Clonal hematopoiesis of indeterminate potential and risk of incident Crohn's disease—a prospective cohort study

Abstract Background and Aims Crohn's disease (CD) is a chronic immune-mediated inflammatory disorder. Its pathophysiology involves dysregulation of both innate and adaptive immune responses, which can occur in clonal hematopoiesis of indeterminate potential (CHIP) individuals. Therefore, we hypothesize that CHIP may influence CD incidence. However, no study has explored the association between CHIP and incident CD. We analyzed UK Biobank data to investigate the association between CHIP and incident CD. Methods CHIP was defined based on the whole-exome sequencing data. The outcome was incident CD. Cox regression models were used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for CD in relation to CHIP. Results This study included 461,913 participants, of whom 14,339 (3.1%) had CHIP. The incidence rate of CD was 21.6 and 37.7 per 100,000 person-years for individuals without and with CHIP, respectively. We found a statistically significant increased risk of CD among individuals with CHIP (HR: 1.68; 95% CI: 1.30-2.16), compared with the reference group. This association was particularly stronger in individuals with JAK2-mutant CHIP (HR: 7.28; 95% CI: 1.82-29.13), ASXL1-mutant CHIP (HR: 3.07; 95% CI: 1.74-5.44) and DNMT3A-mutant CHIP (HR: 1.73; 95% CI: 1.24-2.42). Additionally, the association did not vary greatly by demographic, socioeconomic, lifestyle factors, CHIP clone size, or cancer comorbidity. Conclusions CHIP was associated with a markedly increased risk of subsequent CD. The association was particularly stronger in JAK2-mutant CHIP, ASXL1-mutant CHIP, and DNMT3A-mutant CHIP. The findings of this study may offer potential insights for future investigations into the mechanistic underpinnings of CD.