Clonal Hematopoiesis and the Risk for Rheumatoid Arthritis

ObjectivesClonal hematopoiesis (CH), defined by acquired mutations in hematopoietic stem cells, has been linked to many inflammatory diseases of aging. We investigated whether CH subtypes such as clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alteration (mCA) are associated with the risk of incident rheumatoid arthritis (RA) and whether complement modifies these associations. MethodsCHIP was ascertained in NIH AllOfUs, Vanderbilt BioVU, and the UKBiobank; mCA was detected in UKBiobank. A consistent phenotyping algorithm was applied across biobanks to identify seropositive RA (SPRA) and seronegative RA (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. ResultsAmong 612,989 eligible participants, 30,840 had CHIP, 2,110 had incident SPRA, and 1,310 had incident SNRA. CHIP was associated with an increased risk of incident SPRA (HR 1.29; CI 1.05-1.57; p=1.3x10-2) driven primarily by DNMT3A-mutated CHIP (HR 1.42, CI 1.1-1.82, p=7.1x10-3) but no risk of SNRA. In UKBiobank, autosomal mCA and mosaic loss of 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=1.2x10-2 and 6.1x10-4), but no risk of SNRA. Higher genetically predicted levels of C1r and C1s attenuated the CHIP-SPRA association. ConclusionsDNMT3A-CHIP, autosomal mCA and mLOY are novel risk factors for incident SPRA but not SNRA, supporting a serostatus-specific link between somatic mutation in epigenetic regulators and RA, with the classical complement pathway as a potential modifier of this risk.