Association of Clonal Hematopoiesis With Incident, Late‐Onset, Seropositive Rheumatoid Arthritis

Objective Clonal hematopoiesis (CH), defined by acquired driver mutations in hematopoietic stem cells, is associated with many inflammatory diseases of aging. We investigated whether CH and its subtypes, CH of indeterminate potential (CHIP) and mosaic chromosomal alteration (mCA), are associated with incident rheumatoid arthritis (RA) and whether complement modifies these associations. Methods CHIP was detected in NIH All of Us, Vanderbilt BioVU, and UK Biobank; mCA was detected in UK Biobank. A harmonized, high‐specificity phenotyping algorithm was applied across biobanks to identify participants with seropositive and seronegative RA (SPRA and SNRA). Age‐scale survival models assessed the effect of CH on risk of incident RA. Effect modification was tested with interaction models with genetically predicted complement protein levels. Results Among 612,989 participants, 30,840 had CHIP, 1,535 had incident SPRA, and 1,090 had incident SNRA. CHIP was associated with an increased risk of incident SPRA (pooled hazard ratio [HR] 1.26; confidence interval [CI] 1.03–1.52; P = 2.3 × 10 −2 ), driven primarily by DNMT3A ‐mutated CHIP and late‐onset RA (HR 1.45; CI 1.13–1.96; P = 3.6 × 10 −3 ) but not SNRA. Autosomal mCA and mosaic loss of chromosome Y (mLOY) were associated with an increased risk of incident SPRA (HR 2.12 and 2.85; CI 1.18–3.8 and 1.57–5.19; P = 1.2 × 10 −2 and 6.1 × 10 −4 ) but not SNRA. Higher genetically predicted levels of C1r and C1s attenuated the CHIP–SPRA association. Conclusion Age‐related CH, including DNMT3A ‐CHIP, autosomal mCA, and mLOY, are risk factors for incident SPRA but not SNRA, supporting a genotype‐ and serostatus‐specific link between somatic mutation and RA, with the classical complement pathway as a potential modifier. image