Somatic mutation contributing to clonal haematopoiesis is a risk factor of recurrent stroke in first-ever acute ischaemic stroke:a prospective cohort study

Background Somatic mutation contributes to clonal haematopoiesis of indeterminate potential(CHIP)is related to age and associated with a higher risk of stroke and atherosclerotic cardiovascular disease.Here,we investigated the prognostic significance of CHIP in a large first-ever acute ischaemic stroke(AIS)cohort and explored the underlying mechanisms.Methods We studied a prospective cohort of 6016 patients who had a first-ever AIS in China.Whole-genome sequencing was performed to identify CHIP.High-sensitivity C reactive protein(hs-CRP)levels above 3 mg/L at baseline were defined as hyperinflammation.Recurrent stroke during the 3-month follow-up was the primary outcome.Results Among the 6016 patients who had a first-ever AIS,with a median age was 62 years(IQR,54.0‒70.0),3.70%were identified as CHIP carriers.The most common mutations occurred in the DNMT3A(30.0%)and TET2(11.4%)genes.During a follow-up of 3 months,the presence of CHIP was associated with recurrent stroke(HR 1.62,95%CI 1.04 to 2.51,p=0.03),recurrent ischaemic stroke(HR 1.64,95%CI 1.04 to 2.58,p=0.03)and combined vascular events(HR 1.58,95%CI 1.02 to 2.44,p=0.04)after adjusting for hsCRP levels at baseline in patients who had a first-ever AIS.Subgroup analysis demonstrated that CHIP was only associated with recurrent stroke when patients under hyperinflammation(OR 3.10,95%CI 1.92 to 5.00,p<0.001)but not in those without hyperinflammation(OR 0.18,95%CI 0.03 to 1.04,p=0.06,Pinteraction=0.002).Conclusion Our results suggest that somatic mutations contributing to CHIP increase the risk of short-term recurrent stroke in patients who had a first-ever AIS.Hyperinflammation may be important in the relationship between CHIP and recurrent stroke.