Transcriptional phenotypes of asthma defined by gene expression profiling of induced sputum samples

doi:10.1016/j.jaci.2010.10.024

Journal of Allergy and Clinical Immunology

Volume 127, Issue 1, January 2011, Pages 153-160.e9

https://doi.org/10.1016/j.jaci.2010.10.024 Get rights and content

Background

Previous studies have identified clinical or inflammatory phenotypes of asthma on the basis of clinical and demographic parameters or sputum cell counts; however, few studies have defined transcriptional phenotypes of asthma.

Objective

To investigate asthma phenotypes at a transcriptional level by using gene expression profiling of induced sputum.

Methods

Induced sputum samples were collected from 59 people with asthma with a mean age of 58 years and an FEV₁% predicted of 76%, and 69% were taking inhaled corticosteroids. Thirteen healthy controls without asthma were also assessed. Inflammatory cell counts were performed, and RNA was extracted from selected sputum. Transcriptional profiles were generated (Illumina Humanref-8 V2) and analyzed by using GeneSpring GX11.

Results

Unsupervised hierarchical clustering of gene expression profiles in asthma revealed 3 distinct groups. The first transcriptional phenotype (n = 21) had lower FEV₁% predicted and higher asthma control questionnaire scores, exhaled nitric oxide, and sputum eosinophils. The second transcriptional phenotype (n = 14) had lower FEV₁% predicted and forced vital capacity % predicted and higher sputum neutrophils compared with a third transcriptional phenotype (n = 24) that had higher sputum macrophages and resembled healthy controls. Differentially expressed genes between transcriptional asthma phenotypes were related to inflammatory and immune responses. Genes in the IL-1 and TNF-α/nuclear factor-κB pathways were overexpressed and correlated with clinical parameters and neutrophilic airway inflammation.

Conclusion

Gene expression profiling provides a novel means to investigate the molecular mechanisms and classifications of asthma phenotypes. There are 3 distinct transcriptional phenotypes of asthma that relate to both clinical and inflammatory parameters.

Section snippets

Participants

Adults with stable asthma were recruited from the John Hunter Hospital Ambulatory Care Clinic, Newcastle, Australia. Asthma was diagnosed according to American Thoracic Society guidelines on the basis of current (past 12 months) episodic respiratory symptoms, doctor’s diagnosis (ever), and demonstrated evidence of airway hyperresponsiveness to hypertonic saline.²¹ Healthy controls without asthma (n = 13) were recruited by advertisement. Exclusion criteria included recent (past month)

Results

Characteristics of the participants are summarized in Table I. The patients with asthma (n = 59) had a mean age (SD) of 58 (14) years and moderate lung function impairment with a mean FEV₁% predicted (SD) of 76 (20). There were 25 males and 34 females, and 40 (68%) participants were atopic. Forty-one (69%) people were taking inhaled corticosteroids with a median (Q1-Q3) daily dose of 1000 (400-2000) μg beclomethasone equivalents/d. Twenty-eight (47%) of participants were exsmokers, with a

Discussion

This study demonstrates the use of unsupervised hierarchical clustering of induced sputum gene expression profiles to identify 3 TAPs occurring in the studied population. These 3 distinct phenotypes relate to both the clinical asthma status and the type and degree of airway inflammation present, providing further validation for their existence and relevance. The first 2 TAPs are inflammation-predominant, with TAP1 eosinophil-enriched and TAP2 neutrophil-enriched. The eosinophil-enriched group

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: Supported by the John Hunter Hospital Charitable Trust, HMRI, and XStrata Coal.

: Disclosure of potential conflict of interest: P. G. Gibson has received honoraria from GlaxoSmithKline, AstraZeneca, and Novartis. The rest of the authors have declared that they have no conflict of interest.

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Asthma and lower airway diseaseTranscriptional phenotypes of asthma defined by gene expression profiling of induced sputum samples

Background

Objective

Methods

Results

Conclusion

Section snippets

Participants

Results

Discussion

J Allergy Clin Immunol

Lancet

Chest

Ann Allergy Asthma Immunol

Lancet

Curr Opin Pharmacol

Lancet

Mepolizumab and exacerbations of refractory eosinophilic asthma

N Engl J Med

Mepolizumab for prednisone-dependent asthma with sputum eosinophilia

N Engl J Med

Tailored interventions based on exhaled nitric oxide versus clinical symptoms for asthma in children and adults

Cochrane Database Syst Rev

Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to corticosteroids

Thorax

Exacerbations of asthma without sputum eosinophilia

Thorax

Inflammatory subtypes in asthma: assessment and identification using induced sputum

Respirology

Differential gene expression and cytokine production from neutrophils in asthma phenotypes

Eur Respir J

Innate immune activation in neutrophilic asthma and bronchiectasis

Thorax

T-helper type 2-driven inflammation defines major subphenotypes of asthma

Am J Respir Crit Care Med

Cluster analysis and clinical asthma phenotypes

Am J Respir Crit Care Med

Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program

Am J Respir Crit Care Med

Asthma and lower airway disease
Transcriptional phenotypes of asthma defined by gene expression profiling of induced sputum samples