Publications by authors named "Maarten van den Berge"

179 Publications

Determinants of Lung Fissure Completeness.

Am J Respir Crit Care Med 2021 Jun 14. Epub 2021 Jun 14.

University Medical Center Groningen, Pulmonary diseases, Groningen, Netherlands.

Rationale: New advanced bronchoscopic treatment options for patients with severe COPD have led to increased interest for COPD phenotyping, including fissure completeness.

Objectives: We investigated clinical, environmental, and genetic factors contributing to fissure completeness in patients with and without COPD.

Methods: We used data of 9926 participants of the COPDGene study who underwent chest computed tomography (CT). Fissure completeness was calculated from CT scans following quantitative CT analysis at baseline and five-year follow-up. The clinical and environmental factors sex, race, smoking, COPD, emphysema, maternal smoking during pregnancy and maternal COPD were tested for impact on fissure completeness. Genome-wide association analyses were performed separately in non-Hispanic whites and African-Americans.

Measurements And Main Results: African-Americans had significant higher fissure completeness than non-Hispanic whites for all three fissures (p<0.001). There was no change in fissure completeness between baseline and five-year follow-up. For all fissures, No clinically relevant differences in fissure completeness were found for other clinical or environmental factors, including COPD severity. Rs2173623, rs264866, rs2407284, rs7310342, rs4904145, rs6504172, and rs7209556 showed genome-wide significant associations with fissure completeness in non-Hispanic whites. In African-Americans, rs264866, rs4904145 and rs6504172 were identified as significant associations. Rs2173623, rs6504172, and rs7209556 lead to WNT5A and HOXB antisense RNA expression, which play an important role during embryogenesis.

Conclusions: Fissure completeness is genetically determined and not dependent on age, sex, smoking status, the presence and severity of COPD including exacerbation frequency, maternal smoking during pregnancy, or maternal COPD.
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http://dx.doi.org/10.1164/rccm.202102-0260OCDOI Listing
June 2021

expression in asthmatic epithelium depends on intronic methylation and ZNF263 binding.

ERJ Open Res 2021 Apr 7;7(2). Epub 2021 Jun 7.

Division of Paediatric Pneumology and Allergology, University Medical Centre Schleswig-Holstein, Airway Research Centre North, member of the German Centre for Lung Research (DZL), Lübeck, Germany.

Background: Reduction of COL4A3, one of the six isoforms of collagen 4, in asthmatic airways results in increased inflammation and angiogenesis, implicating it as a central part of asthma pathogenesis. However, to date, the path underlying these diminished COL4A3 levels has been elusive. This study investigated a possible mechanism underlying the reduction of COL4A3 expression.

Methods: Bronchial biopsies of 76 patients with asthma and 83 controls were subjected to RNA-sequencing and DNA methylation bead arrays to identify expression and methylation changes. The binding of ZNF263 was analysed by chromatin-immunoprecipitation sequencing coupled with quantitative (q)PCR. Effects of silencing, using small interfering RNA, on the expression were studied using qPCR.

Results: expression was significantly reduced in bronchial biopsies compared to healthy controls, whereas DNA methylation levels at cg11797365 were increased. expression levels were significantly low in asthmatics without inhaled corticosteroid (ICS) use, whereas the expression was not statistically different between asthmatics using ICS and controls. Methylation levels at cg11797365 were increased upon consecutive rhinovirus infections.

Conclusion: Our data indicate an epigenetic modification as a contributing factor for the loss of expression in asthmatic airway epithelium.
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http://dx.doi.org/10.1183/23120541.00802-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8181658PMC
April 2021

Prioritization of candidate causal genes for asthma in susceptibility loci derived from UK Biobank.

Commun Biol 2021 Jun 8;4(1):700. Epub 2021 Jun 8.

Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Quebec, QC, Canada.

To identify candidate causal genes of asthma, we performed a genome-wide association study (GWAS) in UK Biobank on a broad asthma definition (n = 56,167 asthma cases and 352,255 controls). We then carried out functional mapping through transcriptome-wide association studies (TWAS) and Mendelian randomization in lung (n = 1,038) and blood (n = 31,684) tissues. The GWAS reveals 72 asthma-associated loci from 116 independent significant variants (P < 5.0E-8). The most significant lung TWAS gene on 17q12-q21 is GSDMB (P = 1.42E-54). Other TWAS genes include TSLP on 5q22, RERE on 1p36, CLEC16A on 16p13, and IL4R on 16p12, which all replicated in GTEx lung (n = 515). We demonstrate that the largest fold enrichment of regulatory and functional annotations among asthma-associated variants is in the blood. We map 485 blood eQTL-regulated genes associated with asthma and 50 of them are causal by Mendelian randomization. Prioritization of druggable genes reveals known (IL4R, TSLP, IL6, TNFSF4) and potentially new therapeutic targets for asthma.
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http://dx.doi.org/10.1038/s42003-021-02227-6DOI Listing
June 2021

Variants associated with expression have sex-differential effects on lung function.

Wellcome Open Res 2020 24;5:111. Epub 2021 May 24.

Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, EH4 2XU, UK.

Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P<5x10 ) interactions with sex on lung function, and 21 showed suggestive interactions (P<1x10 ). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV ) (P=3.15x10 ), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV more in males (untransformed FEV β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein ( ) gene and was previously associated with lung function and lung expression. We found expression was significantly different between the sexes (P=6.90x10 ), but we could not detect sex differential effects of rs7697189 on expression. We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the gene. Establishing the mechanism by which SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.
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http://dx.doi.org/10.12688/wellcomeopenres.15846.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938335.2PMC
May 2021

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

Glutathione S-transferases and their implications in the lung diseases asthma and chronic obstructive pulmonary disease: Early life susceptibility?

Redox Biol 2021 Jul 2;43:101995. Epub 2021 May 2.

Department of Respiratory Medicine, Maastricht University Medical Center+, Maastricht, the Netherlands. Electronic address:

Our lungs are exposed daily to airborne pollutants, particulate matter, pathogens as well as lung allergens and irritants. Exposure to these substances can lead to inflammatory responses and may induce endogenous oxidant production, which can cause chronic inflammation, tissue damage and remodeling. Notably, the development of asthma and Chronic Obstructive Pulmonary Disease (COPD) is linked to the aforementioned irritants. Some inhaled foreign chemical compounds are rapidly absorbed and processed by phase I and II enzyme systems critical in the detoxification of xenobiotics including the glutathione-conjugating enzymes Glutathione S-transferases (GSTs). GSTs, and in particular genetic variants of GSTs that alter their activities, have been found to be implicated in the susceptibility to and progression of these lung diseases. Beyond their roles in phase II metabolism, evidence suggests that GSTs are also important mediators of normal lung growth. Therefore, the contribution of GSTs to the development of lung diseases in adults may already start in utero, and continues through infancy, childhood, and adult life. GSTs are also known to scavenge oxidants and affect signaling pathways by protein-protein interaction. Moreover, GSTs regulate reversible oxidative post-translational modifications of proteins, known as protein S-glutathionylation. Therefore, GSTs display an array of functions that impact the pathogenesis of asthma and COPD. In this review we will provide an overview of the specific functions of each class of mammalian cytosolic GSTs. This is followed by a comprehensive analysis of their expression profiles in the lung in healthy subjects, as well as alterations that have been described in (epithelial cells of) asthmatics and COPD patients. Particular emphasis is placed on the emerging evidence of the regulatory properties of GSTs beyond detoxification and their contribution to (un)healthy lungs throughout life. By providing a more thorough understanding, tailored therapeutic strategies can be designed to affect specific functions of particular GSTs.
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http://dx.doi.org/10.1016/j.redox.2021.101995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131726PMC
July 2021

Bronchial gene expression signature associated with rate of subsequent FEV decline in individuals with and at risk of COPD.

Thorax 2021 May 10. Epub 2021 May 10.

Division of Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts, USA

Background: COPD is characterised by progressive lung function decline. Leveraging prior work demonstrating bronchial airway COPD-associated gene expression alterations, we sought to determine if there are alterations associated with differences in the rate of FEV decline.

Methods: We examined gene expression among ever smokers with and without COPD who at baseline had bronchial brushings profiled by Affymetrix microarrays and had longitudinal lung function measurements (n=134; mean follow-up=6.38±2.48 years). Gene expression profiles associated with the rate of FEV decline were identified by linear modelling.

Results: Expression differences in 171 genes were associated with rate of FEV decline (false discovery rate <0.05). The FEV decline signature was replicated in an independent dataset of bronchial biopsies from patients with COPD (n=46; p=0.018; mean follow-up=6.76±1.32 years). Genes elevated in individuals with more rapid FEV decline are significantly enriched among the genes altered by modulation of XBP1 in two independent datasets (Gene Set Enrichment Analysis (GSEA) p<0.05) and are enriched in mucin-related genes (GSEA p<0.05).

Conclusion: We have identified and replicated an airway gene expression signature associated with the rate of FEV decline. Aspects of this signature are related to increased expression of XBP1-regulated genes, a transcription factor involved in the unfolded protein response, and genes related to mucin production. Collectively, these data suggest that molecular processes related to the rate of FEV decline can be detected in airway epithelium, identify a possible indicator of FEV decline and make it possible to detect, in an early phase, ever smokers with and without COPD most at risk of rapid FEV decline.
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http://dx.doi.org/10.1136/thoraxjnl-2019-214476DOI Listing
May 2021

Seasonal prevalence and characteristics of low-dose CT detected lung nodules in a general Dutch population.

Sci Rep 2021 Apr 28;11(1):9139. Epub 2021 Apr 28.

Department of Radiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.

We investigated whether presence and characteristics of lung nodules in the general population using low-dose computed tomography (LDCT) varied by season. Imaging in Lifelines (ImaLife) study participants who underwent chest LDCT-scanning between October 2018 and October 2019 were included in this sub-study. Hay fever season (summer) was defined as 1st April to 30th September and Influenza season (winter) as 1st October to 31st March. All lung nodules with volume of ≥ 30 mm (approximately 3 mm in diameter) were registered. In total, 2496 lung nodules were found in 1312 (38%) of the 3456 included participants (nodules per participant ranging from 1 to 21, median 1). In summer, 711 (54%) participants had 1 or more lung nodule(s) compared to 601 (46%) participants in winter (p = 0.002). Of the spherical, perifissural and left-upper-lobe nodules, relatively more were detected in winter, whereas of the polygonal-, irregular-shaped and centrally-calcified nodules, relatively more were detected in summer. Various seasonal diseases with inflammation as underlying pathophysiology may influence presence and characteristics of lung nodules. Further investigation into underlying pathophysiology using short-term LDCT follow-up could help optimize the management strategy for CT-detected lung nodules in clinical practice.
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http://dx.doi.org/10.1038/s41598-021-88328-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080793PMC
April 2021

Real-life impact of COVID-19 pandemic lockdown on the management of pediatric and adult asthma: A survey by the EAACI Asthma Section.

