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Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide novel insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci with P-value < 5 × 10−8; 47 were previously described in association with either COPD or population-based lung function. Of the remaining 35 novel loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified enrichment for loci in lung tissue, smooth muscle and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups of quantitative imaging features and comorbidity associations. Our analyses provide further support to the genetic susceptibility and heterogeneity of COPD., Editorial summary Genome-wide analysis of chronic obstructive pulmonary disease identifies 82 loci, 35 of which are new. Integration of gene expression and genomic annotation data shows enrichment of signals in lung tissue, smooth muscle and several lung cell types.

Background Small airways dysfunction (SAD) is well-recognized in asthma, yet its role in asthma severity and asthma control is unclear. Our study aimed to assess which (combination of) biomarkers, physiological testing and imaging markers best measures the presence and extent of SAD in asthma. Methods This multinational observational study investigated participants without and with asthma (GINA severity stage 1-5). Asthma inclusion criteria were: 1) age 18-65 years; 2) clinical asthma diagnosis > 6 months, confirmed by a chest physician 2, supported by objective evidence of any of the following at the baseline visit or in the previous 5 years: a) positive airway hyperresponsiveness to methacholine, or b) positive reversibility (ΔFEV1≥ 12% and ≥ 200 mL within 30 minutes after 400 μg of salbutamol pMDI with or without a spacer or c) PEF variability >20%, measured during 7 days or d) documented reversibility after a cycle (e.g. 4 weeks) of maintenance anti-asthma treatment; 3) stable asthma on any previous regular asthma treatment (“rescue” β2-agonists alone included) at a stable dose for > 8 weeks before baseline; 4) lifetime smoking ≤ 10 pack-years. They underwent spirometry, body plethysmography, impulse oscillometry (IOS), Multiple Breath Nitrogen Washout (MBNW), computed tomography (CT) and questionnaires. Structural equation modeling (SEM) was applied in asthma to assess the contribution of all physiological and CT parameters to SAD. With SEM, we defined a clinical-SAD and CT-SAD score. Asthma subjects were classified in SAD groups using model-based clustering. Asthma severity, control and health care utilization in the past year were compared with the SAD scores and SAD groups. Findings We investigated 773 asthma and 99 control participants (median [interquartiles] age 46 [34, 54] and 41 [29, 52] years, 58% and 57% females, respectively). All physiologic measures contributed to the clinical SAD model with SEM analysis. The prevalence of SAD in asthma was dependent on the measure used and lowest with MBNW Sacin that reflects ventilation heterogeneity in the most peripheral, pre-acinar/acinar airways. IOS and spirometry, reflecting dysfunction of small-to-midsized airways, contributed most to the Clinical-SAD score and differentiated the two SAD Groups. Clinical-SAD Group1 (n=452) had “milder“ SAD, i.e. comparable MBNW Sacin with controls. Group2 (n=312) had more abnormal physiologic SAD measures than Group1, particularly IOS and spirometry, and more severe asthma (asthma control, treatments, exacerbations, quality of life). Clinical-SAD scores were higher in Group2 (“more severe” SAD) and related to asthma control, severity, and exacerbations. Clinical-SAD and CT-SAD scores did not significantly correlate. Interpretation SAD is a complex and silent signature of asthma, which is likely to be directly or indirectly captured by combinations of physiologic tests: spirometry, body plethysmography, IOS, and MBNW. SAD is present across all asthma severity and particularly in severe disease. The clinical classification of SAD in two groups, i.e. a “milder” and “more severe” SAD group, by the easy-to conduct measures IOS and spirometry, is meaningful given its association with GINA asthma severity stages, asthma control, quality of life, and exacerbations. The longitudinal part of ATLANTIS will show the relevance of the SAD score for future risks in asthma, and additionally which parameter best associates with future asthma control. Moreover, we will report on development of a Small Airways Dysfunction Tool (SADT), a questionnaire as an easy measure to suggest SAD, and on the measures of inflammation that best discriminate between the large and small airways’ compartments, with bronchial and transbronchial biopsies, in a smaller subset of participants.

