Niu Jingmin, Zhang Pingxin, Liu Wei, Sun Song, Zhang Yingkai, Sang Jinghao, Yang Jialin, Zhang Qin, Chai Limin
Key Laboratory of Chinese lnternal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beiing University of Chinese Medicine, Beijing, China.
Zhongshan College of Dalian Medical University, Dalian, Liaoning Province, China.
Sci Rep. 2025 May 14;15(1):16742. doi: 10.1038/s41598-025-01216-7.
Rheumatoid arthritis (RA) is a chronic inflammatory disorder with complex etiologies involving immune responses and circulating proteins. This study investigates the causal relationships between antibody immune responses, plasma circulating proteins, and the development of RA using Mendelian Randomization (MR) analysis; A two-sample and multivariate MR analysis was conducted to explore the mediating causal relationship between 46 antibody immune responses and RA through 4,907 plasma circulating proteins. Genetic variations were utilized as instrumental variables (IVs) to infer causality, ensuring that they met the assumptions of relevance, independence, and exclusion restriction. Data were sourced from the FinnGen R10 dataset, UK Biobank, and the SomaScan platform, providing a robust foundation for the analysis. Statistical methods including IVW, weighted median, and mode-based approaches were employed, complemented by sensitivity analyses to ensure the robustness of the findings; The study identified significant causal relationships between six antibody immune responses and RA, with three specific responses-Epstein-Barr virus EBNA-1, Epstein-Barr virus ZEBRA, and Anti-polyomavirus 2 IgG seropositivity-showing strong associations. However, reverse causality was detected for EBNA-1 and ZEBRA, leading to their exclusion from further analysis. Additionally, 12 plasma circulating proteins were found to have significant causal relationships with RA, with KCNIP3 emerging as a key protective factor. Multivariate MR analysis revealed that KCNIP3 mediates the relationship between Anti-polyomavirus 2 IgG seropositivity and RA, suggesting a potential protective mechanism. This study highlights the intricate relationships between specific antibody responses, circulating proteins, and RA risk. The findings suggest that certain proteins, particularly KCNIP3, may mediate the effects of immune responses on RA development, offering potential targets for therapeutic intervention.
类风湿性关节炎（RA）是一种慢性炎症性疾病，病因复杂，涉及免疫反应和循环蛋白。本研究使用孟德尔随机化（MR）分析来研究抗体免疫反应、血浆循环蛋白与RA发生之间的因果关系；进行了双样本和多变量MR分析，以通过4907种血浆循环蛋白探索46种抗体免疫反应与RA之间的中介因果关系。利用基因变异作为工具变量（IVs）来推断因果关系，确保它们符合相关性、独立性和排除限制的假设。数据来自芬兰基因库R10数据集、英国生物银行和SomaScan平台，为分析提供了坚实的基础。采用了包括IVW、加权中位数和基于模式的方法在内的统计方法，并辅以敏感性分析以确保研究结果的稳健性；该研究确定了六种抗体免疫反应与RA之间的显著因果关系，其中三种特定反应——爱泼斯坦-巴尔病毒EBNA-1、爱泼斯坦-巴尔病毒ZEBRA和抗多瘤病毒2 IgG血清阳性——显示出强烈关联。然而，检测到EBNA-1和ZEBRA存在反向因果关系，导致它们被排除在进一步分析之外。此外，发现12种血浆循环蛋白与RA存在显著因果关系，其中KCNIP3是一个关键的保护因素。多变量MR分析表明，KCNIP3介导了抗多瘤病毒2 IgG血清阳性与RA之间的关系，提示了一种潜在的保护机制。本研究强调了特定抗体反应、循环蛋白与RA风险之间的复杂关系。研究结果表明，某些蛋白质，特别是KCNIP3，可能介导免疫反应对RA发生的影响，为治疗干预提供了潜在靶点。
