Publications by authors named "Dirkje S Postma"

432 Publications

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

Phenotypic and functional translation of IL1RL1 locus polymorphisms in lung tissue and asthmatic airway epithelium.

JCI Insight 2020 04 23;5(8). Epub 2020 Apr 23.

Department of Human Development and.

The IL1RL1 (ST2) gene locus is robustly associated with asthma; however, the contribution of single nucleotide polymorphisms (SNPs) in this locus to specific asthma subtypes and the functional mechanisms underlying these associations remain to be defined. We tested for association between IL1RL1 region SNPs and characteristics of asthma as defined by clinical and immunological measures and addressed functional effects of these genetic variants in lung tissue and airway epithelium. Utilizing 4 independent cohorts (Lifelines, Dutch Asthma GWAS [DAG], Genetics of Asthma Severity and Phenotypes [GASP], and Manchester Asthma and Allergy Study [MAAS]) and resequencing data, we identified 3 key signals associated with asthma features. Investigations in lung tissue and primary bronchial epithelial cells identified context-dependent relationships between the signals and IL1RL1 mRNA and soluble protein expression. This was also observed for asthma-associated IL1RL1 nonsynonymous coding TIR domain SNPs. Bronchial epithelial cell cultures from asthma patients, exposed to exacerbation-relevant stimulations, revealed modulatory effects for all 4 signals on IL1RL1 mRNA and/or protein expression, suggesting SNP-environment interactions. The IL1RL1 TIR signaling domain haplotype affected IL-33-driven NF-κB signaling, while not interfering with TLR signaling. In summary, we identify that IL1RL1 genetic signals potentially contribute to severe and eosinophilic phenotypes in asthma, as well as provide initial mechanistic insight, including genetic regulation of IL1RL1 isoform expression and receptor signaling.
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http://dx.doi.org/10.1172/jci.insight.132446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205441PMC
April 2020

Integrated proteogenomic approach identifying a protein signature of COPD and a new splice variant of SORBS1.

Thorax 2020 02 14;75(2):180-183. Epub 2020 Jan 14.

Department of Analytical Biochemistry, University of Groningen, Groningen Research Institute of Pharmacy, Groningen, the Netherlands.

Translation of genomic alterations to protein changes in chronic obstructive pulmonary disease (COPD) is largely unexplored. Using integrated proteomic and RNA sequencing analysis of COPD and control lung tissues, we identified a protein signature in COPD characterised by extracellular matrix changes and a potential regulatory role for SUMO2. Furthermore, we identified 61 differentially expressed novel, non-reference, peptides in COPD compared with control lungs. This included two peptides encoding for a new splice variant of SORBS1, of which the transcript usage was higher in COPD compared with control lungs. These explorative findings and integrative proteogenomic approach open new avenues to further unravel the pathology of COPD.
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http://dx.doi.org/10.1136/thoraxjnl-2019-213200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029225PMC
February 2020

IL1RL1 gene variations are associated with asthma exacerbations in children and adolescents using inhaled corticosteroids.

Allergy 2020 04 17;75(4):984-989. Epub 2019 Dec 17.

Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

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http://dx.doi.org/10.1111/all.14125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176513PMC
April 2020

Occupational exposure to gases/fumes and mineral dust affect DNA methylation levels of genes regulating expression.

Hum Mol Genet 2019 08;28(15):2477-2485

Department of Epidemiology.

Many workers are daily exposed to occupational agents like gases/fumes, mineral dust or biological dust, which could induce adverse health effects. Epigenetic mechanisms, such as DNA methylation, have been suggested to play a role. We therefore aimed to identify differentially methylated regions (DMRs) upon occupational exposures in never-smokers and investigated if these DMRs associated with gene expression levels. To determine the effects of occupational exposures independent of smoking, 903 never-smokers of the LifeLines cohort study were included. We performed three genome-wide methylation analyses (Illumina 450 K), one per occupational exposure being gases/fumes, mineral dust and biological dust, using robust linear regression adjusted for appropriate confounders. DMRs were identified using comb-p in Python. Results were validated in the Rotterdam Study (233 never-smokers) and methylation-expression associations were assessed using Biobank-based Integrative Omics Study data (n = 2802). Of the total 21 significant DMRs, 14 DMRs were associated with gases/fumes and 7 with mineral dust. Three of these DMRs were associated with both exposures (RPLP1 and LINC02169 (2×)) and 11 DMRs were located within transcript start sites of gene expression regulating genes. We replicated two DMRs with gases/fumes (VTRNA2-1 and GNAS) and one with mineral dust (CCDC144NL). In addition, nine gases/fumes DMRs and six mineral dust DMRs significantly associated with gene expression levels. Our data suggest that occupational exposures may induce differential methylation of gene expression regulating genes and thereby may induce adverse health effects. Given the millions of workers that are exposed daily to occupational exposures, further studies on this epigenetic mechanism and health outcomes are warranted.
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http://dx.doi.org/10.1093/hmg/ddz067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6643643PMC
August 2019

Genetic risk scores do not improve asthma prediction in childhood.

J Allergy Clin Immunol 2019 09 27;144(3):857-860.e7. Epub 2019 May 27.

Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2019.05.017DOI Listing
September 2019

Pathway analysis of a genome-wide gene by air pollution interaction study in asthmatic children.

