Search

Somatic mutations related to clonal hematopoiesis of indeterminate potential (CHIP) are risk factors for stroke. The impact of DNMT3A, the most mutated gene in CHIP, on clinical functional outcomes of acute ischemic stroke (AIS) remains unclear. In a well‐characterized cohort of 8524 ischemic stroke patients, we demonstrated that DNMT3A‐driven CHIP was significantly associated with neurological disability in these patients. With a stroke mouse model of transient middle cerebral artery occlusion (tMCAO), we demonstrated that DNMT3A protein levels in the brain penumbra increased. The DNMT3A inhibitor RG108 administration amplified neutrophil proliferation in the blood, promoted neutrophil infiltration into the brain penumbra, and exaggerated proinflammatory activation in tMCAO male mice. DNMT3A inhibition also significantly increased infarct volume and worsened neurobehavioral function in tMCAO male mice. In conclusion, DNMT3A somatic mutations are associated with worsened neurological disability in some patients with AIS, potentially through increased neutrophil proliferation and infiltration in the ischemic brain region. These findings suggest a possible mechanism for proinflammatory activation and tissue damage in the affected brain tissue, highlighting the need for further research in this area. [ABSTRACT FROM AUTHOR]

Computed tomography (CT) scans and magnetic resonance imaging (MRI) are commonly utilized to detect brain gliomas and central nervous system inflammation diseases. However, there are instances where depending solely on medical imaging for a precise diagnosis may result in unsuitable medications or treatments. Pathological analysis is regarded as the definitive method for diagnosing brain gliomas or central nervous system inflammation diseases. To achieve this, a craniotomy or stereotaxic biopsy is necessary to collect brain tissue, which can lead to complications such as cerebral hemorrhage, neurological deficits, cerebrospinal fluid leaks, and cerebral edema. Consequently, the advancement of non-invasive or minimally invasive diagnostic techniques is currently a high priority. This study included samples from four glioma patients and five patients with central nervous system inflammatory diseases, comprising both serum and paired cerebrospinal fluid (CSF). A total of 40 human cytokines were identified in these samples. We utilized a receiver operating characteristic (ROC) analysis to assess the sensitivity and specificity for distinguishing central nervous system inflammation diseases and gliomas. Additionally, we examined the correlation of these factors between serum and CSF in the patients. Ultimately, the identified factors were validated using serum from patients with clinically confirmed gliomas and central nervous system inflammation diseases followed by detection and statistical analysis through ELISA. The levels of serum factors IL-4, IFN-α, IFN-γ, IL-6, TNF-α, CCL4, CCL11, and VEGF were found to be significantly higher in gliomas compared with inflammatory diseases of the central nervous system (p < 0.05). Furthermore, a strong correlation was observed between the levels of CCL4 in serum and CSF, with a correlation coefficient of r = 0.92 (95% CI = 0.20-0.99, p = 0.027). We gathered more clinical samples to provide further validation of the abundance of CCL4 expression. A clinical study analyzing serum samples from 19 glioma patients and 22 patients with central nervous system inflammation diseases revealed that CCL4 levels were notably elevated in the inflammatory group compared with the glioma group (p < 0.001). These results suggest that assessing serum CCL4 levels may be useful in distinguishing those patients for clinical diagnostic purposes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer QC declared a shared affiliation, with no collaboration, with several of the authors, T-JL, ZZ, RT, HW, MZ, WX, to the handling editor at the time of the review., (Copyright © 2024 Lyu, Wang, Zhao, Sun, Zhao, Tian, Guo, Wang, Zhao, Ma, Zhang and Xu.)

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, P interaction =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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)