Data Management And Sharing System of China National Clinical Research Center for Neurological Diseases

Journal：MedComm

Publication type: Article

IF(IF): 10.7

PMID: 39006763 Link To Pubmed Full text Download

Ischemic stroke is a cerebrovascular accident and a leading cause of disability worldwide, with an increasing prevalence in recent years[1]. Neurological disability after ischemic stroke is of major concerns to patients and caregivers[2]. However, there is still no specific treatment to repair the neurological damage caused by stroke. Diverse sources of evidence support a causal role for inflammation in the brain injury after stroke[3], suggesting that regulatory mechanisms of inflammation might be an important target for improving neurological disability after stroke. Previous studies have confirmed that microglia, macrophages and neutrophils are the earliest immune cell populations in response to neuroinflammation after ischemic stroke[4, 5]. Among them, neutrophils are the key cells of myeloid hematopoiesis in the immune inflammatory response after stroke[6]. However, the role of immune cells such as neutrophils after stroke remains uncertain. Therefore, the underlying mechanisms of stroke require more in-depth studies. Clonal hematopoiesis of indeterminate potential (CHIP) is used to describe individuals with a somatic mutation associated with hematologic malignancy in blood or bone marrow, but without other diagnostic criteria for a hematologic malignancy[7]. The gene encoding DNA methyltransferase 3a (DNMT3A), the most common acquired mutation causing CHIP, is also one of the important genes in epigenetic regulation and is thought to play a role in de novo methylation[8]. Evidence suggests that global DNA methylation levels are upregulated in the brain of mice after ischemia-reperfusion. Previous study has shown that somatic mutations such as DNMT3A/TET2-driven CHIP was significantly associated with the progression and poor prognosis of chronic ischemic heart failure[9]. Meanwhile, CHIP-associated mutations were reported to provide a proliferative advantage to hematopoietic progenitors and promote the proliferation of myeloid progenitors such as neutrophils[10, 11]. Experimental study also demonstrated that carrying of Dnmt3a mutation contribute to the aggravation of chronic heart failure by increasing the expression of proinflammatory genes in monocytes and activating T-cell[12]. However, the effect of somatic mutation of DNMT3A on the functional outcome of acute ischemic stroke (AIS) is unclear. Thus, we aimed to evaluate the potential role of somatic mutations in DNMT3A in the post-stroke neurological disability in patients with AIS and explore the underlying mechanism of DNMT3A-exacerbated neurological disability using mouse with ischemia/reperfusion brain injury.

Categorical variables were presented as numbers (percentages). Continuous variables were presented as means with standard deviation (SD) or medians (interquartile range [IQR]). Student’s t-test were used for continuous variables, chi-squared test was used for comparison of response rate difference. The association of DNMT3A with neurological functional disability was tested using logistic regression adjusted with inverse probability of treatment weighted (IPTW). We defined a two-sided p-value of <0.05 as statistical significance. The above statistical analyses were conducted using SAS version 9.4 (SAS Institute Inc., Cary, North Carolina).