Noninvasive Analysis of the Sputum Transcriptome Discriminates Clinical Phenotypes of Asthma

Abstract

Rationale: The airway transcriptome includes genes that contribute to the pathophysiologic heterogeneity seen in individuals with asthma.Objectives: We analyzed sputum gene expression for transcriptomic endotypes of asthma (TEA), gene signatures that discriminate phenotypes of disease.Methods: Gene expression in the sputum and blood of patients with asthma was measured using Affymetrix microarrays. Unsupervised clustering analysis based on pathways from the Kyoto Encyclopedia of Genes and Genomes was used to identify TEA clusters. Logistic regression analysis of matched blood samples defined an expression profile in the circulation to determine the TEA cluster assignment in a cohort of children with asthma to replicate clinical phenotypes.Measurements and Main Results: Three TEA clusters were identified. TEA cluster 1 had the most subjects with a history of intubation (P = 0.05), a lower prebronchodilator FEV 1 (P = 0.006), a higher bronchodilator response (P = 0.03), and higher exhaled nitric oxide levels (P = 0.04) compared with the other TEA clusters. TEA cluster 2, the smallest cluster, had the most subjects that were hospitalized for asthma (P = 0.04). TEA cluster 3, the largest cluster, had normal lung function, low exhaled nitric oxide levels, and lower inhaled steroid requirements. Evaluation of TEA clusters in children confirmed that TEA clusters 1 and 2 are associated with a history of intubation (P = 5.58 3 10 26) and hospitalization (P = 0.01), respectively.Conclusions: There are common patterns of gene expression in the sputum and blood of children and adults that are associated with near-fatal, severe, and milder asthma.

The R213G polymorphism in SOD3 protects against allergic airway inflammation

“…Sputum samples from the Yale Center for Asthma and Airway Diseases (YCAAD) cohort were divided into 3 groups based on transcriptomic endotypes of asthma (TEA) (32). TEA1 subjects had the highest percentage of near-fatal asthma and lowest baseline lung function with highest fraction exhaled nitric oxide (FE NO ) levels (Table 1).…”

“…Sputum samples were collected from asthmatics and healthy volunteers aged greater than or equal to 12 years old, between September 2009 and June 2012, that completed the YCAAD phenotyping protocol as described in Yan et al (32) and all subjects gave informed written consent. Briefly, the study excluded anyone who smoked within the past year, had a history chronic lung diseases other than asthma (such as COPD, allergic bronchopulmonary aspergillosis, Churg-Strauss syndrome, pulmonary vascular disease, or interstitial lung disease); had other severe chronic conditions such as congestive heart failure, chronic kidney disease, liver disease, or viral infection; or had an inability to safely tolerate the studies required for participation.…”

“…Sputum SOD3 transcript increases with asthma severity. Sputum samples were collected from the Yale Center for Asthma and Airway Diseases (YCAAD) cohort consisting of asthmatic patients (n = 112) that were divided into 3 groups based on transcriptomic endotypes of asthma (TEA) as described in (32). TEA1 (n = 34) is the most severe endotype followed by TEA2 (n = 19) and TEA3 (n = 47).…”

Gene Expression Profiling in Blood Provides Reproducible Molecular Insights into Asthma Control

“…The Asthma BRIDGE dataset, which has been described previously (9,14,15), comprises a cohort of subjects selected from the EVE asthma genetics consortium (16). Additional detail on subject ascertainment is presented in the METHODS section of the online supplement.…”

“…Using clinical phenotype data available in Asthma BRIDGE and in CAMP, we developed two composite scores summarizing self-reported asthma control in the preceding 6 months (chronic, [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] and 7 days (acute, 0-28), respectively, each modeled on the ACT questionnaire (11), where higher scores indicate worse asthma control. Based on the medians of the corresponding phenotypic distributions, optimal chronic asthma control was defined as a score less than or equal to six in BRIDGE WB and moderately suboptimal asthma control was defined as a score less than or equal to 11 in BRIDGE CD4 ( Figure 2).…”