J Expo Sci Environ Epidemiol 2019 06 26;29(4):539-547. Epub 2019 Apr 26.

Channing Division of Network Medicine, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA, United States.

Objectives: We aimed to investigate the role of genetics in the respiratory response of asthmatic children to air pollution, with a genome-wide level analysis of gene by nitrogen dioxide (NO) and carbon monoxide (CO) interaction on lung function and to identify biological pathways involved.

Methods: We used a two-step method for fast linear mixed model computations for genome-wide association studies, exploring whether variants modify the longitudinal relationship between 4-month average pollution and post-bronchodilator FEV in 522 Caucasian and 88 African-American asthmatic children. Top hits were confirmed with classic linear mixed-effect models. We used the improved gene set enrichment analysis for GWAS (i-GSEA4GWAS) to identify plausible pathways.

Results: Two SNPs near the EPHA3 (rs13090972 and rs958144) and one in TXNDC8 (rs7041938) showed significant interactions with NO in Caucasians but we did not replicate this locus in African-Americans. SNP-CO interactions did not reach genome-wide significance. The i-GSEA4GWAS showed a pathway linked to the HO-1/CO system to be associated with CO-related FEV changes. For NO-related FEV responses, we identified pathways involved in cellular adhesion, oxidative stress, inflammation, and metabolic responses.

Conclusion: The host lung function response to long-term exposure to pollution is linked to genes involved in cellular adhesion, oxidative stress, inflammatory, and metabolic pathways.
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http://dx.doi.org/10.1038/s41370-019-0136-3DOI Listing
June 2019

Exploring the relevance and extent of small airways dysfunction in asthma (ATLANTIS): baseline data from a prospective cohort study.

Lancet Respir Med 2019 05 12;7(5):402-416. Epub 2019 Mar 12.

University of Arizona College of Medicine, Department of Medicine, Tucson, AZ, USA.

Background: Small airways dysfunction (SAD) is well recognised in asthma, yet its role in the severity and control of asthma is unclear. This study aimed to assess which combination of biomarkers, physiological tests, and imaging markers best measure the presence and extent of SAD in patients with asthma.

Methods: In this baseline assessment of a multinational prospective cohort study (the Assessment of Small Airways Involvement in Asthma [ATLANTIS] study), we recruited participants with and without asthma (defined as Global Initiative for Asthma severity stages 1-5) from general practices, the databases of chest physicians, and advertisements at 29 centres across nine countries (Brazil, China, Germany, Italy, Spain, the Netherlands, the UK, the USA, and Canada). All participants were aged 18-65 years, and participants with asthma had received a clinical diagnosis of asthma more than 6 months ago that had been confirmed by a chest physician. This diagnosis required support by objective evidence at baseline or during the past 5 years, which could be: positive airway hyperresponsiveness to methacholine, positive reversibility (a change in FEV ≥12% and ≥200 mL within 30 min) after treatment with 400 μg of salbutamol in a metered-dose inhaler with or without a spacer, variability in peak expiratory flow of more than 20% (measured over 7 days), or documented reversibility after a cycle (eg, 4 weeks) of maintenance anti-asthma treatment. The inclusion criteria also required that patients had stable asthma on any previous regular asthma treatment (including so-called rescue β2-agonists alone) at a stable dose for more than 8 weeks before baseline and had smoked for a maximum of 10 pack-years in their lifetime. Control group participants were recruited by advertisements; these participants were aged 18-65 years, had no respiratory symptoms compatible with asthma or chronic obstructive pulmonary disease, normal spirometry, and normal airways responsiveness, and had smoked for a maximum of 10 pack-years. We assessed all participants with spirometry, body plethysmography, impulse oscillometry, multiple breath nitrogen washout, CT (in selected participants), and questionnaires about asthma control, asthma-related quality of life (both in participants with asthma only), and health status. We applied structural equation modelling in participants with asthma to assess the contribution of all physiological and CT variables to SAD, from which we defined clinical SAD and CT SAD scores. We then classified patients with asthma into SAD groups with model-based clustering, and we compared asthma severity, control, and health-care use during the past year by SAD score and by SAD group. This trial is registered with ClinicalTrials.gov, number NCT02123667.

Findings: Between June 30, 2014, and March 3, 2017, we recruited and evaluated 773 participants with asthma and 99 control participants. All physiological measures contributed to the clinical SAD model with the structural equation modelling analysis. The prevalence of SAD in asthma was dependent on the measure used; we found the lowest prevalence of SAD associated with acinar airway ventilation heterogeneity (S), an outcome determined by multiple breath nitrogen washout that reflects ventilation heterogeneity in the most peripheral, pre-acinar or acinar airways. Impulse oscillometry and spirometry results, which were used to assess dysfunction of small-sized to mid-sized airways, contributed most to the clinical SAD score and differed between the two SAD groups. Participants in clinical SAD group 1 (n=452) had milder SAD than group 2 and comparable multiple breath nitrogen washout S to control participants. Participants in clinical SAD group 2 (n=312) had abnormal physiological SAD results relative to group 1, particularly their impulse oscillometry and spirometry measurements, and group 2 participants also had more severe asthma (with regard to asthma control, treatments, exacerbations, and quality of life) than group 1. Clinical SAD scores were higher (indicating more severe SAD) in group 2 than group 1, and we found that these scores were related to asthma control, severity, and exacerbations. We found no correlation between clinical SAD and CT SAD scores.

