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Objective: This study aims to clarify the causal relationship between immune cells and upper gastrointestinal ulcers, and to explore the potential mediating role of inflammatory proteins. Methods: Univariable Mendelian randomization(UVMR) analysis was used to investigate the causal relationship between immune cells and upper gastrointestinal ulcers; two-step multivariable Mendelian randomization(MVMR) analysis was adopted to explore the potential mediating role of inflammatory proteins. Methods including inverse variance weighting(IVW) were used to assess the causal relationship between exposures and outcomes; MR-Egger intercept method and MR-PRESSO were performed for sensitivity analysis. Results: Leukemia inhibitory factor(LIF) mediated the risk of CD28 on CD4 regulatory T cells for esophageal ulcers, with a mediation proportion of 9.95%; interleukin-20 receptor subunit alpha(IL-20RA) mediated the risk of CD4-CD8-TEM cells for gastric ulcers, with a mediation proportion of 23.09%; leukemia inhibitory factor receptor(LIFR), fibroblast growth factor 19(FGF-19), and neurotrophin-3(NT-3) mediated the risk of CD28-CD8+ T cells, CD45RA+ CD8+ T cells, and FSC-A on CD8+ T cells for duodenal ulcers, with mediation proportions of 13.99%, 6.91%, and 15.25%, respectively; interleukin-5(IL-5) mediated the risk of CD3 on human leukocyte antigen(HLA) DR+ CD4+ T cells for gastroduodenal ulcers, with a mediation proportion of 12.53%. Conclusion: This study supports that inflammatory proteins may act as mediators in the causal relationship between immune cells and upper gastrointestinal ulcers. Future research could further investigate other potential risk factors and establish a comprehensive upper gastrointestinal ulcer-immune cell-inflammation network.

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