Circulating exosomal lncRNAs as predictors of risk and unfavorable prognosis for large artery atherosclerotic stroke.
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ABSTRACT:
SUBMITTER: Zhang S
PROVIDER: S-EPMC8684716 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Large artery atherosclerotic (LAA) stroke is closely associated with atherosclerosis, characterized by the accumulation of immune cells. Early recognition of LAA stroke is crucial. Circulating exosomal circRNAs profiling represents a promising, noninvasive approach for the detection of LAA stroke. Exosomal circRNA sequencing was used to identify differentially expressed circRNAs between LAA stroke and normal controls. From a further validation stage, the results were validated using RT-qPCR. We then built logistic regression models of exosomal circRNAs based on a large replication stage, and receiver operating characteristic (ROC) curves were constructed to assess the diagnostic efficacy. Using exosomal circRNA sequencing, large sample validation, and diagnostic model construction revealed that exosomal circ_0043837 and circ_ 0001801were independent predictive factors for LAA stroke, and had better diagnostic efficacy than plasma circRNAs. In the atherosclerotic group (AS), we developed a nomogram for clinical use that integrated the two-circRNA-based risk factors to predict which patients might have the risk of plaque rupture. Circulating exosomal circRNAs profiling identifies novel predictive biomarkers for the LAA stroke and plaque rupture, with superior diagnostic value than plasma circRNAs. It might facilitate the prevention and better management of this disease.
| S-EPMC8792990 | biostudies-literature
Project description:Exosomal circRNA sequencing was used to identify differentially expressed circRNAs between LAA stroke and normal controls. From a further validation stage, the results were validated using RT-qPCR.
2022-02-02 | GSE190869 | GEO
Project description:Exosomes are crucial vehicles in intercellular communication. Circular RNAs (circRNAs), novel endogenous noncoding RNAs, play diverse roles in ischemic stroke. Recently, the abundance and stability of circRNAs in exosomes have been identified. However, a comprehensive analysis of exosomal circRNAs in large artery atherosclerotic (LAA) stroke has not yet been reported. We performed RNA sequencing (RNA-Seq) to comprehensively identify differentially expressed (DE) exosomal circRNAs in five paired LAA and normal controls. Further, quantitative real-time PCR (qRT-PCR) was used to verify the RNA-Seq results in a cohort of stroke patients (32 versus 32). RNA-Seq identified a total of 462 circRNAs in peripheral exosomes; there were 25 DE circRNAs among them. Additionally, circRNA competing endogenous RNA (ceRNA) network and translatable analysis revealed the potential functions of the exosomal circRNAs in LAA progression. Two ceRNA pathways involving 5 circRNAs, 2 miRNAs, and 3 mRNAs were confirmed by qRT-PCR. In the validation cohort, receiver operating characteristic (ROC) curve analysis identified two circRNAs as possible novel biomarkers, and a logistic model combining two and four circRNAs increased the area under the curve compared with the individual circRNAs. Here, we show for the first time the comprehensive expression of exosomal circRNAs, which displayed the potential diagnostic and biological function in LAA stroke.
| S-EPMC8257506 | biostudies-literature
Project description:Exosomes show diagnostic and therapeutic promise as carriers of ncRNAs in diseases. LncRNAs in exosomes have been identified as being stable and avoided degradation by nucleolytic enzymes. Although lncRNAs have been confirmed to be important in cancers, no studies for exo-lncRNAs have been reported in LAA stroke. High-throughput sequencing was performed to detect the differential expression profiles of lncRNAs in five paired plasma-derived exosome samples from patients with LAA stroke and controls (matched on vascular risk factors). Exo-lncRNA-associated networks were predicted with a combination of multiple databases. The expression of the selected genes in the networks was confirmed by qRT-PCR in a validation set (LAA vs. controls = 30:30). Furthermore, ROC analysis was used to evaluate the diagnostic performance of the lncRNA-related networks. A total of 1,020 differentially expressed lncRNAs were identified in LAA stroke patients. GO and KEGG pathway analyses indicated that their target genes are involved in atherosclerosis-related pathways, including inflammation, cell adhesion, and cell migration. qRT-PCR confirmed that the expression trend of differential expressed genes was consistent with RNA-seq. Furthermore, the AUCs of the lnc_002015-related network and lnc_001350-related network were 0.959 and 0.97, respectively, in LAA stroke. Our study showed the differential expression of lncRNAs in plasma exosomes and presented related diagnostic networks for LAA stroke for the first time. The results suggested that exosomal lncRNA-related networks could be potential diagnostic tools in LAA stroke.
