title: Intracerebral Hemorrhage and Ischemic Stroke of Different Etiologies Have Distinct Alternatively Spliced mRNA Profiles in the Blood: a Pilot RNA-seq Study.
abstract: Whole transcriptome studies have used 3'-biased expression microarrays to study genes regulated in the blood of stroke patients. However, alternatively spliced messenger RNA isoforms have not been investigated for ischemic stroke or intracerebral hemorrhage (ICH) in animals or humans. Alternative splicing is the mechanism whereby different combinations of exons of a single gene produce distinct mRNA and protein isoforms. Here, we used RNA sequencing (RNA-seq) to determine if alternative splicing differs for ICH and cardioembolic, large vessel and lacunar causes of ischemic stroke compared to controls. RNA libraries from 20 whole blood samples were sequenced to 200 M 2 × 100 bp reads using Illumina sequencing-by-synthesis technology. Differential alternative splicing was assessed using one-way analysis of variance (ANOVA), and differential exon usage was calculated. Four hundred twelve genes displayed differential alternative splicing among the groups (false discovery rate, FDR; p < 0.05). They were involved in cellular immune response, cell death, and cell survival pathways. Distinct expression signatures based on usage of 308 exons (292 genes) differentiated the groups (p < 0.0005; fold change >|1.2|). This pilot study demonstrates that alternatively spliced genes from whole blood differ in ICH compared to ischemic stroke and differ between different ischemic stroke etiologies. These results require validation in a separate cohort.
authors.affiliation: Department of Neurology, University of California at Davis, Sacramento, CA, USA.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Dykstra-Aiello
authors.forename: Glen C
authors.initials: GC
authors.lastname: Jickling
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Ander
authors.forename: Xinhua
authors.initials: X
authors.lastname: Zhan
authors.forename: DaZhi
authors.initials: D
authors.lastname: Liu
authors.forename: Heather
authors.initials: H
authors.lastname: Hull
authors.forename: Miles
authors.initials: M
authors.lastname: Orantia
authors.forename: Carolyn
authors.initials: C
authors.lastname: Ho
authors.forename: Boryana
authors.initials: B
authors.lastname: Stamova
mesh_terms: D000368:Aged; D017398:Alternative Splicing / Q000235:genetics*; D002545:Brain Ischemia / Q000150:complications; D002543:Cerebral Hemorrhage / Q000097:blood / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D059906:Neuroimaging; D020411:Oligonucleotide Array Sequence Analysis; D010865:Pilot Projects; D025341:Principal Component Analysis; D012333:RNA, Messenger / Q000378:metabolism*; D012189:Retrospective Studies; D017423:Sequence Analysis, RNA; D020521:Stroke / Q000097:blood / Q000209:etiology / Q000235:genetics*
chemical_list: D012333:RNA, Messenger