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. 2013 Dec;68(12):1114-21.
doi: 10.1136/thoraxjnl-2012-202943. Epub 2013 Jun 19.

Expression of cilium-associated genes defines novel molecular subtypes of idiopathic pulmonary fibrosis

Ivana V Yang  1 , Christopher D Coldren, Sonia M Leach, Max A Seibold, Elissa Murphy, Jia Lin, Rachel Rosen, Amanda J Neidermyer, David F McKean, Steve D Groshong, Carlyne Cool, Gregory P Cosgrove, David A Lynch, Kevin K Brown, Marvin I Schwarz, Tasha E Fingerlin, David A Schwartz
Affiliations

Expression of cilium-associated genes defines novel molecular subtypes of idiopathic pulmonary fibrosis

Ivana V Yang et al. Thorax. 2013 Dec.

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.

Methods and findings: 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.

Keywords: Interstitial Fibrosis.

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Conflict of interest statement

Competing interests DAL is a Board Member for Actelion and consultant for Actelion, Centocor, Gilead, Intermune, and Perceptive. He also receives grant funding from Siemens. KKB is a consultant for Amgen, Array Biopharma, Celgene, Centocor, Genentech, Genzyme, GeNO, Gilead, Glaxo SmithKline, Fibrogen, Ikaria, MondBiotech, Novartis, Pfizer and Stromedix. Other authors declare no competing interests.

Figures

Figure 1
Figure 1
Gene expression profiling identifies two subtypes of idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP). mRNA Profiles from 119 IPF/UIP lungs were subject to hierarchical clustering based on the expression of 472 transcripts that are differentially expressed at 5% false discovery rate (FDR) and with greater than twofold change in IPF/UIP compared with control lung. The distance metric is Euclidean, with complete linkage across samples and Ward’s linkage across genes. Extent of honeycombing and fibroblastic foci in each sample as assessed by pathology is depicted by the color: yellow (unscored/not present), orange (rare), red (present).
Figure 2
Figure 2
Quantitative real-time PCR confirms increased expression of cilium-associated genes in patient Group II. Plotted are average fold change for Group I idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP) compared with control lung (blue bars) and Group II IPF/UIP compared with controls (red bars) for four cilium-associated genes and MUC5B. Y axis is logarithmic scale and error bars represent standard deviations. Significant gene expression differences, as assessed by a two-tailed Student t test, between Group II and Group I IPF/UIP were observed for all genes (p=2.26×10−4 for RPGRIP1, p=4.94×10−16 for DNAH6, p=1.57×10−22 for DNAH7, p=4.96×10−13 for DNAI1, and p=1.28×10−11 for MUC5B).
Figure 3
Figure 3
The most significant network (Network 1; score=51) of genes that are upregulated at >1.5-fold change in Group II compared with Group I IPF/UIP. The score is defined as –log (p value) of the likelihood of the focus genes in a network being found together due to random chance. Networks were constructed using only direct relationships (solid lines). Genes are coloured by fold change. Legend: horizontal ellipse=transcriptional regulator, square=cytokine, double circle=group/complex, diamond=enzyme, trapezoid=transporter, rectangle=ion channel, circle=other.
Figure 4
Figure 4
Expression of cilium-associated genes distinguishes Groups I and II and defines two subcategories of idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP). (A) Representative dot plots of two cilium-associated genes DNAH6 and DNAH7 illustrate bimodal distribution of gene expression in IPF; Group I IPF=blue, Group II IPF=red, control=green. One-way analysis of variance (ANOVA) p values are: <0.0001 for both DNAH6 and DNAH7 and association with disease category. (B) Expression levels of DNAH6 and DNAH7 correlate with the extent of microscopic honeycombing (left) but not with the presence of fibroblastic foci (right). Scores: 0=not present, 1=rare, 2=present. One-way ANOVA p values are: <0.0001 for DNAH6 and 0.0001 for DNAH7 and association with microscopic honeycombing scores; 0.705 for DNAH6 and 0.840 for DNAH7 and association with fibroblastic foci scores.
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Comment in

  • IPF: time for the (ciliary) beat generation?
    Wiscombe S, Forrest IA, Simpson AJ. Wiscombe S, et al. Thorax. 2013 Dec;68(12):1088-9. doi: 10.1136/thoraxjnl-2013-203928. Epub 2013 Sep 4. Thorax. 2013. PMID: 24005445 No abstract available.

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