Early peripheral blood gene expression associated with good and poor 90-day ischemic stroke outcomes

Abstract

Background This study identified early immune gene responses in peripheral blood associated with 90-day ischemic stroke (IS) outcomes. Methods Peripheral blood samples from the CLEAR trial IS patients at ≤ 3 h, 5 h, and 24 h after stroke were compared to vascular risk factor matched controls. Whole-transcriptome analyses identified genes and networks associated with 90-day IS outcome assessed using the modified Rankin Scale (mRS) and the NIH Stroke Scale (NIHSS). Results The expression of 467, 526, and 571 genes measured at ≤ 3, 5 and 24 h after IS, respectively, were associated with poor 90-day mRS outcome (mRS ≥ 3), while 49, 100 and 35 genes at ≤ 3, 5 and 24 h after IS were associated with good mRS 90-day outcome (mRS ≤ 2). Poor outcomes were associated with up-regulated genes or pathways such as IL-6, IL-7, IL-1, STAT3, S100A12, acute phase response, P38/MAPK, FGF, TGFA, MMP9, NF-kB, Toll-like receptor, iNOS, and PI3K/AKT. There were 94 probe sets shared for poor outcomes vs. controls at all three time-points that correlated with 90-day mRS; 13 probe sets were shared for good outcomes vs. controls at all three time-points; and 46 probe sets were shared for poor vs. good outcomes at all three time-points that correlated with 90-day mRS. Weighted Gene Co-Expression Network Analysis (WGCNA) revealed modules significantly associated with 90-day outcome for mRS and NIHSS. Poor outcome modules were enriched with up-regulated neutrophil genes and with down-regulated T cell, B cell and monocyte-specific genes; and good outcome modules were associated with erythroblasts and megakaryocytes. Finally, genes identified by genome-wide association studies (GWAS) to contain significant stroke risk loci or loci associated with stroke outcome including ATP2B, GRK5, SH3PXD2A, CENPQ, HOXC4, HDAC9, BNC2, PTPN11, PIK3CG, CDK6, and PDE4DIP were significantly differentially expressed as a function of stroke outcome in the current study. Conclusions This study suggests the immune response after stroke may impact functional outcomes and that some of the early post-stroke gene expression markers associated with outcome could be useful for predicting outcomes and could be targets for improving outcomes.

Proteomic profiling identifies novel inflammation-related plasma proteins associated with ischemic stroke outcome

“…3 ). Our results are in validation of two small clinical studies, where elevated EN-RAGE plasma protein levels ( n = 171) [ 18 ] and S100A12 mRNA isolated from peripheral blood were associated with unfavorable 3-month functional outcome after stroke [ 19 ]. SIRT2 is an NAD + -dependent deacetylase highly expressed by both neurons and oligodendrocytes and has been implicated in regulating for instance apoptosis [ 20 ] and myelination (Fig.…”

Updates of the role of B-cells in ischemic stroke

“…Ren et al significantly improved stroke in mice using blood replacement and found that the total number of leukocytes and neutrophils in the blood of stroke mice was significantly reduced during and 1 h after BR treatment, and that BR treatment significantly reduced plasma levels of the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α, as well as the chemokines CXCL1 and MMP-9 in stroke mice ( Ren et al, 2020 ) ( Figure 1 ). A recent clinical study has shown that poor stroke outcome modules are enriched with down-regulated B-cell-specific genes in stroke patients identified by whole-transcriptome analyses ( Amini et al, 2023 ).…”

Risk factors for stroke outcomes in adults: Stroke in China

“…Predicting functional outcomes in stroke presents a formidable challenge, largely owing to the intricate nature of the condition. [ 11 ] Consequently, we conducted a comprehensive examination of clinical peripheral blood samples extracted from stroke patients. Our objective was to uncover correlated risk factors linked to 90-day outcomes, as evaluated through the mRS.…”