Allergy 2021 Mar 27. Epub 2021 Mar 27.

Faculty of Medicine, Department of Allergy and Clinical Immunology, Transylvania University Brasov, Brasov, Romania.

Background: The restrictions imposed by the COVID-19 pandemic impact heavily the management of chronic diseases like asthma. This study aimed to evaluate the management of adults and children with asthma during COVID-19-related lockdown.

Methods: A survey was launched by the European Academy of Allergy and Clinical Immunology (EAACI) via e-mail, website, and social media to EAACI members and members of peer societies.

Results: The survey was completed by 339 healthcare professionals from 52 countries. 79% of follow-up consultations were replaced by phone calls, whereas 49% of newly referred patients attended the clinic. 62%, 76%, 66%, 76%, and 87% of responders did not conduct spirometry, impulse oscillometry, bronchodilator test, FeNO, or methacholine provocation, respectively, for asthma diagnosis in adults. The numbers were similar for children. 73% of responders based the initial asthma diagnosis and the prescription of inhaled therapy on clinical parameters only. Lung function tests were used in 29% of cases to monitor asthma worsening, and only 56% of participants were recommended to their patients ambulatory peak expiratory flow (PEF) measurements. Using a 1 (not at all) to 5 (very much) scale, the responders considered that the quality of healthcare provided and the patients' asthma status had deteriorated during the lockdown with 3.2 points and 2.8 points, respectively.

Conclusion: Collectively, these results suggest that all necessary resources should be allocated to ensure the performance of lung function tests for initial diagnosis, whereas digital remote monitoring should be reinforced for the follow-up of children and adults with asthma.
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http://dx.doi.org/10.1111/all.14831DOI Listing
March 2021

Human airway mast cells proliferate and acquire distinct inflammation-driven phenotypes during type 2 inflammation.

Sci Immunol 2021 Feb;6(56)

Jeff and Penny Vinik Immunology Center, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, MA, USA.

Mast cells (MCs) play a pathobiologic role in type 2 (T2) allergic inflammatory diseases of the airway, including asthma and chronic rhinosinusitis with nasal polyposis (CRSwNP). Distinct MC subsets infiltrate the airway mucosa in T2 disease, including subepithelial MCs expressing the proteases tryptase and chymase (MC) and epithelial MCs expressing tryptase without chymase (MC). However, mechanisms underlying MC expansion and the transcriptional programs underlying their heterogeneity are poorly understood. Here, we use flow cytometry and single-cell RNA-sequencing (scRNA-seq) to conduct a comprehensive analysis of human MC hyperplasia in CRSwNP, a T2 cytokine-mediated inflammatory disease. We link discrete cell surface phenotypes to the distinct transcriptomes of CRSwNP MC and MC, which represent polarized ends of a transcriptional gradient of nasal polyp MCs. We find a subepithelial population of CD38CD117 MCs that is markedly expanded during T2 inflammation. These CD38CD117 MCs exhibit an intermediate phenotype relative to the expanded MC and MC subsets. CD38CD117 MCs are distinct from circulating MC progenitors and are enriched for proliferation, which is markedly increased in CRSwNP patients with aspirin-exacerbated respiratory disease, a severe disease subset characterized by increased MC burden and elevated MC activation. We observe that MCs expressing a polyp MC-like effector program are also found within the lung during fibrotic diseases and asthma, and further identify marked differences between MC in nasal polyps and skin. These results indicate that MCs display distinct inflammation-associated effector programs and suggest that in situ MC proliferation is a major component of MC hyperplasia in human T2 inflammation.
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http://dx.doi.org/10.1126/sciimmunol.abb7221DOI Listing
February 2021

Multi-omics highlights ABO plasma protein as a causal risk factor for COVID-19.

Hum Genet 2021 Jun 19;140(6):969-979. Epub 2021 Feb 19.

Centre for Heart Lung Innovation, University of British Columbia, St. Paul's Hospital, Vancouver, BC, Canada.

SARS-CoV-2 is responsible for the coronavirus disease 2019 (COVID-19) and the current health crisis. Despite intensive research efforts, the genes and pathways that contribute to COVID-19 remain poorly understood. We, therefore, used an integrative genomics (IG) approach to identify candidate genes responsible for COVID-19 and its severity. We used Bayesian colocalization (COLOC) and summary-based Mendelian randomization to combine gene expression quantitative trait loci (eQTLs) from the Lung eQTL (n = 1,038) and eQTLGen (n = 31,784) studies with published COVID-19 genome-wide association study (GWAS) data from the COVID-19 Host Genetics Initiative. Additionally, we used COLOC to integrate plasma protein quantitative trait loci (pQTL) from the INTERVAL study (n = 3,301) with COVID-19 loci. Finally, we determined any causal associations between plasma proteins and COVID-19 using multi-variable two-sample Mendelian randomization (MR). The expression of 18 genes in lung and/or blood co-localized with COVID-19 loci. Of these, 12 genes were in suggestive loci (P < 5 × 10). LZTFL1, SLC6A20, ABO, IL10RB and IFNAR2 and OAS1 had been previously associated with a heightened risk of COVID-19 (P < 5 × 10). We identified a causal association between OAS1 and COVID-19 GWAS. Plasma ABO protein, which is associated with blood type in humans, demonstrated a significant causal relationship with COVID-19 in the MR analysis; increased plasma levels were associated with an increased risk of COVID-19 and, in particular, severe COVID-19. In summary, our study identified genes associated with COVID-19 that may be prioritized for future investigations. Importantly, this is the first study to demonstrate a causal association between plasma ABO protein and COVID-19.
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http://dx.doi.org/10.1007/s00439-021-02264-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892327PMC
June 2021

The novel TRPA1 antagonist BI01305834 inhibits ovalbumin-induced bronchoconstriction in guinea pigs.

