Profiling of Gene Expression in Idiopathic Pulmonary Fibrosis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE38958 | GEO | 2014/06/30
SECONDARY ACCESSION(S): PRJNA169421
REPOSITORIES: GEO
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Project description:Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive fibrosing interstitial disease of unknown cause. It remains impractical to conduct early diagnosis and predict IPF progression just based on gene expression information. Moreover, the relationship between gene expression and quantitative phenotypic value in IPF keeps controversial. To identify biomarkers to predict survival in IPF, we profiled protein-coding gene expression in peripheral blood mononuclear cells (PBMCs). We linked the gene expression level with the quantitative phenotypic variation in IPF, including diffusing capacity of the lung for carbon monoxide (DLCO) and forced vital capacity (FVC) percent predicted. In silico analyses on the expression profiles and quantitative phenotypic data allowed for the generation of a set of IPF molecular signature that predicted survival of IPF effectively. Total RNA was isolated from PBMCs using standard molecular biology protocols without DNA contamination or RNA degradation. Sample processing (e.g., cDNA generation, fragmentation, end labeling, hybridization to Affymetrix GeneChip Human Exon 1.0 ST arrays) was performed per manufacturer’s instructions. A total of 45 healthy controls and 70 IPF patients were included in the microarray analysis.
2014-06-30 | E-GEOD-38958 | biostudies-arrayexpress
Project description:Peripheral blood biomarkers are needed to identify and determine the extent of idiopathic pulmonary fibrosis (IPF). Current physiologic and radiographic prognostic indicators diagnose IPF too late in the course of disease. These results demonstrate that the peripheral blood transcriptome can distinguish normal individuals from patients with IPF, as well as extent of disease when samples were classified by percent predicted DLCO, but not FVC. Gene expression profiles of peripheral blood RNA from 93 IPF patients were collected on Agilent microarrays. Blood was collected in PAXRNA tubes. 30 healthy controls are compared to IPF patients classified by disease severity when categorized by DLCO or FVC.
2012-06-30 | E-GEOD-33566 | biostudies-arrayexpress
Project description:We performed longitudinal plasma proteomics analysis and determined absolute protein levels in a Canadian cohort (n=74) at admission day to hospital for acute COVID-19 and at 3 and 6 months after diagnosis of acute COVID-19. We measured plasma protein on a triple quadrupole mass spectrometer operated in multiple reaction monitoring mode and used internal standards to deduce protein absolute concentrations. We used a validated panel of 269 surrogate heavy labeled peptides. We also measured % predicted forced vital capacity (FVC, %) and diffusing capacity of the lungs for carbon monoxide (DLCO, %) by routine pulmonary function testing. We did functional enrichment and pathway analyses and determined proteins that were increased or decreased from hospital admission to 3-months and 6-months, compared females to males and determined associations of proteins with FVC% and DLCO%.
2024-01-26 | PXD041762 | Pride
Project description:Peripheral blood biomarkers are needed to identify and determine the extent of idiopathic pulmonary fibrosis (IPF). Current physiologic and radiographic prognostic indicators diagnose IPF too late in the course of disease. These results demonstrate that the peripheral blood transcriptome can distinguish normal individuals from patients with IPF, as well as extent of disease when samples were classified by percent predicted DLCO, but not FVC.
