title: Altered gene expression in blood and sputum in COPD frequent exacerbators in the ECLIPSE cohort.
abstract: Patients with chronic obstructive pulmonary disease (COPD) who are defined as frequent exacerbators suffer with 2 or more exacerbations every year. The molecular mechanisms responsible for this phenotype are poorly understood. We investigated gene expression profile patterns associated with frequent exacerbations in sputum and blood cells in a well-characterised cohort. Samples from subjects from the ECLIPSE COPD cohort were used; sputum and blood samples from 138 subjects were used for microarray gene expression analysis, while blood samples from 438 subjects were used for polymerase chain reaction (PCR) testing. Using microarray, 150 genes were differentially expressed in blood (>±1.5 fold change, p≤0.01) between frequent compared to non-exacerbators. In sputum cells, only 6 genes were differentially expressed. The differentially regulated genes in blood included downregulation of those involved in lymphocyte signalling and upregulation of pro-apoptotic signalling genes. Multivariate analysis of the microarray data followed by confirmatory PCR analysis identified 3 genes that predicted frequent exacerbations; B3GNT, LAF4 and ARHGEF10. The sensitivity and specificity of these 3 genes to predict the frequent exacerbator phenotype was 88% and 33% respectively. There are alterations in systemic immune function associated with frequent exacerbations; down-regulation of lymphocyte function and a shift towards pro-apoptosis mechanisms are apparent in patients with frequent exacerbations.
authors.affiliation: University of Manchester, Medicines Evaluation Unit, Manchester, United Kingdom.
authors.forename: Dave
authors.initials: D
authors.lastname: Singh
authors.affiliation: GlaxoSmithKline, Medicines Research Centre, Stevenage, United Kingdom.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Fox
authors.affiliation: GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America.
authors.forename: Ruth
authors.initials: R
authors.lastname: Tal-Singer
authors.affiliation: GlaxoSmithKline, Medicines Research Centre, Stevenage, United Kingdom.
authors.forename: Stewart
authors.initials: S
authors.lastname: Bates
authors.affiliation: GlaxoSmithKline, Stockley Park, Uxbridge, United Kingdom.
authors.forename: John H
authors.initials: JH
authors.lastname: Riley
authors.affiliation: Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Bartolome
authors.initials: B
authors.lastname: Celli
mesh_terms: D000368:Aged; D015331:Cohort Studies; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020411:Oligonucleotide Array Sequence Analysis; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D013183:Sputum / Q000378:metabolism*