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Boudewijn et al. Respiratory Research (2017) 18:213 DOI 10.1186/s12931-017-0696-5 RESEARCH Open Access Nasal gene expression differentiates COPD from controls and overlaps bronchial gene expression Ilse M. Boudewijn1,2* , Alen Faiz1,2, Katrina Steiling3,4, Erica van der Wiel1,2, Eef D. Telenga1,2, Susan J. M. Hoonhorst1,2, Nick H. T. ten Hacken1,2, Corry-Anke Brandsma2,5, Huib A. M. Kerstjens1,2, Wim Timens2,5, Irene H. Heijink1,2,5, Marnix R. Jonker5, Harold G. de Bruin5, J. Sebastiaan Vroegop6, Henk R. Pasma7, Wim G. Boersma8, Pascal Wielders9, Frank van den Elshout10, Khaled Mansour11, Avrum Spira3,4, Marc E. Lenburg3,4, Victor Guryev12, Dirkje S. Postma1,2 and Maarten van den Berge1,2 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). Keywords: COPD, Nasal epithelium, Bronchial epithelium, Genome wide gene expression, Microarray * Correspondence: [email protected] 1University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases, Groningen, the Netherlands 2University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, the Netherlands Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This 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. Boudewijn et al. Respiratory Research (2017) 18:213 Page 2 of 10 Background Center Groningen (UMCG) and seven other participating Chronic obstructive pulmonary disease (COPD) is one of hospitals in The Netherlands between 2011 and 2012. the most common chronic diseases affecting over 10% of From this study, we only included current smokers adults older than 65 years worldwide [1]. It is characterized aged 40 years and older with at least 10 pack years, a by incompletely reversible airflow obstruction, which re- forced expiratory volume in 1 s (FEV1)/forced vital sults in reduced quality of life and increased mortality. capacity (FVC) < 0.7 and an FEV1 < 60% predicted. COPD is currently the fourth leading cause of death world- Controls were recruited in the UMCG between 2009 wide, according to the World Health Organization [2]. and 2012, including only current smokers aged 40 years Some genetic factors, such as alpha-1 anti-trypsin defi- and older with normal pulmonary function (i.e. post- ciency, and environmental exposures, such as cigarette bronchodilator FEV1/FVC > lower limit of normal, ab- smoking, are well-established contributors to COPD, yet sence of bronchial hyperresponsiveness and reversibility the precise molecular mechanisms of the disease remain of FEV1 to salbutamol <10% predicted). Spirometry and to be elucidated. Genome-wide gene expression profiling body plethysmography measurements were performed ac- offers opportunities to develop new insights in the origins cording to international guidelines [6, 7]. Symptom scores of COPD based on molecular features. were assessed using the Clinical COPD Questionnaire The airway epithelium is the initial site of exposure (CCQ) [8]. to cigarette smoke and reflects molecular changes asso- Nasal epithelial brushings were obtained using a soft ciated with both cigarette smoke exposure and smoking- cytology brush sampling the inferior turbinate of the associated lung disease. We have previously demonstrated nose [5, 9]. Total RNA was isolated and microarray that the bronchial airway epithelium responds to cigarette hybridization to Affymetrix Human Gene 1.0 ST Arrays smoke exposure with characteristic alterations in gene ex- was performed. pression [3]. Building upon this observation, we identified a bronchial airway gene expression signature associated Data normalization, preprocessing and analysis with COPD and disease severity that is similarly altered in Statistical analyses were performed using R version 3.3.2. COPD-affected lung tissue [4]. These data suggest that The quality of the microarray hybridization was assessed bronchial gene expression obtained by bronchoscopy may as previously described [4]. Nasal gene expression pro- be applied to monitor disease activity in COPD. However, files associated with COPD were identified using a linear the relative invasiveness of this procedure precludes its regression model with the log2-transformed expression use in large populations. We therefore characterized the of each gene as dependent variable, and COPD, age, gen- upper airway genomic response to cigarette smoke expos- der, packyears, RNA integrity number (RIN), and the ure by profiling epithelial cells collected by brushing the first 4 principal components (PCs) as independent vari- inferior turbinate of the nose. Using paired bronchial and ables. We adjusted for PCs to reduce technical variation nasal airway samples obtained from the same healthy in the microarray data (online Additional file 1). A individuals, we showed that smoking-induced changes in Benjamini-Hochberg False Discovery Rate (FDR) proced- bronchial airway gene expression are similarly altered in ure was applied to account for multiple testing, with an the nasal epithelium [5]. Therefore, nasal epithelial gene FDR < 0.01 indicating statistical significance [10]. expression profiling could potentially function as a non-invasive biomarker in COPD. Comparison of COPD-associated gene expression changes In the present study, we investigated whether gene ex- in the nasal and bronchial epithelium pression profiling of the nasal epithelium can distinguish We compared nasal COPD-associated gene expression with between patients with and without COPD. Additionally, bronchial COPD-associated gene expression in two inde- we established whether COPD-associated gene expres- pendent datasets of bronchial brushings (comparator co- sion changes in nasal epithelium reflect those occurring hort 1 and comparator cohort 2 as described below), using in the bronchial epithelium. Gene Set Enrichment Analysis (GSEA) version 2.2.4 [11]. The local ethical committees approved the two studies and Methods all included subjects gave their written informed consent. The online supplement provides additional details and a flowchart of the identification cohort and comparator – Comparator cohort 1 was a previously published cohorts (online Additional file 1: Figure E1). dataset of bronchial airway gene expression in current and former smokers with and without Identification cohort, sample collection and processing moderate-to-severe COPD (GSE37147) [4]. The local ethical committees approved the studies and all – Comparator cohort 2 was an independent cohort of included subjects gave their written informed consent. current and former smokers with and without COPD patients were recruited in the University Medical moderate-to-severe COPD who participated in a Boudewijn et al. Respiratory Research (2017) 18:213 Page 3 of 10 previous study in the UMCG [12, 13]. COPD was we performed Gene Ontology enrichment analyses defined as FEV1/FVC ≤ 0.7. Bronchial brushes were (GOrilla) on COPD-associated genes exhibiting dif- taken during bronchoscopy and RNA was isolated ferential expression in nasal samples. and processed as described in the online supplement. Results We performed GSEA for genes associated with COPD Study populations in nasal and bronchial epithelium. First, we investigated The identification cohort consisted of 31 COPD patients COPD-associated nasal gene expression with COPD- and 22 controls
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