Aspirin remains a key treatment for acute ischemic stroke (AIS), though patient responses can vary widely. This study sought to develop a pharmacogenetic polygenic response score (PgxRS) capable of predicting adverse clinical outcomes in AIS patients receiving aspirin therapy. A retrospective cohort of 828 AIS patients treated with aspirin was analyzed. Fifteen candidate single nucleotide polymorphisms (SNPs) within genes influencing aspirin’s pharmacodynamics, transport, metabolism, and platelet activity were genotyped. Logistic regression was used to examine the relationship between each SNP and poor prognosis, defined as a modified Rankin Scale score exceeding 1 at 90 days. Multivariable predictive models integrating both genetic and clinical factors were then constructed. Patients carrying the ABCB1 rs1045642 GG genotype showed a lower likelihood of poor outcomes, while the P2Y1 rs1371097 T allele was linked to higher risk. A predictive model incorporating these SNPs alongside relevant clinical variables achieved moderate discriminative performance for forecasting adverse outcomes (AUC = 0.78, 95% CI: 0.74–0.81). The findings indicate that variation in the ABCB1 and P2Y1 genes contributes to differences in aspirin responsiveness among AIS patients. The PgxRS developed in this study, combining these genetic variants with clinical information, offers potential utility in guiding individualized antiplatelet therapy and stratifying patient risk. Validation in larger, ethnically diverse populations is necessary to confirm these results.