Interpretation: SAD is a complex and silent signature of asthma that is likely to be directly or indirectly captured by combinations of physiological tests, such as spirometry, body plethysmography, impulse oscillometry, and multiple breath nitrogen washout. SAD is present across patients with all severities of asthma, but it is particularly prevalent in severe disease. The clinical classification of SAD into two groups (a milder and a more severe group) by use of impulse oscillometry and spirometry, which are easy to use, is meaningful given its association with GINA severity stages, asthma control, quality of life, and exacerbations.

Funding: Chiesi Farmaceutici SpA.
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http://dx.doi.org/10.1016/S2213-2600(19)30049-9DOI Listing
May 2019

Effect of long-term corticosteroid treatment on microRNA and gene-expression profiles in COPD.

Eur Respir J 2019 04 25;53(4). Epub 2019 Apr 25.

University of Groningen, University Medical Center Groningen, Dept of Pulmonary Diseases, Groningen, The Netherlands.

The aim was to investigate whether microRNA (miRNA) expression is modulated by inhaled corticosteroid (ICS) treatmentWe performed genome-wide miRNA analysis on bronchial biopsies of 69 moderate/severe chronic obstructive pulmonary disease (COPD) patients at baseline and after 6- and 30-month treatment with the ICS fluticasone propionate or placebo. The effect of ICS on miRNA expression was validated in differentiated primary bronchial epithelial cultures, and functional studies were conducted in BEAS-2B cells. MiRNAs affected by ICS and their predicted targets were compared to an independent miRNA dataset of bronchial brushings from COPD patients and healthy controls.Treatment with ICS for both 6 and 30 months significantly altered the expression of four miRNAs, including miR-320d, which was increased during ICS treatment compared with placebo. The ICS-induced increase of miR-320d was confirmed in primary airway epithelial cells. MiR-320d negatively correlated targets were enriched for pro-inflammatory genes and were increased in the bronchial brushes of patients with lower lung function in the independent dataset. Overexpression of miR-320d in BEAS-2B cells dampened cigarette smoke extract-induced pro-inflammatory activity inhibition of nuclear factor-κB.Collectively, we identified miR-320d as a novel mediator of ICS, regulating the pro-inflammatory response of the airway epithelium.
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http://dx.doi.org/10.1183/13993003.01202-2018DOI Listing
April 2019

Limited overlap in significant hits between genome-wide association studies on two airflow obstruction definitions in the same population.

BMC Pulm Med 2019 Mar 7;19(1):58. Epub 2019 Mar 7.

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

Background: Airflow obstruction is a hallmark of chronic obstructive pulmonary disease (COPD), and is defined as either the ratio between forced expiratory volume in one second and forced vital capacity (FEV/FVC) < 70% or < lower limit of normal (LLN). This study aimed to assess the overlap between genome-wide association studies (GWAS) on airflow obstruction using these two definitions in the same population stratified by smoking.

Methods: GWASes were performed in the LifeLines Cohort Study for both airflow obstruction definitions in never-smokers (NS = 5071) and ever-smokers (ES = 4855). The FEV/FVC < 70% models were adjusted for sex, age, and height; FEV/FVC < LLN models were not adjusted. Ever-smokers models were additionally adjusted for pack-years and current-smoking. The overlap in significantly associated SNPs between the two definitions and never/ever-smokers was assessed using several p-value thresholds. To quantify the agreement, the Pearson correlation coefficient was calculated between the p-values and ORs. Replication was performed in the Vlagtwedde-Vlaardingen study (NS = 432, ES = 823). The overlapping SNPs with p < 10 were validated in the Vlagtwedde-Vlaardingen and Rotterdam Study cohorts (NS = 1966, ES = 3134) and analysed for expression quantitative trait loci (eQTL) in lung tissue (n = 1087).

Results: In the LifeLines cohort, 96% and 93% of the never- and ever-smokers were classified concordantly based on the two definitions. 26 and 29% of the investigated SNPs were overlapping at p < 0.05 in never- and ever-smokers, respectively. At p < 10 the overlap was 4% and 6% respectively, which could be change findings as shown by simulation studies. The effect estimates of the SNPs of the two definitions correlated strongly, but the p-values showed more variation and correlated only moderately. Similar observations were made in the Vlagtwedde-Vlaardingen study. Two overlapping SNPs in never-smokers (NFYC and FABP7) had the same direction of effect in the validation cohorts and the NFYC SNP was an eQTL for NFYC-AS1. NFYC is a transcription factor that binds to several known COPD genes, and FABP7 may be involved in abnormal pulmonary development.

Conclusions: The definition of airflow obstruction and the population under study may be important determinants of which SNPs are associated with airflow obstruction. The genes FABP7 and NFYC(-AS1) could play a role in airflow obstruction in never-smokers specifically.
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http://dx.doi.org/10.1186/s12890-019-0811-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407273PMC
March 2019

Diagnosis and management of asthma, COPD and asthma-COPD overlap among primary care physicians and respiratory/allergy specialists: A global survey.

Clin Respir J 2019 Jun 24;13(6):355-367. Epub 2019 Mar 24.

Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom.

Introduction: Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) is a heterogenous condition with clinical features shared by both asthma and COPD.