Respir Res 2021 Feb 8;22(1):48. Epub 2021 Feb 8.

Department of Molecular Pharmacology, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.

Background: Asthma is a chronic respiratory disease in which the nervous system plays a central role. Sensory nerve activation, amongst others via Transient Receptor Potential Ankyrin 1 (TRPA1) channels, contributes to asthma characteristics including cough, bronchoconstriction, mucus secretion, airway hyperresponsiveness (AHR) and inflammation. In the current study, we evaluated the efficacy of the novel TRPA1 antagonist BI01305834 against AHR and inflammation in guinea-pig models of asthma.

Methods: First, a pilot study was performed in a guinea-pig model of allergic asthma to find the optimal dose of BI01305834. Next, the effect of BI01305834 on (1) AHR to inhaled histamine after the early and late asthmatic reaction (EAR and LAR), (2) magnitude of EAR and LAR and (3) airway inflammation was assessed. Precision-cut lung slices and trachea strips were used to investigate the bronchoprotective and bronchodilating-effect of BI01305834. Statistical evaluation of differences of in vivo data was performed using a Mann-Whitney U test or One-way nonparametric Kruskal-Wallis ANOVA, for ex vivo data One- or Two-way ANOVA was used, all with Dunnett's post-hoc test where appropriate.

Results: A dose of 1 mg/kg BI01305834 was selected based on AHR and exposure data in blood samples from the pilot study. In the subsequent study, 1 mg/kg BI01305834 inhibited AHR after the EAR, and the development of EAR and LAR elicited by ovalbumin in ovalbumin-sensitized guinea pigs. BI01305834 did not inhibit allergen-induced total and differential cells in the lavage fluid and interleukin-13 gene expression in lung homogenates. Furthermore, BI01305834 was able to inhibit allergen and histamine-induced airway narrowing in guinea-pig lung slices, without affecting histamine release, and reverse allergen-induced bronchoconstriction in guinea-pig trachea strips.

Conclusions: TRPA1 inhibition protects against AHR and the EAR and LAR in vivo and allergen and histamine-induced airway narrowing ex vivo, and reverses allergen-induced bronchoconstriction independently of inflammation. This effect was partially dependent upon histamine, suggesting a neuronal and possible non-neuronal role for TRPA1 in allergen-induced bronchoconstriction.
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http://dx.doi.org/10.1186/s12931-021-01638-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871391PMC
February 2021

ACE inhibition and cardiometabolic risk factors, lung and gene expression, and plasma ACE2 levels: a Mendelian randomization study.

R Soc Open Sci 2020 Nov 18;7(11):200958. Epub 2020 Nov 18.

Computer Science Department and Center for Statistics and Machine Learning, Princeton University, Princeton, NJ, USA.

Angiotensin-converting enzyme 2 (ACE2) and serine protease TMPRSS2 have been implicated in cell entry for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). The expression of and in the lung epithelium might have implications for the risk of SARS-CoV-2 infection and severity of COVID-19. We use human genetic variants that proxy angiotensin-converting enzyme (ACE) inhibitor drug effects and cardiovascular risk factors to investigate whether these exposures affect lung and gene expression and circulating ACE2 levels. We observed no consistent evidence of an association of genetically predicted serum ACE levels with any of our outcomes. There was weak evidence for an association of genetically predicted serum ACE levels with gene expression in the Lung eQTL Consortium ( = 0.014), but this finding did not replicate. There was evidence of a positive association of genetic liability to type 2 diabetes mellitus with lung gene expression in the Gene-Tissue Expression (GTEx) study ( = 4 × 10) and with circulating plasma ACE2 levels in the INTERVAL study ( = 0.03), but not with lung expression in the Lung eQTL Consortium study ( = 0.68). There were no associations of genetically proxied liability to the other cardiometabolic traits with any outcome. This study does not provide consistent evidence to support an effect of serum ACE levels (as a proxy for ACE inhibitors) or cardiometabolic risk factors on lung and expression or plasma ACE2 levels.
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http://dx.doi.org/10.1098/rsos.200958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735342PMC
November 2020

Predicted values for the forced expiratory flow adjusted for forced vital capacity, a descriptive study.

ERJ Open Res 2020 Oct 14;6(4). Epub 2020 Dec 14.

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

Background: The forced expiratory flows (FEFs) towards the end of the expiration may be more sensitive in detecting peripheral airways obstruction compared to the forced expiratory volume in 1 s and forced vital capacity (FVC). However, they are highly variable. A partial solution is to adjust the FEFs for FVC (FEF/FVC). Here we provide reference equations for these adjusted FEFs at 25%, 50%, 75% and 25-75% of FVC, which are currently lacking.

