Protective Causal Effects of CCL19, CCL23, and IL17A on Achilles Tendinitis: Insights from Bidirectional Mendelian Randomization and Metabolite-Mediated Pathway Analysis

Lu Wei,1,2 Wenqiang Wang,1 Xiang Chen,1 Shunan Dong,1 Hongjie Su,1 Puxiang Zhen,1 Xinyu Nie,3 Qikai Hua1,4 1Department of Bone and Joint Surgery, (Guangxi Diabetic Foot Salvage Engineering Research Center/Research Centre for Regenerative Medicine), The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China; 2Department of Orthopedics, Liuzhou Workers’ Hospital, Liuzhou, Guangxi, People’s Republic of China; 3Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China; 4Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-Constructed by the Province and Ministry, Guangxi Medical University, Nanning, Guangxi, People’s Republic of ChinaCorrespondence: Qikai Hua, Email hqk100@yeah.netBackground: Achilles tendinitis (AT) is a prevalent musculoskeletal disorder with unclear etiology. This study aimed to investigate the causal relationships between circulating inflammatory cytokines (ICs), metabolites, and AT risk using bidirectional Mendelian randomization (MR), and to identify potential metabolite-mediated pathways.Methods: A bidirectional MR design was implemented, integrating genetic instruments for 91 ICs and 1400 metabolites with GWAS summary statistics from the FinnGen consortium. Causal inferences were drawn using inverse variance weighting (IVW), MR-Egger regression, and weighted median approaches, accompanied by sensitivity and mediated analyses.Results: CCL19, CCL23, and IL17A were identified as protective factors for AT, with CCL23 demonstrating consistent associations across multiple MR methods. 65 metabolite traits were significantly associated with disease risk. Glycochenodeoxycholate glucuronide showed a protective effect (P = 0.002), whereas the alpha-tocopherol to glycerol ratio increased risk (P = 0.011). Mediation analysis indicated six pathways: CCL19 - pantothenate - AT; CCL19 - Picolinate - AT; CCL19 - X-21845- AT; CCL23 - X-12822 - AT; CCL23 - X-18921 - AT; IL17A - cysteinylglycine disulfide - AT.Conclusion: This is the first MR study to systematically assess the causal roles of ICs and metabolites in AT, identifying CCL19, CCL23, and IL17A as protective factors and highlighting multiple metabolite signatures linked to disease risk, offering novel insights for mechanistic research and targeted intervention.Keywords: achilles tendinitis, mendelian randomization, inflammatory cytokines, metabolites