Abstract Background Clonal hematopoiesis of indeterminate potential (CHIP) is an emerging risk factor for cardiovascular diseases and some respiratory diseases. Genetic interleukin-4 (IL-4) signaling deficiency reduces asthma risk. However, the association of CHIP and asthma remained unclear. Objectives To investigate whether CHIP are associated with asthma diagnosis, severity, and exacerbations. To assess whether IL-4 signaling inhibition attenuates asthma exacerbations among individuals with CHIP. Methods The association of CHIP and asthma prevalence and severity was ascertained by analyzing whole exome sequencing data in UK Biobank (asthma, n = 47,045; non-asthmatics, n = 335,084). To test the relationship between CHIP and asthma exacerbations, we conducted further analyses in a sub-cohort of moderate-to-severe asthma (MSA) (n = 5,835). The protective role of IL4R p.Ile75Val, a genetic proxy for IL-4 receptor inhibition, was tested after stratification by CHIP status. We performed analyses for three most common types of CHIP mutations, including DNMT3A, TET2, and ASXL1. Results The presence of CHIP was associated with increased asthma prevalence and severity (asthma: odd ratio (OR), 1.29 95% CI, 1.24 - 1.35; mild asthma: OR, 1.22 95% CI, 1.17 - 1.29; MSA: OR, 1.45 95% CI, 1.34 - 1.57). All three common CHIP mutations were significantly associated with greater asthma severity. In the MSA sub-cohort, only TET2-driven CHIP were significantly associated with increased risk of asthma exacerbations (hazard ratio (HR), 1.40 95% CI, 1.03 - 1.91), while DNMT3A and ASXL1 showed no significant effects. The presence of IL4R p.Ile75Val alleles attenuated the risk of asthma exacerbations in CHIP carriers (HR, 0.55 95% CI, 0.40-0.76), specifically in TET2-driven CHIP (HR, 0.47 95% CI, 0.24-0.91). Conclusions CHIP is associated with increased asthma risk and severity. TET2-driven CHIP confers a higher risk of asthma exacerbations, which may be attenuated by impaired IL-4 signaling. CHIP may serve as an attractive target for the treatment of asthma. This abstract is funded by: None
Zhang et al. (Fri,) studied this question.