Sputum gene expression signature of 6 biomarkers discriminates asthma inflammatory phenotypes

Baines, K. J., Simpson, J. L., Wood, L. G., Scott, R. J., Fibbens, N. L., Powell, H., Cowan, D. C. , Robin Taylor, D., Cowan, J. O. and Gibson, P. G. (2014) Sputum gene expression signature of 6 biomarkers discriminates asthma inflammatory phenotypes. Journal of Allergy and Clinical Immunology, 133(4), pp. 997-1007. (doi: 10.1016/j.jaci.2013.12.1091) (PMID:24582314)

Abstract

Background: Airway inflammation is associated with asthma exacerbation risk, treatment response, and disease mechanisms. Objective: This study aimed to identify and validate a sputum gene expression signature that discriminates asthma inflammatory phenotypes. Methods: An asthma phenotype biomarker discovery study generated gene expression profiles from induced sputum of 47 asthmatic patients. A clinical validation study (n = 59 asthmatic patients) confirmed differential expression of key genes. A 6-gene signature was identified and evaluated for reproducibility (n = 30 asthmatic patients and n = 20 control subjects) and prediction of inhaled corticosteroid (ICS) response (n = 71 asthmatic patients). Receiver operating characteristic curves were calculated, and area under the curve (AUC) values were reported. Results: From 277 differentially expressed genes between asthma inflammatory phenotypes, we identified 23 genes that showed highly significant differential expression in both the discovery and validation populations. A signature of 6 genes, including Charcot-Leydon crystal protein (CLC); carboxypeptidase A3 (CPA3); deoxyribonuclease I-like 3 (DNASE1L3); IL-1β (IL1B); alkaline phosphatase, tissue-nonspecific isozyme (ALPL); and chemokine (C-X-C motif) receptor 2 (CXCR2), was reproducible and could significantly (P < .0001) discriminate eosinophilic asthma from other phenotypes, including patients with noneosinophilic asthma (AUC, 89.6%), paucigranulocytic asthma (AUC, 92.6%), or neutrophilic asthma (AUC, 91.4%) and healthy control subjects (AUC, 97.6%), as well as discriminating patients with neutrophilic asthma from those with paucigranulocytic asthma (AUC, 85.7%) and healthy control subjects (AUC, 90.8). The 6-gene signature predicted ICS response (>12% change in FEV1; AUC, 91.5%). ICS treatment reduced the expression of CLC, CPA3, and DNASE1L3 in patients with eosinophilic asthma. Conclusions: A sputum gene expression signature of 6 biomarkers reproducibly and significantly discriminates inflammatory phenotypes of asthma and predicts ICS treatment response. This signature has the potential to become a useful diagnostic tool to assist in the clinical diagnosis and management of asthma.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Cowan, Douglas
• Authors: Baines, K. J., Simpson, J. L., Wood, L. G., Scott, R. J., Fibbens, N. L., Powell, H., Cowan, D. C., Robin Taylor, D., Cowan, J. O., and Gibson, P. G.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Journal of Allergy and Clinical Immunology
• Publisher: Elsevier
• ISSN: 0091-6749