Gene expression data from lymphoblastoid cell lines from participants in the Genetics of Microangiopathic Brain Injury study
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Stephen Turner
PROVIDER: E-GEOD-49531 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:While blood transcriptional profiling has improved diagnosis and understanding of disease pathogenesis of adult tuberculosis (TB), no studies applying gene expression profiling of children with TB have been described so far. In this study, we have compared whole blood gene expression in childhood TB patients, as well as in healthy latently infected (LTBI) and uninfected (HC) children in a cohort of Warao Amerindians in the Delta Amacuro in Venezuela. We identified a 116-gene signature set by means of random forest analysis that showed an average prediction error of 11% for TB vs. LTBI and for TB vs. LTBI vs. HC in our dataset. Furthermore, a minimal set of only 9 genes showed a significant predictive value for all previously published adult studies using whole blood gene expression, with average prediction errors between 17% and 23%. Additionally, a minimal gene set of 42 genes with a comparable predictive value to the 116-gene set in both our dataset and the previously published literature cohorts for the comparsion of TB vs. LTBI vs. HC was identified. In order to identify a robust representative gene set that would hold stand among different ethnic populations, we selected ten genes that were highly discriminative between TB, LTBI and HC in all literature datasets as well as in our dataset. Functional annotation of these ten genes highlights a possible role for genes involved in calcium signaling and calcium metabolism as biomarkers for active TB. These ten genes were validated by quantitative real-time polymerase chain reaction in an additional cohort of 54 Warao Amerindian children with LTBI, HC and non-TB pneumonia. Decision tree analysis indicated that five of the ten genes were sufficient to diagnose 78% of the TB cases correctly with 100% specificity. We conclude that our data justify the further exploration of our signature set as biomarkers to diagnose childhood TB. Furthermore, as the identification of different biomarkers in ethnically distinct cohorts is apparent, it is important to cross-validate newly identified markers in all available cohorts. In this study, 27 children 1 to 15 years of age with TB (n=9), LTBI (n=9) and HC (n=9) were recruited between May 2010 and December 2010. Tuberculin skin test (TST) and QuantiFERON-TB Gold In-Tube assay (QFT-GIT) were performed on all children. A sputum sample was collected from all children with expectoration and a gastric aspirate was taken from all children under 6 years of age. Children with active TB were diagnosed based on culture of M. tuberculosis (n=2) or on the basis of clinical, epidemiological and radiological features (n=7). The latter group were children with a TST = 10 mm or a positive QFT-GIT result who presented all of: persistent fever >38M-BM-0C objectively recorded daily for at least two weeks, persistent cough for more than three weeks, weight loss (>5% reduction in weight compared with the highest weight recorded in last three months) or failure to thrive (documented crossing of percentile lines in the preceding three months), persistent lethargy or decrease in playfulness/activity reported by the parent and absence of clinical response on broad-spectrum antibiotics. Standard antero-posterior and lateral chest radiographs (CXRs) were taken from all children. Two independent experts, blinded to all clinical information, evaluated the CXRs and documented their findings on a standard report form. Where the two objective experts disagreed, a third expert was consulted and final consensus was achieved. A diagnosis of TB was only made when the CXR was consistent with TB9 and the child showed a positive clinical response to anti-TB treatment. Children were followed up clinically, radiologically and, in case of a negative TST at inclusion, by means of TST at six and 12 months after inclusion. LTBI was defined as a TST = 10mm and a positive QFT-GIT with a negative culture result on inclusion in the absence of radiological and clinical evidence of TB disease on inclusion as well as on t=6 and t=12 months. HC were children with a TST = 0 mm at inclusion and at t=6 and t=12 months. The HC had a negative QFT-GIT and a negative culture result at inclusion without radiological or clinical evidence of TB disease on inclusion nor on t=6 and t=12 months. TB patients were sampled before initiation of anti-TB treatment. Of three of the nine TB patients, a follow-up sample was taken when the patient was in anti-TB treatment for five months. All children were HIV-negative. 27 samples in total where analyzed, active TB infection (TB, n=9), Latent TB infection (LTBI, n=9) and healthy controls (HC, n=9) . Gene expression values were log2-transformed and differentially expressed genes were identified based on log2 fold changes (M-values). P values were calculated with a Bayes-regularized one-way ANOVA. Random Forest recursive feature elimination was used to find a signature geneset capable of discrimination active TB from latent TB and from non-infected individuals.
