EPITHELIAL CELL GENE NETWORKS UPREGULATED IN OBESE ASTHMATIC CHILDREN

Abstract

Introduction Obesity is a major pediatric health concern affecting almost 20% of American children and adolescents. Obesity is a risk factor for the development of asthma and is associated with increased asthma severity. Children with obesity and asthma have reduced responsiveness to inhaled corticosteroids, increased use of systemic corticosteroids during exacerbations, and a reduced FEV1/FVC ratio. The mechanisms underlying the influence of obesity on asthma pathogenesis remain poorly understood. Methods Children (ages 6-17 years) with a priori defined exacerbation-prone asthma and blood eosinophils ≥150/mm3 had repeated nasal lavage sampling during a one-week period following reported URI symptoms. Nasal cell differentials were determined by cytospin and nasal gene expression assessed by RNA-sequencing. Differential gene expression was assessed by cell deconvolution and modular analysis. Results 154 URI events from 106 participants were captured and 47 of those events resulted in asthma exacerbation. 42/106 participants were obese defined by a BMI ≥95th percentile. Children with obesity had higher expression levels of 7 geneset modules when compared to those without obesity. These modules were associated with the airway epithelium and represent molecular functions including keratinization, tissue kallikrein induction, extracellular matrix production, and EGFR signaling. Measured effect sizes ranged from 1.24-2.05 fold higher. Conclusions We identified several airway epithelial associated gene networks upregulated in children with obesity and asthma. Previous studies of obesity and asthma have focused largely on metabolic and inflammatory alterations. Our results highlight the relevance of epithelial response pathways, which may serve as novel targets for biomarkers or therapies for obesity associated asthma.