Airway Epithelium Gene Expression Endotyping of Asthma and Airway Obstruction in Urban Children

Abstract

Measurements of gene transcription in airway epithelium can provide mechanistic insights into the development of distinct asthma phenotypes. Clinical characteristics were collected prospectively from 456 children in the URECA (Urban Environment and Childhood Asthma) birth cohort through age 10 years. Children were then classified into one of six respiratory health phenotypes based upon longitudinal analysis of wheezing illnesses, aeroallergen sensitization, and lung function. Nasal epithelial brushings were obtained at age 11 years; cell differentials were assessed by cytology and nasal gene expression by RNA-sequencing. Differential gene expression was assessed by modular analysis and linear mixed-effects modeling. Through 10 years of age, 12% (56/456) of children had frequent wheezing, high levels of allergic sensitization, and evidence of airway obstruction and small airway dysfunction. Compared to the other 5 phenotypes, transcriptomic analysis of the nasal epithelium of this high-wheeze/high-atopy/low-lung-function group showed significantly elevated expression of multiple molecular modules including MUC5AC hypersecretion, leukotriene metabolism, and epithelial IL-13 response (fold changes [FC]s 1.3-2; FDRs<0.001). Another 17% (76/456) of children had moderate wheezing, but low or no allergic sensitization; this medium-wheeze/low-atopy group showed significantly decreased expression of a module of epithelial integrity and leukocyte migration genes (FC=0.9, FDR<0.001) and elevated expression of a module of epithelial injury response genes (FC=1.1, FDR<0.001). Our results demonstrate specific molecular modules are differentially expressed in the airways of children with distinct respiratory phenotypes, including allergic and non-allergic asthma. Notably, MUC5AC hypersecretion and IL-13 response over-expression are associated with a distinct respiratory phenotype that includes significant airflow obstruction.