Publications by authors named "Ilse M Boudewijn"

13 Publications

  • Page 1 of 1

Current-Smoking alters Gene Expression and DNA Methylation in the Nasal Epithelium of Asthmatics.

Am J Respir Cell Mol Biol 2021 May 14. Epub 2021 May 14.

University of Technology Sydney, 1994, Respiratory Bioinformatics and Molecular Biology (RBMB), School of Life Sciences, Sydney, New South Wales, Australia.

Current-smoking contributes to worsened asthma prognosis, more severe symptoms and limits the beneficial effects of corticosteroids. As the nasal epithelium can reflect smoking-induced changes in the lower airways, it is a relevant source to investigate changes in gene expression and DNA methylation. This study explores gene expression and DNA methylation changes in current and ex-smokers with asthma. Matched gene expression and epigenome-wide DNA methylation samples collected from nasal brushings of 55 patients enrolled in a clinical trial investigation of current and ex-smoker asthma patients were analysed. Differential gene expression and DNA methylation analyses were conducted comparing current- vs ex-smokers. Expression quantitative trait methylation (eQTM) analysis was completed to explore smoking relevant genes by CpG sites that differ between current and ex-smokers. To investigate the relevance of the smoking-associated DNA methylation changes for the lower airways, significant CpG sites were explored in bronchial biopsies from patients who had stopped smoking. 809 genes and 18,814 CpG sites were differentially associated with current-smoking in the nose. The cis-eQTM analysis uncovered 171 CpG sites whose methylation status associated with smoking-related gene expression, including AHRR, ALDH3A1, CYP1A1 and CYP1B1. Methylation status of CpG sites altered by current-smoking reversed with one-year smoking cessation. We confirm current-smoking alters epigenetic patterns and affects gene expression in the nasal epithelium of asthma patients, which is partially reversible in bronhcial biopsies after smoking cessation. We demonstrate the ability to discern molecular changes in the nasal epithelium, presenting this as a tool in future investigations into disease-relevant effects of tobacco smoke.
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http://dx.doi.org/10.1165/rcmb.2020-0553OCDOI Listing
May 2021

Identifying a nasal gene expression signature associated with hyperinflation and treatment response in severe COPD.

Sci Rep 2020 10 15;10(1):17415. Epub 2020 Oct 15.

Department of Pulmonology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands.

Hyperinflation contributes to dyspnea intensity in COPD. Little is known about the molecular mechanisms underlying hyperinflation and how inhaled corticosteroids (ICS) affect this important aspect of COPD pathophysiology. To investigate the effect of ICS/long-acting β-agonist (LABA) treatment on both lung function measures of hyperinflation, and the nasal epithelial gene-expression profile in severe COPD. 117 patients were screened and 60 COPD patients entered a 1-month run-in period on low-dose ICS/LABA budesonide/formoterol (BUD/F) 200/6 one inhalation b.i.d. Patients were then randomly assigned to 3-month treatment with either a high dose BDP/F 100/6 two inhalations b.i.d. (n = 31) or BUD/F 200/6 two inhalations b.i.d. (n = 29). Lung function measurements and nasal epithelial gene-expression were assessed before and after 3-month treatment and validated in independent datasets. After 3-month ICS/LABA treatment, residual volume (RV)/total lung capacity (TLC)% predicted was reduced compared to baseline (p < 0.05). We identified a nasal gene-expression signature at screening that associated with higher RV/TLC% predicted values. This signature, decreased by ICS/LABA treatment was enriched for genes associated with increased p53 mediated apoptosis was replicated in bronchial biopsies of COPD patients. Finally, this signature was increased in COPD patients compared to controls in nasal, bronchial and small airways brushings. Short-term ICS/LABA treatment improves RV/TLC% predicted in severe COPD. Furthermore, it decreases the expression of genes involved in the signal transduction by the p53 class mediator, which is a replicable COPD gene expression signature in the upper and lower airways.Trial registration: ClinicalTrials.gov registration number NCT01351792 (registration date May 11, 2011), ClinicalTrials.gov registration number NCT00848406 (registration date February 20, 2009), ClinicalTrials.gov registration number NCT00158847 (registration date September 12, 2005).
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http://dx.doi.org/10.1038/s41598-020-72551-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7562702PMC
October 2020

A Novel Role for Bronchial MicroRNAs and Long Noncoding RNAs in Asthma Remission.

Am J Respir Crit Care Med 2020 08;202(4):614-618

University Medical Center Groningen, University of GroningenGroningen, the Netherlands.

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http://dx.doi.org/10.1164/rccm.201908-1610LEDOI Listing
August 2020

Current Smoking is Associated with Decreased Expression of miR-335-5p in Parenchymal Lung Fibroblasts.

