Abstract
BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) is a common age-related condition that increases risk for cardiovascular disease. However, its relationship with stroke remains uncertain. METHODS: To resolve these conflicting findings, we analyzed genomic and clinical data from 800 160 participants with genetic sequencing and medical records across 3 large-scale cohorts: the Vanderbilt BioVU biobank (United States; enrollment 2007-2022), the National Institutes of Health All of Us Research Program (United States; enrollment 2018-2023), and the UK Biobank (United Kingdom; enrollment 2006-2010). The median follow-up time was 4.4 years (interquartile range, 1.8-10.2) in BioVU, 1.9 years (interquartile range, 0.4-3.9) in All of Us, and 12.4 years (interquartile range, 11.7-13.1) in UK Biobank. Stroke events were identified and classified as ischemic or hemorrhagic using International Classification of Diseases codes. Subgroup analyses were conducted by driver gene, clone size, sex, and menopausal status. Genetically predicted levels of 27 cytokines were assessed for modification of CHIP-associated stroke risk. RESULTS: CHIP was associated with increased risk of incident stroke in the meta-analysis (hazard ratio [HR], 1.20 [95% CI, 1.14-1.27]; P=1.92×10(-10)). This association was observed for ischemic (HR, 1.18) and hemorrhagic (HR, 1.25) stroke subtypes. Gene-specific analyses showed strong associations for JAK2 (HR, 2.52) and TET2 (HR, 1.23). DNMT3A demonstrated weak but significant associations (HR, 1.13). CHIP was associated with stroke risk in both sexes; however, among women, the association was evident in postmenopausal (HR, 1.49 [95% CI, 1.16-1.92]; P=1.91×10(-3)) but not in premenopausal participants (HR, 0.70 [95% CI, 0.36-1.43]; P=0.33). Among participants with CHIP, but not among participants without CHIP, genetically predicted levels of IL-1RAP (interleukin-1 receptor accessory protein) were predictive of risk for stroke, suggesting IL-1RAP as a modifier of the CHIP-associated risk for stroke. CONCLUSIONS: Our large-scale, multicohort study establishes CHIP as a determinant of incident stroke risk and IL (interleukin)-1-mediated inflammation as a targetable pathway to reduce this risk.