Altered Expression of Long Noncoding RNAs in Blood After Ischemic Stroke and Proximity to Putative Stroke Risk Loci

Abstract

Background and Purpose Though peripheral blood mRNA and microRNA change following ischemic stroke, any role for long noncoding RNA (lncRNA), which comprise most of the genome and have been implicated in various diseases, is unknown. Thus, we hypothesized that lncRNA expression also changes following stroke. Methods lncRNA expression was assessed in 266 whole-blood RNA samples drawn once per individual from ischemic stroke patients and matched vascular risk factor controls. Differential lncRNA expression was assessed by Analysis of Covariance (ANCOVA, p-value < 0.005; fold change > |1.2|), principal components analysis and hierarchical clustering on a derivation set (n=176) and confirmed on a validation set (n=90). Post-stroke temporal lncRNA expression changes were assessed using ANCOVA with confounding factor correction (p<0.005; partial correlation with time since event >|0.4|). Because sexual dimorphism exists in stroke, analyses were performed for each sex separately. Results 299 lncRNAs were differentially expressed between stroke and control males, whereas 97 lncRNAs were differentially expressed between stroke and control females. Significant changes of lncRNA expression with time after stroke were detected for 49 lncRNAs in males and 31 lncRNAs in females. Some differentially expressed lncRNAs mapped close to genomic locations of previously identified putative stroke-risk genes, including Lipoprotein, Lp(A)-Like 2, ABO blood group, Prostaglandin 12 Synthase, and α-Adducins. Conclusions This study provides evidence of altered and sexually dimorphic lncRNA expression in peripheral blood of stroke patients compared to controls and suggests lncRNAs have potential for stroke biomarker development. Some regulated lncRNA could regulate some previously identified putative stroke-risk genes.

Identification of Novel LncRNA Biomarkers and Construction of LncRNA-Related Networks in Han Chinese Patients with Ischemic Stroke

“…In the lncRNA-miRNA-mRNA regulatory network, KEGG pathway analysis indicated that lncRNAs may regulate relative mRNAs via "PI3K-Akt signaling pathway", "p53 signaling pathway", "AMPK signaling pathway", "MAPK signaling pathway", "Wnt signaling pathway", and "TGF-beta signaling pathway" to perform functions. LncRNAs are dysregulated in several diseases, such as obesity, ischemic heart failure, moyamoya disease, and stroke [12][13][14][15]. Dykstra-Aiello explored the lncRNA expression profile of IS and stroke risk loci by using human peripheral blood obtained from American and Canadian subjects; the results identified 299 and 97 differentially expressed lncRNAs in males and females, respectively (P < 0.005, |FC| > 1.2) [12].…”

“…LncRNAs are dysregulated in several diseases, such as obesity, ischemic heart failure, moyamoya disease, and stroke [12][13][14][15]. Dykstra-Aiello explored the lncRNA expression profile of IS and stroke risk loci by using human peripheral blood obtained from American and Canadian subjects; the results identified 299 and 97 differentially expressed lncRNAs in males and females, respectively (P < 0.005, |FC| > 1.2) [12]. Affymetrix GeneChip Human Transcriptome 2.0 arrays (> 40, 000 lncRNAs and > 245, 000 coding transcripts) were used to detect significantly altered lncRNAs in the Dykstra-Aiello study; meanwhile, we used Arraystar Human LncRNA Microarray v4.0 (40, 173 lncRNAs and 20, 730 coding transcripts) in the present study.…”

“…Dykstra-Aiello performed microarray analysis and identified 299 and 97 differentially expressed lncRNAs in the peripheral blood of male and female patients with stroke compared with controls (P < 0.005, absolute fold change (|FC|) > 1.2) [12]. However, qRT-PCR analysis was not performed to verify the expression of the identified differentially expressed lncRNAs.…”

MALAT1 Activates the P53 Signaling Pathway by Regulating MDM2 to Promote Ischemic Stroke

“…One study demonstrated abnormal expression of lncRNAs in stroke, some of which bound to co-repressors of REST, a transcription factor that affects stroke-mediated cell death [5]. LncRNAs are potential novel biomarkers that should be explored further for use in the diagnosis, treatment and prognosis of stroke [6]. Metastasisassociated lung adenocarcinoma transcript 1 (MALAT1) is a highly abundant lncRNA that exerts anti-inflammatory and anti-apoptotic roles in the brain microvasculature to reduce ischemia in the cerebral vasculature [7].…”

Noncoding RNAs in ischemic stroke: time to translate

“…They can also be transcribed bidirectionally within 100 bp of their promoters (Fig. C) . Future studies of lncRNAs may enable new approaches to understanding, diagnosis, and treatment of neurological disorders …”