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

Abstract

BackgroundSomatic 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.MethodsWe 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.ResultsAmong 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).ConclusionOur 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.

DNMT3A dysfunction promotes neuroinflammation and exacerbates acute ischemic stroke

“…In our study, due to the WGS data being sequenced at a depth of 30X to broadly cover the whole genome, we have conservatively defined a variation as having a variant allele fraction (VAF) greater than 5% to enhance the robustness of our study. This threshold is higher than the 2%, or even 1.5%, typically referenced in previous study 4,7,11 . These measures were taken to ensure that our identification of DNMT3A ‐CHIP is both reliable and significant within the context of our research parameters.…”

“…This threshold is higher than the 2%, or even 1.5%, typically referenced in previous study. 4 , 7 , 11 These measures were taken to ensure that our identification of DNMT3A ‐CHIP is both reliable and significant within the context of our research parameters. Furthermore, the clinical finding was verified in a mouse model in which inhibition of DNMT3A by RG108 increased infarct volume via proinflammatory pathways.…”

“… 3 A previous study of our large‐scale cohort of stroke patients that was based on a nationwide prospective registry, including 15,166 patients diagnosed with acute ischemic stroke (AIS) or transient ischemic attack (TIA), has shown that the presence of CHIP increases the risk of short‐term recurrent stroke in first‐ever AIS patients. 4 …”

“… 8 As we previously reported, CHIP presence correlates with a higher likelihood of recurrent stroke and other vascular events within three months post‐AIS. 9 Single‐cell transcriptome analysis in leukocytes from patients with heart failure indicates that DNMT3A mutations drive an increase in monocyte inflammatory gene expression, which can lead to enhanced proinflammatory activation and endothelial adhesion upon DNMT3A silencing in monocytes. 10 , 11 …”

Molecular and clinical aspects relevant for counseling individuals with clonal hematopoiesis of indeterminate potential

“…Furthermore, TET2 mutations are highly enriched in patients with ischemic stroke (57), suggesting a central role of TET2-driven CH in stroke pathogenesis (57). Other studies have identified DNMT3A (30.0%) and TET2 (11.4%) as the most common mutations in individuals with CHIP who experienced a first-ever acute ischemic stroke, and CHIP was specifically a s s o c i a t e d w i t h r e c u r r e n t s t r o k e i n p a t i e n t s w i t h hyperinflammation (56). TET2 showed the strongest association with total and ischemic strokes, while both DNMT3A and TET2 were associated with an increased risk of hemorrhagic stroke (55).…”