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Multi-omics in nasal epithelium reveals three axes of dysregulation for asthma risk in the African Diaspora populations

ABSTRACT: Background: Asthma, a complex chronic lung disease affecting the airways, has striking disparities across ancestral groups, but the molecular underpinning of these differences is poorly understood and minimally studied. A major goal of the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) is to understand multi-omics signatures of asthma risk in the nasal epithelium focusing on populations of African ancestry. Methods: RNASeq data were generated from nasal epithelium in subjects recruited from up to 7 sites (Baltimore, Washington DC, Chicago, Denver, Salvador Brazil, Barbados, and Nigeria). Current asthma cases (N=253) were compared to never-asthma controls (N=283) to identify differentially expressed genes (DEGs; q <0.05). Network analyses were performed with Ingenuity Pathway Analysis (IPA; DEGs with q<0.05) and weighted gene co-expression network analysis (WGCNA; DEGs with q<0.15). All models were fully adjusted for ancestry, sampling site, and appropriate latent factors. Findings: CAAPA represents diversity across the African Diaspora with a wide range of continental African ancestry (9%-100%). We identified 389 DEGs; the top DEG, FN1, was downregulated in asthma cases (q=3.26x10-9) and encodes fibronectin which plays a role in wound healing. Others in the top 10 DEGs have high relevance for asthma: SNTG2 (q = 1.12x10-4) is the target of multiple miRNAs related to asthma; PPP1R9A expression (q=7.60x10-5) was previously determined to be influenced by IL-13 in mouse lung; and SPTBN1 (q=1.12x10-4) plays a key role in mediating TGFβ signaling. IPA revealed networks with upstream regulators relevant for immune response (IL4; p=7.25x10-10 and TGFβ1; p=5.47x10-8) and drug response (dexamethasone; p=4.31x10-10 and fluticasone propionate; p=9.42x10-8). Among asthma cases, genes regulated by dexamethasone and fluticasone propionate were not associated with inhaled corticosteroid medication use. The top three WGCNA modules implicate networks related to immune response (CEACAM5; p=9.62x10-16 and CPA3; p=2.39x10-14) and wound healing (FN1; p=7.63x10-9). Multi-omic analysis identified FKBP5 as a key contributor to asthma risk, whereby the association between nasal epithelium gene expression is mediated through methylation and is associated with increased use of inhaled corticosteroids. FKBP5 is a co-chaperone of glucocorticoid receptor signaling and known to be involved in drug response in asthma. Interpretation: Our analyses reveal genes and networks in asthma that are differentially expressed in nasal epithelium of asthma cases of African ancestry in CAAPA. Importantly, this work reveals molecular dysregulation on three axes – increased Th2 inflammation, decreased capacity for wound healing, and impaired drug response – that may play a critical role in asthma within the African Diaspora.

ORGANISM(S): Homo sapiens

PROVIDER: GSE240567 | GEO | 2023/08/16

REPOSITORIES: GEO

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Project description:Background: Asthma, a complex chronic lung disease affecting the airways, has striking disparities across ancestral groups, but the molecular underpinning of these differences is poorly understood and minimally studied. A major goal of the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) is to understand multi-omics signatures of asthma risk in the nasal epithelium focusing on populations of African ancestry. Methods: DNA methylation (DNAm) quantification was performed using Illumina’s Infinium MethylationEPIC array® using genomic DNA from nasal airway epithelial cells collected across the 4 US recruitment sites (Baltimore, Chicago, Denver, and Washington DC) for 331 subjects (N=149 asthma cases, N= 182 never asthmatic controls). We performed association analysis to identify eQTMs (CpG-gene associations) for DEGs limiting to CpGs ≤5kb from the transcription start site or within enhancer regions identified through promoter-capture HiC in bronchial epithelial cells. CpGs from significant eQTMs (p<0.05) were tested for differential methylation by asthma (DMCs) to assess the relative contribution of expression and methylation in asthma risk. All models were fully adjusted for ancestry, sampling site, and appropriate latent factors. Findings: Multi-omic analysis identified FKBP5 as a key contributor to asthma risk, where the association between nasal epithelium gene expression is likely regulated by methylation and is associated with increased use of inhaled corticosteroids. FKBP5 is a co-chaperone of glucocorticoid receptor signaling and known to be involved in drug response in asthma. Interpretation: Our analyses reveal genes and networks in asthma that are differentially expressed in nasal epithelium of current asthma cases of African ancestry in CAAPA. Importantly, this work reveals molecular dysregulation on three axes – increased Th2 inflammation, decreased capacity for wound healing, and impaired drug response – that may play a critical role in asthma within the African Diaspora.

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

Project description:Background: In asthma, airway epithelium remodeling can already be detected during childhood, and epithelial cells are more susceptible to virus and oxidative stress. Their exact role in natural history and severity of children allergic respiratory disease remains however surprisingly unexplored. Aim: To analyze dysfunctions of epithelium in dust mite allergic respiratory disease (rhinitis ¬± asthma) in children. Methods: Expression profilings of nasal epithelial cells collected by brushing were performed on Affymetrix Hugene 1.0 ST arrays. All allergic patients were sensitized to dust mite. 19 patients had an isolated allergic rhinitis (AR). 14 patients had AR associated with asthma. Patients were compared to 12 controls, their severity and control being assessed according to NAEPP and ARIA criteria. Infections by respiratory viruses were excluded by real-time PCR measurements. Results: 61 probes were able to distinguish allergic rhinitis children from healthy controls. A majority of these probes was under the control of Th2 cytokines, as evidenced by parallel experiments performed on primary cultures of nasal epithelial cells. In uncontrolled asthmatic patients, we observed not only an enhanced expression of these Th2-responsive transcripts, but also a down-regulation of interferon-responsive genes. Conclusion: Our study identifies a Th2 driven epithelial phenotype common to all dust mite allergic children. Besides, it suggests that epithelium is involved in the severity of the disease. Expression profiles observed in uncontrolled asthmatic patients suggest that severity of asthma is linked at the same time to atopy and to impaired viral response. Nasal epithelium gene expression profiling of dust mite allergic children with isolated rhinitis, rhinitis associated with asthma and controls. 38 samples classified in 4 categories : 14 isolated rhinitis (R), 6 rhinitis with uncontrolled asthma (UA), 7 rhinitis with controlled asthma (CA) and 11 healthy subjects (C )

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Multi-omics in nasal epithelium reveals three axes of dysregulation for asthma risk in the African Diaspora populations

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