Exposure to ambient air pollution is associated with a substantial burden of morbidity and mortality worldwide [1]. In a recent paper, Adam et al. [2] showed significantly impaired levels of forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) associated with exposure to the ambient air pollutants nitrogen dioxide (NO2) and particles with a 50% cut-off aerodynamic diameter of 10 μm (PM10) in 7613 adults included in the European Study of Cohorts for Air Pollution Effects (ESCAPE). Effect estimates for FVC were of similar magnitude (for NO2) or larger (for PM10) than those for FEV1. In line with these findings, Forbes et al. [3] showed negative associations of PM10 and NO2 with the level of FEV1 in 40 329 adults included in the Health Survey for England between 1995 and 2001, whereas no significant associations with FEV1/FVC were observed. In 1997, the Swiss Study on Air Pollution and Lung Disease in Adults (SAPALDIA), including 9651 adults, showed negative associations of ambient air pollutants NO2 and PM10 with both FEV1 and FVC [4]. The effect estimates for FVC were stronger than for FEV1 for various pollutants, and this was consistently the case in most subgroups (according to smoking status and respiratory symptoms). Reduced FVC, with FEV1 being normal or reduced to a lesser degree than FVC, suggests restrictive rather than obstructive lung disease (in which FEV1 specifically is reduced, resulting in a low FEV1/FVC ratio). Thus, findings from several European studies suggest that restrictive rather than obstructive ventilatory patterns associate with long-term low levels of exposure to ambient air pollution. A study with slightly different findings is the German Study on the influence of Air Pollution on Lung Function, Inflammation and Ageing (SALIA), including 2593 women. This study also found negative associations of NO2 and PM10 exposure with both FEV1 and FVC, yet the effects estimates for FEV1 were stronger than for FVC, and consequently there were small significant negative associations with the FEV1/FVC ratio [5]. A review article concluded that despite biological plausible mechanisms, there is suggestive, but not conclusive evidence that chronic exposure to air pollution is associated with the prevalence and incidence of chronic obstructive pulmonary disease (COPD), a disease characterised by airway obstruction [6]. Thus far, no studies have focused explicitly on whether air pollution exposure is associated with obstructive or restrictive ventilatory patterns.

Table S1. Baseline characteristics. Table S2. Baseline values of measurements of small airways dysfunction. Table S3. Difference in Î PD20 adenosine in patients with and without small airways dysfunction after treatment with QVAR, Clenil and Flixotide. Table S4. Univariate linear regression analysis of baseline variables and change in airway hyperresponsiveness (Î PD20) in patients treated with QVAR, Clenil and Flixotide. Figure S1. Scatterplots of significant correlations between baseline variables and Î PD20 adenosine. (PDF 731 kb)

Interleukin-1 receptor-like 1 (IL1RL1) is an important asthma gene. (Epi)genetic regulation ofIL1RL1protein expression has not been established. We assessed the association betweenIL1RL1single nucleotide polymorphisms (SNPs),IL1RL1methylation and serum IL1RL1-a protein levels, and aimed to identify causal pathways in asthma.Associations ofIL1RL1SNPs 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 DNAIL1RL1methylation 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 ofIL1RL1CpG 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).IL1RL1asthma-risk SNPs strongly associated withIL1RL1methylation (rs1420101; p=3.7×10-16) and serum IL1RL1-a levels (p=2.8×10-56).IL1RL1methylation 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-associatedIL1RL1SNPs strongly regulateIL1RL1methylation and serum IL1RL1-a levels, yet neither theseIL1RL1-methylation CpG sites nor IL1RL1-a levels are associated with asthma.

© 2018 Asian Pacific Society of Respirology 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 (FEV1), 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 FEV1 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.

