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Published in: Respiratory Research 1/2017

Open Access 01-12-2017 | Research

Nasal gene expression differentiates COPD from controls and overlaps bronchial gene expression

Authors: Ilse M. Boudewijn, Alen Faiz, Katrina Steiling, Erica van der Wiel, Eef D. Telenga, Susan J. M. Hoonhorst, Nick H. T. ten Hacken, Corry-Anke Brandsma, Huib A. M. Kerstjens, Wim Timens, Irene H. Heijink, Marnix R. Jonker, Harold G. de Bruin, J. Sebastiaan Vroegop, Henk R. Pasma, Wim G. Boersma, Pascal Wielders, Frank van den Elshout, Khaled Mansour, Avrum Spira, Marc E. Lenburg, Victor Guryev, Dirkje S. Postma, Maarten van den Berge

Published in: Respiratory Research | Issue 1/2017

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Abstract

Background

Nasal gene expression profiling is a promising method to characterize COPD non-invasively. We aimed to identify a nasal gene expression profile to distinguish COPD patients from healthy controls. We investigated whether this COPD-associated gene expression profile in nasal epithelium is comparable with the profile observed in bronchial epithelium.

Methods

Genome wide gene expression analysis was performed on nasal epithelial brushes of 31 severe COPD patients and 22 controls, all current smokers, using Affymetrix Human Gene 1.0 ST Arrays. We repeated the gene expression analysis on bronchial epithelial brushes in 2 independent cohorts of mild-to-moderate COPD patients and controls.

Results

In nasal epithelium, 135 genes were significantly differentially expressed between severe COPD patients and controls, 21 being up- and 114 downregulated in COPD (false discovery rate < 0.01). Gene Set Enrichment Analysis (GSEA) showed significant concordant enrichment of COPD-associated nasal and bronchial gene expression in both independent cohorts (FDRGSEA < 0.001).

Conclusion

We identified a nasal gene expression profile that differentiates severe COPD patients from controls. Of interest, part of the nasal gene expression changes in COPD mimics differentially expressed genes in the bronchus. These findings indicate that nasal gene expression profiling is potentially useful as a non-invasive biomarker in COPD.

