Objectives:
Intracerebral hemorrhage (ICH) volume is a major determinant of functional outcome. The peripheral immune system plays a critical role in post-ICH damage and repair. Identifying potential modulators of ICH volume may guide the search for therapeutic targets. We performed a whole genome expression study in peripheral blood to examine the immune response following ICH with respect to ICH volume.
Methods:
Whole-genome RNA expression from 18 ICH subjects (14M/4F) was assessed on Affymetrix HTA 2.0 microarrays. Volumetric measurements were conducted on CT images using AnalyzePro. Multiple Regression including ICH volume while accounting for time from ICH onset to blood draw and interval between scan time and blood draw, was performed. A partial correlation between gene expression and ICH volume was calculated, with FDR p<0.3 (nominal p<0.005) and Pearson Correlation coefficient r>|0.6| considered significant. Pathway analysis and activation/suppression prediction of over-represented pathways was performed (Benjamini-Hochberg p<0.05, pathway activation/suppression Z-score >|2|).
Results:
Gene expression levels of 281 genes, including coding (mRNA) and non-coding RNA (i.e. several miRNAs) were associated with ICH volume. Major pathways, such as Neuroinflammation Signaling, were predicted to be activated in subjects with larger ICH volumes. So were Inflammasome Pathway, Toll-like Receptor, Leukocyte Extravasation, NF-kB signaling and FC? Receptor-Mediated Phagocytosis – some of which have been associated with poor clinical outcomes. Scavenger mechanisms, such as FC? Receptor-Mediated Phagocytosis, have been implicated in hematoma resolution. Thrombin Signaling, involved in coagulation, was also activated in subjects with larger ICH volumes. Peroxisome Proliferator-Activated Receptor (PPAR) Signaling was predicted to be suppressed in subjects with larger ICH volumes. PPAR pathway activation may have a neuroprotective effect following experimental ICH.
Conclusions:
We provide human data on genes and pathways associated with ICH volume. The results reveal major inflammatory pathways associated with ICH volume, which may be therapeutic targets for human ICH.
Critical Role of the Sphingolipid Pathway in Stroke: a Review of Current Utility and Potential Therapeutic Targets