Objectives: This online global survey of respiratory/allergy specialists and primary care practitioners (PCPs) was performed to understand current clinical approaches to the differential diagnosis and management of asthma, COPD and ACO.

Methods: Respondents were recruited through: (a) a global online physician respondent community (49,980 PCPs and 7205 specialists); (b) market research agents; (c) experts; (d) professional societies; (e) colleague invitation. Respondents were presented with a survey including hypothetical clinical scenarios of diagnostic uncertainty to identify management approaches.

Results: 891 responses (447 PCPs and 444 specialists) were collected across 13 countries. Reported features used for diagnosis of asthma and COPD were consistent with practice guidelines, but there was variability in those selected for ACO diagnosis. Features typically selected by specialists focused on spirometry/history, while PCPs focused on previous treatment/symptoms. Most respondents could correctly diagnose patients with features of ACO; however, features selected for theoretical diagnosis were often different to those selected in the case scenarios. Additionally, treatment selection was often inconsistent with guidelines, with over half of respondents not recommending inhaled corticosteroids in a patient with ACO and dominant features of asthma.

Conclusion: While most PCPs and respiratory/allergy specialists can reach a working diagnosis of ACO, there remains uncertainty around which diagnostic features are most important and what constitutes optimal management. It is imperative that clinical studies including patients with ACO are initiated, allowing the generation of evidence-based management strategies.
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http://dx.doi.org/10.1111/crj.13016DOI Listing
June 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

microRNA-mRNA regulatory networks underlying chronic mucus hypersecretion in COPD.

Eur Respir J 2018 09 6;52(3). Epub 2018 Sep 6.

Dept of Pathology and Medical Biology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.

Chronic mucus hypersecretion (CMH) is a common feature in chronic obstructive pulmonary disease (COPD) and is associated with worse prognosis and quality of life. This study aimed to identify microRNA (miRNA)-mRNA regulatory networks underlying CMH.The expression profiles of miRNA and mRNA in bronchial biopsies from 63 COPD patients were associated with CMH using linear regression. Potential mRNA targets of each CMH-associated miRNA were identified using Pearson correlations. Gene set enrichment analysis (GSEA) and STRING (search tool for the retrieval of interacting genes/proteins) analysis were used to identify key genes and pathways.20 miRNAs and 539 mRNAs were differentially expressed with CMH in COPD. The expression of 10 miRNAs was significantly correlated with the expression of one or more mRNAs. Of these, miR-134-5p, miR-146a-5p and the let-7 family had the highest representation of CMH-associated mRNAs among their negatively correlated predicted targets. and were identified as key regulators of CMH and were negatively correlated predicted targets of miR-134-5p and let-7a-5p, let-7d-5p, and let-7f-5p, respectively. GSEA suggested involvement of -related genes and several other relevant gene sets in CMH. The lower expression of miR-134-5p was confirmed in primary airway fibroblasts from COPD patients with CMH.We identified miR-134-5p, miR-146a-5p and let-7 family, along with their potential target genes including and , as potential key miRNA-mRNA networks regulating CMH in COPD.
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http://dx.doi.org/10.1183/13993003.01556-2017DOI Listing
September 2018

A Genome-Wide Linkage Study for Chronic Obstructive Pulmonary Disease in a Dutch Genetic Isolate Identifies Novel Rare Candidate Variants.

Front Genet 2018 19;9:133. Epub 2018 Apr 19.

Department of Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands.

Chronic obstructive pulmonary disease (COPD) is a complex and heritable disease, associated with multiple genetic variants. Specific familial types of COPD may be explained by rare variants, which have not been widely studied. We aimed to discover rare genetic variants underlying COPD through a genome-wide linkage scan. Affected-only analysis was performed using the 6K Illumina Linkage IV Panel in 142 cases clustered in 27 families from a genetic isolate, the Erasmus Rucphen Family (ERF) study. Potential causal variants were identified by searching for shared rare variants in the exome-sequence data of the affected members of the families contributing most to the linkage peak. The identified rare variants were then tested for association with COPD in a large meta-analysis of several cohorts. Significant evidence for linkage was observed on chromosomes 15q14-15q25 [logarithm of the odds (LOD) score = 5.52], 11p15.4-11q14.1 (LOD = 3.71) and 5q14.3-5q33.2 (LOD = 3.49). In the chromosome 15 peak, that harbors the known COPD locus for nicotinic receptors, and in the chromosome 5 peak we could not identify shared variants. In the chromosome 11 locus, we identified four rare (minor allele frequency (MAF) <0.02), predicted pathogenic, missense variants. These were shared among the affected family members. The identified variants localize to genes including neuroblast differentiation-associated protein (), previously associated with blood biomarkers in COPD, phospholipase C Beta 3 (), shown to increase airway hyper-responsiveness, solute carrier family 22-A11 (), involved in amino acid metabolism and ion transport, and metallothionein-like protein 5 (), involved in nicotinate and nicotinamide metabolism. Association of and variants were confirmed in the meta-analysis of 9,888 cases and 27,060 controls. In conclusion, we have identified novel rare variants in plausible genes related to COPD. Further studies utilizing large sample whole-genome sequencing should further confirm the associations at chromosome 11 and investigate the chromosome 15 and 5 linked regions.
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http://dx.doi.org/10.3389/fgene.2018.00133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916965PMC
April 2018

Predictive value of eosinophils and neutrophils on clinical effects of ICS in COPD.