Trial registration

ClinicalTrials.​gov registration number NCT01351792 (registration date May 10, 2011), ClinicalTrials.​gov registration number NCT00848406 (registration date February 19, 2009), ClinicalTrials.​gov registration number NCT00807469 (registration date December 11, 2008).
Appendix
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Literature
1.
go back to reference Halbert RJ, Natoli JL, Gano A, Badamgarav E, Buist AS, Mannino DM. Global burden of COPD: systematic review and meta-analysis. Eur Respir J. 2006;28:523–32.CrossRefPubMed Halbert RJ, Natoli JL, Gano A, Badamgarav E, Buist AS, Mannino DM. Global burden of COPD: systematic review and meta-analysis. Eur Respir J. 2006;28:523–32.CrossRefPubMed
3.
go back to reference Spira A, Beane J, Shah V, Liu G, Schembri F, Yang X, et al. Effects of cigarette smoke on the human airway epithelial cell transcriptome. Proc Natl Acad Sci U S A. 2004;101:10143–8.CrossRefPubMedPubMedCentral Spira A, Beane J, Shah V, Liu G, Schembri F, Yang X, et al. Effects of cigarette smoke on the human airway epithelial cell transcriptome. Proc Natl Acad Sci U S A. 2004;101:10143–8.CrossRefPubMedPubMedCentral
4.
go back to reference Steiling K, van den Berge M, Hijazi K, Florido R, Campbell J, Liu G, et al. A dynamic bronchial airway gene expression signature of chronic obstructive pulmonary disease and lung function impairment. Am J Respir Crit Care Med. 2013;187:933–42.CrossRefPubMedPubMedCentral Steiling K, van den Berge M, Hijazi K, Florido R, Campbell J, Liu G, et al. A dynamic bronchial airway gene expression signature of chronic obstructive pulmonary disease and lung function impairment. Am J Respir Crit Care Med. 2013;187:933–42.CrossRefPubMedPubMedCentral
5.
go back to reference Zhang X, Sebastiani P, Liu G, Schembri F, Zhang X, Dumas YM, et al. Similarities and differences between smoking-related gene expression in nasal and bronchial epithelium. Physiol Genomics. 2010;41:1–8.CrossRefPubMed Zhang X, Sebastiani P, Liu G, Schembri F, Zhang X, Dumas YM, et al. Similarities and differences between smoking-related gene expression in nasal and bronchial epithelium. Physiol Genomics. 2010;41:1–8.CrossRefPubMed
6.
go back to reference Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation of spirometry. Eur Respir J. 2005;26:319–38.CrossRefPubMed Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation of spirometry. Eur Respir J. 2005;26:319–38.CrossRefPubMed
7.
go back to reference Wanger J, Clausen JL, Coates A, Pedersen OF, Brusasco V, Burgos F, et al. Standardisation of the measurement of lung volumes. Eur Respir J. 2005;26:511–22.CrossRefPubMed Wanger J, Clausen JL, Coates A, Pedersen OF, Brusasco V, Burgos F, et al. Standardisation of the measurement of lung volumes. Eur Respir J. 2005;26:511–22.CrossRefPubMed
8.
go back to reference van der Molen T, Willemse BW, Schokker S, ten Hacken NH, Postma DS, Juniper EF. Development, validity and responsiveness of the clinical COPD questionnaire. Health Qual Life Outcomes. 2003;1:13.CrossRefPubMedPubMedCentral van der Molen T, Willemse BW, Schokker S, ten Hacken NH, Postma DS, Juniper EF. Development, validity and responsiveness of the clinical COPD questionnaire. Health Qual Life Outcomes. 2003;1:13.CrossRefPubMedPubMedCentral
9.
go back to reference Sridhar S, Schembri F, Zeskind J, Shah V, Gustafson AM, Steiling K, et al. Smoking-induced gene expression changes in the bronchial airway are reflected in nasal and buccal epithelium. BMC Genomics. 2008;9:259–2164. -9-259CrossRefPubMedPubMedCentral Sridhar S, Schembri F, Zeskind J, Shah V, Gustafson AM, Steiling K, et al. Smoking-induced gene expression changes in the bronchial airway are reflected in nasal and buccal epithelium. BMC Genomics. 2008;9:259–2164. -9-259CrossRefPubMedPubMedCentral
