Dataset Information

Extracellular microRNAs in blood differentiate between ischaemic and haemorrhagic stroke subtypes.

ABSTRACT: Rapid identification of patients suffering from cerebral ischaemia, while excluding intracerebral haemorrhage, can assist with patient triage and expand patient access to chemical and mechanical revascularization. We sought to identify blood-based, extracellular microRNAs 15 (ex-miRNAs) derived from extracellular vesicles associated with major stroke subtypes using clinical samples from subjects with spontaneous intraparenchymal haemorrhage (IPH), aneurysmal subarachnoid haemorrhage (SAH) and ischaemic stroke due to cerebral vessel occlusion. We collected blood from patients presenting with IPH (n = 19), SAH (n = 17) and ischaemic stroke (n = 21). We isolated extracellular vesicles from plasma, extracted RNA cargo, 20 sequenced the small RNAs and performed bioinformatic analyses to identify ex-miRNA biomarkers predictive of the stroke subtypes. Sixty-seven miRNAs were significantly variant across the stroke subtypes. A subset of exmiRNAs differed between haemorrhagic and ischaemic strokes, and LASSO analysis could distinguish SAH from the other subtypes with an accuracy of 0.972 ± 0.002. Further analyses predicted 25 miRNA classifiers that stratify IPH from ischaemic stroke with an accuracy of 0.811 ± 0.004 and distinguish haemorrhagic from ischaemic stroke with an accuracy of 0.813 ± 0.003. Blood-based, ex-miRNAs have predictive value, and could be capable of distinguishing between major stroke subtypes with refinement and validation. Such a biomarker could one day aid in the triage of patients to expand the pool eligible for effective treatment.

SUBMITTER: Kalani MYS

PROVIDER: S-EPMC7034450 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Extracellular microRNAs in blood differentiate between ischaemic and haemorrhagic stroke subtypes.

Kalani M Yashar S MYS Alsop Eric E Meechoovet Bessie B Beecroft Taylor T Agrawal Komal K Whitsett Timothy G TG Huentelman Matthew J MJ Spetzler Robert F RF Nakaji Peter P Kim Seungchan S Van Keuren-Jensen Kendall K

Journal of extracellular vesicles 20200124 1

Rapid identification of patients suffering from cerebral ischaemia, while excluding intracerebral haemorrhage, can assist with patient triage and expand patient access to chemical and mechanical revascularization. We sought to identify blood-based, extracellular microRNAs 15 (ex-miRNAs) derived from extracellular vesicles associated with major stroke subtypes using clinical samples from subjects with spontaneous intraparenchymal haemorrhage (IPH), aneurysmal subarachnoid haemorrhage (SAH) and is ...[more]

PMID: 32128071

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Project description:BackgroundThe clinical epidemiology of stroke has been widely investigated in Caucasian populations, but the changes over time in the proportion of ischaemic to haemorrhagic strokes is less clear, especially in the Chinese population.AimsOur objective was to study the determinants and time trends for ischaemic and haemorrhagic stroke, in relation to age, in a large Chinese population cohort.MethodsUsing a medical insurance database in the southwest of China from 2001 to 2012, time trends in age-adjusted ischaemic and haemorrhagic stroke incidence and the contributing risk factors associated with age were investigated.ResultsAmong 425,901 individuals without prior stroke (52.4% male, median age 54), the rate of ischaemic stroke (per 1000 patient-years) decreased between 2002-2007, then remained broadly similar between 2008-2012. The rate of haemorrhagic stroke showed a similar trend, being approximately 1.3-1.9 from 2008-2012. Compared to patients age<65, ischaemic and haemorrhagic stroke incidences (rate, 95% confidential interval, CI) were higher in the elderly population (age <65 versus age ?65: ischaemic: 3.64, 3.33-4.00, vs 14.33, 14.01-14.60; haemorrhagic: 1.09, 1.00-1.10 vs 2.52,2.40-2.70, respectively, both p<0.001). There were no significant differences in haemorrhagic stroke rates between the elderly and the very elderly population. Ischaemic and haemorrhagic stroke shared similar risk factors (age, hypertension, coronary artery disease (CAD), vascular disease, and diabetes mellitus) (all p<0.05). In subjects age<75 years, CAD (7.17, 4.14-12.37) and diabetes mellitus (3.27, 2.42-4.42) contributed most to the developing of haemorrhagic stroke (all p<0.001). Amongst the very elderly, vascular disease (2.24, 1.49-3.37) was an additional major risk factor for haemorrhagic stroke, together with CAD and diabetes mellitus (all p<0.001).ConclusionIn this large Chinese cohort, there was an increased risk of ischaemic stroke compared to haemorrhagic stroke with ageing. CAD, vascular disease, diabetes mellitus, and hypertension were major contributors to the development of hemorrhagic stroke in the very elderly Chinese population.