Methods: We included pulmonary healthy, never-smoker adults; 14 472 subjects from Lifelines, a biobank for health research, and 338 subjects from the department's control cohorts (NORM and Fiddle). Reference equations were obtained by linear regression on 80% of the Lifelines dataset and validated on the remaining data. The best model was defined as the one with the highest adjusted R-value. The difference in variability between adjusted and unadjusted FEFs was evaluated using the coefficient of variation.

Results: For all adjusted FEFs, the best model contained age, height and weight. The adjustment improved the coefficient of variation of the FEF from 39% to 36% and from 43% to 40%, respectively, in males and females. The highest percentage of explained variance by the reference equation was obtained for FEF/FVC, 32%-38% for males, and 41%-46% for females, depending on the validation set.

Conclusion: We developed reference equations for FVC-adjusted FEF values. We demonstrated minimally yet significantly improved variability. Future studies in obstructive airway diseases should demonstrate whether it is worthwhile to use these (predicted) adjusted FEF values.
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http://dx.doi.org/10.1183/23120541.00426-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737427PMC
October 2020

An assessment of the correlation between robust CT-derived ventilation and pulmonary function test in a cohort with no respiratory symptoms.

Br J Radiol 2021 Feb 15;94(1118):20201218. Epub 2020 Dec 15.

Department of Radiation Oncology, Beaumont Health, OUWB School of Medicine, Auburn Hills, MI, USA.

Objective: To evaluate CT-ventilation imaging (CTVI) within a well-characterized, healthy cohort with no respiratory symptoms and examine the correlation between CTVI and concurrent pulmonary function test (PFT).

Methods: CT scans and PFTs from 77 Caucasian participants in the NORM dataset (clinicaltrials.gov NCT00848406) were analyzed. CTVI was generated using the robust Integrated Jacobian Formulation (IJF) method. IJF estimated total lung capacity (TLC) was computed from CTVI. Bias-adjusted Pearson's correlation between PFT and IJF-based TLC was computed.

Results: IJF- and PFT-measured TLC showed a good correlation for both males and females [males: 0.657, 95% CI (0.438-0.797); females: 0.667, 95% CI (0.416-0.817)]. When adjusting for age, height, smoking, and abnormal CT scan, correlation moderated [males: 0.432, 95% CI (0.129-0.655); females: 0.540, 95% CI (0.207-0.753)]. Visual inspection of CTVI revealed participants who had functional defects, despite the fact that all participant had normal high-resolution CT scan.

Conclusion: In this study, we demonstrate that IJF computed CTVI has good correlation with concurrent PFT in a well-validated patient cohort with no respiratory symptoms.

Advances In Knowledge: IJF-computed CTVI's overall numerical robustness and consistency with PFT support its potential as a method for providing spatiotemporal assessment of high and low function areas on volumetric non-contrast CT scan.
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http://dx.doi.org/10.1259/bjr.20201218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934322PMC
February 2021

Gene expression network analysis provides potential targets against SARS-CoV-2.

Sci Rep 2020 12 14;10(1):21863. Epub 2020 Dec 14.

Centre for Heart Lung Innovation, University of British Columbia, Vancouver, BC, Canada.

Cell entry of SARS-CoV-2, the novel coronavirus causing COVID-19, is facilitated by host cell angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). We aimed to identify and characterize genes that are co-expressed with ACE2 and TMPRSS2, and to further explore their biological functions and potential as druggable targets. Using the gene expression profiles of 1,038 lung tissue samples, we performed a weighted gene correlation network analysis (WGCNA) to identify modules of co-expressed genes. We explored the biology of co-expressed genes using bioinformatics databases, and identified known drug-gene interactions. ACE2 was in a module of 681 co-expressed genes; 10 genes with moderate-high correlation with ACE2 (r > 0.3, FDR < 0.05) had known interactions with existing drug compounds. TMPRSS2 was in a module of 1,086 co-expressed genes; 31 of these genes were enriched in the gene ontology biologic process 'receptor-mediated endocytosis', and 52 TMPRSS2-correlated genes had known interactions with drug compounds. Dozens of genes are co-expressed with ACE2 and TMPRSS2, many of which have plausible links to COVID-19 pathophysiology. Many of the co-expressed genes are potentially targetable with existing drugs, which may accelerate the development of COVID-19 therapeutics.
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http://dx.doi.org/10.1038/s41598-020-78818-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736291PMC
December 2020

COPD-derived fibroblasts secrete higher levels of senescence-associated secretory phenotype proteins.

Thorax 2020 Dec 3. Epub 2020 Dec 3.

Pathology and Medical Biology, University Medical Centre Groningen, Groningen, The Netherlands

COPD-derived fibroblasts have increased cellular senescence. Senescent cell accumulation can induce tissue dysfunction by their senescence-associated secretory phenotype (SASP). We aimed to determine the SASP of senescent fibroblasts and COPD-derived lung fibroblasts, including severe, early-onset (SEO)-COPD. SASP protein secretion was measured after paraquat-induced senescence in lung fibroblasts using Olink Proteomics and compared between (SEO-)COPD-derived and control-derived fibroblasts. We identified 124 SASP proteins of senescent lung fibroblasts, of which 42 were secreted at higher levels by COPD-derived fibroblasts and 35 by SEO-COPD-derived fibroblasts compared with controls. Interestingly, the (SEO-)COPD-associated SASP included proteins involved in chronic inflammation, which may contribute to (SEO-)COPD pathogenesis.
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http://dx.doi.org/10.1136/thoraxjnl-2020-215114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070616PMC
December 2020

Acute cigarette smoke-induced eQTL affects formyl peptide receptor expression and lung function.

