DNase1 RS1053874 Polymorphism is Associated with Early Neurological Recovery through NET Modulation and with Long-Term Survival in Ischemic Stroke: A Prospective Cohort Study.

Abstract

Immunothrombosis contributes to ischemic stroke pathophysiology through neutrophil extracellular trap (NET) formation, which promotes thrombus stabilization and microvascular dysfunction. DNase1 is the principal endonuclease responsible for NET degradation. The rs1053874 polymorphism in DNase1 gene influences enzymatic activity and protein stability in vitro, but its clinical relevance in ischemic stroke remains unexplored. We investigated whether this variant modulates systemic NET burden and impacts stroke-related outcomes. We conducted a prospective observational cohort study including 492 patients with acute ischemic stroke. Genotyping of rs1053874 was performed via Sanger sequencing and categorized into AA versus GG + GA genotypes (dominant model). Clinical variables, NET biomarkers (elastase, myeloperoxidase [MPO], and dsDNA), DNAse1 activity, infarct volume, thrombectomy metrics, and survival were assessed. Multivariable regression and Cox proportional hazards models were used to explore associations between genotype and outcomes. AA genotype carriers (7.9%) had a significantly lower burden of prior vascular events compared to GG + GA carriers. At admission, they exhibited higher DNAse1 activity, reduced levels of circulating NET markers (elastase, MPO, and dsDNA), and lower neutrophil and monocyte counts. Despite similar initial stroke severity, AA carriers required fewer thrombectomy passes and had significantly better early neurological recovery and smaller infarcts. In adjusted models, both the AA genotype and dyslipidemia were independently associated with improved long-term survival. However, stratified analyses revealed the most robust survival benefit among AA carriers without dyslipidemia. No significant interaction was observed. DNase1 rs1053874 polymorphism influences NET-related inflammation and is associated with improved vascular profile, procedural efficiency, and long-term outcomes in ischemic stroke. These findings support the potential of DNase1 as a therapeutic and prognostic target in personalized stroke care. ANN NEUROL 2026;99:1210-1223.