代谢产物介导的免疫调节失衡与骨关节恶性肿瘤发生的关系：孟德尔随机化研究

The relationship between metabolite mediated immune regulatory imbalance and the occurrence of malignant tumors of bone and articular cartilage: a Mendelian randomization study

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Frontiers in Immunology

影响因子:5.9

分区:医学2区 / 免疫学2区

发表日期:2024

作者: Kehan Long, Ao Gong, Tengfei Zheng, Shoushen Liu, Zhendong Ying, Cong Xiao

DOI: 10.3389/fimmu.2024.1433219

摘要

本研究旨在评估免疫细胞特征与骨及关节软骨恶性肿瘤之间的因果关系，特别关注代谢产物的中介作用。通过孟德尔随机化方法，基于遗传变异评估这些关系，旨在识别潜在的生物标志物和治疗靶点。利用GWAS数据，对免疫细胞特征和1400种代谢产物进行双样本孟德尔随机分析，探讨直接及中介作用。选取有效的工具变量（IVs），并使用R软件进行反向方差加权（IVW）、加权中位数和基于模态的方法的统计分析。这一方法评估了免疫细胞特征与骨及关节软骨恶性肿瘤之间的直接因果关系，以及代谢产物在其中的潜在中介作用。结果显示，26个免疫表型与骨及关节软骨恶性肿瘤的风险存在显著的因果关系。其中，HLA DR+ NK细胞表型SSC-A与这些恶性肿瘤的风险呈正相关。进一步分析发现，67种代谢产物中，有38种与之呈正相关，29种呈负相关。中介分析提示免疫监视和代谢失调在肿瘤发生中起作用，免疫表型SSC-A在HLA DR+ NK细胞与代谢产物5-羟基己酮酸之间的关联，为肿瘤发展提供了机制依据。研究结果表明，免疫表型与骨关节恶性肿瘤之间存在重要的因果关系，代谢产物可能作为中介。这些发现为未来研究提供了基础，有助于开发新的生物标志物和治疗策略。

Abstract

This study aims to assess the causal relationship between immune cell characteristics and malignant tumors of bone and articular cartilage, focusing on the mediating role of metabolites. Using Mendelian randomization, we evaluated these relationships based on genetic variations to identify potential biomarkers and therapeutic targets.A two-sample Mendelian randomization analysis was conducted using GWAS data for immune cell features and 1,400 metabolites to investigate direct and mediating effects. Effective instrumental variables (IVs) were selected, and statistical analyses-including inverse variance weighting (IVW), weighted median, and mode-based methods-were performed using R software. This approach enabled the assessment of direct causal relationships as well as the potential mediating role of metabolites in the association between immune cell features and malignancies.Significant causal relationships were identified between 26 immune phenotypes and the risk of malignant tumors of bone and articular cartilage. Notably, the HLA DR+ NK cell phenotype SSC-A showed a positive correlation with the risk of these malignancies. Further analysis revealed causal relationships with 67 metabolites, 38 of which were positively correlated and 29 negatively correlated. Mediation analysis highlighted the role of immune surveillance and metabolic dysregulation in tumor development, as evidenced by the association between the immune phenotype SSC-A on HLA DR+ NK cells and the metabolite 5-hydroxyhexanoate.The findings suggest significant causal relationships between immune phenotypes and malignant tumors of bone and articular cartilage, with metabolites potentially mediating these relationships. These insights lay the groundwork for further research and could contribute to the development of new biomarkers and treatment strategies.