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Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.
World J Orthop. Nov 18, 2026; 17(11): 125433
Published online Nov 18, 2026. doi: 10.5312/wjo.125433
Integrating Mendelian randomization and enzyme-linked immunosorbent assay validation identifies candidate mediators across the rheumatoid arthritis disease continuum
Yuan-Song Song, Jun-Ling Luo, Xi-Fan Zheng, Ye-Ping Chen, Ze-Ming Li, Jun Yao
Yuan-Song Song, Jun-Ling Luo, Xi-Fan Zheng, Ye-Ping Chen, Ze-Ming Li, Jun Yao, Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
Co-first authors: Yuan-Song Song and Jun-Ling Luo.
Author contributions: Song YS and Luo JL jointly designed the study methodology, performed the Mendelian randomization analyses, conducted the statistical analyses, and drafted the original manuscript; Zheng XF participated in study conceptualization and critical revision of the manuscript; Chen YP and Li ZM contributed to sample collection, serum processing, and enzyme-linked immunosorbent assay experiments and assisted in data curation and visualization; Yao J conceived and supervised the overall research project, secured funding, and provided administrative and technical support; and all authors thoroughly reviewed and endorsed the final manuscript. Song YS and Luo JL contributed equally to the study methodology, Mendelian randomization analyses, statistical analyses, and manuscript drafting, and these contributions justify their designation as co-first authors.
AI contribution statement: AI tools, specifically DeepSeek V4, were used solely for language polishing and formatting assistance. No AI tool was used to generate research data, interpret results, or formulate conclusions. All AI-assisted content was critically reviewed and revised by the authors, who take full responsibility for the accuracy, originality, and integrity of the manuscript.
Supported by the Guangxi Traditional Chinese Medicine Appropriate Technology Development and Promotion Project, No. GZSY22-62; the Guangxi Natural Science Foundation, No. 2023GXNSFAA026402; and the First Affiliated Hospital of Guangxi Medical University Innovation Team Cultivation Program, No. YYZS2023004.
Institutional review board statement: This study was approved by the Medical Ethics Committee of the First Affiliated Hospital of Guangxi Medical University (approval No. 2026-E0384).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
Corresponding author: Jun Yao, MD, Chief Physician, Professor, Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning 530021, Guangxi Zhuang Autonomous Region, China. yaojun800524@126.com
Received: July 7, 2026
Revised: August 16, 2026
Accepted: October 8, 2026
Published online: November 18, 2026
Processing time: 126 Days and 19.2 Hours
Core Tip

Core Tip: This study integrates Mendelian randomization with enzyme-linked immunosorbent assay validation to identify CD40, C-C motif chemokine ligand 28, and matrix metalloproteinase-1 as candidate mediators in rheumatoid arthritis, while interleukin-18 receptor 1 shows discordant Mendelian randomization (protective) and enzyme-linked immunosorbent assay (elevated) findings requiring mechanistic reconciliation. A hypothesized spatiotemporal cascade links CD40 to lymphoid immunity, C-C motif chemokine ligand 28 to synovitis, and matrix metalloproteinase-1 to cartilage degradation. Their positive intercorrelations suggest a potential synergistic loop, supporting further exploration of composite biomarker panels and combination strategies. Experimental validation demonstrates protein-level consistency rather than proof of causality, and all findings should be considered hypothesis-generating.

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