Focus on CCL19: A Mendelian randomization study on genetic evidence of immune cells influencing osteoarthritis severity via inflammatory proteins

Osteoarthritis (OA) is a prevalent degenerative joint disorder whose pathogenesis involves immune-inflammatory regulation. Immune cells may influence OA progression by modulating inflammatory proteins; however, the underlying mechanisms remain inadequately understood. This study used Mendelian randomization (MR) analysis to investigate the causal effects of immune cells on OA. Additionally, it evaluated the mediating role of inflammatory proteins, particularly chemokine (C-C motif) ligand 19 (CCL19). Public genome-wide association study datasets were utilized, encompassing genetic data for 471 immune cell types, 91 inflammatory proteins, and OA (including generalized OA, knee osteoarthritis (KOA), and KOA with surgery). A bidirectional bivariate MR approach was employed to assess causal relationships between immune cells and OA; while mediating MR quantified the mediating effects of inflammatory proteins. Instrument selection criteria were P < 5 × 10-8 and F > 10. The inverse variance weighted (IVW) method was the primary analytic technique, further validated through MR-Egger regression for robustness. MR analysis revealed that myeloid cell activation (e.g., CD33+ monocytes) positively correlated with OA risk (odds ratio [OR] = 1.014-1.049, P < .05), whereas regulatory T cell expression (e.g., CD4 on CD39+ activated Tregs) negatively correlated with risk (OR = 0.921-0.958, P < .05). The inflammatory protein CCL19 exhibited a protective effect against OA (OR = 0.876-0.924, P < .001), yet mediated an enhanced risk effect of immune cells on OA. Mediation analysis identified 5 significant pathways (P < .05), with mediation proportions ranging from -13..5 to 20.5%, all showing CCL19 as a positive risk mediator. The findings suggest that immune cells influence the progression of OA through the mediation of CCL19, underscoring the critical role of the immune-inflammatory axis in the pathogenesis of OA. CCL19 may represent a promising therapeutic target, paving the way for the development of therapies aimed at inflammation modulation.