Abstract
Rationale: Severe asthma is a heterogeneous disease with multiple molecular mechanisms. Gene expression studies of asthmatic bronchial epithelial cells have provided biological insights and underscored possible pathological mechanisms; however, the molecular basis in severe asthma is still poorly understood. Objective: The objective of this study was to identify the features of asthma and uncover the molecular basis of severe asthma in distinct molecular phenotype. Methods: The k-means clustering and differentially expressed genes (DEGs) were performed in 129 asthma individuals in the Severe Asthma Research Program. The DEG profiles were analyzed by weighted gene co-expression network analysis (WGCNA), and the expression value of each gene module in each individual was annotated by gene set variation analysis (GSVA). Results: Expression analysis defined five stable asthma subtype (AS): 1) Phagocytosis-Th2, 2) Normal-like, 3) Neutrophils, 4) Mucin-Th2, and 5) Interferon-Th1 and 15 co-expressed gene modules. “Phagocytosis-Th2” enriched for receptor-mediated endocytosis, upregulation of Toll-like receptor signal, and myeloid leukocyte activation. “Normal-like” is most similar to normal samples. “Mucin-Th2” preferentially expressed genes involved in O-glycan biosynthesis and unfolded protein response. “Interferon-Th1” displayed upregulation of genes that regulate networks involved in cell cycle, IFN gamma response, and CD8 TCR. The dysregulation of neural signal, REDOX, apoptosis, and O-glycan process were related to the severity of asthma. In non-TH2 subtype (Neutrophils and Interferon-Th1) with severe asthma individuals, the neural signals and IL26-related co-expression module were dysregulated more significantly compared to that in non-severe asthma. These data infer differences in the molecular evolution of asthma subtypes and identify opportunities for therapeutic development. Conclusions: Asthma is a heterogeneous disease. The co-expression analysis provides new insights into the biological mechanisms related to its phenotypes and the severity.
Highlights
Asthma is a chronic disorder, characterized by airway hyperresponsiveness (AHR) and remodeling with variable degrees of eosinophilic and neutrophilic inflammation resulting in significant morbidity and mortality (Wilson et al, 2006; Kim et al, 2010)
The differentially expressed genes (DEGs) profiles were analyzed by weighted gene co-expression network analysis (WGCNA), and the expression value of each gene module in each individual was annotated by gene set variation analysis (GSVA)
“Mucin-Th2” preferentially expressed genes involved in O-glycan biosynthesis and unfolded protein response
Summary
Asthma is a chronic disorder, characterized by airway hyperresponsiveness (AHR) and remodeling with variable degrees of eosinophilic and neutrophilic inflammation resulting in significant morbidity and mortality (Wilson et al, 2006; Kim et al, 2010). It affects about 5% of the population (Global et al, 2017). Environmental stimuli promote epithelial cell synthesis and secretion by a variety of mediators, such as cytokines, chemokines, reactive oxygen species, lipid, and peptide mediators and eventually involved in recruiting leukocytes, mucus secretion, vascular permeability, bronchoconstriction, and airway hyper-responsiveness (Whitsett, 2018)
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