2013-02-05 | E-GEOD-41055 | biostudies-arrayexpress
Project description:Hypoxia may cause pulmonary and brain edema, pulmonary hypertension, aberrant metabolism and early mortality. To better understand pathological processes associated with hypoxia, we examined gene expression in Chuvash polycythemia (CP) blood mononuclear cells. CP is a congenital disorder of up-regulated hypoxic response at normoxia wherein VHLR200W homozygosity leads to elevated hypoxia inducible factor (HIF)-1 and HIF-2 levels, thromboses, pulmonary hypertension, lower systemic blood pressure (SBP) and increased mortality. VHLR200W homozygotes are often treated by phlebotomy resulting in iron deficiency, allowing us to evaluate an interaction of augmented hypoxia sensing with iron deficiency. Expression was profiled for 8 VHLR200W homozygotes (CP21, CP23, CP26_2, CP37, CP40, CP43, CP45, CP46) and 17 VHL wildtype individuals (CP48, CP49, CP50, CP51, CP52, CP53, CP55, CP57, CP58, CP59, CP61, CP62, CP63, CP65, CP66, CP67_2, CP68), matched for normal iron status as reflected in serum ferritin concentration. Additional studies including 16 VHLR200W homozygotes with low ferritin (CP22, CP24, CP25, CP28, CP29, CP30, CP31, CP32, CP34, CP35, CP36, CP39, CP41, CP42, CP44, CP47) indicated that iron deficiency generally affects the induction effect of VHLR200W. Two wildtype individuals (CP54, CP56) had no serum ferritin concentration record and two wildtype individuals (CP60, CP64) were defined as iron deficiency subject, which were not included in further expression analysis.
2014-04-23 | E-GEOD-40227 | biostudies-arrayexpress
Project description:Gene expression was influenced most by the tissue source, followed by culture methodology, next by location where the cells were cultured and lastly the donor variability. On the normalized log2 expression values per gene a multifactorial Analyses of Variance (ANOVA) was conducted. Factors CELL CULTURES (cell source), MEDIUM (culture methodology), LOCATION (culture location), and SCAN DATE (hybridization batch) were included in the ANOVA model as independent factors. The following pairwise comparisons were made; Fetal calf serum vs. Human platelet lysate, Bone marrow vs. Adipose tissue, Utrecht vs. Leiden, Utrecht vs Nijmegen, and Leiden vs Nijmegen. Changes ≥2 and Benjamini Hochberg corrected p-values <0.05 were considered significant.
2013-01-01 | E-GEOD-42245 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-02-11 | E-GEOD-41410 | biostudies-arrayexpress
Project description:Expression data from 22 human myotubes (7 healthy controls, 4 Dysferlinopathy (DYSF), 4 Caveolinopathy 3 (CAV3), 4 Facioscapulohumeral muscular dystrophy(FSHD) and 3 Four and a half LIM 1 protein deficiency FHL1).cDNA microarray data showed that cyclin A1 levels are specifically elevated in FSHD vs. other muscular disorders such as CAV3, DYSF, FHL1 and healthy control. Data could be confirmed with RT-PCR and Western blot analysis showing up-regulated levels of cyclin A1 also on the protein level. Comparison of gene expression among 4 different muscular dystrophies and helathy controls. Looking for genes expression specifically changed (down/upregulated) in FSHD. In these data sheet we include expression data obtained for human cells lines derived from human V.lateralis muscle, shown as mean value. From 59 different expressed genes, Cyclin A1 was selected as a highly overexpressed (28 fold) gene in FSHD if compared to DYSF, CAV3, FHL1 and healyhy controls. Expression data from 22 human myotubes (7 healthy controls, 4 Dysferlinopathy (DYSF), 4 Caveolinopathy 3 (CAV3), 4 Facioscapulohumeral muscular dystrophy(FSHD) and 3 Four and a half LIM 1 protein deficiency FHL1)
2013-08-08 | E-GEOD-44874 | biostudies-arrayexpress
Project description:AoSMC and FB were cultured and exposed to transforming growth factor beta1 (TGFb1) prior to the exon array analysis The objective was to study the TGFb responsivness, at the gene expression level, in AoSMC and FB form BAV and TAV patients 54 samples in total were generated from biopsies obtained from 23 different individuals. We performed paired analyses to compare the un-treated (c) versus the TGFb1 (t1) treated cells, for each patient
2015-01-15 | E-GEOD-61128 | biostudies-arrayexpress
