Clonal Hematopoiesis and Risk of Stroke: Evidence From Over 800 000 Individuals Across 3 Cohorts.

Abstract (English)

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 <i>International Classification of Diseases</i> 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]; <i>P</i>=1.92&#xd7;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 <i>JAK2</i> (HR, 2.52) and <i>TET2</i> (HR, 1.23). <i>DNMT3A</i> 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]; <i>P</i>=1.91&#xd7;10^-3) but not in premenopausal participants (HR, 0.70 [95% CI, 0.36-1.43]; <i>P</i>=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.