Noninvasive Analysis of the Sputum Transcriptome Discriminates Clinical Phenotypes of Asthma

Abstract

INTRODUCTION It is increasingly recognized that asthma is a heterogeneous disease. Therefore, it is possible that analysis of gene expression in the airway will reveal clinically meaningful transcriptional endotypes of asthma (TEA clusters). METHODS We measured whole transcriptome gene expression profiles in the sputum and whole blood of 100 individuals with asthma and 12 control subjects using the Affymetrix HuGene ST 1.0 gene arrays. Unsupervised clustering was conducted using pathways from Kyoto Encyclopedia of Genes and Genomes (KEGG). This identified three TEA clusters that were correlated with clinical, physiologic, and inflammatory characteristics of the disease. TEA cluster 1 is a cluster of patients with asthma with a significantly higher rate of intubation (P = 0.05), a lower prebronchodilator FEV1 (P = 0.006), a higher bronchodilator response (P = 0.03), and higher exhaled nitric oxide levels (P = 0.04) than the other two TEA clusters. TEA cluster 2 has a higher rate of hospitalization for asthma (P = 0.04) and is heterogeneous. TEA cluster 3 is the largest cluster and has normal lung function, low exhaled nitric oxide levels, and lower inhaled steroid requirements. TEA cluster 1 had the highest sputum Th2 gene signature (IL-4, -5, and -13) compared with the other clusters. A classifier was developed that predicts TEA cluster assignment using 53 predictive genes in the circulation. The classifier was applied to gene expression data of children from the Asthma Biorepository for Integrative Genomic Exploration (Asthma BRIDGE) consortium cohort and confirmed that TEA clusters 1 and 2 are associated with history of intubation (P = 5.58 × 10(-06)) and hospitalization (P = 0.01), respectively. CONCLUSIONS Analysis of the sputum transcriptome reveals three TEA clusters with different clinical and physiologic characteristics of disease in children and adults with asthma. This suggests that there are common transcriptomic signatures in the blood in children and adults with asthma that are associated with features of severe asthma.