Respirology 2021 Mar 19;26(3):233-240. Epub 2020 Oct 19.

Respiratory Bioinformatics and Molecular Biology, University of Technology Sydney, Sydney, NSW, Australia.

Background And Objective: Cigarette smoking is one of the most prevalent causes of preventable deaths worldwide, leading to chronic diseases, including chronic obstructive pulmonary disease (COPD). Cigarette smoke is known to induce significant transcriptional modifications throughout the respiratory tract. However, it is largely unknown how genetic profiles influence the smoking-related transcriptional changes and how changes in gene expression translate into altered alveolar epithelial repair responses.

Methods: We performed a candidate-based acute cigarette smoke-induced eQTL study, investigating the association between SNP and differential gene expression of FPR family members in bronchial epithelial cells isolated 24 h after smoking and after 48 h without smoking. The effects FPR1 on lung epithelial integrity and repair upon damage in the presence and absence of cigarette smoke were studied in CRISPR-Cas9-generated lung epithelial knockout cells.

Results: One significant (FDR < 0.05) inducible eQTL (rs3212855) was identified that induced a >2-fold change in gene expression. The minor allele of rs3212855 was associated with significantly higher gene expression of FPR1, FPR2 and FPR3 upon smoking. Importantly, the minor allele of rs3212855 was also associated with lower lung function. Alveolar epithelial FPR1 knockout cells were protected against CSE-induced reduction in repair capacity upon wounding.

Conclusion: We identified a novel smoking-related inducible eQTL that is associated with a smoke-induced increase in the expression of FPR1, FPR2 and FPR3, and with lowered lung function. in vitro FPR1 down-regulation protects against smoke-induced reduction in lung epithelial repair.
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http://dx.doi.org/10.1111/resp.13960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983955PMC
March 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

Genetic regulation of gene expression of MIF family members in lung tissue.

Sci Rep 2020 10 12;10(1):16980. Epub 2020 Oct 12.

Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Groningen, The Netherlands.

Macrophage migration inhibitory factor (MIF) is a cytokine found to be associated with chronic obstructive pulmonary disease (COPD). However, there is no consensus on how MIF levels differ in COPD compared to control conditions and there are no reports on MIF expression in lung tissue. Here we studied gene expression of members of the MIF family MIF, D-Dopachrome Tautomerase (DDT) and DDT-like (DDTL) in a lung tissue dataset with 1087 subjects and identified single nucleotide polymorphisms (SNPs) regulating their gene expression. We found higher MIF and DDT expression in COPD patients compared to non-COPD subjects and found 71 SNPs significantly influencing gene expression of MIF and DDTL. Furthermore, the platform used to measure MIF (microarray or RNAseq) was found to influence the splice variants detected and subsequently the direction of the SNP effects on MIF expression. Among the SNPs found to regulate MIF expression, the major LD block identified was linked to rs5844572, a SNP previously found to be associated with lower diffusion capacity in COPD. This suggests that MIF may be contributing to the pathogenesis of COPD, as SNPs that influence MIF expression are also associated with symptoms of COPD. Our study shows that MIF levels are affected not only by disease but also by genetic diversity (i.e. SNPs). Since none of our significant eSNPs for MIF or DDTL have been described in GWAS for COPD or lung function, MIF expression in COPD patients is more likely a consequence of disease-related factors rather than a cause of the disease.
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http://dx.doi.org/10.1038/s41598-020-74121-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552402PMC
October 2020

Gene signatures from scRNA-seq accurately quantify mast cells in biopsies in asthma.

Clin Exp Allergy 2020 12 23;50(12):1428-1431. Epub 2020 Sep 23.

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

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http://dx.doi.org/10.1111/cea.13732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756890PMC
December 2020

Determinants of SARS-CoV-2 receptor gene expression in upper and lower airways.

medRxiv 2020 Sep 2. Epub 2020 Sep 2.

The recent outbreak of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has led to a worldwide pandemic. One week after initial symptoms develop, a subset of patients progresses to severe disease, with high mortality and limited treatment options. To design novel interventions aimed at preventing spread of the virus and reducing progression to severe disease, detailed knowledge of the cell types and regulating factors driving cellular entry is urgently needed. Here we assess the expression patterns in genes required for COVID-19 entry into cells and replication, and their regulation by genetic, epigenetic and environmental factors, throughout the respiratory tract using samples collected from the upper (nasal) and lower airways (bronchi). Matched samples from the upper and lower airways show a clear increased expression of these genes in the nose compared to the bronchi and parenchyma. Cellular deconvolution indicates a clear association of these genes with the proportion of secretory epithelial cells. Smoking status was found to increase the majority of COVID-19 related genes including ACE2 and TMPRSS2 but only in the lower airways, which was associated with a significant increase in the predicted proportion of goblet cells in bronchial samples of current smokers. Both acute and second hand smoke were found to increase ACE2 expression in the bronchus. Inhaled corticosteroids decrease ACE2 expression in the lower airways. No significant effect of genetics on ACE2 expression was observed, but a strong association of DNA- methylation with ACE2 and TMPRSS2- mRNA expression was identified in the bronchus.
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http://dx.doi.org/10.1101/2020.08.31.20169946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480059PMC
September 2020

Periostin: contributor to abnormal airway epithelial function in asthma?

