Peripheral Blood Gene Expression at 3 to 24 Hours Correlates with and Predicts 90-Day Outcome Following Human Ischemic Stroke

This study identified early immune gene responses in peripheral blood associated with 90-day ischemic stroke (IS) outcomes and an early gene profile that predicted 90-day outcomes. Peripheral blood from the CLEAR trial IS patients was compared to vascular risk factor matched controls. Whole-transcriptome analyses identified genes and networks associated with 90-day IS outcome (NIHSS-NIH Stroke Scale, mRS-modified Rankin Scale). The expression of 467, 526, and 571 genes measured at [≤]3, 5 and 24 hours after IS, respectively, were associated with poor 90-day mRS outcome (mRS=3-6), while 49, 100 and 35 associated with good mRS 90-day outcome (mRS=0-2). Poor outcomes were associated with up-regulated MMP9, S100A12, interleukin-related and STAT3 pathways. Weighted Gene Co-Expression Network Analysis (WGCNA) revealed modules significantly associated with 90-day outcome. Poor outcome modules were enriched in down-regulated T cell and monocyte-specific genes plus up-regulated neutrophil genes and good outcome modules were associated with erythroblasts and megakaryocytes. Using the difference in gene expression between 3 and 24 hours, 10 genes correctly predicted 100% of patients with Good 90-day mRS outcome and 67% with Poor mRS outcome (AUC=0.88) in a validation set. The predictors included AVPR1A, which mediates platelet aggregation, release of coagulation factors and exacerbates the brain inflammatory response; and KCNK1 (TWIK-1), a member of a two-pore potassium channel family, which like other potassium channels likely modulates stroke outcomes. This study suggests the immune response after stroke impacts long-term functional outcomes. Furthermore, early post-stroke gene expression may predict stroke outcomes and outcome-associated genes could be targets for improving outcomes.