Project description:Alternative mRNA splicing is a major mechanism for gene regulation and transcriptome diversity. Despite the extent of the phenomenon, the regulation and specificity of the splicing machinery are only partially understood. Adenosine-to-inosine (A-to-I) RNA editing of pre-mRNA by ADAR enzymes has been linked to splicing regulation in several cases. Here we used bioinformatics approaches, RNA-seq and exon-specific microarray of ADAR knockdown cells to globally examine how ADAR and its A-to-I RNA editing activity influence alternative mRNA splicing. Although A-to-I RNA editing only rarely targets canonical splicing acceptor, donor, and branch sites, it was found to affect splicing regulatory elements (SREs) within exons. Cassette exons were found to be significantly enriched with A-to-I RNA editing sites compared with constitutive exons. RNA-seq and exon-specific microarray revealed that ADAR knockdown in hepatocarcinoma and myelogenous leukemia cell lines leads to global changes in gene expression, with hundreds of genes changing their splicing patterns in both cell lines. This global change in splicing pattern cannot be explained by putative editing sites alone. Genes showing significant changes in their splicing pattern are frequently involved in RNA processing and splicing activity. Analysis of recently published RNA-seq data from glioblastoma cell lines showed similar results. Our global analysis reveals that ADAR plays a major role in splicing regulation. Although direct editing of the splicing motifs does occur, we suggest it is not likely to be the primary mechanism for ADAR-mediated regulation of alternative splicing. Rather, this regulation is achieved by modulating trans-acting factors involved in the splicing machinery. HepG2 and K562 cell lines were stably transfected with plasmids containing siRNA designed to specifically knock down ADAR expression (ADAR KD). This in order to examine how ADAR affects alternative splicing globally.
2013-06-15 | E-GEOD-47945 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-06-17 | E-GEOD-47998 | biostudies-arrayexpress
Project description:MiR-142 is upregulated in neurons in HIV and SIV encephalitis. We have created stable clones of the BE(2)M17 human neuroblastoma cell line overexpressing miR-142. Gene expression in these miR-142-expressing clones was compared to stable clones transfected with control miR-null in order to identify miR-142 targets relevant to neuronal dysfunction in HIV encephalitis. RNA was extracted from 3 independent miR-142-expressing clones (6B, 6C, 6G) and 3 independent miR-null expressing clones (1A, 2A, 2B) for expression analysis. Partek genomics suite was used for data analysis. Genes that had fold change > -2.5 and p <0.001 were chosen for validation by RT-PCR
2013-08-23 | E-GEOD-50133 | biostudies-arrayexpress
Project description:Genome wide association studies of schizophrenia encompassing the major histocompatibility locus (MHC) were highly significant following genome wide correction. This broad region implicates many genes including the MHC complex class II. Within this interval we examined the expression of two MHC II genes (HLA-DPA1 and HLA-DRB1) in brain from individual subjects with schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and controls by differential gene expression methods. A third MHC II mRNA, CD74, was studied outside of the MHC II locus, as it interacts within the same immune complex. HLA-DPA1 and CD74 were both reduced in hippocampus, amygdala, and dorsolateral prefrontal cortex regions in SZ and BD compared to controls by specific qPCR assay. We found several novel HLA-DPA1 mRNA variants spanning HLA-DPA1 exons 2-3-4 as suggested by an exon microarray study. The intronic rs9277341 SNP was a significant cis expression quantitative trait locus (eQTL) that was associated with the total expression of HLA-DPA1 in five brain regions. A biomarker study of MHC II mRNAs was conducted in SZ, BD, MDD, and control lymphoblastic cell lines (LCL) by qPCR assay of 87 subjects. There was significantly decreased expression of HLA-DPA1 and CD74 in BD, and trends for reductions in SZ in LCLs. The discovery of multiple splicing variants in brain for HLA-DPA1 is important as the HLA-DPA1 gene is highly conserved, there are no reported splicing variants, and the functions in brain are unknown. Future work on the function and localization of MHC Class II proteins in brain will help to understand the role of alterations in neuropsychiatric disorders. The HLA-DPA1 eQTL is located within a large linkage disequilibrium block that has an irrefutable association with schizophrenia. Future tests in a larger cohort are needed to determine the significance of this eQTL association with schizophrenia. Our findings support the long held hypothesis that alterations in immune function are associated with the pathophysiology of psychiatric disorders. There were 20 anterior cingulate postmortem brain samples that were extracted for total RNA, and analyzed using Affymetrix Exon Array (bipolar disorder subjects n = 9, controls n = 11).
2016-02-25 | E-GEOD-78246 | biostudies-arrayexpress