title: Expression of cilium-associated genes defines novel molecular subtypes of idiopathic pulmonary fibrosis.
abstract: BACKGROUND
  Idiopathic pulmonary fibrosis (IPF) is an untreatable lung disease with a median survival of only 3-5 years that is diagnosed using a combination of clinical, radiographic and pathologic criteria. Histologically, IPF is characterised by usual interstitial pneumonia (UIP), a fibrosing interstitial pneumonia with a pattern of heterogeneous, subpleural regions of fibrotic and remodelled lung. We hypothesised that gene expression profiles of lung tissue may identify molecular subtypes of disease that could classify subtypes of IPF/UIP that have clinical implications.
  
  
  RESULTS
  We collected transcriptional profiles on lung tissue from 119 patients with IPF/UIP and 50 non-diseased controls. Differential expression of individual transcripts was identified using an analysis of covariance (ANCOVA) model incorporating the clinical diagnosis of each patient as well as age, gender and smoking status. Validation was performed in an independent cohort of 111 IPF/UIP and 39 non-diseased controls. Our analysis identified two subtypes of IPF/UIP based on a strong molecular signature associated with expression of genes previously associated with fibrosis (matrix metalloproteinases, osteopontin, keratins), cilium genes and genes with unknown function. We demonstrate that elevated expression of cilium genes is associated with more extensive microscopic honeycombing and higher expression of both the airway mucin gene MUC5B and the metalloproteinase MMP7, a gene recently implicated in attenuating ciliated cell differentiation during wound repair.
  
  
  CONCLUSIONS
  Expression of cilium genes appears to identify two unique molecular phenotypes of IPF/UIP. The different molecular profiles may be relevant to therapeutic responsiveness in patients with IPF/UIP.
authors.affiliation: Department of Medicine, University of Colorado School of Medicine, , Aurora, Colorado, USA.
authors.forename: Ivana V
authors.initials: IV
authors.lastname: Yang
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Coldren
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Leach
authors.forename: Max A
authors.initials: MA
authors.lastname: Seibold
authors.forename: Elissa
authors.initials: E
authors.lastname: Murphy
authors.forename: Jia
authors.initials: J
authors.lastname: Lin
authors.forename: Rachel
authors.initials: R
authors.lastname: Rosen
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Neidermyer
authors.forename: David F
authors.initials: DF
authors.lastname: McKean
authors.forename: Steve D
authors.initials: SD
authors.lastname: Groshong
authors.forename: Carlyne
authors.initials: C
authors.lastname: Cool
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Cosgrove
authors.forename: David A
authors.initials: DA
authors.lastname: Lynch
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Brown
authors.forename: Marvin I
authors.initials: MI
authors.lastname: Schwarz
authors.forename: Tasha E
authors.initials: TE
authors.lastname: Fingerlin
authors.forename: David A
authors.initials: DA
authors.lastname: Schwartz
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002923:Cilia / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics* / Q000473:pathology*; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000235:genetics*; D008875:Middle Aged; D055257:Mucin-5B / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D012313:RNA / Q000032:analysis; D059467:Transcriptome
chemical_list: C524578:MUC5B protein, human; D055257:Mucin-5B; D012313:RNA; D020783:Matrix Metalloproteinase 7
keywords: Interstitial Fibrosis