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Smith D.,Amgen Inc. | Smith D.,Insight Bio Consulting LLC | Helgason H.,Amgen Inc. | Helgason H.,University of Iceland | And 50 more authors.
PLoS Genetics | Year: 2017

IL-33 is a tissue-derived cytokine that induces and amplifies eosinophilic inflammation and has emerged as a promising new drug target for asthma and allergic disease. Common variants at IL33 and IL1RL1, encoding the IL-33 receptor ST2, associate with eosinophil counts and asthma. Through whole-genome sequencing and imputation into the Icelandic population, we found a rare variant in IL33 (NM_001199640:exon7:c.487-1G>C (rs146597587-C), allele frequency = 0.65%) that disrupts a canonical splice acceptor site before the last coding exon. It is also found at low frequency in European populations. rs146597587-C associates with lower eosinophil counts (β = -0.21 SD, P = 2.5×10–16, N = 103,104), and reduced risk of asthma in Europeans (OR = 0.47; 95%CI: 0.32, 0.70, P = 1.8×10–4, N cases = 6,465, N controls = 302,977). Heterozygotes have about 40% lower total IL33 mRNA expression than non-carriers and allele-specific analysis based on RNA sequencing and phased genotypes shows that only 20% of the total expression is from the mutated chromosome. In half of those transcripts the mutation causes retention of the last intron, predicted to result in a premature stop codon that leads to truncation of 66 amino acids. The truncated IL-33 has normal intracellular localization but neither binds IL-33R/ST2 nor activates ST2-expressing cells. Together these data demonstrate that rs146597587-C is a loss of function mutation and support the hypothesis that IL-33 haploinsufficiency protects against asthma. © 2017 Smith et al.


van der Toorn M.,Laboratory Allergology and Pulmonary Diseases | van der Toorn M.,GRIAC Research Institute | Slebos D.-J.,University of Groningen | de Bruin H.G.,Laboratory Allergology and Pulmonary Diseases | And 9 more authors.
Respiratory Research | Year: 2013

Background: Cigarette smoking (CS) is the most important risk factor for COPD, which is associated with neutrophilic airway inflammation. We hypothesize, that highly reactive aldehydes are critical for CS-induced neutrophilic airway inflammation.Methods: BALB/c mice were exposed to CS, water filtered CS (WF-CS) or air for 5 days. Levels of total particulate matter (TPM) and aldehydes in CS and WF-CS were measured. Six hours after the last exposure, inflammatory cells and cytokine levels were measured in lung tissue and bronchoalveolar lavage fluid (BALF). Furthermore, Beas-2b bronchial epithelial cells were exposed to CS extract (CSE) or WF-CS extract (WF-CSE) in the absence or presence of the aldehyde acrolein and IL-8 production was measured after 24 hrs.Results: Compared to CS, in WF-CS strongly decreased (CS; 271.1 ± 41.5 μM, WF-CS; 58.5 ± 8.2 μM) levels of aldehydes were present whereas levels of TPM were only slightly reduced (CS; 20.78 ± 0.59 mg, WF-CS; 16.38 ± 0.36 mg). The numbers of mononuclear cells in BALF (p<0.01) and lung tissue (p<0.01) were significantly increased in the CS- and WF-CS-exposed mice compared to air control mice. Interestingly, the numbers of neutrophils (p<0.001) in BALF and neutrophils and eosinophils (p<0.05) in lung tissue were significantly increased in the CS-exposed but not in WF-CS-exposed mice as compared to air control mice. Levels of the neutrophil and eosinophil chemoattractants KC, MCP-1, MIP-1α and IL-5 were all significantly increased in lung tissue from CS-exposed mice compared to both WF-CS-exposed and air control mice. Interestingly, depletion of aldehydes in WF-CS extract significantly reduced IL-8 production in Beas-2b as compared to CSE, which could be restored by the aldehyde acrolein.Conclusion: Aldehydes present in CS play a critical role in inflammatory cytokine production and neutrophilic- but not mononuclear airway inflammation. © 2013 Toorn et al.; licensee BioMed Central Ltd.


Willers S.M.,University Utrecht | Brunekreef B.,University Utrecht | Abrahamse-Berkeveld M.,Center for Specialised Nutrition | Van De Heijning B.,Center for Specialised Nutrition | And 5 more authors.
Annals of Nutrition and Metabolism | Year: 2015

Background/Aims: Visfatin has been suggested as a marker of visceral adiposity. We hypothesized that visfatin, but not leptin, would be specifically associated with visceral adiposity. We investigated the relation of serum visfatin and leptin with measures of adiposity and body fat distribution in children. Methods: Serum leptin and visfatin levels were measured in 1,022 12-year-old children participating in the PIAMA birth cohort. BMI, waist, hip and upper arm circumference were available for all children. Multiple linear regression analyses were conducted to study associations between different anthropometric indices and log serum visfatin and leptin levels. Results: All anthropometric indices showed positive and strong dose-response relationships with serum leptin. Visfatin was increased only in children with a high waist-to-hip ratio. The effect size was small compared to those observed for leptin and the association was present in overweight children (n = 133) but not in normal weight children. Conclusion: Serum leptin levels strongly increased with increasing adiposity, but were not related to a specific type of fat distribution. In contrast, serum visfatin was associated only with high waist-to-hip ratio in overweight children. Based on our study we would currently not recommend visfatin as a marker of visceral adiposity in the general population of children. © 2015 S. Karger AG, Basel.