10.
go back to reference Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc. 1995;57:289–900. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc. 1995;57:289–900.
11.
go back to reference Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102:15545–50.CrossRefPubMedPubMedCentral Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102:15545–50.CrossRefPubMedPubMedCentral
12.
go back to reference Lo Tam Loi AT, Hoonhorst SJ, Franciosi L, Bischoff R, Hoffmann RF, Heijink I, et al. Acute and chronic inflammatory responses induced by smoking in individuals susceptible and non-susceptible to development of COPD: from specific disease phenotyping towards novel therapy. Protocol of a cross-sectional study. BMJ Open. 2013;3 https://doi.org/10.1136/bmjopen-2012-002178. Print 2013 Lo Tam Loi AT, Hoonhorst SJ, Franciosi L, Bischoff R, Hoffmann RF, Heijink I, et al. Acute and chronic inflammatory responses induced by smoking in individuals susceptible and non-susceptible to development of COPD: from specific disease phenotyping towards novel therapy. Protocol of a cross-sectional study. BMJ Open. 2013;3 https://​doi.​org/​10.​1136/​bmjopen-2012-002178. Print 2013
13.
go back to reference Hoonhorst S, Timens W, Koenderman L, Lo Tam Loi AT, Lammers JW, Boezen H, et al. Increased activation of blood neutrophils after cigarette smoking in young individuals susceptible to COPD. Respir Res. 2014;15:121.CrossRefPubMedPubMedCentral Hoonhorst S, Timens W, Koenderman L, Lo Tam Loi AT, Lammers JW, Boezen H, et al. Increased activation of blood neutrophils after cigarette smoking in young individuals susceptible to COPD. Respir Res. 2014;15:121.CrossRefPubMedPubMedCentral
14.
go back to reference Obeidat M, Nie Y, Fishbane N, Li X, Bosse Y, Joubert P, et al. Integrative genomics of emphysema-associated genes reveals potential disease biomarkers. Am J Respir Cell Mol Biol. 2017;57:411–8.CrossRefPubMed Obeidat M, Nie Y, Fishbane N, Li X, Bosse Y, Joubert P, et al. Integrative genomics of emphysema-associated genes reveals potential disease biomarkers. Am J Respir Cell Mol Biol. 2017;57:411–8.CrossRefPubMed
15.
go back to reference Leikauf GD, Borchers MT, Prows DR, Simpson LG. Mucin apoprotein expression in COPD. Chest. 2002;121:166S–82S.CrossRefPubMed Leikauf GD, Borchers MT, Prows DR, Simpson LG. Mucin apoprotein expression in COPD. Chest. 2002;121:166S–82S.CrossRefPubMed
16.
17.
go back to reference Choi IW, Ahn do W, Choi JK, Cha HJ, Ock MS, You E, et al. Regulation of airway inflammation by G-protein regulatory motif peptides of AGS3 protein. Sci Rep. 2016;6:27054.CrossRefPubMedPubMedCentral Choi IW, Ahn do W, Choi JK, Cha HJ, Ock MS, You E, et al. Regulation of airway inflammation by G-protein regulatory motif peptides of AGS3 protein. Sci Rep. 2016;6:27054.CrossRefPubMedPubMedCentral
18.
go back to reference Ishikawa N, Mazur W, Toljamo T, Vuopala K, Ronty M, Horimasu Y, et al. Ageing and long-term smoking affects KL-6 levels in the lung, induced sputum and plasma. BMC Pulm Med. 2011;11:22–2466. -11-22CrossRefPubMedPubMedCentral Ishikawa N, Mazur W, Toljamo T, Vuopala K, Ronty M, Horimasu Y, et al. Ageing and long-term smoking affects KL-6 levels in the lung, induced sputum and plasma. BMC Pulm Med. 2011;11:22–2466. -11-22CrossRefPubMedPubMedCentral
19.
