Abstract
BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the age-related expansion of blood cells carrying preleukemic mutations, is associated with immune aging. This study aimed to investigate the association between CHIP and established autoimmune diseases. METHODS: We analyzed baseline data from 456,692 UK Biobank participants with available whole-exome sequences. The primary outcome was 19 autoimmune disorders. Associations among any CHIP (variant allele fraction ≥2%), large CHIP clones (variant allele fraction ≥10%), and gene-specific CHIP subtypes with the incidence of autoimmune diseases were assessed using Cox regression. Mediation analysis was performed to explore the role of inflammation in the link between CHIP and autoimmune diseases. RESULTS: We identified 17,433 any CHIP and 11,970 large CHIP at baseline. Participants with any and large CHIP were associated with 44% and 43% higher risk for Crohn's disease, 25% and 33% higher risk for psoriasis, 13% and 14% higher risk for rheumatoid arthritis, and 35% and 55% higher risk for vasculitis, respectively. Participants with CHIP status were associated with increased levels of inflammatory markers, including white blood cell, platelets, neutrophils, and neutrophil-to-lymphocyte ratio, with overall mediation ratios of 16.3% for Crohn's disease, 7.1% for psoriasis, 23.2% for rheumatoid arthritis, and 7.2% for vasculitis. CONCLUSIONS: CHIP was associated with an increased risk for incident multiple autoimmune diseases, including Crohn's disease, psoriasis, vasculitis, and rheumatoid arthritis, potentially mediated by elevated inflammatory levels. Future research is needed to clarify the mechanisms underlying these associations and to explore potential interventions to reduce the associated risk.