Foster J.M.,University of Sydney | Schokker S.,GRIAC Research Institute | Sanderman R.,Health Psychology Section | Postma D.S.,GRIAC Research Institute | And 2 more authors.
Allergy: European Journal of Allergy and Clinical Immunology | Year: 2014

Background: Side-effect concerns impede adherence with inhaled corticosteroids (ICS) and often underlie poor asthma control. We developed a brief version (ICQ-S) of the 57-item Inhaled Corticosteroids side-effect Questionnaire (ICQ) to facilitate side-effect monitoring in busy clinics. Methods: Part 1: After completion by 482 patients with doctor-diagnosed asthma, each ICQ item underwent item reduction analysis. Part 2: Patients prescribed ICS for asthma completed the ICQ at baseline (BL), ICQ-S at day 14 (D14) and day 28 (D28), and 6-item Asthma Control Questionnaire (ACQ) and Mini Asthma Quality of Life Questionnaire (MiniAQLQ) at BL, D14 and D28. 14-day test-retest reliability was assessed by intraclass correlation coefficient (ICC) between ICQ-S scores and internal consistency by Cronbach's alpha (α) coefficient and item-total correlations of ICQ-S. Criterion validity was assessed by correlations (Spearman's rho) between ICQ and ICQ-S total score. Patients reported duration and difficulty of ICQ-S completion at D28. Results: Part 1: The ICQ-S consists of fifteen local/systemic ICS side-effects of similar range to the full ICQ. Part 2: 62 asthma patients (mean ACQ score 0.79 ± SD 0.83) prescribed daily ICS [BDP-equivalent median dose 1000 μg (IQR: 500, 1000)] participated. ICC between ICQ-S scores was 0.90. All item-total correlations were rho ≥ 0.20. The ICQ-S demonstrated criterion validity, for example, ICQ and ICQ-S were strongly associated (rho = 0.86). 81% of patients completed the ICQ-S within 5 minutes and 97% found completion 'not difficult'. Conclusion: The ICQ-S is a brief, patient-friendly tool with good reliability and validity, which may be useful for monitoring ICS side-effects in clinical practice. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


Vrijlandt E.J.L.E.,Beatrix Childrens Hospital | Vrijlandt E.J.L.E.,GRIAC Research Institute | Kerstjens J.M.,Beatrix Childrens Hospital | Duiverman E.J.,Beatrix Childrens Hospital | And 3 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2013

Rationale: Pulmonary outcomes of moderate-preterm children (MP) are unknown. Objectives: To investigate the prevalence of respiratory symptoms during infancy and at preschool age of MP compared with full-term (FT) and early pretermchildren (EP) and to determine factors associated with respiratory symptoms of MP at school age. Methods: Prospective cohort study. Outcome variables: number of rehospitalizations caused by respiratory problems, prevalence of respiratory symptoms determined by ISAAC Questionnaires, and factors associated with respiratory symptoms determined by univariate and multivariate analyzes. Measurements and Main Results: A total of 988 MP, 551 EP, and 573 FT children were included. The number of hospitalizations caused by respiratory problems during the first year of life was doubled in MP compared with FT (6% vs. 3%; P < 0.001). At preschool age, compared with FT, MP reported more cough or wheeze during a cold (63% vs. 50%; P < 0.001); cough or wheeze without a cold (23% vs. 15%; P = 0.001); nocturnal cough (33% vs. 26%; P = 0.005); dyspnea (8% vs. 4%; P = 0.011); and use of medication (inhaled steroids, 9% vs. 6%; P = 0.042) (antibiotics, 12% vs. 7%; P = 0.002). Factors associated with respiratory symptoms at 5 years among MP were respiratory problems, eczema, rehospitalization in infancy, passive smoking in infancy, family history of asthma, and higher social class. Multivariate analyzes showed the same results except for rehospitalization in infancy. Conclusions: MP have more respiratory symptoms than FT during early childhood. Factors associated with respiratory symptoms at school age are early respiratory problems, family history of asthma, higher social class, and passive smoking. Copyright © 2013 by the American Thoracic Society.


Brandsma C.-A.,University of Groningen | Brandsma C.-A.,GRIAC Research Institute | Timens W.,University of Groningen | Timens W.,GRIAC Research Institute | And 7 more authors.
American Journal of Physiology - Lung Cellular and Molecular Physiology | Year: 2013

Chronic obstructive pulmonary disease (COPD) is characterized by abnormal repair in the lung resulting in airway obstruction associated with emphysema and peripheral airway fibrosis. Because the presence and degree of airways disease and emphysema varies between COPD patients, this may explain the heterogeneity in the response to treatment. It is currently unknown whether and to what extent inhaled steroids can affect the abnormal repair process in the airways and lung parenchyma in COPD. We investigated the effects of fluticasone on transforming growth factor (TGF)-β- and cigarette smoke-induced changes in mothers against deca-pentaplegic homolog (Smad) signaling and extracellular matrix (ECM) production in airway and parenchymal lung fibroblasts from patients with severe COPD. We showed that TGF-β-induced ECM production by pulmonary fibroblasts, but not activation of the Smad pathway, was sensitive to the effects of fluticasone. Fluticasone induced decorin production by airway fibroblasts and partly reversed the negative effects of TGF-β treatment. Fluticasone inhibited biglycan production in both airway and parenchymal fibroblasts and procollagen 1 production only in parenchymal fibroblasts, thereby restoring the basal difference in procollagen 1 production between airway and parenchymal fibroblasts. Our findings suggest that the effects of steroids on the airway compartment may be beneficial for patients with severe COPD, i.e., restoration of decorin loss around the airways, whereas the effects of steroids on the parenchyma may be detrimental, since the tissue repair response, i.e., biglycan and procollagen production, is inhibited. More research is needed to further disentangle these differential effects of steroid treatment on the different lung compartments and its impact on tissue repair and remodeling in COPD. © 2013 the American Physiological Society.

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