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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1444222
This article is part of the Research Topic Unveiling Biomarkers and Mechanisms in the Tumor-Immune Nexus View all 15 articles

Causal effects and metabolites mediators between immune cell and risk of Colorectal Cancer: a Mendelian randomization study

Provisionally accepted
Qian Yang Qian Yang 1,2,3Bixia Duan Bixia Duan 4*Jian Yue Jian Yue 5Donglin Zhang Donglin Zhang 6*Xueping Chen Xueping Chen 1,7*Mengjia Shi Mengjia Shi 1*Jie Kan Jie Kan 1*Ruochan Li Ruochan Li 6*Hongda Li Hongda Li 3*Lin Gan Lin Gan 2*
  • 1 Clinical Molecular Medicine Testing Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
  • 2 Chongqing Key Laboratory of Molecular Oncology and Epigenetics, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
  • 3 Key Laboratory of Major Brain Disease and Aging Research, Institute for Brain Science and Disease, Chongqing Medical University, Chongqing, China
  • 4 Department of Oncology,Yongchuan Hospital of Chongqing Medical University, Chongqing, China
  • 5 Department of Breast Surgery, The People’s Hospital of Gaozhou, Gaozhou, China
  • 6 Department for General, Visceral and Transplant Surgery, LMU Munich University Hospital, Munich, Bavaria, Germany
  • 7 First Affiliated Hospital of Chongqing Medical University, Chongqing, China

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

    Abstract Objective: The involvement of immune cells in colorectal cancer (CRC) and their interplay with metabolic disorders are yet to be fully elucidated. This study examines how peripheral immune cells, inferred genetically, affect CRC and investigates the intermediary roles of metabolites. Methods: We employed a two-sample bidirectional Mendelian randomization (MR) approach to assess the causal influence of immune cells on CRC. Additionally, a two-step MR strategy was utilized to pinpoint potential metabolites that mediate this effect. Our analysis incorporated data from genome-wide association studies (GWAS), involving 731 immune cell types, 1,400 metabolites, and CRC outcomes. The primary method of analysis was randomized inverse variance weighting (IVW), supported by MR-Egger, weighted median, simple mode, and weighted mode analyses. Sensitivity checks were conducted using Cochran’s Q test, MR-PRESSO test, MR-Egger regression intercept, and leave-one-out analysis. Results: The study identified 23 immune cell types and 17 metabolites that are causally linked to CRC. Our mediation analysis highlighted that nine metabolites act as intermediaries in the relationship between nine specific immune cells and CRC risk. Notably, The ratios of Adenosine 5'-monophosphate (AMP) to aspartate and Retinol (Vitamin A) to linoleoyl-arachidonoyl-glycerol (18:2 to 20:4) were found to concurrently mediate the promoting effects of Myeloid DC %DC and BAFF-R on B cells in colorectal cancer (CRC). Moreover, iminodiacetate (IDA) was found to mediate the protective effect of CD14+ CD16- monocytes on CRC, contributing 11.8% to this mediation. In contrast, IDA was also seen to decrease the protective effect of IgD+ CD38br %B cells on CRC risk, with a mediation effect proportion of -10.4%. Conclusion: This study delineates a complex network involving immune cells, metabolites, and CRC, suggesting a multifaceted pathophysiological interaction. The identified causal links and mediation pathways underscore potential therapeutic targets, providing a foundation for interventions aimed at modulating immune responses to manage CRC.

    Keywords: immune cell, Metabolites, Mendelian randomization, colorectal cancer, Mediation analysis

    Received: 05 Jun 2024; Accepted: 22 Aug 2024.

    Copyright: © 2024 Yang, Duan, Yue, Zhang, Chen, Shi, Kan, Li, Li and Gan. 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:
    Bixia Duan, Department of Oncology,Yongchuan Hospital of Chongqing Medical University, Chongqing, China
    Donglin Zhang, Department for General, Visceral and Transplant Surgery, LMU Munich University Hospital, Munich, 81377, Bavaria, Germany
    Xueping Chen, Clinical Molecular Medicine Testing Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
    Mengjia Shi, Clinical Molecular Medicine Testing Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
    Jie Kan, Clinical Molecular Medicine Testing Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
    Ruochan Li, Department for General, Visceral and Transplant Surgery, LMU Munich University Hospital, Munich, 81377, Bavaria, Germany
    Hongda Li, Key Laboratory of Major Brain Disease and Aging Research, Institute for Brain Science and Disease, Chongqing Medical University, Chongqing, China
    Lin Gan, Chongqing Key Laboratory of Molecular Oncology and Epigenetics, First Affiliated Hospital of Chongqing Medical University, Chongqing, China

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