2012-07-01 | GSE33566 | GEO
Project description:Intratracheal application of bleomycin is known to induce inflammatory and fibrotic reactions in the lung within a short period of time and histological features include infiltration of inflammatory cells, collagen deposition and obliteration of alveolar spaces. Because some of these features are found in patients with idiopathic pulmonary fibrosis (IPF), the bleomycin-induced lung fibrosis animal model is commonly used. However, exploratory treatments that were successfully used in this animal model and progressed to clinical trials lacked significant efficacy in humans. Here, the bleomycin-induced rat lung fibrosis model was studied using whole genome expression data that was collected at various time points and the relevance to human disease was evaluated through comparison with whole genome expression data from IPF patient-derived lung biopsies. The highest gene expression correlation between both species was observed in animals 7 days after bleomycin instillation. These gene expression signatures helped to identify a set of twelve novel disease-relevant translational gene markers that were able to separate IPF patients from controls. Furthermore, three Wnt/-catenin pathway-related genes that belong to this translational gene marker set showed, together with clinical diffusing capacity of the lung for carbon monoxide (DLCO) measurements, the potential to stratify IPF patients according to disease severity. Pirfenidone attenuated a subset of the translational gene markers in the bleomycin-induced fibrosis model, in particular those related to Wnt/-catenin-signaling. This novel translational gene marker panel offers improved possibilities to evaluate disease-modifying efficacy of novel therapeutic concepts in the bleomycin-induced rat lung fibrosis model and could be applied as a diagnostic and prognostic tool for IPF patient care. Comparison of bleomycin-treated and control rats after 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks and 8 weeks; 5 animals per group
2014-10-28 | E-GEOD-48455 | biostudies-arrayexpress
Project description:Rationale: Molecular markers of disease progression in idiopathic pulmonary fibrosis are needed. Objective: Derive and validate a blood transcriptomic predictor of forced vital capacity (FVC) decline. Methods: A training cohort (n=74) of IPF patients was stratified according to the presence of progressive disease, defined as ≥10% relative decline in FVC over 12 months. Baseline to 4-month within-patient changes in gene expression were correlated with categorical FVC decline. Genes predictive of FVC decline were identified by two-group comparison with false discovery rate <5% followed by logistic LASSO regression and 10-Fold Cross-Validation for gene list prioritization. Independent validation cohorts with differing transcriptome assay platforms and blood transcriptome sampling times from UChicago (n=27), UPMC (n=35), and Imperial (n=24) underwent receiver operating characteristic with area under the curve (AUC) analyses for validation. Results: A longitudinally-derived FVC-gene predictor accurately discriminated most patients with stable and progressive IPF across four independent IPF cohorts with variable transcriptomic assay platforms and sampling times. The FVC-gene predictorand demonstrated sensitivity and specificity of 74.3% and 82.4% in the combined replication cohort. The likelihood ratio, LR+ and LR- were 4.11 and 0.32, respectively. TGF-beta was the highest-ranking canonical pathway by Gene Set Enrichment Analysis. An approach using longitudinal gene expression changes approach dramatically reduced within-group variation compared to cross-sectional expression for improved prediction modeling. Conclusions: This novel FVC-gene predictor developed from short-term longitudinal gene expression changes successfully discriminates most patients with high likelihood of one-year 10% FVC decline. This tool may better reflect disease activity and prove useful for predictive enrichment of clinical trial populations.
2019-09-30 | GSE133298 | GEO
Project description:Background: HIV infection is associated with impaired gas transfer in the lung as indicated by a low diffusing capacity (DLCO). Mechanisms for reduced DLCO in the setting of HIV infection are not well understood. We hypothesized that HIV-associated gas exchange impairment is indicative of system-wide perturbations that could be reflected by alterations in peripheral blood gene expression. Methods: A total of 40 HIV-infected (HIV+) and uninfected (HIV-) men with preserved versus reduced DLCO were selected from a larger cohort study of lung function. All subjects were current smokers and those with acute illness, lung diseases other than COPD or asthma were excluded. Total RNA was extracted from peripheral blood leukocytes (PBLs) and hybridized to whole-genome microarrays. Gene set enrichment analysis (GSEA) was performed between HIV+ vs. HIV- subjects with preserved DLCO and those with impaired DLCO to identify differentially activated pathways. Results: Using pathway-based analyses we found that in subjects with preserved DLCO, HIV infection is associated with activation of processes involved in immunity, cell cycle, and apoptosis. When we applied a similar analysis to subjects with low DLCO, we identified a much broader repertoire of inflammatory and immune-related pathways in HIV+ patients relative to HIV- subjects, with up-regulation of multiple interleukin pathways, interferon signaling, Toll-like receptor signaling, and T cell/B cell receptor signaling. We confirmed elevated circulating levels of IL-6 in HIV+ patients with reduced DLCO relative to the other groups. Conclusions: Our findings reveal that PBLs of subjects with HIV infection and low DLCO are distinguished by widespread enrichment of immuno-inflammatory programs. Activation of these pathways may alter the biology of circulating leukocytes and play a role in the pathogenesis of HIV-associated pulmonary gas exchange impairment. Total RNA was isolated from peripheral blood leukocytes in four subject groups: 1. HIV-, low DLCO (N = 11); 2. HIV+, low DLCO (N = 10); 3. HIV-, preserved DLCO (N = 9); 4. HIV+, preserved DLCO (N = 9). Each sample was hybridized to an Affymetrix PrimeView Human Gene Expression microarray for a total of 39 experiments.
