Association of clonal hematopoiesis of indeterminate potential with cardiometabolic multimorbidity progression and mortality: a prospective study of UK Biobank.

backgroundClonal hematopoiesis of indeterminate potential (CHIP) is defined as the aging-related clonal expansion of preleukemic mutations in hematopoietic stem cells. While CHIP has been studied in cardiometabolic diseases (CMDs), its role in the long-term progression from the absence of CMD to the development of a single CMD, cardiometabolic multimorbidity (CMM), and eventual mortality remains uncertain. This study aimed to investigate the association between CHIP and gene-specific CHIP subtypes with the progression of CMD transitions.

methodsWe included UK Biobank participants without CMD at baseline. The primary outcomes were the first CMD, CMM, and death. We evaluated associations between any CHIP (variant allele fraction [VAF] ≥ 2%), large CHIP (VAF ≥ 10%), and gene-specific CHIP subtypes (DNMT3 A, TET2, ASXL1, JAK2, PPM1D/TP53 [DNA damage genes], and SF3B1/SRSF2/U2 AF1 [spliceosome genes]) with CMD transitions via multistate model analyses. We estimated multivariable-adjusted hazard ratios (HRs) and 95% CIs with age as the time scale, and adjusted for sex, race, Townsend Deprivation Index, body mass index (BMI), smoking, alcohol, physical activity, sleep duration, and hypertension.

resultsThe study included 371,544 participants, with a mean age of 56.60 (± 8.03) years, and 44.2% of whom were male (CHIP: n = 11,570 [3.1%]; large CHIP: n = 7156 [1.9%]). During a median follow-up period of 14.49 years, 54,805 individuals developed at least one CMD, 8090 experienced CMM, and 26,218 died. In the fully adjusted multistate models, CHIP and large CHIP were associated with adjusted hazard ratios (HR) of 1.11 (95% CI 1.07-1.16) and 1.14 (95% CI 1.08-1.20), respectively, for transitioning from a CMD-free condition to a single CMD. The mortality risk associations were strongest, with adjusted HR of 1.45 (95% CI 1.36-1.55) and 1.64 (95% CI 1.52-1.77) for those without CMD, 1.39 (95% CI 1.26-1.54) and 1.59 (95% CI 1.41-1.79) for individuals with single CMD, and 1.58 (95% CI 1.31-1.91) and 1.61 (95% CI 1.29-2.02) for those with CMM. No significant association was observed with CMM development. Gene-specific analyses identified DNMT3 A, TET2, DNA damage genes, and spliceosome genes as the primary contributors to increased CMD risk. While CHIP showed no association with CMM progression, spliceosome genes were linked to a 1.72-fold higher risk (adjusted HR 1.72, 95% CI 1.14-2.59) of recurrent CMD events. All CHIP subtypes were strongly related to a heightened risk of mortality, with JAK2 presenting the highest adjusted odds ratio at 6.79 (95% CI 4.12-11.2).

conclusionsCHIP serves as an independent risk factor for transitioning to the first CMD incidence and for mortality but is not associated with CMM development. CHIP-targeted management may represent a promising strategy for the primary prevention of CMD and for reducing mortality risk.