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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Autoimmune and Autoinflammatory Disorders: Autoinflammatory Disorders
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1434369

Evaluating the Causal Effect of Circulating Proteome on the Risk of Inflammatory Bowel Disease-Related Traits Using Mendelian Randomization

Provisionally accepted
Beining Li Beining Li 1*Ping Hu Ping Hu 2Hongyan Liang Hongyan Liang 3,4,5*Xingliang Zhao Xingliang Zhao 3,4,5*Aiting Zhang Aiting Zhang 3,4,5*Yingchong Xu Yingchong Xu 3,4,5*Bin Zhang Bin Zhang 2*Jie Zhang Jie Zhang 3,4,5*
  • 1 Second Hospital of Tianjin Medical University, Tianjin, China
  • 2 Department of orthopedic, Tianjin Medical University General Hospital, Tianjin, China
  • 3 Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
  • 4 Tianjin Institute of Digestive Diseases, Tianjin, China
  • 5 Tianjin Key Laboratory of Digestive Diseases, Tianjin, China

The final, formatted version of the article will be published soon.

    This study sought to identify circulating proteins causally linked to Inflammatory Bowel Disease (IBD) traits through a Mendelian Randomization (MR) analytical framework.Methods: Using a large-scale, two-sample MR approach, we estimated the genetic links of numerous plasma proteins with IBD and its subtypes, leveraging information from the Inflammatory Bowel Disease Genetics Consortium. To assess the robustness of MR findings, methods like Bayesian colocalization, , and Steiger filtering analysis, evaluation of protein-altering variants.Further insights into IBD's underlying mechanisms and therapeutic targets were gleaned from single-cell sequencing analyses, protein-protein interaction assessments, pathway enrichment analyses, and evaluation of drug targets.Results: By cis-only MR analysis, we identified 83 protein-phenotype associations involving 27 different proteins associated with at least one IBD subtype. Among these proteins, DAG1, IL10, IL12B, IL23R, MST1, STAT3 and TNFRSF6B showed overlapping positive or negative associations in all IBD phenotypes. Extending to cis + trans MR analysis, we further identified 117 protein-feature associations, including 44 unique proteins, most of which were not detected in the cis-only analysis. In addition, by performing co-localization analysis and Steiger filtering analysis on the prioritized associations, we further confirmed the causal relationship between these proteins and the IBD phenotype and verified the exact causal direction from the protein to the IBD-related feature.Conclusion: MR analysis facilitated the identification of numerous circulating proteins associated with IBD traits, unveiling protein-mediated mechanisms and promising therapeutic targets.

    Keywords: inflammatory bowel disease, Mendelian randomization, protein, Therapeutic target, Singer cell

    Received: 17 May 2024; Accepted: 17 Jul 2024.

    Copyright: © 2024 Li, Hu, Liang, Zhao, Zhang, Xu, Zhang and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Beining Li, Second Hospital of Tianjin Medical University, Tianjin, China
    Hongyan Liang, Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
    Xingliang Zhao, Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
    Aiting Zhang, Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
    Yingchong Xu, Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
    Bin Zhang, Department of orthopedic, Tianjin Medical University General Hospital, Tianjin, China
    Jie Zhang, Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.