A prospective study on the regulation of osteoarthritis risk through inflammatory pathways in clonal hematopoiesis

Osteoarthritis (OA) is a common degenerative joint disease characterized by articular cartilage degeneration, joint inflammation, and bone hyperplasia. Clonal hematopoiesis of indeterminate potential (CHIP) refers to the presence of cancer-related variants in blood cells of individuals without malignancies. However, it is unclear whether the proinflammatory state induced by CHIP affects the onset of OA. Thus, we investigated CHIP as a risk factor for OA. Here, we analyzed whole-exome sequence (WES) data from 45,380 UK Biobank participants without OA at baseline to identify CHIP. Multivariate Cox regression models were used to evaluate the association between CHIP and incident OA as well as different sites of OA onset. Additionally, enrichment and mediation analyses were conducted on 1463 unique protein datasets to identify protein markers and biological pathways related to both CHIP and OA. We found that the incidence of OA was higher in individuals with CHIP than in those without CHIP. Importantly, individuals with CHIP and VAF > 10% had an increased risk of OA (hazard ratio [HR], 1.46; 95% CI, 1.28-1.68; P < 0.001). The results of classification of OA sites showed that polyarticular OA and hip OA were most significantly associated with CHIP. In addition, analysis of OA and CHIP-related expression proteins and pathways revealed that both were mainly involved in extracellular matrix organization, inflammation, and metabolic pathways. Moreover, the proteomic analysis results suggested that CHIP may influence the occurrence of OA by affecting seven proteins: CD5, CD79B, CEACAM1, FOLR2, LILRA5, SIRPB1, and TXNDC15. CHIP is significantly associated with the risk of incident OA and may exacerbate the progression of OA through inflammatory and immune response mechanisms. This research provides new insights into the pathogenesis of OA, offering a theoretical basis for the early prevention of OA, although a causal relationship remains to be investigated.