Research questions: Clonal haematopoiesis of indeterminate potential (CHIP) is an age-related expansion of mutant blood cell clones that has been linked to cardiovascular and inflammatory diseases, but its role in degenerative musculoskeletal conditions is unclear. We will ask: (1) Is CHIP associated with prevalent and incident intervertebral disc degeneration (IVDD) and osteoarthritis (OA)? (2) Do specific CHIP driver genes and clone size (variant allele fraction) show differential associations with IVDD and OA, including severe forms requiring surgery? (3) Are these associations modified or mediated by age, sex, adiposity, smoking, physical activity and inflammatory or haematological markers?
Objectives: To identify CHIP carriers in UK Biobank using established gene panels and variant allele fraction thresholds applied to blood sequencing data; to define IVDD using ICD-10 M51 and related “first occurrence” variables, and OA using ICD-10 M15-M19 and joint replacement procedures; to quantify cross-sectional and longitudinal associations between CHIP and IVDD/OA using multivariable regression and time-to-event models; and to generate a shortlist of genes and pathways for downstream experimental investigation and therapeutic targeting.
Scientific rationale: IVDD and OA are major causes of disability, driven by ageing, mechanical stress and chronic low-grade inflammation. CHIP provides a systemic, lifelong pro-inflammatory stimulus that might accelerate disc and joint degeneration, but this potential link has not been systematically evaluated. UK Biobank, with its large sample size, deep phenotyping, genetic data and long-term follow-up, offers a unique opportunity to test whether CHIP is a novel, potentially druggable determinant of degenerative spine and joint disease. Findings will guide subsequent in vitro and in vivo experiments outside UK Biobank, including mechanistic studies and pharmacological interventions aimed at mitigating IVDD and OA.