Abstract Body: Introduction
Clonal Hematopoiesis (CH) is an age-related clonal disorder of the hematopoietic system previously thought to be mostly benign with a low risk of transforming into malignancies. Over the last decade, several high impact studies have highlighted CH as a novel risk factor in cardiovascular injuries. Recently, the association between CH and stroke has begun to be appreciated. However, the conclusions from these observational studies are inconsistent due to the complicated genetic architecture of CH and stroke subtypes.
Method
Here, we comprehensively characterized the mutation-specific effects of CH on stroke subtypes and functional outcomes across multiple publicly available GWAS cohorts with Mendelian Randomization, mediation analysis, and Bayesian colocalization. Briefly, we used a meta-analysis of GWAS of CH, divided into specific mutation, from UK Biobank Cohort and deCODE Cohort as the exposure, to interrogate their effect on overall, ischemic, and hemorrhagic stroke incidence and post ischemic stroke function outcome derived from multiple large-scale GWAS. Table 1 shows the data sources used in this study.
Results
We revealed the mutation-specific effect of CH on the risk of stroke. TET2 CH was associated with overall ischemic stroke (OR = 1.05, P = 0.04), transient ischemic attack (TIA) (OR= 1.07, P = 0.01) and small vessel stroke (OR = 1.29, P = 0.01), as well as worse post-ischemic stroke functional outcomes unadjusted (OR = 1.34, P = 0.005) and adjusted for age, sex, and stroke severity (OR = 1.30, P = 0.02) at 90 days. Accounting for all mutations, CH was associated with intracerebral hemorrhage (ICH) (OR = 1.21, P = 0.02). Splicing factor mutation SRSF2 was protective against ICH (OR = 0.9, P = 0.04) and TIA (OR = 0.96, P = 0.02), and SF3B1 was protective against worse ischemic stroke outcome (OR = 0.85, P = 0.05, unadjusted; OR = 0.72, P = 0.007, adjusted). AXSL1 mutation was found to be protective against subarachnoid hemorrhage (OR = 0.92, P = 0.03).
Conclusion
In conclusion, our study provided genetic evidence for the association between TET2 CH, the risk of ischemic stroke, and post-ischemic stroke recovery, providing additional consideration for the management of high-risk patients.