Respirology 2018 11 26;23(11):1023-1031. Epub 2018 Apr 26.

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

Background And Objective: Inflammation is present to a variable degree and composition in patients with COPD. This study investigates associations between both eosinophils and neutrophils in blood, sputum, airway wall biopsies and bronchoalveolar lavage (BAL) and their potential use as biomarkers for clinical response to inhaled corticosteroids (ICS).

Methods: In total, 114 steroid-naïve COPD patients of the Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease (GLUCOLD) study using ICS or placebo during 30-month follow-up were included. Cell counts in blood, sputum, biopsies and BAL were evaluated at baseline. In addition, at baseline, 6 and 30 months, forced expiratory flow in 1 s (FEV ), residual volume/total lung capacity (hyperinflation) and Clinical COPD Questionnaire were evaluated.

Results: Cross-sectional analyses at baseline showed that higher blood eosinophils were significantly associated with higher eosinophil counts in sputum, biopsies and BAL. However, blood neutrophils did not significantly correlate with neutrophil counts in the other compartments. Baseline eosinophils and neutrophils, in whichever compartment measured, did not predict longitudinal FEV changes. Higher baseline biopsy eosinophils were associated with an increase in symptoms during 6- and 30-month ICS treatment. In addition, higher biopsy neutrophils were associated with a more marked reduction in hyperinflation during 6-month ICS treatment compared with placebo.

Conclusion: Our findings indicate that blood eosinophils reflect eosinophils in other compartments, in contrast to neutrophils, in ICS-naïve COPD patients. Both baseline eosinophils and neutrophils do not predict ICS-induced lung function changes over a period of 6-30 months. The associations of biopsy eosinophils with worsening respiratory symptoms and biopsy neutrophils with improvement in hyperinflation during ICS treatment deserve further investigation.
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http://dx.doi.org/10.1111/resp.13312DOI Listing
November 2018

Genetic regulation of methylation and IL1RL1-a protein levels in asthma.

Eur Respir J 2018 03 8;51(3). Epub 2018 Mar 8.

Dept of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

() is an important asthma gene. (Epi)genetic regulation of protein expression has not been established. We assessed the association between single nucleotide polymorphisms (SNPs), methylation and serum IL1RL1-a protein levels, and aimed to identify causal pathways in asthma.Associations of SNPs with asthma were determined in the Dutch Asthma Genome-wide Association Study cohort and three European birth cohorts, BAMSE (Children/Barn, Allergy, Milieu, Stockholm, an Epidemiological survey), INMA (Infancia y Medio Ambiente) and PIAMA (Prevention and Incidence of Asthma and Mite Allergy), participating in the Mechanisms of the Development of Allergy study. We performed blood DNA methylation quantitative trait locus (QTL) analysis (n=496) and (epi)genome-wide protein QTL analysis on serum IL1RL1-a levels (n=1462). We investigated the association of CpG methylation with asthma (n=632) and IL1RL1-a levels (n=548), with subsequent causal inference testing. Finally, we determined the association of IL1RL1-a levels with asthma and its clinical characteristics (n=1101). asthma-risk SNPs strongly associated with methylation (rs1420101; p=3.7×10) and serum IL1RL1-a levels (p=2.8×10). methylation was not associated with asthma or IL1RL1-a levels. IL1RL1-a levels negatively correlated with blood eosinophil counts, whereas there was no association between IL1RL1-a levels and asthma.In conclusion, asthma-associated SNPs strongly regulate methylation and serum IL1RL1-a levels, yet neither these methylation CpG sites nor IL1RL1-a levels are associated with asthma.
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http://dx.doi.org/10.1183/13993003.01377-2017DOI Listing
March 2018

Occupational exposure to pesticides is associated with differential DNA methylation.

Occup Environ Med 2018 06 19;75(6):427-435. Epub 2018 Feb 19.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Objectives: Occupational pesticide exposure is associated with a wide range of diseases, including lung diseases, but it is largely unknown how pesticides influence airway disease pathogenesis. A potential mechanism might be through epigenetic mechanisms, like DNA methylation. Therefore, we assessed associations between occupational exposure to pesticides and genome-wide DNA methylation sites.

Methods: 1561 subjects of LifeLines were included with either no (n=1392), low (n=108) or high (n=61) exposure to any type of pesticides (estimated based on current or last held job). Blood DNA methylation levels were measured using Illumina 450K arrays. Associations between pesticide exposure and 420 938 methylation sites (CpGs) were assessed using robust linear regression adjusted for appropriate confounders. In addition, we performed genome-wide stratified and interaction analyses by gender, smoking and airway obstruction status, and assessed associations between gene expression and methylation for genome-wide significant CpGs (n=2802).

Results: In total for all analyses, high pesticide exposure was genome-wide significantly (false discovery rate P<0.05) associated with differential DNA methylation of 31 CpGs annotated to 29 genes. Twenty of these CpGs were found in subjects with airway obstruction. Several of the identified genes, for example, , , , , and , are genes previously linked to either pesticide exposure or lung-related diseases. Seven out of 31 CpGs were associated with gene expression levels.

Conclusions: We show for the first time that occupational exposure to pesticides is genome-wide associated with differential DNA methylation. Further research should reveal whether this differential methylation plays a role in the airway disease pathogenesis induced by pesticides.
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http://dx.doi.org/10.1136/oemed-2017-104787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5969365PMC
June 2018

Understanding the role of the chromosome 15q25.1 in COPD through epigenetics and transcriptomics.