go back to reference Wang G, Xu Z, Wang R, Al-Hijji M, Salit J, Strulovici-Barel Y, et al. Genes associated with MUC5AC expression in small airway epithelium of human smokers and non-smokers. BMC Med Genet. 2012;5:21–8794. -5-21 Wang G, Xu Z, Wang R, Al-Hijji M, Salit J, Strulovici-Barel Y, et al. Genes associated with MUC5AC expression in small airway epithelium of human smokers and non-smokers. BMC Med Genet. 2012;5:21–8794. -5-21
20.
go back to reference Chen Q, Lee CE, Denard B, Ye J. Sustained induction of collagen synthesis by TGF-beta requires regulated intramembrane proteolysis of CREB3L1. PLoS One. 2014;9:e108528.CrossRefPubMedPubMedCentral Chen Q, Lee CE, Denard B, Ye J. Sustained induction of collagen synthesis by TGF-beta requires regulated intramembrane proteolysis of CREB3L1. PLoS One. 2014;9:e108528.CrossRefPubMedPubMedCentral
21.
go back to reference Ramos FL, Krahnke JS, Kim V. Clinical issues of mucus accumulation in COPD. Int J Chron Obstruct Pulmon Dis. 2014;9:139–50.PubMedPubMedCentral Ramos FL, Krahnke JS, Kim V. Clinical issues of mucus accumulation in COPD. Int J Chron Obstruct Pulmon Dis. 2014;9:139–50.PubMedPubMedCentral
22.
go back to reference Pini L, Pinelli V, Modina D, Bezzi M, Tiberio L, Tantucci C. Central airways remodeling in COPD patients. Int J Chron Obstruct Pulmon Dis. 2014;9:927–32.CrossRefPubMedPubMedCentral Pini L, Pinelli V, Modina D, Bezzi M, Tiberio L, Tantucci C. Central airways remodeling in COPD patients. Int J Chron Obstruct Pulmon Dis. 2014;9:927–32.CrossRefPubMedPubMedCentral
23.
go back to reference Fliegauf M, Horvath J, von Schnakenburg C, Olbrich H, Muller D, Thumfart J, et al. Nephrocystin specifically localizes to the transition zone of renal and respiratory cilia and photoreceptor connecting cilia. J Am Soc Nephrol. 2006;17:2424–33.CrossRefPubMed Fliegauf M, Horvath J, von Schnakenburg C, Olbrich H, Muller D, Thumfart J, et al. Nephrocystin specifically localizes to the transition zone of renal and respiratory cilia and photoreceptor connecting cilia. J Am Soc Nephrol. 2006;17:2424–33.CrossRefPubMed
24.
go back to reference McClintock TS, Glasser CE, Bose SC, Bergman DA. Tissue expression patterns identify mouse cilia genes. Physiol Genomics. 2008;32:198–206.CrossRefPubMed McClintock TS, Glasser CE, Bose SC, Bergman DA. Tissue expression patterns identify mouse cilia genes. Physiol Genomics. 2008;32:198–206.CrossRefPubMed
25.
go back to reference Firat-Karalar EN, Sante J, Elliott S, Stearns T. Proteomic analysis of mammalian sperm cells identifies new components of the centrosome. J Cell Sci. 2014;127:4128–33.CrossRefPubMedPubMedCentral Firat-Karalar EN, Sante J, Elliott S, Stearns T. Proteomic analysis of mammalian sperm cells identifies new components of the centrosome. J Cell Sci. 2014;127:4128–33.CrossRefPubMedPubMedCentral
26.
go back to reference Yaghi A, Dolovich MB. Airway epithelial cell cilia and obstructive lung disease. Cell. 2016;5:E40.CrossRef Yaghi A, Dolovich MB. Airway epithelial cell cilia and obstructive lung disease. Cell. 2016;5:E40.CrossRef
27.
go back to reference Hobbs BD, de Jong K, Lamontagne M, Bosse Y, Shrine N, Artigas MS, et al. Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis. Nat Genet. 2017;49:426–32.CrossRefPubMedPubMedCentral Hobbs BD, de Jong K, Lamontagne M, Bosse Y, Shrine N, Artigas MS, et al. Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis. Nat Genet. 2017;49:426–32.CrossRefPubMedPubMedCentral
28.
go back to reference Brooke MA, Nitoiu D, Kelsell DP. Cell-cell connectivity: desmosomes and disease. J Pathol. 2012;226:158–71.CrossRefPubMed Brooke MA, Nitoiu D, Kelsell DP. Cell-cell connectivity: desmosomes and disease. J Pathol. 2012;226:158–71.CrossRefPubMed