| S-EPMC8176956 | biostudies-literature
Project description:Purpose: This study aimed to explore the differential expression profiles of exosomal lncRNAs and evaluated their potential utility in the accurate diagnosis of LAA stroke. Methods: LncRNA profiles of exosomes in large artery atherosclerosis stroke and controls were generated by high-throughput sequencing. The sequence reads that passed quality filters were analyzed at the transcript isoform level with Hisat2, Trapnell, STAR. qRT–PCR validation was performed using TaqMan and SYBR Green assays. Results: A total of 1020 differentially expressed lncRNAs were identified in LAA stroke patients. GO and KEGG pathway analyses indicated that their target genes are involved in atherosclerosis-related pathways, including inflammation, cell adhesion, and cell migration. 8 exosomal lncRNAs were confirmed with qRT–PCR.The result showed that the expression trend of differential expressed lncRNAs in validation was consistent with RNA-seq.Conclusion: Our study showed the differential expression of lncRNAs in plasma exosomes and presented related diagnostic potential for LAA stroke for the first time. The results suggested that exosomal lncRNA could be potential diagnostic tools in LAA stroke. Circular RNAs (circRNAs), novel endogenous noncoding RNAs, play diverse roles in ischemic stroke. Recently, the abundance and stability of circRNAs in exosomes have been identified. However, a comprehensive analysis of exosomal circRNAs in large artery atherosclerotic (LAA) stroke has not yet been reported. We performed RNA sequencing (RNA-Seq) to comprehensively identify differentially expressed exosomal circRNAs in five paired LAA and normal controls. RNA-Seq identified a total of 462 circRNAs in peripheral exosomes; there were 25 differentially expressed circRNAs among them. Additionally, circRNA competing endogenous RNA (ceRNA) network and translatable analysis revealed the potential functions of the exosomal circRNAs in LAA progression. Two ceRNA pathways involving 5 circRNAs, 2 miRNAs, and 3 mRNAs were confirmed by qRT-PCR. In the validation cohort, receiver operating characteristic (ROC) curve analysis identified two circRNAs as possible novel biomarkers, and a logistic model combining two and four circRNAs increased the area under the curve compared with the individual circRNAs.
2021-06-08 | GSE173719 | GEO
Project description:High-throughput Sequencing of exosomal circRNAs in large artery atherosclerotic stroke
| PRJNA788768 | ENA
Project description:BACKGROUND AND PURPOSE:Epidemiological studies show strong associations between kidney dysfunction and risk of ischemic stroke (IS), the mechanisms of which are incompletely understood. We investigated whether these associations may reflect shared heritability because of a common polygenic basis and whether this differed for IS subtypes. METHODS:Polygenic models were derived using genome-wide association studies meta-analysis results for 3 kidney traits: estimated glomerular filtration rate using serum creatinine (eGFRcrea: n=73?998), eGFR using cystatin C (eGFRcys: n=22?937), and urinary albumin to creatinine ratio (n=31?580). For each, single nucleotide polymorphisms passing 10 P value thresholds were used to form profile scores in 4561 IS cases and 7094 controls from the United Kingdom, Germany, and Australia. Scores were tested for association with IS and its 3 aetiological subtypes: large artery atherosclerosis, cardioembolism, and small vessel disease. RESULTS:Polygenic scores correlating with higher eGFRcrea were associated with reduced risk of large artery atherosclerosis, with 5 scores reaching P<0.05 (peak P=0.004) and all showing the epidemiologically expected direction of effect. A similar pattern was observed for polygenic scores reflecting higher urinary albumin to creatinine ratio, of which 3 associated with large artery atherosclerosis (peak P=0.01) and all showed the expected directional association. One urinary albumin to creatinine ratio-based score also associated with small vessel disease (P=0.03). The global pattern of results was unlikely to have occurred by chance (P=0.02). CONCLUSIONS:This study suggests possible polygenic correlation between renal dysfunction and IS. The shared genetic components may be specific to stroke subtypes, particularly large artery atherosclerotic stroke. Further study of the genetic relationships between these disorders seems merited.