Eur J Hum Genet 2018 05 8;26(5):709-722. Epub 2018 Feb 8.

Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.

Chronic obstructive pulmonary disease (COPD) is a major health burden in adults and cigarette smoking is considered the most important environmental risk factor of COPD. Chromosome 15q25.1 locus is associated with both COPD and smoking. Our study aims at understanding the mechanism underlying the association of chromosome 15q25.1 with COPD through epigenetic and transcriptional variation in a population-based setting. To assess if COPD-associated variants in 15q25.1 are methylation quantitative trait loci, epigenome-wide association analysis of four genetic variants, previously associated with COPD (P < 5 × 10) in the 15q25.1 locus (rs12914385:C>T-CHRNA3, rs8034191:T>C-HYKK, rs13180:C>T-IREB2 and rs8042238:C>T-IREB2), was performed in the Rotterdam study (n = 1489). All four variants were significantly associated (P < 1.4 × 10) with blood DNA methylation of IREB2, CHRNA3 and PSMA4, of which two, including IREB2 and PSMA4, were also differentially methylated in COPD cases and controls (P < 0.04). Further additive and multiplicative effects of smoking were evaluated and no significant effect was observed. To evaluate if these four genetic variants are expression quantitative trait loci, transcriptome-wide association analysis was performed in 1087 lung samples. All four variants were also significantly associated with differential expression of the IREB2 3'UTR in lung tissues (P < 5.4 × 10). We conclude that regulatory mechanisms affecting the expression of IREB2 gene, such as DNA methylation, may explain the association between genetic variants in chromosome 15q25.1 and COPD, largely independent of smoking.
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http://dx.doi.org/10.1038/s41431-017-0089-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5945654PMC
May 2018

SIRT1/FoxO3 axis alteration leads to aberrant immune responses in bronchial epithelial cells.

J Cell Mol Med 2018 04 7;22(4):2272-2282. Epub 2018 Feb 7.

Istituto di Biomedicina e Immunologia Molecolare-Consiglio Nazionale delle Ricerche, Palermo, Italy.

Inflammation and ageing are intertwined in chronic obstructive pulmonary disease (COPD). The histone deacetylase SIRT1 and the related activation of FoxO3 protect from ageing and regulate inflammation. The role of SIRT1/FoxO3 in COPD is largely unknown. This study evaluated whether cigarette smoke, by modulating the SIRT1/FoxO3 axis, affects airway epithelial pro-inflammatory responses. Human bronchial epithelial cells (16HBE) and primary bronchial epithelial cells (PBECs) from COPD patients and controls were treated with/without cigarette smoke extract (CSE), Sirtinol or FoxO3 siRNA. SIRT1, FoxO3 and NF-κB nuclear accumulation, SIRT1 deacetylase activity, IL-8 and CCL20 expression/release and the release of 12 cytokines, neutrophil and lymphocyte chemotaxis were assessed. In PBECs, the constitutive FoxO3 expression was lower in patients with COPD than in controls. Furthermore, CSE reduced FoxO3 expression only in PBECs from controls. In 16HBE, CSE decreased SIRT1 activity and nuclear expression, enhanced NF-κB binding to the IL-8 gene promoter thus increasing IL-8 expression, decreased CCL20 expression, increased the neutrophil chemotaxis and decreased lymphocyte chemotaxis. Similarly, SIRT1 inhibition reduced FoxO3 expression and increased nuclear NF-κB. FoxO3 siRNA treatment increased IL-8 and decreased CCL20 expression in 16HBE. In conclusion, CSE impairs the function of SIRT1/FoxO3 axis in bronchial epithelium, dysregulating NF-κB activity and inducing pro-inflammatory responses.
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http://dx.doi.org/10.1111/jcmm.13509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867095PMC
April 2018

Long-term Air Pollution Exposure, Genome-wide DNA Methylation and Lung Function in the LifeLines Cohort Study.

Environ Health Perspect 2018 02 6;126(2):027004. Epub 2018 Feb 6.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.

Background: Long-term air pollution exposure is negatively associated with lung function, yet the mechanisms underlying this association are not fully clear. Differential DNA methylation may explain this association.

Objectives: Our main aim was to study the association between long-term air pollution exposure and DNA methylation.

Methods: We performed a genome-wide methylation study using robust linear regression models in 1,017 subjects from the LifeLines cohort study to analyze the association between exposure to nitrogen dioxide (NO) and particulate matter (PM, fine particulate matter with aerodynamic diameter ≤2.5 μm; PM, particulate matter with aerodynamic diameter ≤10 μm) and PM, indicator of elemental carbon content (estimated with land-use-regression models) with DNA methylation in whole blood (Illumina HumanMethylation450K BeadChip). Replication of the top hits was attempted in two independent samples from the population-based Cooperative Health Research in the Region of Augsburg studies (KORA).

Results: Depending on the -value threshold used, we found significant associations between NO exposure and DNA methylation for seven CpG sites (Bonferroni corrected threshold p<1.19×10) or for 4,980 CpG sites (False Discovery Rate<0.05). The top associated CpG site was annotated to the gene (i.e., cg04908668). None of the seven Bonferroni significant CpG-sites were significantly replicated in the two KORA-cohorts. No associations were found for PM exposure.

