Kruimelpad

ERS 2017

  • Aanvrager: Dr K. Imkamp

Nasal epithelial gene expression as a new biomarker in obstructive airways disease. European Respiratory Society International Congress 2017, Milan, 9-13 September 2017 K. Imkamp and I.M. Boudewijn University of Groningen, University Medical Center Groningen, Department of pulmonary diseases, Groningen, The Netherlands

Introduction
Airway epithelial gene expression is a promising technique to characterize pulmonary diseases. It has been shown that bronchial epithelial gene expression obtained by bronchial brushes can discriminate COPD patients from healthy controls(1). Additionally, 30-month treatment with inhaled corticosteroids changed the expression of 278 genes in bronchial epithelium of COPD patients(2). Of interest, a more pronounced change in expression of these 278 genes was associated with a lower decline in FEV1 and improvement in respiratory symptoms. These findings indicate that bronchial epithelial gene expression can function as a biomarker in distinguishing respiratory diseases or in prediction of response to treatment.
The gold standard to study airway epithelial gene expression is the investigation of biosamples of the lower airways, which are usually obtained by bronchoscopy. However, this is an invasive procedure, with a substantial burden to patients, that is associated with high costs and cannot be used on a large scale. Non-invasive alternatives are needed and it has been shown by Shridhar et al that the expression of several genes is commonly altered by smoking in bronchial, nasal and buccal epithelium, suggesting a common airway-wide response to tobacco smoke(3). Other studies support these findings by showing overlap in nasal and bronchial gene expression in healthy subjects and children with asthma (4,5). These studies support the concept of an airway field of injury throughout the respiratory tract. Due to this relationship in gene expression between upper- and lower airway epithelium, nasal epithelium could potentially serve as a biomarker for the lower airways.
However, a drawback of previous studies is that they used non-matched samples (3,4) or have investigated a very limited number of samples (5) to support the validity of this approach. To determine to what extent nasal epithelium can be used as a proxy for bronchial epithelium, we performed a study to investigate the overlap in gene expression between both locations within 77 respiratory healthy controls. Focusing on genes not-ubiquitously expressed in all tissues, we identified 6,806 and 6,797 genes to be expressed in nasal and bronchial epithelium, respectively, with an overlap of 98.2% (6). When comparing the expression of individual genes between nasal and bronchial epithelium, we found 619 genes (3.4% of total, BH-adjusted p<0.05) that were significantly correlated between bronchial and nasal samples. We also investigated which genes drive the differences between the two locations and found 723 genes with higher and 969 with lower expression (Fold-change±2, FDR-adjusted p<0.05, figure 1) in nasal compared to bronchial brushes. Our findings underscore the hypothesis that nasal epithelium can be used as a proxy for the bronchus, however this is highly gene-dependent.
As overlap between bronchial and nasal epithelial gene expression has been demonstrated by Imkamp et al, it is clear that nasal epithelial gene expression has the potential to serve as a biomarker in respiratory diseases. We have performed a study in which we investigated nasal epithelial gene expression between smoking COPD patients and smoking controls and found 135 genes to be differentially expressed between COPD patients and controls (FDR<0.01)(7). We subsequently compared nasal- and bronchial COPD-associated gene expression using Gene Set Enrichment Analysis (GSEA), and found significant overlap of genes associated with COPD in the nose and the bronchus in 2 independent cohorts (figure 2). At the ERS, one other study compared nasal and bronchial gene expression in asthma patients with or without allergic rhinitis and controls (8). They compared nasal and bronchial gene expression signatures associated with Th2 inflammation (a hallmark of an important asthma phenotype) in the nose and the bronchus and found that the Th2 gene signature was concordant between the nose and bronchus, emphasizing that nasal epithelium can be used to study respiratory diseases of the ‘lower airways’ such as asthma or COPD.
In conclusion, nasal epithelial gene expression is a promising technique to characterize pulmonary diseases non-invasively. We have shown that nasal gene expression reflects bronchial expression, both in healthy subjects and COPD patients. Further studies are warranted to explore future applications, such as distinguishing distinct phenotypes or prediction of treatment response.

References

1. 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(9):933–42.
2. van den Berge M, Steiling K, Timens W, Hiemstra PS, Sterk PJ, Heijink IH, et al. Airway gene expression in COPD is dynamic with inhaled corticosteroid treatment and reflects biological pathways associated with disease activity. Thorax 2014;69(1):14-23.
3. 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.
4. Poole A, Urbanek C, Eng C et al. Dissecting Childhood Asthma with Nasal Transcriptomics Distinguishes Subphenotypes of Disease. JACI 2014;133(3):1–18.
5. 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.
6. Imkamp K, Berg M, Vermeulen CJ, Heijink IH, Guryev V, Koppelman GH, van den Berge M, Faiz A. Comparison of gene expression profiles from nasal and bronchial brushes. Eur Respir J. Sep 2017; Abstract n. OA2910
7. Boudewijn IM, Faiz A, Steiling K, van der Wiel E, Telenga E, Hoonhorst SJ, ten Hacken NHT et al. A nasal gene expression profile differentiates individuals with and without COPD and overlaps bronchial gene expression Eur Respir J. 2017;Abstract n. PA4470
8. Giovannini-Chami L, Paquet A, Sanfiorenzo C, Pons N, Cazareth J et al. The “one airway, one disease” concept at the light of Th2 inflammation. Eur Respir J. 2017;Abstract n.PA4938