2016-04-01 | E-GEOD-76403 | biostudies-arrayexpress
Project description:Background: HIV infection is associated with impaired gas transfer in the lung as indicated by a low diffusing capacity (DLCO). Mechanisms for reduced DLCO in the setting of HIV infection are not well understood. We hypothesized that HIV-associated gas exchange impairment is indicative of system-wide perturbations that could be reflected by alterations in peripheral blood gene expression. Methods: A total of 40 HIV-infected (HIV+) and uninfected (HIV-) men with preserved versus reduced DLCO were selected from a larger cohort study of lung function. All subjects were current smokers and those with acute illness, lung diseases other than COPD or asthma were excluded. Total RNA was extracted from peripheral blood leukocytes (PBLs) and hybridized to whole-genome microarrays. Gene set enrichment analysis (GSEA) was performed between HIV+ vs. HIV- subjects with preserved DLCO and those with impaired DLCO to identify differentially activated pathways. Results: Using pathway-based analyses we found that in subjects with preserved DLCO, HIV infection is associated with activation of processes involved in immunity, cell cycle, and apoptosis. When we applied a similar analysis to subjects with low DLCO, we identified a much broader repertoire of inflammatory and immune-related pathways in HIV+ patients relative to HIV- subjects, with up-regulation of multiple interleukin pathways, interferon signaling, Toll-like receptor signaling, and T cell/B cell receptor signaling. We confirmed elevated circulating levels of IL-6 in HIV+ patients with reduced DLCO relative to the other groups. Conclusions: Our findings reveal that PBLs of subjects with HIV infection and low DLCO are distinguished by widespread enrichment of immuno-inflammatory programs. Activation of these pathways may alter the biology of circulating leukocytes and play a role in the pathogenesis of HIV-associated pulmonary gas exchange impairment.
2016-04-01 | GSE76403 | GEO
Project description:Intratracheal application of bleomycin is known to induce inflammatory and fibrotic reactions in the lung within a short period of time and histological features include infiltration of inflammatory cells, collagen deposition and obliteration of alveolar spaces. Because some of these features are found in patients with idiopathic pulmonary fibrosis (IPF), the bleomycin-induced lung fibrosis animal model is commonly used. However, exploratory treatments that were successfully used in this animal model and progressed to clinical trials lacked significant efficacy in humans. Here, the bleomycin-induced rat lung fibrosis model was studied using whole genome expression data that was collected at various time points and the relevance to human disease was evaluated through comparison with whole genome expression data from IPF patient-derived lung biopsies. The highest gene expression correlation between both species was observed in animals 7 days after bleomycin instillation. These gene expression signatures helped to identify a set of twelve novel disease-relevant translational gene markers that were able to separate IPF patients from controls. Furthermore, three Wnt/-catenin pathway-related genes that belong to this translational gene marker set showed, together with clinical diffusing capacity of the lung for carbon monoxide (DLCO) measurements, the potential to stratify IPF patients according to disease severity. Pirfenidone attenuated a subset of the translational gene markers in the bleomycin-induced fibrosis model, in particular those related to Wnt/-catenin-signaling. This novel translational gene marker panel offers improved possibilities to evaluate disease-modifying efficacy of novel therapeutic concepts in the bleomycin-induced rat lung fibrosis model and could be applied as a diagnostic and prognostic tool for IPF patient care.
2014-10-28 | GSE48455 | GEO
Project description:The Rationale: Molecular markers of disease activity that are predictive of forced vital capacity (FVC) progression in idiopathic pulmonary fibrosis are needed. Objectives: Develop a predictor using longitudinal within-patient gene expression differences (ΔGE) in peripheral blood mononuclear cells (PBMC) to predict of FVC progression. Methods: Patients in the training cohort (n=74) experiencing ≥10% relative reduction in FVC% of predicted over 12 months were categorized as progressors in contrast to the remaining stable patients. Baseline to 4-month within-patient ΔGE were correlated with FVC status. FVC-predictor genes were prioritized by two-group comparison with FDR<5%, logistic LASSO regression with p<0.05, and 10-Fold Cross-Validation with ≥50% support. Receiver operating characteristic with area under the curve (AUC) analyses were conducted in training subsets and independent validation cohorts from UChicago (n=27), UPMC (n=35), and Imperial (n=24) where different transcriptome assay platforms and varying transcriptome sampling times were used to derive ΔGE. Results: Intra-subject Compared to cross-sectional analysis of baseline GE, our longitudinal ΔGE variation approach demonstratedlargely reduced within-group sample variation and increased statistic power fin progressor and stable groups for prediction model development. A 25-gene FVC-predictor separated “progressors” from “stable” by Principal Component Analysis in the training and subsets of the training cohort. The resulting FVC-predictor consistently demonstrated high discriminatory performance independent of transcriptome assay platforms and varying sampling times in validation cohorts (AUC= 0.77-0.80). TGF beta was the highest-ranking canonical pathway by Gene Set Enrichment Analysis. Conclusions: Our novel short-term longitudinal within-patient ΔGE approach identified a FVC-predictor which may reflect disease activity and prove to be a reliable biomarker predictive of future FVC decline.
2019-09-30 | GSE132607 | GEO