Abstract WP230: Human Peripheral Blood Gene Expression Associated With 90day Ischemic Stroke Outcomes

Abstract

Objective: Identifying the molecular underpinnings associated with long-term functional outcome after ischemic stroke (IS) could guide search for treatments for improved outcome. Thus, we identified early peripheral immune gene expression (GE) responses associated with 90-day IS outcome, as measured by the Barthel Index (BI). Methods: RNA from 108 samples from three peripheral blood draws (≤3h – before thrombolytic treatment; 5h and 24h - post-treatment) from 36 CLEAR-trial subjects was analyzed on Affymetrix arrays. We performed Analysis of Covariance accounting for treatment (tPA or tPA+eptifibatide), hypercholesterolemia, hypertension, diabetes, age, sex and BI. Genes whose partial correlation with BI was significant ( P <0.005) were identified. Results: There were 206, 865, and 209 genes that significantly correlated with 90-day BI at ≤3h, 5h and 24h post ictus , respectively. The gene lists at all three time-points were enriched in B-cell specific genes (hypergeometric probability p<0.05), while the 5h gene list was also enriched in neutrophil-specific genes, and the 24h gene list was also enriched in monocyte-specific genes. B Cell Receptor Signaling pathway was predicted activated in subjects with better 90-day outcome at the ≤3h time-point, while ICOS-ICOSL Signaling in T Helper Cells and Role of NFAT in Regulation of the Immune Response were predicted activated at the 24h time-point.Immune-related pathways were enriched at three time-points including B cell-related, IL-7, and T cell signaling pathways. Apoptosis was suppressed in patients with better 90-day outcome at 3h and 24h post ictus . Among the genes associated with the 90-day BI were genes important for stroke and repair after stroke, such as KCNG1 , Potassium voltage-gated channel subfamily G member 1, which like other potassium channels could modulate stroke outcome. KCNG1 expression was positively correlated with 90-day BI at ≤3h and 5h. TERML4 , implicated in inflammatory response and human coronary arterial calcification had expression that positively correlated with BI at all three time-points. Conclusion: The findings expand our understanding of the early molecular biology associated with long-term stroke outcome and may serve as potential targets to improve outcome.