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

Erin E Baschal,Herman A Jenkins,Eric D Larson,Elyse Handley,Stephen P Cass,Shivani Pathak,Jordyn Dinwiddie,Melissa A Scholes,Tori C Bootpetch Roberts,Samuel P Gubbels,Vijay R Ramakrishnan,Molly Moloney,Daniel N Frank,Ivana V Yang,David A Schwartz,Patricia J Yoon,Regie Lyn P Santos-Cortez,Gretchen Frank

doi:10.3389/fgene.2019.01352

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.

Highlights

The unified airway theory proposes that the respiratory tract acts as an integrated unit, from the middle ear through the distant bronchioles (Krouse, 2008)
The study is divided into three parts (Supplementary Methods; Supplementary Figure 1): Part 1 consists of network analyses and pathway identification using published genes based on genome-wide significant variants from DNA studies and eGenes derived from expression quantitative trait loci; Part 2 includes analyses of RNA-sequence data from middle ear, sinus, and lung tissue, and identification of common genes and pathways from network analyses across different sites; and Part 3 involves the comparison of network analysis results from DNA literature and RNA-sequence data in order to find common genes and pathways across the upper and lower airways
No variants overlap between phenotypes, but there is some overlap at the gene level, namely, HLA-DRB1 in both otitis media (OM) and pneumonia and MUC6 in both bronchiolitis and pneumonia

Summary

Introduction

The unified airway theory proposes that the respiratory tract acts as an integrated unit, from the middle ear through the distant bronchioles (Krouse, 2008). Treatment of allergic rhinitis symptoms has been found to improve asthma symptoms and pulmonary function. This is believed to be due to a shared inflammation model, with local inflammatory processes producing systemic mediators that affect disease in other areas of the respiratory tract (Krouse, 2008). Atopic patients undergoing surgery for otitis media (OM) with effusion have similar cellular and cytokine profiles in both the middle ear effusion and nasopharynx (Nguyen et al, 2004). It is hypothesized that the middle ear is capable of participating in a TH2 inflammatory response and that the inflammation in OM with effusion is not limited to the middle ear (Nguyen et al, 2004)

Methods

Results

Conclusion