Clonal hematopoiesis of indeterminate potential and risk of intervertebral disc degeneration: a large prospective cohort study

Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition characterized by somatic mutations in hematopoietic stem cells and is increasingly recognized as a driver of systemic inflammation and diverse age-related diseases. Whether CHIP contributes to intervertebral disc degeneration (IDD) remains unknown. Thus, this study aimed to examine the association between CHIP and the incident risk of IDD and its subtypes—cervical and lumbar disc degeneration (CDD and LDD). Using data from 258,566 eligible UK Biobank participants with available exome sequencing data for CHIP and complete covariate information, this study employed Cox proportional hazards models to estimate hazard ratios (HRs) across three adjustment models. Incident IDD was identified from ICD-coded clinical diagnoses. Exploratory gene-specific analyses were conducted to evaluate particular CHIP driver mutations associated with IDD risk. Mediation analyses were performed to investigate the roles of systemic inflammatory markers in mediating the CHIP–IDD relationship. Among 258,566 eligible participants, 8113 (3.14%) carried CHIP. Any CHIP [variant allele fraction (VAF) ≥ 2%] was associated with a significantly elevated risk of incident IDD (HR 1.153, 95% CI 1.030–1.300, P = 0.016) after full adjustment. Large CHIP (VAF ≥ 10%) conferred a particularly elevated risk (HR 1.162, 95% CI 1.010–1.340, P = 0.037). Exploratory gene-specific analyses suggested that SRSF2 , STAG2 , GNAS , IDH2 , and BRAF mutations may be associated with increased IDD risk. Mediation analyses suggested that systemic immunity-inflammation index, leukocyte count, and neutrophil count may partially mediate the CHIP–IDD association, although the mediated proportions were modest (2.15%–4.41%). Analogous associations were observed for LDD, whereas the association with CDD did not reach statistical significance. CHIP was associated with increased risks of overall IDD and LDD, whereas evidence for CDD was less consistent. Systemic inflammatory markers may partially mediate this association. These findings suggest CHIP as a potential hematopoietic risk factor for musculoskeletal degeneration and a possible role of inflammatory signaling in disc pathobiology.