Eur Respir J 2021 Feb 17;57(2). Epub 2021 Feb 17.

Dept of Pathology and Medical Biology, Experimental Pulmonology and Inflammation Research, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.

Periostin (POSTN) may serve as a biomarker for Type-2 mediated eosinophilic airway inflammation in asthma. We hypothesised that a Type-2 cytokine, interleukin (IL)-13, induces airway epithelial expression of , which in turn contributes to epithelial changes observed in asthma.We studied the effect of IL-13 on expression in BEAS-2B and air-liquid interface differentiated primary bronchial epithelial cells (PBECs). Additionally, the effects of recombinant human POSTN on epithelial-to-mesenchymal transition (EMT) markers and mucin genes were assessed. single cell gene expression and protein levels were analysed in bronchial biopsies and induced sputum from asthma patients and healthy controls.IL-13 increased expression in both cell types and this was accompanied by EMT-related features in BEAS-2B. In air-liquid interface differentiated PBECs, IL-13 increased POSTN basolateral and apical release. Apical administration of POSTN increased the expression of , and In bronchial biopsies, expression was mainly confined to basal epithelial cells, ionocytes, endothelial cells and fibroblasts, showing higher expression in basal epithelial cells from asthma patients those from controls. A higher level of POSTN protein expression in epithelial and subepithelial layers was confirmed in bronchial biopsies from asthma patients when compared to healthy controls. Although sputum POSTN levels were not higher in asthma, levels correlated with eosinophil numbers and with the coughing-up of mucus. expression is increased by IL-13 in bronchial epithelial cells and is higher in bronchial biopsies from asthma patients. This may have important consequences, as administration of POSTN increases epithelial expression of mucin genes, supporting the relationship of POSTN with Type-2 mediated asthma and mucus secretion.
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http://dx.doi.org/10.1183/13993003.01286-2020DOI Listing
February 2021

RAGE and TLR4 differentially regulate airway hyperresponsiveness: Implications for COPD.

Allergy 2021 04 15;76(4):1123-1135. Epub 2020 Oct 15.

Graduate School of Health, Faculty of Health, The University of Technology Sydney, Ultimo, NSW, Australia.

Background: The receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4) is implicated in COPD. Although these receptors share common ligands and signalling pathways, it is not known whether they act in concert to drive pathological processes in COPD. We examined the impact of RAGE and/or TLR4 gene deficiency in a mouse model of COPD and also determined whether expression of these receptors correlates with airway neutrophilia and airway hyperresponsiveness (AHR) in COPD patients.

Methods: We measured airway inflammation and AHR in wild-type, RAGE , TLR4 and TLR4 RAGE mice following acute exposure to cigarette smoke (CS). We also examined the impact of smoking status on AGER (encodes RAGE) and TLR4 bronchial gene expression in patients with and without COPD. Finally, we determined whether expression of these receptors correlates with airway neutrophilia and AHR in COPD patients.

Results: RAGE mice were protected against CS-induced neutrophilia and AHR. In contrast, TLR4 mice were not protected against CS-induced neutrophilia and had more severe CS-induced AHR. TLR4 RAGE mice were not protected against CS-induced neutrophilia but were partially protected against CS-induced mediator release and AHR. Current smoking was associated with significantly lower AGER and TLR4 expression irrespective of COPD status, possibly reflecting negative feedback regulation. However, consistent with preclinical findings, AGER expression correlated with higher sputum neutrophil counts and more severe AHR in COPD patients. TLR4 expression did not correlate with neutrophilic inflammation or AHR.

Conclusions: Inhibition of RAGE but not TLR4 signalling may protect against airway neutrophilia and AHR in COPD.
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http://dx.doi.org/10.1111/all.14563DOI Listing
April 2021

Differences in lung clearance index and functional residual capacity between two commercial multiple-breath nitrogen washout devices in healthy children and adults.

ERJ Open Res 2020 Apr 29;6(2). Epub 2020 Jun 29.

University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Dept of Paediatric Pulmonology and Paediatric Allergy, Groningen, The Netherlands.

Multiple-breath nitrogen washout (MBNW) and its clinical parameter lung clearance index (LCI) are gaining increasing attention for the assessment of small airway function. Measurement of LCI relies on accurate assessment of functional residual capacity (FRC). The EasyOne Pro LAB (ndd) and Exhalyzer D (EM) are two commercially available MBNW devices. The aim of the study was to compare these two devices and in healthy subjects with regard to FRC, LCI and secondary outcome parameters and to relate FRC to FRC measured by body plethysmography (pleth) and helium dilution technique. MBNW measurements were performed using a lung model (FRC between 500 and 4000 mL) and in 38 subjects aged 6-65 years followed by helium dilution and pleth using fixed and relaxed breathing techniques. accuracy within 5% of lung model FRC was 67.3% for ndd, FRC was >5% higher for EM in all tests. , FRC ranged from 1.2 to 5.6 L. Mean differences (limits of agreement) between FRC and FRC were -7.0%, (-23.2 to 9.2%) and 5.7% (-11.2 to 22.6%) using ndd and EM, respectively. FRC was consistently lower than FRC (-11.8% (-25.6 to 2%)). LCI was comparable between the two devices (-1.3% (-21.9 to 19.3%)). There was a difference of >10 % in LCI in 12 of 38 subjects. Using the most recent software updates, both devices show relevant deviations in FRC measurement both and and individual differences in LCI in a significant proportion of subjects. The devices are therefore not interchangeable.
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http://dx.doi.org/10.1183/23120541.00247-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322914PMC
April 2020

Link between increased cellular senescence and extracellular matrix changes in COPD.

