Gene Expression in Relation to Exhaled Nitric Oxide Identifies Novel Asthma Phenotypes with Unique Biomolecular Pathways
Year: 2014
Type: article
Abstract: RATIONALE: Although asthma is recognized as a heterogeneous disease associated with clinical phenotypes, the molecular basis of these phenotypes remains poorly understood. Although genomic studies have successfully broadened our understanding in diseases such as cancer, they have not been widely used in asthma studies. OBJECTIVES: To link gene expression patterns to clinical asthma phenotypes. METHODS: We used a microarray platform to analyze bronchial airway epithelial cell gene expression in relation to the asthma biomarker fractional exhaled nitric oxide (FeNO) in 155 subjects with asthma and healthy control subjects from the Severe Asthma Research Program (SARP). MEASUREMENTS AND MAIN RESULTS: We first identified a diverse set of 549 genes whose expression correlated with FeNO. We used k-means to cluster the patient samples according to the expression of these genes, identifying five asthma clusters/phenotypes with distinct clinical, physiological, cellular, and gene transcription characteristics-termed "subject clusters" (SCs). To then investigate differences in gene expression between SCs, a total of 1,384 genes were identified that highly differentiated the SCs at an unadjusted P value < 10(-6). Hierarchical clustering of these 1,384 genes identified nine gene clusters or "biclusters," whose coexpression suggested biological characteristics unique to each SC. Although genes related to type 2 inflammation were present, novel pathways, including those related to neuronal function, WNT pathways, and actin cytoskeleton, were noted. CONCLUSIONS: These findings show that bronchial epithelial cell gene expression, as related to the asthma biomarker FeNO, can identify distinct asthma phenotypes, while also suggesting the presence of underlying novel gene pathways relevant to these phenotypes.
Institutions: University of Pittsburgh, University of Pittsburgh Medical Center, Wake Forest University Health Sciences, Wake Forest University, Carnegie Mellon University, Cleveland Clinic, Cleveland Clinic Research, Rainbow Babies & Children's Hospital, Case Western Reserve University, University of Wisconsin–Madison, Yale University
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G105720905, Cellular S-nitrosothiol signaling in respiratory biology, Asthma Inflammation Research, G2020628740, Linking Genetics, Genomics and Phenomics to Better Understand Asthma Severity, Inflammation of Myofibroblasts and Loss of Elastic Recoil in Severe Asthma, G3240917872, G3698465645, University of Pittsburgh Clinical and Translational Science Institute, Institutional Clinical and Translational Science Award (UW-Madison)(UL1), Airway redox biochemistry as a deteriminant of asthma phenotype during adolescen*, Institutional Clinical and Translational Science Award, Severe Asthma from Respiratory Infections, Genotype-Phenotype Interactions in Severe Asthma, G827725844
OpenAlex ID: W2161650328