Abstract
OBJECTIVES: Clonal haematopoiesis of indeterminate potential (CH), somatic genetic mutations conferring stem cells selective advantage, are associated with increased inflammatory cytokine production, cardiovascular disease (CVD), and malignancy. We investigated whether CH was related to risk of rheumatoid arthritis (RA), an inflammatory autoimmune disease. METHODS: Within the UK Biobank, we studied 186,577 unrelated individuals with baseline data collection, genome-wide genotyping, whole exome sequencing (WES) read for CHIP, and linked general practice (GP) data for identification of incident RA in follow-up. We excluded those with prevalent RA or taking RA medications at baseline. We tested for associations between variant allele fraction (VAF) >2% and >10% for the 8 most common CHIP mutations in the general population, and incident RA, identified by billing code algorithms. Cox regression models estimated hazard ratios (HR, 95% confidence interval) for incident RA. RESULTS: 594 participants developed incident RA over median follow-up 7.1 years (IQR 6.4-8.0); median time to RA was 3.9 years (IQR 2.0-5.6). Incident RA cases were slightly older at enrolment, more likely to be female, have smoked, have higher body mass index (BMI), and have prevalent CVD, and hypercholesterolaemia at baseline. However, there was no difference in the presence of CHIP mutations at baseline; 6.3% vs. 6.4% of those who did and did not develop incident RA in follow-up had any CHIP mutation at >2% VAF. CONCLUSIONS: Common CHIP mutations, including TET2, TP53, and SF3B1 mutations, were not associated with risk of incident RA when restricted to those with most complete general outpatient and hospital record follow-up in the UK Biobank.