Int J Mol Sci 2019 Oct 18;20(20). Epub 2019 Oct 18.

University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, 9713 GZ Groningen, The Netherlands.

Cigarette smoking causes lung inflammation and tissue damage. Lung fibroblasts play a major role in tissue repair. Previous studies have reported smoking-associated changes in fibroblast responses and methylation patterns. Our aim was to identify the effect of current smoking on miRNA expression in primary lung fibroblasts. Small RNA sequencing was performed on lung fibroblasts from nine current and six ex-smokers with normal lung function. MiR-335-5p and miR-335-3p were significantly downregulated in lung fibroblasts from current compared to ex-smokers (false discovery rate (FDR) <0.05). Differential miR-335-5p expression was validated with RT-qPCR (-value = 0.01). The results were validated in lung tissue from current and ex-smokers and in bronchial biopsies from non-diseased smokers and never-smokers (-value <0.05). The methylation pattern of the miR-335 host gene, determined by methylation-specific qPCR, did not differ between current and ex-smokers. To obtain insights into the genes regulated by miR-335-5p in fibroblasts, we overlapped all proven miR-335-5p targets with our previously published miRNA targetome data in lung fibroblasts. This revealed , , and as likely targets of miR-335-5p in lung fibroblasts. Our study indicates that miR-335-5p downregulation due to current smoking may affect its function in lung fibroblasts by targeting , and .
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http://dx.doi.org/10.3390/ijms20205176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829537PMC
October 2019

MiR-31-5p: A shared regulator of chronic mucus hypersecretion in asthma and chronic obstructive pulmonary disease.

Allergy 2020 03 23;75(3):703-706. Epub 2019 Oct 23.

Groningen Research Institute for Asthma and COPD, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.

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http://dx.doi.org/10.1111/all.14060DOI Listing
March 2020

Associations of AMP and adenosine induced dyspnea sensation to large and small airways dysfunction in asthma.

BMC Pulm Med 2019 Jan 28;19(1):23. Epub 2019 Jan 28.

Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, PO box 30.0001, 9700, RB, Groningen, The Netherlands.

Background: Bronchial provocation is often used to confirm asthma. Dyspnea sensation, however, associates poorly with the evoked drop in FEV. Provocation tests only use the large airways parameter FEV, although dyspnea is associated with both large- and small airways dysfunction. Aim of this study was to explore if adenosine 5'-monophosphate (AMP) and adenosine evoke an equal dyspnea sensation and if dyspnea associates better with large or small airways dysfunction.

Methods: We targeted large airways with AMP and small airways with dry powder adenosine in 59 asthmatic (ex)-smokers with ≥5 packyears, 14 ± 7 days apart. All subjects performed spirometry, impulse oscillometry (IOS), and Borg dyspnea score. In 36 subjects multiple breath nitrogen washout (MBNW) was additionally performed. We analyzed the association of the change (Δ) in Borg score with the change in large and small airways parameters, using univariate and multivariate linear regression analyses. MBNW was analyzed separately.

Results: Provocation with AMP and adenosine evoked similar levels of dyspnea. ΔFEV was not significantly associated with ΔBorg after either AMP or adenosine provocation, in both univariate and multivariate analyses. In multivariate linear regression, a decrease in FEF during adenosine provocation was independently associated with an increase in Borg. In the multivariate analyses for AMP provocation, no significant associations were found between ΔBorg and any large or small airways parameters.

Conclusion: AMP and adenosine induce equally severe dyspnea sensations. Our results suggest that dyspnea induced with dry powder adenosine is related to small airways involvement, while neither large nor small airways dysfunction was associated with AMP-induced dyspnea.

Trail Registration: NCT01741285 at www.clinicaltrials.gov , first registered Dec 4th, 2012.
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http://dx.doi.org/10.1186/s12890-019-0783-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348600PMC
January 2019

Predictors of clinical response to extrafine and non-extrafine particle inhaled corticosteroids in smokers and ex-smokers with asthma.

Respir Res 2018 Dec 18;19(1):256. Epub 2018 Dec 18.

Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, PO Box 30.0001, 9700, RB, Groningen, The Netherlands.

We performed a post-hoc analysis of the OLiVIA-study investigating whether current and ex-smoking asthmatics with small airways dysfunction (SAD) show a better response in airway hyperresponsiveness (AHR) to small particle adenosine after treatment with extrafine compared to non-extrafine particle inhaled corticosteroids (ICS), and to investigate which clinical parameters predict a favorable response to both treatments. We show that smoking and ex-smoking asthmatics with and without SAD have a similar treatment response with either extrafine or non-extrafine particle ICS. We also found that lower blood neutrophils are associated with a smaller ICS-response in smokers and ex-smokers with asthma, independent from the level of blood eosinophils.
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http://dx.doi.org/10.1186/s12931-018-0961-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299530PMC
December 2018

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

Respir Res 2017 12 21;18(1):213. Epub 2017 Dec 21.

