., F.Y., J.Y., and H.C. contributed to the conception or design of the work. P.S. and Y.C. contributed to the acquisition, analysis, or interpretation of data for the work. T.H. wrote the first draft of the manuscript with critical revisions from P.S., F.Y., and H.C. All gave final approval and agreed to be accountable for all aspects of work ensuring integrity and accuracy.

^* These authors have contributed equally to this work.

Publication History

Received: 30 July 2023

Accepted: 26 October 2023

Article published online:
18 December 2023

© 2023. 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/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

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