Characteristic DNA methylation profiles in peripheral blood monocytes are associated with inflammatory phenotypes of asthma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE59339 | GEO | 2015/03/18
SECONDARY ACCESSION(S): PRJNA255106
REPOSITORIES: GEO
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Project description:Asthma is a complex syndrome associated with episodic decompensations provoked by aeroaller-gen exposures. The underlying pathophysiological states driving exacerbations are latent in the resting state and do not adequately inform biomarker-driven therapy. A better understanding of the pathophysiological pathways driving allergic exacerbations is needed. We hypothesized that disease-associated pathways could be identified in humans by unbiased metabolomics of bron-choalveolar fluid (BALF) during the peak inflammatory response provoked by a bronchial aller-gen challenge. We analyzed BALF metabolites in samples from 12 volunteers who underwent segmental bronchial antigen provocation (SBP-Ag). Metabolites were quantified using liquid chromatography-tandem mass spectrometry (LC–MS/MS) followed by pathway analysis and cor-relation with airway inflammation. SBP-Ag induced statistically significant changes in 549 fea-tures that mapped to 72 uniquely identified metabolites. From these features, two distinct induci-ble metabolic phenotypes were identified by the principal component analysis, partitioning around medoids (PAM) and k-means clustering. Ten index metabolites were identified that in-formed the presence of asthma-relevant pathways, including unsaturated fatty acid produc-tion/metabolism, mitochondrial beta oxidation of unsaturated fatty acid, and bile acid metabolism. Pathways were validated using proteomics in eosinophils. A segmental bronchial allergen chal-lenge induces distinct metabolic responses in humans, providing insight into pathogenic and pro-tective endotypes in allergic asthma.
2022-06-09 | PXD033172 | Pride
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Project description:Severe asthma is a complex disease with different inflammatory phenotypes. Transcriptomic profiling has contributed to understanding the pathogenesis of asthma, especially type-2 inflammation; however, there is still poor understanding of non-eosinophilic asthma, and consequently there are limited treatment options. The aim of this study was to determine transcriptomic profiles in endobronchial biopsies of adults with severe asthma and different inflammatory phenotypes (neutrophilic, eosinophilic and paucigranulocytic) compared with healthy controls.
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Project description:Background: Asthma is highly heterogeneous and severity evaluation is key to asthma management. DNA methylation (DNAm) contributes to asthma pathogenesis. This study aimed to identify nasal epithelial DNAm differences between severe and non-severe asthmatic children and evaluate the impact of environmental exposures. Methods: Thirty-three non-severe and 22 severe asthmatic African-American children were included in an epigenome-wide association study. Genome-wide nasal epithelial DNAm and gene expression were measured. CpG sites associated with asthma severity and environmental exposures and predictive of severe asthma were identified. DNAm was correlated with gene expression. Enrichment for transcription factor (TF) binding sites or histone modifications surrounding DNAm differences were determined. Results: We identified 816 differentially methylated CpG positions (DMPs) and 10 differentially methylated regions (DMRs) associated with asthma severity. Three DMPs exhibited discriminatory ability for severe asthma. Intriguingly, six DMPs were simultaneously associated with asthma, allergic asthma, total IgE, environmental IgE, and FeNO in an independent cohort of children. 27 DMPs were associated with traffic-related air pollution or secondhand smoke. DNAm at 22 DMPs were altered by diesel particles or allergen in human bronchial epithelial cells. DNAm levels at 39 DMPs were correlated with mRNA expression. Proximal to 816 DMPs, three histone marks and several TFs involved in asthma pathogenesis were enriched. Conclusions: Significant differences in nasal epithelial DNAm were observed between non-severe and severe asthma in African-American children, a subset of which may be useful to predict disease severity. These CpG sites are subject to the influences of environmental exposures and may regulate gene expression.
2022-04-15 | GSE161485 | GEO
Project description:Obesity-associated asthma is recognized as a distinct entity with non-atopic T-helper 1 polarized systemic inflammation. DNA methylation is linked with T helper cell maturation and is associated with inflammatory patterns in asthma and obesity. However, it is unknown whether pathologic dysregulation of DNA methylation patterns occurs in obesity-associated asthma. Using HELP-tagging, we studied epigenome wide DNA methylation in peripheral blood mononuclear cells in 8 urban minority obese asthmatic pre-adolescent children and compared it to methylation in groups of 8 children with asthma alone, obesity alone and healthy controls. Ingenuity Pathway Analysis was used to identify biological pathways that were differentially targeted by methylation dysregulation. We found that obese asthmatics had distinct epigenome wide methylation patterns associated with decreased promoter methylation of a subset of genes, including RANTES, IL-12R and TBX21 and increased promoter methylation of CD23, a low affinity receptor for IgE and of TGFM-NM-2, inhibitor of Th cell activation. T cell signaling and macrophage activation were the two primary pathways that were selectively hypomethylated in obese asthmatics. These methylation patterns suggest that methylation is associated with non-atopic inflammation observed in obese asthmatic children compared to children with asthma alone and obesity alone. Our findings suggest a role of DNA methylation in the observed inflammatory patterns in pediatric obesity-associated asthma in minorities. 32 HpaII test
2014-04-14 | E-GEOD-43705 | biostudies-arrayexpress
Project description:Obesity-associated asthma is recognized as a distinct entity with non-atopic T-helper 1 polarized systemic inflammation. DNA methylation is linked with T helper cell maturation and is associated with inflammatory patterns in asthma and obesity. However, it is unknown whether pathologic dysregulation of DNA methylation patterns occurs in obesity-associated asthma. Using HELP-tagging, we studied epigenome wide DNA methylation in peripheral blood mononuclear cells in 8 urban minority obese asthmatic pre-adolescent children and compared it to methylation in groups of 8 children with asthma alone, obesity alone and healthy controls. Ingenuity Pathway Analysis was used to identify biological pathways that were differentially targeted by methylation dysregulation. We found that obese asthmatics had distinct epigenome wide methylation patterns associated with decreased promoter methylation of a subset of genes, including RANTES, IL-12R and TBX21 and increased promoter methylation of CD23, a low affinity receptor for IgE and of TGFβ, inhibitor of Th cell activation. T cell signaling and macrophage activation were the two primary pathways that were selectively hypomethylated in obese asthmatics. These methylation patterns suggest that methylation is associated with non-atopic inflammation observed in obese asthmatic children compared to children with asthma alone and obesity alone. Our findings suggest a role of DNA methylation in the observed inflammatory patterns in pediatric obesity-associated asthma in minorities.