Am J Physiol Lung Cell Mol Physiol 2020 07 27;319(1):L48-L60. Epub 2020 May 27.

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

Chronic obstructive pulmonary disease (COPD) is associated with features of accelerated aging, including cellular senescence, DNA damage, oxidative stress, and extracellular matrix (ECM) changes. We propose that these features are particularly apparent in patients with severe, early-onset (SEO)-COPD. Whether fibroblasts from COPD patients display features of accelerated aging and whether this is also present in relatively young SEO-COPD patients is unknown. Therefore, we aimed to determine markers of aging in (SEO)-COPD-derived lung fibroblasts and investigate the impact on ECM. Aging hallmarks and ECM markers were analyzed in lung fibroblasts from SEO-COPD and older COPD patients and compared with fibroblasts from matched non-COPD groups ( = 9-11 per group), both at normal culture conditions and upon Paraquat-induced senescence. COPD-related differences in senescence and ECM expression were validated in lung tissue. Higher levels of cellular senescence, including senescence-associated β-galactosidase (SA-β-gal)-positive cells (19% for COPD vs. 13% for control) and p16 expression, DNA damage (γ-H2A.X-positive nuclei), and oxidative stress () were detected in COPD compared with control-derived fibroblasts. Most effects were also different in SEO-COPD, with SA-β-gal-positive cells only being significant in SEO-COPD vs. matched controls. Lower decorin expression in COPD-derived fibroblasts correlated with higher p16 expression, and this association was confirmed in lung tissue. Paraquat treatment induced cellular senescence along with clear changes in ECM expression, including decorin. Fibroblasts from COPD patients, including SEO-COPD, display higher levels of cellular senescence, DNA damage, and oxidative stress. The association between cellular senescence and ECM expression changes may suggest a link between accelerated aging and ECM dysregulation in COPD.
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http://dx.doi.org/10.1152/ajplung.00028.2020DOI Listing
July 2020

Phenotypic and functional translation of IL33 genetics in asthma.

J Allergy Clin Immunol 2021 Jan 19;147(1):144-157. Epub 2020 May 19.

Department of Health Sciences, University of Leicester, Leicester, United Kingdom; National Institute for Health Research Leicester Respiratory Biomedical Research Centre, Leicester, United Kingdom.

Background: Asthma is a complex disease with multiple phenotypes that may differ in disease pathobiology and treatment response. IL33 single nucleotide polymorphisms (SNPs) have been reproducibly associated with asthma. IL33 levels are elevated in sputum and bronchial biopsies of patients with asthma. The functional consequences of IL33 asthma SNPs remain unknown.

Objective: This study sought to determine whether IL33 SNPs associate with asthma-related phenotypes and with IL33 expression in lung or bronchial epithelium. This study investigated the effect of increased IL33 expression on human bronchial epithelial cell (HBEC) function.

Methods: Association between IL33 SNPs (Chr9: 5,815,786-6,657,983) and asthma phenotypes (Lifelines/DAG [Dutch Asthma GWAS]/GASP [Genetics of Asthma Severity & Phenotypes] cohorts) and between SNPs and expression (lung tissue, bronchial brushes, HBECs) was done using regression modeling. Lentiviral overexpression was used to study IL33 effects on HBECs.

Results: We found that 161 SNPs spanning the IL33 region associated with 1 or more asthma phenotypes after correction for multiple testing. We report a main independent signal tagged by rs992969 associating with blood eosinophil levels, asthma, and eosinophilic asthma. A second, independent signal tagged by rs4008366 presented modest association with eosinophilic asthma. Neither signal associated with FEV, FEV/forced vital capacity, atopy, and age of asthma onset. The 2 IL33 signals are expression quantitative loci in bronchial brushes and cultured HBECs, but not in lung tissue. IL33 overexpression in vitro resulted in reduced viability and reactive oxygen species-capturing of HBECs, without influencing epithelial cell count, metabolic activity, or barrier function.

Conclusions: We identify IL33 as an epithelial susceptibility gene for eosinophilia and asthma, provide mechanistic insight, and implicate targeting of the IL33 pathway specifically in eosinophilic asthma.
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http://dx.doi.org/10.1016/j.jaci.2020.04.051DOI Listing
January 2021

Withdrawn: The novel TRPA1 antagonist BI01305834 inhibits ovalbumin-induced bronchoconstriction in guinea pigs.

Br J Pharmacol 2020 10;177(20):4809

Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands.

The above article from the British Journal of Pharmacology, published online on May 20, 2020 in Wiley Online Library (http://wileyonlinelibrary.com) has been withdrawn due to a lack of full disclosure of the chemical structure of the novel TRPA1 antagonist BI01305834, by agreement between the Editor-in-Chief and John Wiley & Sons Inc on behalf of The British Pharmacology Society.
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http://dx.doi.org/10.1111/bph.15133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520438PMC
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