Project description:Thrombosis and platelet activation play a central role in stroke pathogenesis, and antiplatelet and anticoagulant therapies are central to stroke prevention. However, whether haematological traits contribute equally to all ischaemic stroke subtypes is uncertain. Furthermore, identification of associations with new traits may offer novel treatment opportunities. The aim of this research was to ascertain causal relationships between a wide range of haematological traits and ischaemic stroke and its subtypes. We obtained summary statistics from 27 published genome-wide association studies of haematological traits involving over 375 000 individuals, and genetic associations with stroke from the MEGASTROKE Consortium (n = 67 000 stroke cases). Using two-sample Mendelian randomization we analysed the association of genetically elevated levels of 36 blood cell traits (platelets, mature/immature red cells, and myeloid/lymphoid/compound white cells) and 49 haemostasis traits (including clotting cascade factors and markers of platelet function) with risk of developing ischaemic (AIS), cardioembolic (CES), large artery (LAS), and small vessel stroke (SVS). Several factors on the intrinsic clotting pathway were significantly associated (P < 3.85 × 10-4) with CES and LAS, but not with SVS (e.g. reduced factor VIII activity with AIS/CES/LAS; raised factor VIII antigen with AIS/CES; and increased factor XI activity with AIS/CES). On the common pathway, increased gamma (γ') fibrinogen was significantly associated with AIS/CES. Furthermore, elevated plateletcrit was significantly associated with AIS/CES, eosinophil percentage of white cells with LAS, and thrombin-activatable fibrinolysis inhibitor activation peptide antigen with AIS. We also conducted a follow-up analysis in UK Biobank, which showed that amongst individuals with atrial fibrillation, those with genetically lower levels of factor XI are at reduced risk of AIS compared to those with normal levels of factor XI. These results implicate components of the intrinsic and common pathways of the clotting cascade, as well as several other haematological traits, in the pathogenesis of CES and possibly LAS, but not SVS. The lack of associations with SVS suggests thrombosis may be less important for this stroke subtype. Plateletcrit and factor XI are potentially tractable new targets for secondary prevention of ischaemic stroke, while factor VIII and γ' fibrinogen require further population-based studies to ascertain their possible aetiological roles.

Project description:The discovery of disease-associated loci through genome-wide association studies (GWAS) is the leading genetic approach to the identification of novel biological pathways underlying diseases in humans. Until recently, GWAS in ischaemic stroke have been limited by small sample sizes and have yielded few loci associated with ischaemic stroke. We did a large-scale GWAS to identify additional susceptibility genes for stroke and its subtypes.To identify genetic loci associated with ischaemic stroke, we did a two-stage GWAS. In the first stage, we included 16?851 cases with state-of-the-art phenotyping data and 32?473 stroke-free controls. Cases were aged 16 to 104 years, recruited between 1989 and 2012, and subtypes of ischaemic stroke were recorded by centrally trained and certified investigators who used the web-based protocol, Causative Classification of Stroke (CCS). We constructed case-control strata by identifying samples that were genotyped on nearly identical arrays and were of similar genetic ancestral background. We cleaned and imputed data by use of dense imputation reference panels generated from whole-genome sequence data. We did genome-wide testing to identify stroke-associated loci within each stratum for each available phenotype, and we combined summary-level results using inverse variance-weighted fixed-effects meta-analysis. In the second stage, we did in-silico lookups of 1372 single nucleotide polymorphisms identified from the first stage GWAS in 20?941 cases and 364?736 unique stroke-free controls. The ischaemic stroke subtypes of these cases had previously been established with the Trial of Org 10?172 in Acute Stroke Treatment (TOAST) classification system, in accordance with local standards. Results from the two stages were then jointly analysed in a final meta-analysis.We identified a novel locus (G allele at rs12122341) at 1p13.2 near TSPAN2 that was associated with large artery atherosclerosis-related stroke (first stage odds ratio [OR] 1·21, 95% CI 1·13-1·30, p=4·50?×?10-8; joint OR 1·19, 1·12-1·26, p=1·30?×?10-9). Our results also supported robust associations with ischaemic stroke for four other loci that have been reported in previous studies, including PITX2 (first stage OR 1·39, 1·29-1·49, p=3·26?×?10-19; joint OR 1·37, 1·30-1·45, p=2·79?×?10-32) and ZFHX3 (first stage OR 1·19, 1·11-1·27, p=2·93?×?10-7; joint OR 1·17, 1·11-1·23, p=2·29?×?10-10) for cardioembolic stroke, and HDAC9 (first stage OR 1·29, 1·18-1·42, p=3·50?×?10-8; joint OR 1·24, 1·15-1·33, p=4·52?×?10-9) for large artery atherosclerosis stroke. The 12q24 locus near ALDH2, which has previously been associated with all ischaemic stroke but not with any specific subtype, exceeded genome-wide significance in the meta-analysis of small artery stroke (first stage OR 1·20, 1·12-1·28, p=6·82?×?10-8; joint OR 1·17, 1·11-1·23, p=2·92?×?10-9). Other loci associated with stroke in previous studies, including NINJ2, were not confirmed.Our results suggest that all ischaemic stroke-related loci previously implicated by GWAS are subtype specific. We identified a novel gene associated with large artery atherosclerosis stroke susceptibility. Follow-up studies will be necessary to establish whether the locus near TSPAN2 can be a target for a novel therapeutic approach to stroke prevention. In view of the subtype-specificity of the associations detected, the rich phenotyping data available in the Stroke Genetics Network (SiGN) are likely to be crucial for further genetic discoveries related to ischaemic stroke.US National Institute of Neurological Disorders and Stroke, National Institutes of Health.

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Extracellular microRNAs in blood differentiate between ischaemic and haemorrhagic stroke subtypes.

Publications

Extracellular microRNAs in blood differentiate between ischaemic and haemorrhagic stroke subtypes.

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