2014-04-14 | GSE43705 | GEO
Project description:Asthma bronchiale is an inflammatory disease of the respiratory airways and a major factor of increasing health care costs worldwide. The molecular actors leading to asthma are not fully understood and require further investigation. The aim of this study was to monitor the proteome during asthma development from early inflammatory to late fibrotic stages. A time-course-based ovalbumin (OVA) mouse model was applied to establish an asthma phenotype and the lung proteome was analysed at four time points during asthma development (0 weeks = control, 5 weeks, 8 weeks and 12 weeks of OVA treatment).
2021-02-11 | PXD011159 | Pride
Project description:Background: Nasal epithelia are emerging as a proxy measure of gene expression of the airway epithelium in asthma. We hypothesized that epigenetic marks regulate gene expression of the nasal epithelia and consequently may provide a novel target for allergic asthma. Methods: We compared genomic DNA methylation patterns and gene expression in African American children with persistent atopic asthma [N=36] versus healthy controls [N=36]. Results were validated in an independent population of asthmatics [N=30]. Results: We identified 186 genes with significant methylation changes, either as regions (differentially methylated regions [DMRs]) or single CpGs (differentially methylated probes [DMPs]) after adjustment for age, gender, race/ethnicity, batch effects, inflation, and multiple comparisons (false discovery rate-adjusted q<0.05). Genes differentially methylated include those with established roles in asthma and atopy, components of the extracellular matrix, genes related to immunity, cell adhesion, epigenetic regulation, and airway obstruction. The methylation changes are large (median 9.5%, range: 2.6-29.5% methylation change) and similar in magnitude to those observed in malignancies. Hypo- and hyper-methylated genes were associated with increased and decreased gene expression respectively (P<2.8x10-6 for DMRs and P<7.8x10-10 for DMPs). Quantitative analysis of methylation-expression relationships in 53 differentially expressed genes demonstrated that 32 (60%) have significant (q<0.05) methylation-expression relationships within 5kb of the gene. 10 loci selected based on the relevance to asthma, magnitude of methylation change, and asthma specific methylation-expression relationships were validated in an independent cohort of children with asthma. Conclusions: Our findings that epigenetic marks in respiratory epithelia are associated with allergic asthma in inner-city children provide new targets for biomarker development, and novel approaches to understanding disease pathogenesis. case control design with nasal epithelial cells from 36 atopic asthmatic and 36 nonatopic nonasthmatic children from the inner city
2015-11-01 | E-GEOD-65163 | biostudies-arrayexpress
Project description:We compared genomic DNA methylation patterns and gene expression in African American children with persistent atopic asthma versus healthy controls. We identified 119 differentially methylated regions (DMRs) and 118 differentially methylated probes (DMPs) after adjustment for age, gender, race/ethnicity, batch effects, inflation, and multiple comparisons (false discovery rate-adjusted q<0.05). Genes differentially methylated include those with established roles in asthma and atopy, components of the extracellular matrix, genes related to immunity, cell adhesion, epigenetic regulation, and airway obstruction. Hypo- and hypermethylated genes were associated with increased and decreased gene expression respectively (P<2.8x10-6 for DMRs and P<7.8x10-10 for DMPs). Quantitative analysis of methylation-expression relationships in 53 differentially expressed genes demonstrated that 32 (60%) have significant (q<0.05) methylation-expression relationships within 5kb of the gene. 10 loci selected based on the relevance to asthma, magnitude of methylation change, and asthma specific methylation-expression relationships were validated in an independent cohort of children with asthma. case control design with nasal epithelial cells from 36 atopic asthmatic and 33 nonatopic nonasthmatic children from the inner city
2015-11-01 | E-GEOD-65204 | biostudies-arrayexpress
Project description:In the first decade of life, high-asthma risk urban children develop stable phenotypes of respiratory health versus disease that link early life environmental exposures to childhood allergic sensitization and asthma. Moreover, unique patterns of nasal gene expression demonstrate how specific molecular pathways underlie distinct respiratory phenotypes, including allergic and non-allergic asthma.
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