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Identification of Novel Genes and Biological Pathways That Overlap in Infectious and Nonallergic Diseases of the Upper and Lower Airways Using Network Analyses.

ABSTRACT: Previous genetic studies on susceptibility to otitis media and airway infections have focused on immune pathways acting within the local mucosal epithelium, and outside of allergic rhinitis and asthma, limited studies exist on the overlaps at the gene, pathway or network level between the upper and lower airways. In this report, we compared [1] pathways identified from network analysis using genes derived from published genome-wide family-based and association studies for otitis media, sinusitis, and lung phenotypes, to [2] pathways identified using differentially expressed genes from RNA-sequence data from lower airway, sinus, and middle ear tissues, in particular cholesteatoma tissue compared to middle ear mucosa. For otitis media, a large number of genes (n = 1,806) were identified as differentially expressed between cholesteatoma and middle ear mucosa, which in turn led to the identification of 68 pathways that are enriched in cholesteatoma. Two differentially expressed genes CR1 and SAA1 overlap in middle ear, sinus, and lower airway samples and are potentially novel genes for otitis media susceptibility. In addition, 56 genes were differentially expressed in both tissues from the middle ear and either sinus or lower airways. Pathways that are common in upper and lower airway diseases, whether from published DNA studies or from our RNA-sequencing analyses, include chromatin organization/remodeling, endocytosis, immune system process, protein folding, and viral process. Taken together, our findings from genetic susceptibility and differential tissue expression studies support the hypothesis that the unified airway theory wherein the upper and lower respiratory tracts act as an integrated unit also applies to infectious and nonallergic airway epithelial disease. Our results may be used as reference for identification of genes or pathways that are relevant to upper and lower airways, whether common across sites, or unique to each disease.

SUBMITTER: Baschal EE

PROVIDER: S-EPMC6979043 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Identification of Novel Genes and Biological Pathways That Overlap in Infectious and Nonallergic Diseases of the Upper and Lower Airways Using Network Analyses.

Baschal Erin E EE Larson Eric D ED Bootpetch Roberts Tori C TC Pathak Shivani S Frank Gretchen G Handley Elyse E Dinwiddie Jordyn J Moloney Molly M Yoon Patricia J PJ Gubbels Samuel P SP Scholes Melissa A MA Cass Stephen P SP Jenkins Herman A HA Frank Daniel N DN Yang Ivana V IV Schwartz David A DA Ramakrishnan Vijay R VR Santos-Cortez Regie Lyn P RLP

Frontiers in genetics 20200117

Previous genetic studies on susceptibility to otitis media and airway infections have focused on immune pathways acting within the local mucosal epithelium, and outside of allergic rhinitis and asthma, limited studies exist on the overlaps at the gene, pathway or network level between the upper and lower airways. In this report, we compared [1] pathways identified from network analysis using genes derived from published genome-wide family-based and association studies for otitis media, sinusitis ...[more]

PMID: 32010199

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Project description:BackgroundThe expression and localization of transforming growth factor-? (TGF-?) pathway proteins in different compartments of the lower airways of patients with stable COPD is unclear. We aimed to determine TGF-? pathway protein expression in patients with stable COPD.MethodsThe expression and localization of TGF-? pathway components was measured in the bronchial mucosa and peripheral lungs of patients with stable COPD (n = 44), control smokers with normal lung function (n = 24), and control nonsmoking subjects (n = 11) using immunohistochemical analysis.ResultsTGF-?1, TGF-?3, and connective tissue growth factor expression were significantly decreased in the bronchiolar epithelium, with TGF-?1 also decreased in alveolar macrophages, in patients with stable COPD compared with control smokers with normal lung function. TGF-?3 expression was increased in the bronchial lamina propria of both control smokers with normal lung function and smokers with mild/moderate stable COPD compared with control nonsmokers and correlated significantly with pack-years of smoking. However, TGF-?3+ cells decreased in patients with severe/very severe COPD compared with control smokers. Latent TGF-? binding protein 1 expression was increased in the bronchial lamina propria in subjects with stable COPD of all severities compared with control smokers with normal lung function. Bone morphogenetic protein and activin membrane-bound inhibitor expression (BAMBI) in the bronchial mucosa was significantly increased in patients with stable COPD of all severities compared with control subjects. No other significant differences were observed between groups for all the other molecules studied in the bronchial mucosa and peripheral lung.ConclusionsExpression of TGF-?s and their regulatory proteins is distinct within different lower airway compartments in stable COPD. Selective reduction in TGF-?1 and enhanced BAMBI expression may be associated with the increase in autoimmunity in COPD.

Dataset Information

Identification of Novel Genes and Biological Pathways That Overlap in Infectious and Nonallergic Diseases of the Upper and Lower Airways Using Network Analyses.

Publications

Identification of Novel Genes and Biological Pathways That Overlap in Infectious and Nonallergic Diseases of the Upper and Lower Airways Using Network Analyses.

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