Clonal Hematopoiesis and Risk of Stroke: Evidence from Over 800,000 Individuals Across Three Cohorts

Abstract

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: some studies have reported a significant association between CHIP and stroke risk, while others, including large biobank analyses, found no association after adjustment. To resolve these conflicting findings, we analyzed genomic and clinical data from 800,160 participants with genetic sequencing and medical records across the Vanderbilt BioVU, NIH AllofUs, and UK Biobank. Stroke events were identified and classified as ischemic or hemorrhagic using ICD codes. Results from the three cohorts were meta-analyzed with previously published results. Subgroup analyses were conducted by driver gene, clone size, sex and menopausal status. In addition, genetically predicted levels of 27 plasma cytokines were assessed as potential modifiers of CHIP-associated stroke risk. CHIP was associated with increased risk of incident stroke in each cohort and in the meta-analysis (HR = 1.20, 95% CI 1.13-1.27; P = 2.21 x 10-10). This association was observed for both ischemic (HR = 1.18) and hemorrhagic (HR = 1.30) stroke subtypes. Gene-specific analyses showed strong associations for JAK2 (HR = 2.46) and TET2 (HR = 1.40). DNMT3A demonstrated weak but significant associations (HR = 1.11). 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 x 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 were predictive of risk for stroke, suggesting IL-1RAP as a modifier of the CHIP-associated risk for stroke. Collectively, this large-scale, multi-cohort study establishes CHIP as an important determinant of incident stroke risk and IL-1-mediated inflammation as a targetable pathway to reduce this risk.