Subtype-specific effects of clonal hematopoiesis on cerebrovascular and cardiometabolic disease risk

Background Cerebrovascular and related cardiometabolic diseases frequently cluster in aging populations characterized by metabolic dysfunction and chronic inflammation. Clonal hematopoiesis of indeterminate potential (CHIP) has emerged as an age-related modifier associated with inflammation, metabolic disturbance, and vascular risk. However, whether CHIP exerts subtype-specific effects on cerebrovascular outcomes within a broader cardiometabolic context remains incompletely understood. Objectives This study aimed to investigate the causal associations of CHIP and its major genetic subtypes with cerebrovascular and cardiovascular diseases, while examining cancer outcomes as broader systemic context. Methods We performed Mendelian randomization analyses of overall CHIP and its five subtypes (DNMT3A, TET2, JAK2, TP53, and ASXL1) in relation to 20 cerebrovascular and cardiovascular diseases and 19 site-specific cancers. Complementary in vitro experiments were conducted to validate the biological contribution of the key subtype under inflammatory and metabolic stress conditions. Results Genetically predicted CHIP showed marked heterogeneity across cerebrovascular and cardiovascular outcomes. Among the CHIP subtypes, TET2-CHIP showed the clearest cerebrovascular signal, with significant associations with ischemic stroke, intracerebral hemorrhage, and hypertension. ASXL1-CHIP also showed directional risk elevations for intracerebral hemorrhage and hypertension. In contrast, JAK2-CHIP exhibited inverse associations with intracerebral hemorrhage and atrial fibrillation, whereas DNMT3A-CHIP was positively associated with atrial fibrillation and inversely associated with abdominal aortic aneurysm. Cancer analyses showed additional subtype-specific associations across disease outcomes. Experimental studies further showed that TET2 deficiency promoted macrophage lipid accumulation and inflammatory activation and induced endothelial dysfunction, supporting the biological relevance of the cerebrovascular and cardiometabolic associations. Conclusions CHIP is associated with subtype-specific patterns of cerebrovascular risk within a broader cardiometabolic context. TET2-CHIP showed the most consistent associations with cerebrovascular outcomes. The marked heterogeneity across CHIP subtypes indicates that clonal hematopoiesis should not be considered a uniform exposure, but rather a mutation-defined condition with distinct clinical consequences.