Objective: Rheumatoid arthritis (RA) is a systemic autoimmune disease with complex pathogenesis involving the innate and adaptive immune system. Clonal hematopoiesis of indeterminate potential (CHIP) is defined by clonal proliferation of one hematopoietic stem cell and is typically asymptomatic. Both are common among older adults. CHIP is associated with multiple autoimmune diseases, but has not been thoroughly evaluated for its relationship with RA. Methods: We examined three large biobanks where CHIP status of participants has been determined from whole genome sequencing data. We ascertained cases of RA, seropositive RA (SPRA), and seronegative RA (SNRA) using established methods and used survival analysis to test whether CHIP status was predictive of incident disease. We combined the results of the three biobank studies using random effects meta-analysis. For validation, we performed deep, targeted sequencing of CHIP-causing genes in an established clinical cohort of 132 RA cases, 56 controls, and 544 external controls. We compared the rates of CHIP between cases and controls using logistic linear regression. Results: In the UKBiobank and in meta-analysis, the presence of a large CHIP clone was associated with an increased risk for SPRA (HR = 2.57 with CI [1.46, 4.52] and p = 0.001) and RA (HR = 1.43 with CI [1.16, 1.75] and p = 7 x 10-4). Medium CHIP clones were associated with smaller increases in risk for SPRA and RA, and small CHIP clones carried no increased risk of any outcome. There were no associations detected between SNRA and CHIP of any size. In the clinical RA cohort, cases were more likely to have CHIP than controls after correcting for age, age2, and sex (OR: 2.08, HR [1.09, 3.83], p = 0.02). Conclusion: In a meta-analysis combing data from three large biobanks, large CHIP clones were associated with an increased risk for incident SPRA and, to a lesser extent, increased risk for RA. Validating this biobank-based finding, in a well-phenotyped clinical cohort, cases had higher rates of CHIP than age-matched controls. The mechanism by which CHIP drives the increased risk for SPRA is not known, but if it were discovered, could inform early intervention for patients with CHIP to prevent RA or personalized therapy for patients with RA based on CHIP status.

AGB: Advisory board & Equity holder: TenSixteen Bio.

This work was supported by NIH DP5 OD029586, a Burroughs Wellcome Fund Career Award for Medical Scientists, an E.P. Evans Foundation grant, a RUNX1 Research Program grant, a Pew Charitable Trusts and Alexander and Margaret Stewart Trust Pew-Stewart Scholar for Cancer Research award, a Vanderbilt University Medical Center Brock Family Endowment grant, and a Young Ambassador Award (A.G.B.), NIH T32 GM007347 (Y.P.), NIH T32 AR059039 (R.W.C.), and Arthritis National Research Foundation grant 128808 (R.W.C.). We would also like to acknowledge DNANexus for providing cloud computing credits.

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IRB of Vanderbilt University Medical Center gave ethical approval for this work (IRB #000567)

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