title: Airway gene expression of IL-1 pathway mediators predicts exacerbation risk in obstructive airway disease.
abstract: BACKGROUND
  Exacerbations of asthma and COPD are a major cause of morbidity and mortality and are responsible for significant health care costs. This study further investigates interleukin (IL)-1 pathway activation and its relationship with exacerbations of asthma and COPD.
  
  
  METHODS
  In this prospective cohort study, 95 participants with stable asthma (n=35) or COPD (n=60) were recruited and exacerbations recorded over the following 12 months. Gene expressions of IL-1 pathway biomarkers, including the IL-1 receptors (IL1R1,IL1R2, andIL1RN), and signaling molecules (IRAK2,IRAK3, andPELI1), were measured in sputum using real-time quantitative polymerase chain reaction. Mediators were compared between the frequent (≥2 exacerbations in the 12 months) and infrequent exacerbators, and the predictive relationships investigated using receiver operating characteristic curves and area under the curve (AUC) values.
  
  
  RESULTS
  Of the 95 participants, 89 completed the exacerbation follow-up, where 30 participants (n=22 COPD, n=8 asthma) had two or more exacerbations. At the baseline visit, expressions of IRAK2, IRAK3, PELI1, and IL1R1 were elevated in participants with frequent exacerbations of both asthma and COPD combined and separately. In the combined population, sputum gene expression of IRAK3 (AUC=75.4%;P<0.001) was the best predictor of future frequent exacerbations, followed by IL1R1 (AUC=72.8%;P<0.001), PELI1 (AUC=71.2%;P<0.001), and IRAK2 (AUC=68.6;P=0.004). High IL-1 pathway gene expression was associated with frequent prior year exacerbations and correlated with the number and severity of exacerbations.
  
  
  CONCLUSIONS
  The upregulation of IL-1 pathway mediators is associated with frequent exacerbations of obstructive airway disease. Further studies should investigate these mediators as both potential diagnostic biomarkers predicting at-risk patients and novel treatment targets.
authors.affiliation: Faculty of Health and Medicine, Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, The University of Newcastle; Department of Respiratory and Sleep Medicine, John Hunter Hospital, New Lambton, NSW, Australia.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Baines
authors.affiliation: Respiratory Group, Department of Integrated Traditional Chinese and West Medicine, West China Hospital, Sichuan University, People's Republic of China.
authors.forename: Juan-Juan
authors.initials: JJ
authors.lastname: Fu
authors.affiliation: Faculty of Health and Medicine, Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, The University of Newcastle; Department of Respiratory and Sleep Medicine, John Hunter Hospital, New Lambton, NSW, Australia.
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: McDonald
authors.affiliation: Faculty of Health and Medicine, Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, The University of Newcastle; Department of Respiratory and Sleep Medicine, John Hunter Hospital, New Lambton, NSW, Australia.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Gibson
mesh_terms: D000368:Aged; D019540:Area Under Curve; D001249:Asthma / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics; D007375:Interleukin-1 / Q000235:genetics* / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics; D008168:Lung / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D011237:Predictive Value of Tests; D011446:Prospective Studies; D029424:Pulmonary Disease, Chronic Obstructive / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012372:ROC Curve; D060888:Real-Time Polymerase Chain Reaction; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics; D053574:Receptors, Interleukin-1 Type II / Q000235:genetics; D012307:Risk Factors; D012720:Severity of Illness Index; D015398:Signal Transduction; D013183:Sputum / Q000737:chemistry; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
chemical_list: C508590:IL1R1 protein, human; C508592:IL1R2 protein, human; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D009687:Nuclear Proteins; D012333:RNA, Messenger; D053573:Receptors, Interleukin-1 Type I; D053574:Receptors, Interleukin-1 Type II; C485959:PELI1 protein, human; D044767:Ubiquitin-Protein Ligases; C507771:IRAK3 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases
keywords: COPD; asthma; exacerbations; interleukin-1