29.
go back to reference Holz O, Zuhlke I, Jaksztat E, Muller KC, Welker L, Nakashima M, et al. Lung fibroblasts from patients with emphysema show a reduced proliferation rate in culture. Eur Respir J. 2004;24:575–9.CrossRefPubMed Holz O, Zuhlke I, Jaksztat E, Muller KC, Welker L, Nakashima M, et al. Lung fibroblasts from patients with emphysema show a reduced proliferation rate in culture. Eur Respir J. 2004;24:575–9.CrossRefPubMed
30.
go back to reference Noordhoek JA, Postma DS, Chong LL, Vos JT, Kauffman HF, Timens W, et al. Different proliferative capacity of lung fibroblasts obtained from control subjects and patients with emphysema. Exp Lung Res. 2003;29:291–302.CrossRefPubMed Noordhoek JA, Postma DS, Chong LL, Vos JT, Kauffman HF, Timens W, et al. Different proliferative capacity of lung fibroblasts obtained from control subjects and patients with emphysema. Exp Lung Res. 2003;29:291–302.CrossRefPubMed
31.
go back to reference Perotin JM, Adam D, Vella-Boucaud J, Delepine G, Sandu S, Jonvel AC, et al. Delay of airway epithelial wound repair in COPD is associated with airflow obstruction severity. Respir Res. 2014;15:151–014. -0151-9CrossRefPubMedPubMedCentral Perotin JM, Adam D, Vella-Boucaud J, Delepine G, Sandu S, Jonvel AC, et al. Delay of airway epithelial wound repair in COPD is associated with airflow obstruction severity. Respir Res. 2014;15:151–014. -0151-9CrossRefPubMedPubMedCentral
32.
go back to reference Wopereis S, Lefeber DJ, Morava E, Wevers RA. Mechanisms in protein O-glycan biosynthesis and clinical and molecular aspects of protein O-glycan biosynthesis defects: a review. Clin Chem. 2006;52:574–600.CrossRefPubMed Wopereis S, Lefeber DJ, Morava E, Wevers RA. Mechanisms in protein O-glycan biosynthesis and clinical and molecular aspects of protein O-glycan biosynthesis defects: a review. Clin Chem. 2006;52:574–600.CrossRefPubMed
33.
go back to reference Allende ML, Proia RL. Simplifying complexity: genetically resculpting glycosphingolipid synthesis pathways in mice to reveal function. Glycoconj J. 2014;31:613–22.CrossRefPubMedPubMedCentral Allende ML, Proia RL. Simplifying complexity: genetically resculpting glycosphingolipid synthesis pathways in mice to reveal function. Glycoconj J. 2014;31:613–22.CrossRefPubMedPubMedCentral
34.
go back to reference Telenga ED, Hoffmann RF, Ruben T, Hoonhorst SJ, Willemse BW, van Oosterhout AJ, et al. Untargeted lipidomic analysis in chronic obstructive pulmonary disease. Uncovering sphingolipids. Am J Respir Crit Care Med. 2014;190:155–64.CrossRefPubMed Telenga ED, Hoffmann RF, Ruben T, Hoonhorst SJ, Willemse BW, van Oosterhout AJ, et al. Untargeted lipidomic analysis in chronic obstructive pulmonary disease. Uncovering sphingolipids. Am J Respir Crit Care Med. 2014;190:155–64.CrossRefPubMed
35.
go back to reference Bahr TM, Hughes GJ, Armstrong M, Reisdorph R, Coldren CD, Edwards MG, et al. Peripheral blood mononuclear cell gene expression in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol. 2013;49:316–23.CrossRefPubMedPubMedCentral Bahr TM, Hughes GJ, Armstrong M, Reisdorph R, Coldren CD, Edwards MG, et al. Peripheral blood mononuclear cell gene expression in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol. 2013;49:316–23.CrossRefPubMedPubMedCentral
36.
