Gene Expression Profiling of Blood for the Prediction of Ischemic Stroke

Department of Neurology and the MIND Institute, University of California at Davis, Sacramento, Calif 95817, USA.
Stroke (Impact Factor: 5.72). 10/2010; 41(10):2171-7. DOI: 10.1161/STROKEAHA.110.588335
Source: PubMed


A blood-based biomarker of acute ischemic stroke would be of significant value in clinical practice. This study aimed to (1) replicate in a larger cohort our previous study using gene expression profiling to predict ischemic stroke; and (2) refine prediction of ischemic stroke by including control groups relevant to ischemic stroke.
Patients with ischemic stroke (n=70, 199 samples) were compared with control subjects who were healthy (n=38), had vascular risk factors (n=52), and who had myocardial infarction (n=17). Whole blood was drawn ≤3 hours, 5 hours, and 24 hours after stroke onset and from control subjects. RNA was processed on whole genome microarrays. Genes differentially expressed in ischemic stroke were identified and analyzed for predictive ability to discriminate stroke from control subjects.
The 29 probe sets previously reported predicted a new set of ischemic strokes with 93.5% sensitivity and 89.5% specificity. Sixty- and 46-probe sets differentiated control groups from 3-hour and 24-hour ischemic stroke samples, respectively. A 97-probe set correctly classified 86% of ischemic strokes (3 hour+24 hour), 84% of healthy subjects, 96% of vascular risk factor subjects, and 75% with myocardial infarction.
This study replicated our previously reported gene expression profile in a larger cohort and identified additional genes that discriminate ischemic stroke from relevant control groups. This multigene approach shows potential for a point-of-care test in acute ischemic stroke.

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Available from: Renee J Turner, Oct 09, 2015
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    • "The crucial issue now is to elucidate exactly how any identified neuroprotective molecules exert their effects. Over the last decade, and particularly within the last 3 years, researchers have begun focusing their attention on genomic approaches to investigate brain ischemia and physiological responses to it (Jin et al., 2001; Büttner et al., 2008; Meschia, 2008; Qin et al., 2008; Juul et al., 2009; Grond-Ginsbach et al., 2009; Haramati, 2009; Nakajima, 2009; Popa-Wagner et al., 2009; Yao et al., 2009; Di Pietro et al., 2010; Pruissen et al., 2009; Stamova et al., 2010; Zhan et al., 2010). These studies have shown the importance of high-throughput transcript profiling, such as the DNA microarray technique (DeRisi et al., 1997), for gaining insight into the ischemic brain. "
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    ABSTRACT: Brain ischemia, also termed cerebral ischemia, is a condition in which there is insufficient blood flow to the brain to meet metabolic demand, leading to tissue death (cerebral infarction) due to poor oxygen supply (cerebral hypoxia). Our group is interested in the protective effects of neuropeptides for alleviating brain ischemia, as well as the underlying mechanisms of their action. The present study was initiated to investigate molecular responses at the level of gene expression in ischemic brain tissue. To achieve this, we used a mouse permanent middle cerebral artery occlusion (PMCAO) model in combination with high-throughput DNA microarray analysis on an Agilent microarray platform. Briefly, the right (ipsilateral) and left (contralateral) hemispheres of PMCAO model mice were dissected at two time points, 6 and 24 hours post-ischemia. Total RNA from the ischemic (ipsilateral) hemisphere was subjected to DNA microarray analysis on a mouse whole genome 4x44K DNA chip using a dye-swap approach. Functional categorization using the gene ontology (GO, MGD/AMIGO) of numerous changed genes revealed expression pattern changes in the major categories of cellular process, biological regulation, regulation of biological process, metabolic process and response to stimulus. Reverse-transcriptase PCR (RT-PCR) analysis on randomly selected highly up- or downregulated genes validated, in general, the microarray data. Using two time points for this analysis, major and minor trends in gene expression and/or functions were observed in relation to early- and late-response genes and differentially regulated genes that were further classified into specific pathways or disease states. We also examined the expression of these genes in the contralateral hemisphere, which suggested the presence of bilateral effects and/or differential regulation. This study provides the first ischemia-related transcriptome analysis of the mouse brain, laying a strong foundation for studies designed to elucidate the mechanisms regulating ischemia and to explore the neuroprotective effects of agents such as target neuropeptides.
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    • "Over half of these genes overlapped our previously reported IS genes ( Stamova et al , 2010 ) . Thus , the current common IS genes , especially the 107 probe sets common to both genders at all three time points ( Supplementary Table 15 ) , could be poten - tially used for IS predictors within 24 hours after stroke onset . "
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    ABSTRACT: This study examined the effects of gender on RNA expression after ischemic stroke (IS). RNA obtained from blood of IS patients (n=51; 153 samples at < or =3, 5, and 24 hours) and from matched controls (n=52) were processed on Affymetrix microarrays. Analyses of covariance for stroke versus control samples were performed separately for both genders and the regulated genes for females compared with males. In all, 242, 227, and 338 male-specific genes were regulated at < or =3, 5, and 24 hours after IS, respectively, of which 59 were regulated at all time points. Overall, 774, 3,437, and 571 female-specific stroke genes were regulated at < or =3, 5, and 24 hours, respectively, of which 152 were regulated at all time points. Male-specific stroke genes were associated with integrin, integrin-liked kinase, actin, tight junction, Wnt/β-catenin, RhoA, fibroblast growth factors (FGF), granzyme, and tumor necrosis factor receptor (TNFR)2 signaling. Female-specific stroke genes were associated with p53, high-mobility group box-1, hypoxia inducible factor (HIF)1α, interleukin (IL)1, IL6, IL12, IL18, acute-phase response, T-helper, macrophage, and estrogen signaling. Cell death signaling was overrepresented in both genders, although the molecules and pathways differed. Gender affects gene expression in the blood of IS patients, which likely implies gender differences in immune, inflammatory, and cell death responses to stroke.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 12/2011; 32(5):780-91. DOI:10.1038/jcbfm.2011.179 · 5.41 Impact Factor
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    • "More recently studies have been examining the possibility of ignoring the DNA level and trying to perform transcription profiling (examination of all the RNA's being produced at a specific time point). By examining changes in the level of transcription of a subset of RNAs and correlating these with changes in disease state, disease subtype or disease severity, we may be able to better understand how genetic differences influence disease processes [35]. "
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    ABSTRACT: Stroke is the third commonest cause of death and the major cause of adult neurological disability worldwide. While much is known about conventional risk factors such as hypertension, diabetes and incidence of smoking, these environmental factors only account for a proportion of stroke risk. Up to 50% of stroke risk can be attributed to genetic risk factors, although to date no single risk allele has been convincingly identified as contributing to this risk. Advances in the field of genetics, most notably genome wide association studies (GWAS), have revealed genetic risks in other cardiovascular disease and these techniques are now being applied to ischaemic stroke. This paper covers previous genetic studies in stroke including candidate gene studies, discusses the genome wide association approach, and future techniques such as next generation sequencing and the post-GWAS era. The review also considers the overlap from other cardiovascular diseases and whether findings from these may also be informative in ischaemic stroke.
    Stroke Research and Treatment 08/2011; 2011(2):179061. DOI:10.4061/2011/179061
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