Conclusions: Long-term NO exposure was genome-wide significantly associated with DNA methylation in the identification cohort but not in the replication cohort. Future studies are needed to further elucidate the potential mechanisms underlying -exposure-related respiratory disease. https://doi.org/10.1289/EHP2045.
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http://dx.doi.org/10.1289/EHP2045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6047358PMC
February 2018

Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks.

Nat Genet 2018 01 22;50(1):42-53. Epub 2017 Dec 22.

Hospital Infantil de Mexico Federico Gomez, Mexico City, Mexico.

We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.
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http://dx.doi.org/10.1038/s41588-017-0014-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5901974PMC
January 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

Lung tissue gene-expression signature for the ageing lung in COPD.

Thorax 2017 Dec 6. Epub 2017 Dec 6.

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

Introduction: COPD is a chronic, progressive, inflammatory disease of the lungs and the third leading cause of death worldwide. The current knowledge of the pathophysiology of COPD is limited and novel insights in underlying disease mechanisms are urgently needed. Since there are clear parallels between ageing and COPD, we investigated genes underlying lung ageing in general and abnormal lung ageing in COPD.

Methods: Whole genome mRNA profiling was performed on lung tissue samples (n=1197) and differential gene expression with increasing age was analysed using an adjusted linear regression model. Subsequent pathway analysis was performed using GeneNetwork and the gene-expression signature was compared with lung ageing in the Genotype-Tissue Expression (GTEx) project. In a subset of patients with COPD (n=311) and non-COPD controls (n=270), we performed an interaction analysis between age and COPD to identify genes differentially expressed with age in COPD compared with controls, followed by gene set enrichment pathway analysis.

Results: We identified a strong gene-expression signature for lung ageing with 3509 differentially expressed genes, of which 33.5% were found nominal significant in the GTEx project. Interestingly, we found as a strong candidate gene for lung ageing. The age*COPD interaction analysis revealed 69 genes significantly differentially expressed with age between COPD and controls.

Conclusions: Our study indicates that processes related to lung development, cell-cell contacts, calcium signalling and immune responses are involved in lung ageing in general. Pathways related to extracellular matrix, mammalian target of rapamycin signalling, splicing of introns and exons and the ribosome complex are proposed to be involved in abnormal lung ageing in COPD.
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http://dx.doi.org/10.1136/thoraxjnl-2017-210074DOI Listing
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

COPD GWAS variant at 19q13.2 in relation with DNA methylation and gene expression.

Hum Mol Genet 2018 01;27(2):396-405

Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.

Chronic obstructive pulmonary disease (COPD) is among the major health burdens in adults. While cigarette smoking is the leading risk factor, a growing number of genetic variations have been discovered to influence disease susceptibility. Epigenetic modifications may mediate the response of the genome to smoking and regulate gene expression. Chromosome 19q13.2 region is associated with both smoking and COPD, yet its functional role is unclear. Our study aimed to determine whether rs7937 (RAB4B, EGLN2), a top genetic variant in 19q13.2 region identified in genome-wide association studies of COPD, is associated with differential DNA methylation in blood (N = 1490) and gene expression in blood (N = 721) and lungs (N = 1087). We combined genetic and epigenetic data from the Rotterdam Study (RS) to perform the epigenome-wide association analysis of rs7937. Further, we used genetic and transcriptomic data from blood (RS) and from lung tissue (Lung expression quantitative trait loci mapping study), to perform the transcriptome-wide association study of rs7937. Rs7937 was significantly (FDR < 0.05) and consistently associated with differential DNA methylation in blood at 4 CpG sites in cis, independent of smoking. One methylation site (cg11298343-EGLN2) was also associated with COPD (P = 0.001). Additionally, rs7937 was associated with gene expression levels in blood in cis (EGLN2), 42% mediated through cg11298343, and in lung tissue, in cis and trans (NUMBL, EGLN2, DNMT3A, LOC101929709 and PAK2). Our results suggest that changes of DNA methylation and gene expression may be intermediate steps between genetic variants and COPD, but further causal studies in lung tissue should confirm this hypothesis.
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http://dx.doi.org/10.1093/hmg/ddx390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886099PMC
January 2018

Targeting the small airways with dry powder adenosine: a challenging concept.

Eur Clin Respir J 2017 6;4(1):1369328. Epub 2017 Sep 6.

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

: Small-particle inhaled corticosteroids (ICS) provide a higher small airway deposition than large-particle ICS. However, we are still not able to identify asthma patients who will profit most from small-particle treatment. : We aimed to identify these patients by selectively challenging the small and large airways. We hypothesized that the airways could be challenged selectively using small- and large-particle adenosine, both inhaled at a high and a low flow rate. : In this cross-over study 11 asthma subjects performed four dry powder adenosine tests, with either small (MMAD 2.7 µm) or large (MMAD 6.0 µm) particles, inhaled once with a low flow rate (30 l min) and once with a high flow rate (60 l min). Spirometry and impulse oscillometry were performed after every bronchoprovocation step. We assumed that FEV reflects the large airways, and FEF, R5-R20 and X5 reflect the small airways. : The four adenosine tests were not significantly different with respect to the threshold values of FEV ( = 0.12), FEF ( = 0.37), R5-R20 ( = 0.60) or X5 ( = 0.46). Both small- and large-particle adenosine induced a response in the small airways in the majority of the tests. : In contrast to our hypothesis, all four adenosine tests provoked a response in the small airways and we could not identify different large- or small-airway responders. Interestingly, even the test with large particles and a high flow rate induced a small-airway response, suggesting that selective challenging of the small airways is not necessary. Future studies should investigate the relation between particle deposition and the site of an airway response.
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http://dx.doi.org/10.1080/20018525.2017.1369328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642194PMC
September 2017

Extrafine Versus Fine Inhaled Corticosteroids in Relation to Asthma Control: A Systematic Review and Meta-Analysis of Observational Real-Life Studies.

