The GNB3 C825T Polymorphism Is Associated With Decreased Risk of Recurrence of Large‐Artery Atherosclerotic Acute Ischemic Stroke

Background GNB3 C825T polymorphism affects G protein–coupled receptor signaling, influencing platelet function, inflammation, and cardiovascular risk. This study aimed to investigate the unknown effects of the GNB3 C825T polymorphism on recurrent stroke risk in large‐artery atherosclerosis and its potential interaction with antiplatelet therapy. Methods Using the CNSR‐III (Third China National Stroke Registry) data, we analyzed 1233 patients with large‐artery atherosclerotic acute ischemic stroke enrolled within 72 hours of onset. Whole‐genome sequencing was performed to identify the GNB3 C825T polymorphism. Cox regression analysis was used to assess its association with 1‐year recurrent ischemic stroke after adjusting for vascular risk factors. Associations with antiplatelet regimens and mediating effects of inflammatory biomarkers in the overall cohort were also evaluated. Results Carriers of the GNB3 825T‐allele (CT/TT, 72.7%) exhibited a significantly lower risk of 1‐year recurrent ischemic stroke than noncarriers (adjusted hazard ratio, 0.67 95% CI, 0.48–0.93; P =0.02). In exploratory analyses, the association was observed in the aspirin monotherapy subgroup, but the interaction with aspirin use was not significant. Elevated baseline interleukin‐6 partially attenuated this genetic protection in the overall cohort (mediation proportion, –9.82%; P =0.02). Conclusions The GNB3 825T‐allele was associated with a reduced risk of recurrent stroke in patients with large‐artery atherosclerotic acute ischemic stroke. In exploratory analyses, this association was observed in the aspirin monotherapy subgroup; however, the formal interaction with aspirin use was not statistically significant. These findings support a potential prognostic role of the GNB3 C825T polymorphism and warrant further validation in independent cohorts.