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

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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 (FDR GSEA < 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).

          Electronic supplementary material

          The online version of this article (10.1186/s12931-017-0696-5) contains supplementary material, which is available to authorized users.

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          Most cited references34

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          Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

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            Plasma sphingolipids associated with chronic obstructive pulmonary disease phenotypes.

            Chronic obstructive pulmonary disease (COPD) occurs in a minority of smokers and is characterized by intermittent exacerbations and clinical subphenotypes such as emphysema and chronic bronchitis. Although sphingolipids as a class are implicated in the pathogenesis of COPD, the particular sphingolipid species associated with COPD subphenotypes remain unknown.
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              Smoking-induced gene expression changes in the bronchial airway are reflected in nasal and buccal epithelium

              Background Cigarette smoking is a leading cause of preventable death and a significant cause of lung cancer and chronic obstructive pulmonary disease. Prior studies have demonstrated that smoking creates a field of molecular injury throughout the airway epithelium exposed to cigarette smoke. We have previously characterized gene expression in the bronchial epithelium of never smokers and identified the gene expression changes that occur in the mainstem bronchus in response to smoking. In this study, we explored relationships in whole-genome gene expression between extrathorcic (buccal and nasal) and intrathoracic (bronchial) epithelium in healthy current and never smokers. Results Using genes that have been previously defined as being expressed in the bronchial airway of never smokers (the "normal airway transcriptome"), we found that bronchial and nasal epithelium from non-smokers were most similar in gene expression when compared to other epithelial and nonepithelial tissues, with several antioxidant, detoxification, and structural genes being highly expressed in both the bronchus and nose. Principle component analysis of previously defined smoking-induced genes from the bronchus suggested that smoking had a similar effect on gene expression in nasal epithelium. Gene set enrichment analysis demonstrated that this set of genes was also highly enriched among the genes most altered by smoking in both nasal and buccal epithelial samples. The expression of several detoxification genes was commonly altered by smoking in all three respiratory epithelial tissues, suggesting a common airway-wide response to tobacco exposure. Conclusion Our findings support a relationship between gene expression in extra- and intrathoracic airway epithelial cells and extend the concept of a smoking-induced field of injury to epithelial cells that line the mouth and nose. This relationship could potentially be utilized to develop a non-invasive biomarker for tobacco exposure as well as a non-invasive screening or diagnostic tool providing information about individual susceptibility to smoking-induced lung diseases.
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                Author and article information

                Contributors
                +31-50-3614916 , i.m.boudewijn@umcg.nl
                a.faiz@umcg.nl
                steiling@bu.edu
                e.van.der.wiel@umcg.nl
                e.d.telenga@umcg.nl
                susanhoonhorst@gmail.com
                n.h.t.ten.hacken@umcg.nl
                c.a.brandsma@umcg.nl
                h.a.m.kerstjens@umcg.nl
                w.timens@umcg.nl
                h.i.heijink01@umcg.nl
                m.r.jonker@umcg.nl
                h.g.de.bruin@umcg.nl
                j.s.vroegop@gmail.com
                h.pasma@znb.nl
                w.boersma@gmail.com
                pascal.wielders@catharinaziekenhuis.nl
                fvandenelshout@alysis.nl
                k.mansour@orbisconcern.nl
                avspira@gmail.com
                mlenburg@bu.edu
                v.guryev@umcg.nl
                d.s.postma@umcg.nl
                m.van.den.berge@umcg.nl
                Journal
                Respir Res
                Respir. Res
                Respiratory Research
                BioMed Central (London )
                1465-9921
                1465-993X
                21 December 2017
                21 December 2017
                2017
                : 18
                : 213
                Affiliations
                [1 ]University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases, Groningen, the Netherlands
                [2 ]University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, the Netherlands
                [3 ]ISNI 0000 0004 0367 5222, GRID grid.475010.7, Division of Computational Biomedicine, , Boston University School of Medicine, ; Boston, MA USA
                [4 ]ISNI 0000 0004 1936 7558, GRID grid.189504.1, Bioinformatics Program, Boston University, ; Boston, MA USA
                [5 ]University of Groningen, University Medical Center Groningen, Department of Pathology, section Medical Biology, Groningen, the Netherlands
                [6 ]ISNI 0000 0004 0631 9063, GRID grid.416468.9, Martini Hospital, Department of Pulmonary Diseases, ; Groningen, the Netherlands
                [7 ]ISNI 0000 0004 0419 3743, GRID grid.414846.b, Medical Center Leeuwarden, Department of Pulmonary Diseases, ; Leeuwarden, the Netherlands
                [8 ]Noordwest Ziekenhuisgroep, Department of Pulmonary Diseases, Alkmaar, the Netherlands
                [9 ]ISNI 0000 0004 0398 8384, GRID grid.413532.2, Catharina Hospital, Department of Pulmonary Diseases, ; Eindhoven, the Netherlands
                [10 ]GRID grid.415930.a, Rijnstate Hospital, Department of Pulmonary Diseases, ; Arnhem, the Netherlands
                [11 ]Orbis Concern, Department of Pulmonary Diseases, Sittard, the Netherlands
                [12 ]European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
                Author information
                http://orcid.org/0000-0003-0438-696X
                Article
                696
                10.1186/s12931-017-0696-5
                5740586
                29268739
                e332fb84-156f-4154-bc1a-a94a59610f67
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 30 August 2017
                : 11 December 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100007560, Chiesi Farmaceutici;
                Funded by: FundRef http://dx.doi.org/10.13039/501100001722, Koninklijke Nederlandse Akademie van Wetenschappen;
                Funded by: FundRef http://dx.doi.org/10.13039/501100004344, Stichting Astma Bestrijding;
                Funded by: FundRef http://dx.doi.org/10.13039/501100004522, Top Institute Pharma;
                Funded by: FundRef http://dx.doi.org/10.13039/501100001721, Rijksuniversiteit Groningen;
                Funded by: University Medical Center Utrecht
                Funded by: Nycomed BV
                Funded by: FundRef http://dx.doi.org/10.13039/100004330, GlaxoSmithKline;
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: NIH/NHLBI 1R01 HL095388
                Award ID: KL2RR025770
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100008503, Center for Integration of Medicine and Innovative Technology;
                Award ID: CIMIT Young Clinician Research Award
                Award Recipient :
                Funded by: RESPIRE2 fellowship
                Award ID: PCOFUNDGA-2012-600368
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2017

                Respiratory medicine
                copd,nasal epithelium,bronchial epithelium,genome wide gene expression,microarray

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