go back to reference Bowler RP, Jacobson S, Cruickshank C, Hughes GJ, Siska C, Ory DS, et al. Plasma Sphingolipids associated with COPD phenotypes. Am J Respir Crit Care Med. 2014;191(3):275–84.CrossRef Bowler RP, Jacobson S, Cruickshank C, Hughes GJ, Siska C, Ory DS, et al. Plasma Sphingolipids associated with COPD phenotypes. Am J Respir Crit Care Med. 2014;191(3):275–84.CrossRef
37.
go back to reference Hirakawa M, Takimoto R, Tamura F, Yoshida M, Ono M, Murase K, et al. Fucosylated TGF-beta receptors transduces a signal for epithelial-mesenchymal transition in colorectal cancer cells. Br J Cancer. 2014;110:156–63.CrossRefPubMed Hirakawa M, Takimoto R, Tamura F, Yoshida M, Ono M, Murase K, et al. Fucosylated TGF-beta receptors transduces a signal for epithelial-mesenchymal transition in colorectal cancer cells. Br J Cancer. 2014;110:156–63.CrossRefPubMed
38.
39.
go back to reference Delmotte P, Degroote S, Lafitte JJ, Lamblin G, Perini JM, Roussel P. Tumor necrosis factor alpha increases the expression of glycosyltransferases and sulfotransferases responsible for the biosynthesis of sialylated and/or sulfated Lewis x epitopes in the human bronchial mucosa. J Biol Chem. 2002;277:424–31.CrossRefPubMed Delmotte P, Degroote S, Lafitte JJ, Lamblin G, Perini JM, Roussel P. Tumor necrosis factor alpha increases the expression of glycosyltransferases and sulfotransferases responsible for the biosynthesis of sialylated and/or sulfated Lewis x epitopes in the human bronchial mucosa. J Biol Chem. 2002;277:424–31.CrossRefPubMed
40.
go back to reference O'Connell MJ, Walworth NC, Carr AM. The G2-phase DNA-damage checkpoint. Trends Cell Biol. 2000;10:296–303.CrossRefPubMed O'Connell MJ, Walworth NC, Carr AM. The G2-phase DNA-damage checkpoint. Trends Cell Biol. 2000;10:296–303.CrossRefPubMed
41.
go back to reference Yao NY, Johnson A, Bowman GD, Kuriyan J, O'Donnell M. Mechanism of proliferating cell nuclear antigen clamp opening by replication factor C. J Biol Chem. 2006;281:17528–39.CrossRefPubMed Yao NY, Johnson A, Bowman GD, Kuriyan J, O'Donnell M. Mechanism of proliferating cell nuclear antigen clamp opening by replication factor C. J Biol Chem. 2006;281:17528–39.CrossRefPubMed
42.
go back to reference Qian L, Luo Q, Zhao X, Huang J. Pathways enrichment analysis for differentially expressed genes in squamous lung cancer. Pathol Oncol Res. 2014;20:197–202.CrossRefPubMed Qian L, Luo Q, Zhao X, Huang J. Pathways enrichment analysis for differentially expressed genes in squamous lung cancer. Pathol Oncol Res. 2014;20:197–202.CrossRefPubMed
43.
go back to reference Kim YR, Song SY, Kim SS, An CH, Lee SH, Yoo NJ. Mutational and expressional analysis of RFC3, a clamp loader in DNA replication, in gastric and colorectal cancers. Hum Pathol. 2010;41:1431–7.CrossRefPubMed Kim YR, Song SY, Kim SS, An CH, Lee SH, Yoo NJ. Mutational and expressional analysis of RFC3, a clamp loader in DNA replication, in gastric and colorectal cancers. Hum Pathol. 2010;41:1431–7.CrossRefPubMed
Metadata
Title
Nasal gene expression differentiates COPD from controls and overlaps bronchial gene expression
Authors
Ilse M. Boudewijn
Alen Faiz
Katrina Steiling
Erica van der Wiel
Eef D. Telenga
Susan J. M. Hoonhorst
Nick H. T. ten Hacken
Corry-Anke Brandsma
Huib A. M. Kerstjens
Wim Timens
Irene H. Heijink
Marnix R. Jonker
Harold G. de Bruin
J. Sebastiaan Vroegop
Henk R. Pasma
Wim G. Boersma
Pascal Wielders
Frank van den Elshout
Khaled Mansour
Avrum Spira
Marc E. Lenburg
Victor Guryev
Dirkje S. Postma
Maarten van den Berge
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2017
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/s12931-017-0696-5

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