| S-EPMC4245455 | biostudies-literature
Project description:Recently, exosomal miRNAs have been reported to be associated with some diseases, and these miRNAs can be used for diagnosis and treatment. However, diagnostic biomarkers of exosomal miRNAs for ischemic stroke have rarely been studied. In the present study, we aimed to identify exosomal miRNAs that are associated with large-artery atherosclerosis (LAA) stroke, the most common subtype of ischemic stroke; to further verify their diagnostic efficiency; and to obtain promising biomarkers. High-throughput sequencing was performed on samples from 10 subjects. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed on exosomes and plasma in the discovery phase (66 subjects in total) and the validation phase (520 subjects in total). We identified 5 candidate differentially expressed miRNAs (miR-369-3p, miR-493-3p, miR-379-5p, miR-1296-5p, and miR-1277-5p) in the discovery phase according to their biological functions, 4 of which (miR-369-3p, miR-493-3p, miR-379-5p, and miR-1296-5p) were confirmed in the validation phase. These four exosomal miRNAs could be used to distinguish LAA samples from small artery occlusion (SAO) samples, LAA samples from atherosclerosis (AS) samples, and LAA samples from control samples and were superior to plasma miRNAs. In addition, composite biomarkers achieved higher area under the curve (AUC) values than single biomarkers. According to our analysis, the expression levels of exosomal miR-493-3p and miR-1296-5p were negatively correlated with the National Institutes of Health Stroke Scale (NIHSS) score. The four identified exosomal miRNAs are promising biomarkers for the diagnosis of LAA stroke, and their diagnostic efficiency is superior to that of their counterparts in plasma.
| S-EPMC8661454 | biostudies-literature
Project description:Genome-wide association studies (GWAS) have not consistently detected replicable genetic risk factors for ischemic stroke, potentially due to etiological heterogeneity of this trait. We performed GWAS of ischemic stroke and a major ischemic stroke subtype (large artery atherosclerosis, LAA) using 1,162 ischemic stroke cases (including 421 LAA cases) and 1,244 population controls from Australia. Evidence for a genetic influence on ischemic stroke risk was detected, but this influence was higher and more significant for the LAA subtype. We identified a new LAA susceptibility locus on chromosome 6p21.1 (rs556621: odds ratio (OR)=1.62, P=3.9×10(-8)) and replicated this association in 1,715 LAA cases and 52,695 population controls from 10 independent population cohorts (meta-analysis replication OR=1.15, P=3.9×10(-4); discovery and replication combined OR=1.21, P=4.7×10(-8)). This study identifies a genetic risk locus for LAA and shows how analyzing etiological subtypes may better identify genetic risk alleles for ischemic stroke.
| S-EPMC3651583 | biostudies-literature
Project description:ObjectiveTo investigate the association of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors, osteoprotegerin (OPG) and death receptor 5 (DR5) with large-artery atherosclerosis (LAA) stroke and its prognosis.MethodsWe included patients with LAA stroke (n = 132) according to the TOAST classification system and controls (n = 60). To evaluate the extent and severity of cerebral atherosclerosis, the LAA stroke group was subdivided into 3 subgroups by number of cerebral arteries with atherosclerotic stenosis (≥50%): single, double and multiple (≥3). Plasma levels of TRAIL, OPG and DR5 were measured by ELISA. Ordinal logistic regression was used to analyze the association between the plasma levels of TRAIL, OPG, DR5 and the severity of cerebral atherosclerosis. Prognosis was determined by the Modified Rankin Scale at 3 months after stroke. Receiver operating characteristic (ROC) curve was used to evaluated TRAIL as a predictor of prognosis.ResultsPlasma TRAIL level was significantly lower for LAA patients than controls (P<0.001), while plasma OPG and DR5 levels were higher (both P<0.001). Logistic regression analysis revealed that risk of severe cerebral atherosclerosis was reduced significantly with increased plasma level of TRAIL (OR 0.438; 95% CI 0.282-0.681; P<0.001), whereas increased with high plasma levels of OPG and DR5 (OR 2.707; 95% CI 1.702-4.302, P <0.001; OR 3.593; 95% CI 1.878-6.869, P <0.001). Plasma TRAIL level was negatively correlated with the prognosis (r = - 0.372, P <0.001). The optimal cut-off value of TRAIL for prognosis was 848.63 pg/mL. The sensitivity and specificity at this cut-off value were 63.1% and 86.2%, respectively. After adding the plasma TRAIL level into the multivariate model of ROC, the area under the ROC curve was increased from 0.639 to 0.785, but the change was not statistical significant (P = 0.146).ConclusionsTRAIL and its receptors OPG and DR5 may be involved in LAA stroke and the plasma level of TRAIL may be a biomarker predicting the severity of cerebral atherosclerosis and the prognosis of LAA stroke.
| S-EPMC4559459 | biostudies-literature