To investigate the causal associations of clonal hematopoiesis of indeterminate potential (CHIP) and its major genetic subtypes with cerebrovascular and cardiovascular diseases, while also examining cancer outcomes as part of a broader systemic context.
Key Findings:
Genetically predicted CHIP showed marked heterogeneity across cerebrovascular and cardiovascular outcomes.
TET2-CHIP had significant associations with ischemic stroke, intracerebral hemorrhage, and hypertension.
ASXL1-CHIP showed notable associations for intracerebral hemorrhage and hypertension.
JAK2-CHIP exhibited inverse associations with intracerebral hemorrhage and atrial fibrillation.
DNMT3A-CHIP was positively associated with atrial fibrillation and inversely associated with abdominal aortic aneurysm.
Experimental studies indicated that TET2 deficiency promoted macrophage lipid accumulation and inflammatory activation.
Interpretation:
CHIP is associated with subtype-specific patterns of cerebrovascular risk, with TET2-CHIP showing the most consistent associations. The heterogeneity across CHIP subtypes suggests distinct clinical consequences.
Limitations:
Observational studies may have residual confounding from shared risk factors.
Most mechanistic investigations have focused on atherosclerotic cardiovascular disease, leaving the specific cerebrovascular relevance insufficiently characterized.
Conclusion:
Clonal hematopoiesis should be viewed as a mutation-defined condition with distinct clinical consequences, particularly regarding cerebrovascular outcomes.