J Allergy Clin Immunol Pract 2018 May - Jun;6(3):907-915.e7. Epub 2017 Sep 20.

Observational and Pragmatic Research Institute Pte Ltd, Singapore; Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, United Kingdom. Electronic address:

Background: The particle size of inhaled corticosteroids (ICSs) may affect airway drug deposition and effectiveness.

Objective: To compare the effectiveness of extrafine ICSs (mass median aerodynamic diameter, <2 μm) versus fine-particle ICSs administered as ICS monotherapy or ICS-long-acting β-agonist combination therapy by conducting a meta-analysis of observational real-life asthma studies to estimate the treatment effect of extrafine ICSs.

Methods: MEDLINE and EMBASE databases were reviewed for asthma observational comparative effectiveness studies from January 2004 to June 2016. Studies were included if they reported odds and relative risk ratios and met all inclusion criteria (Respiratory Effectiveness Group/European Academy of Allergy and Clinical Immunology quality standards, comparison of extrafine ICSs with same or different ICS molecule, ≥12-month follow-up). End-point data (asthma control, exacerbations, prescribed ICS dose) were pooled. Random-effects meta-analysis modeling was used. The study protocol is published in the PROSPERO register CRD42016039137.

Results: Seven studies with 33,453 subjects aged 5 to 80 years met eligibility criteria for inclusion. Six studies used extrafine beclometasone propionate and 1 study used both extrafine beclometasone propionate and extrafine ciclesonide as comparators with fine-particle ICSs. The overall odds of achieving asthma control were significantly higher for extrafine ICSs compared with fine-particle ICSs (odds ratio, 1.34; 95% CI, 1.22-1.46). Overall exacerbation rate ratios (0.84; 95% CI, 0.73-0.97) and ICS dose (weighted mean difference, -170 μg; 95% CI, -222 to -118 μg) were significantly lower for extrafine ICSs compared with fine-particle ICSs.

Conclusions: This meta-analysis demonstrates that extrafine ICSs have significantly higher odds of achieving asthma control with lower exacerbation rates at significantly lower prescribed doses than fine-particle ICSs.
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http://dx.doi.org/10.1016/j.jaip.2017.07.032DOI Listing
October 2019

Identification of transforming growth factor-beta-regulated microRNAs and the microRNA-targetomes in primary lung fibroblasts.

PLoS One 2017 14;12(9):e0183815. Epub 2017 Sep 14.

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

Background: Lung fibroblasts are involved in extracellular matrix homeostasis, which is mainly regulated by transforming growth factor-beta (TGF-β), and are therefore crucial in lung tissue repair and remodeling. Abnormal repair and remodeling has been observed in lung diseases like COPD. As miRNA levels can be influenced by TGF-β, we hypothesized that TGF-β influences miRNA expression in lung fibroblasts, thereby affecting their function.

Materials And Methods: We investigated TGF-β1-induced miRNA expression changes in 9 control primary parenchymal lung fibroblasts using miRNA arrays. TGF-β1-induced miRNA expression changes were validated and replicated in an independent set of lung fibroblasts composted of 10 controls and 15 COPD patients using qRT-PCR. Ago2-immunoprecipitation followed by mRNA expression profiling was used to identify the miRNA-targetomes of unstimulated and TGF-β1-stimulated primary lung fibroblasts (n = 2). The genes affected by TGF-β1-modulated miRNAs were identified by comparing the miRNA targetomes of unstimulated and TGF-β1-stimulated fibroblasts.

Results: Twenty-nine miRNAs were significantly differentially expressed after TGF-β1 stimulation (FDR<0.05). The TGF-β1-induced miR-455-3p and miR-21-3p expression changes were validated and replicated, with in addition, lower miR-455-3p levels in COPD (p<0.05). We identified 964 and 945 genes in the miRNA-targetomes of unstimulated and TGF-β1-stimulated lung fibroblasts, respectively. The TGF-β and Wnt pathways were significantly enriched among the Ago2-IP enriched and predicted targets of miR-455-3p and miR-21-3p. The miR-455-3p target genes HN1, NGF, STRADB, DLD and ANO3 and the miR-21-3p target genes HHEX, CHORDC1 and ZBTB49 were consistently more enriched after TGF-β1 stimulation.

Conclusion: Two miRNAs, miR-455-3p and miR-21-3p, were induced by TGF-β1 in lung fibroblasts. The significant Ago2-IP enrichment of targets of these miRNAs related to the TGF-β and/or Wnt pathways (NGF, DLD, HHEX) in TGF-β1-stimulated fibroblasts suggest a role for these miRNAs in lung diseases by affecting lung fibroblast function.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0183815PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5599028PMC
October 2017