University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases, Groningen, the Netherlands.

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 < 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).
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http://dx.doi.org/10.1186/s12931-017-0696-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740586PMC
December 2017

Extrafine compared to non-extrafine particle inhaled corticosteroids in smokers and ex-smokers with asthma.

Respir Med 2017 Sep 8;130:35-42. Epub 2017 Jul 8.

University of Groningen, University Medical Centre Groningen, Department of Pulmonary Diseases, PO Box 30.0001, 9700 RB Groningen, The Netherlands; University of Groningen, University Medical Centre Groningen, Groningen Research Institute for Asthma and COPD, PO Box 30.0001, 9700 RB Groningen, The Netherlands. Electronic address:

Background: Smoking is as prevalent in asthmatics as in the general population. Asthmatic smokers benefit less from inhaled corticosteroids (ICS) than non-smoking asthmatics, possibly due to more smoking-induced small airways disease. Thus targeting small airways may be important in treating asthmatic (ex-)smokers. We hypothesized that extrafine particle ICS improve small airways function more than non-extrafine particle ICS in asthmatic (ex-)smokers.

Methods: We performed an open-label, randomized, three-way cross-over study comparing extrafine beclomethasone (HFA-QVAR) to non-extrafine beclomethasone (HFA-Clenil) and fluticasone (HFA-Flixotide) in 22 smokers and 21 ex-smokers with asthma (?5 packyears).

Results: Improvement from baseline in PD adenosine after using QVAR, Clenil or Flixotide was 1.04 ± 1.71, 1.09 ± 2.12 and 0.94 ± 1.97 doubling doses, mean ± standard deviation (SD), respectively. The change from baseline in R-R at PD adenosine after using QVAR, Clenil or Flixotide was ?0.02 ± 0.27, 0.02 ± 0.21, and ?0.02 ± 0.31 kPa sL, mean ± SD, respectively. The change in PD adenosine and R-R at PD adenosine were neither statistically significant different between QVAR and Clenil (p = 0.86 and p = 0.82) nor between QVAR and Flixotide (p = 0.50 and p = 0.96).

Conclusion: Similar effectiveness in improving small airways function was found for extrafine and non-extrafine particle ICS treatment for asthmatic smokers and ex-smokers.
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http://dx.doi.org/10.1016/j.rmed.2017.07.005DOI Listing
September 2017

Effects of ageing and smoking on pulmonary computed tomography scans using parametric response mapping.

Eur Respir J 2015 Oct 25;46(4):1193-6. Epub 2015 Jun 25.

Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands Both authors contributed equally

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http://dx.doi.org/10.1183/09031936.00009415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4591191PMC
October 2015

Nocturnal dry cough in the first 7 years of life is associated with asthma at school age.

Pediatr Pulmonol 2015 Sep 26;50(9):848-55. Epub 2014 Aug 26.

University of Groningen, University Medical Center Groningen, Department of Epidemiology, GRIAC Research Institute, Groningen, The Netherlands.

Background: Childhood wheeze is an important, well-known risk factor for asthma, yet little is known about the contribution of nocturnal dry cough. We investigated the association of nocturnal dry cough at ages 1-7 years with doctor-diagnosed asthma at 8 years of age, both in the presence and absence of wheeze.

Methods: Data of 3,252 children from the PIAMA birth cohort were studied. Parents reported the presence of nocturnal dry cough, wheeze, and doctor-diagnosed asthma in the past 12 months yearly, from birth up to the age of 8 years.

Results: Nocturnal dry cough without wheeze was significantly associated with doctor-diagnosed asthma at age 8, except for age 1 (range of Relative Risks (RR) at ages 2-7: 1.8 (age 5) - 7.1 (age 7), all P-values <0.048). As expected, wheeze without nocturnal dry cough was strongly associated with doctor-diagnosed asthma at age 8 (range of RR: 2.0 (age 1) - 22.2 (age 7), all P-values <0.003). Of interest, nocturnal dry cough with wheeze showed the strongest association with doctor-diagnosed asthma at age 8 (range of RR: 3.7 (age 1) - 26.0 (age 7), all P-values <0.001). The relative excess risk of asthma at age 8 due to interaction of nocturnal dry cough with wheeze at age 1 year was 1.8 (0.1-3.6, P < 0.01).

Conclusion: Nocturnal dry cough and wheeze in early childhood are both independently associated with asthma at school age. The presence of both nocturnal dry cough and wheeze at age 1 almost doubles the risk of asthma at age 8 compared to wheeze alone.
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http://dx.doi.org/10.1002/ppul.23092DOI Listing
September 2015
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