Association between PPARγ polymorphisms and neurological functional disability of ischemic stroke.

Peroxisome proliferator-activated receptor-γ (PPARγ) plays a protective role against brain injury after stroke in mice. However, the relationship between PPARγ gene polymorphisms and the functional outcome of acute ischemic stroke (AIS) remains unknown. 8822 patients from The Third China National Stroke Registry (CNSR-III) after whole-genome sequencing, two functional single nucleotide polymorphisms(SNPs) in PPARγ, rs1801282 C > G and rs3856806 C > T, were further analysed. The primary outcome was neurological functional disability at three months. Of the 8822 patients, 968 (11.0%) and 3497 (39.6%) were carriers of rs1801282 and rs3856806, respectively. Carriers of rs3856806 showed reduced risks for three-month neurological functional disability (OR, 0.84; 95% CI, 0.73-0.98; p = 0.02) and reduced risks for higher infarct volume (OR 0.90, 95% CI, 0.81-0.99, p = 0.04). They also had a reduced risk of neurological functional disability only in case of lower baseline IL-6 levels (OR 0.64, 95% CI 0.48-0.84, Pinteraction = 0.01). Carriers of rs1801282 had a reduced risk for three-month neurological functional disability (OR 0.77, 95% CI, 0.61-0.99, p = 0.04). Our study suggested that PPARγ polymorphisms are associated with a reduced risk for neurological functional disability and higher infarct volume in AIS. Therefore, PPARγ can be a potential therapeutic target in AIS.

DNMT3A dysfunction promotes neuroinflammation and exacerbates acute ischemic stroke.

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.

Association between clonal hematopoiesis-related gene mutations and unfavorable functional outcome in patients with large-artery atherosclerotic stroke.

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) is a phenomenon that characterizes individuals with somatic mutations that are related to hematologic malignancy but without hematologic abnormalities. Presence of CHIP is associated with the atherosclerotic cardiovascular disease through the activation of the interleukin 6 (IL-6) pathway; however, its role on unfavorable functional outcomes in different etiologies of ischemic stroke remains unclear. We aimed to investigate the association between CHIP-related gene mutations and unfavorable functional outcomes of ischemic stroke with different etiologies. METHODS: We prospectively studied a cohort of 3396 stroke patients with identified etiologies, and identified CHIP and the presence of the IL6R variant (IL6R p.Asp358Ala) by whole-genome sequencing. The IL6R p.Asp358Ala coding mutation was used as a genetic inhibition for IL-6 signaling. The primary outcome was unfavorable functional outcome [(Modified Rankin Scale), mRS 2-6] at 3 months. RESULTS: Of the 3396 patients, 110 (3.2%) were CHIP carriers and the median age was 62 years (IQR, 54.0-69.0). The CHIP increased the risk of unfavorable functional outcome among patients with hyper-inflammation status of high-sensitivity C-reactive protein (hsCRP) > median levels in patients with large-artery atherosclerosis (LAA) (OR 2.45, 95% CI 1.00-5.98, p = 0.049, pinteraction = 0.01). Presence of IL6R variant (IL6R p.Asp358Ala) could attenuate the risk of unfavorable functional outcome only in patients with CHIP (OR 0.30, 95%CI 0.12-0.76, p = 0.01, pinteraction = 0.02), and especially in LAA patients with CHIP (OR 0.1, 95%CI 0.02-0.42, p = 0.002; pinteraction = 0.001). CONCLUSION: CHIP is associated with unfavorable functional outcomes in patients with LAA stroke and hyper-inflammation. Genetic IL-6 signaling inhibition might attenuate the risk of unfavorable functional outcomes in CHIP carriers, especially in LAA stroke patients.