Rationale: Genetic polymorphisms in the asthma susceptibility gene, urokinase plasminogen activator receptor (uPAR/PLAUR) have been associated with lung function decline and uPAR blood levels in asthma subjects. Preliminary studies have identified uPAR elevation in asthma; however, a definitive study regarding which clinical features of asthma uPAR may be driving is currently lacking.Objectives: We aimed to comprehensively determine the uPAR expression profile in asthma and control subjects utilizing bronchial biopsies and serum, and to relate uPAR expression to asthma clinical features.Methods: uPAR levels were determined in control (n = 9) and asthmatic (n = 27) bronchial biopsies using immunohistochemistry, with a semi-quantitative score defining intensity in multiple cell types. Soluble-cleaved (sc) uPAR levels were determined in serum through ELISA in UK (cases n = 129; controls n = 39) and Dutch (cases n = 514; controls n = 96) cohorts.Measurements and main results: In bronchial tissue, uPAR was elevated in inflammatory cells in the lamina propria (P = 0.0019), bronchial epithelial (P = 0.0002) and airway smooth muscle cells (P = 0.0352) of patients with asthma, with uPAR levels correlated between the cell types. No correlation with disease severity or asthma clinical features was identified. scuPAR serum levels were elevated in patients with asthma (1.5-fold; P = 0.0008), and we identified an association between high uPAR serum levels and severe, nonatopic disease.Conclusions: This study provides novel data that elevated airway and blood uPAR is a feature of asthma and that blood uPAR is particularly related to severe, nonatopic asthma. The findings warrant further investigation and may provide a therapeutic opportunity for this refractory population.

SUMF1 expression in blood from COPD patients and controls. Total SUMF1 mRNA expression was examined in whole blood from COPD patients and controls in the Lund cohort. A.U. = Arbitrary units. Figure S2. SUMF1 expression in sputum cells and lung fibroblasts divided by rs793391 genotypes. SUMF1 expression, including the three splice variants, was examined for the SNP rs793391 genotype in sputum cells (A-D) from controls and COPD patients and in lung fibroblasts (E-H) obtained from COPD patients from the Lund cohort. Open symbols = controls, filled symbols = COPD patients, A.U. = Arbitrary units. Genotype is presented with the reference/reference genotype to the left. Figure S3. Lung function in COPD patients and controls divided by SNP rs11915920 genotype. FEV1/FVC (A), FEV1 (B) and DLCO %predicted (C) of subjects from the Lund cohort are divided according to the genotype of rs11915920. Open symbols = controls, filled symbols = COPD patients. Genotype is presented with the reference/reference genotype to the left. (PPTX 275 kb)

Cumulative APF at the different airway diameters per lung lobe. Table S2. Airway wall thickness per lobe. Table S3. Airway wall area per lobe. Table S4. Airway wall thickness according to smoking status. Table S5. Airway wall area according to smoking status. Table S6: Associations between airway wall thickness and age, gender and smoking status. Table S7. Associations between airway wall area and age, gender and smoking status. Table S8. Association between pulmonary function parameters and airway wall thickness, independent of age, gender, smoking status and height. Table S9. Association between pulmonary function parameters and airway wall area, independent of age, gender, smoking status and height. (DOCX 51 kb)

Primer sequences used for qPCR. Table S2. Characteristics of controls and COPD patients who could expectorate an adequate sputum. Table S3. Characteristics of COPD patients from whom lung fibroblasts were obtained. Table S4. Characteristics of subjects included in the LifeLines cohort. Table S5. Associations between SNP rs793391 and FEV1/FVC, FEV1%predicted and DLCO%predicted using linear regression models adjusted for current smoking status, age, and COPD. (DOCX 18Â kb)

Clinical characteristics of patients with COPD by rs37973 genotype (Studies 1 and 2). Table S2. Clinical characteristics of patients with COPD by rs37973 genotype (GLUCOLD study). Appendix 1. Sensitivity analyses exploring the effect of transformation and covariate adjustment in Study 2. Table S3. The influence of transformation and covariate adjustment on the analysis of change in FEV1 versus rs37973 genotype in patients with COPD (Study 2). Appendix 2. List of Institutional Review Boards/Independent Ethics Committees and the Chairperson (s) for each site. (DOCX 68 kb)

Cross-sectional studies have shown that occupational exposure to vapors, gases, dusts, and fumes (VGDF) and pesticides is associated with a lower level of lung function. These associations seem to be stronger in ever smokers. In the current study, we aimed to assess whether occupational exposure to VGDF and pesticides is associated with longitudinal decline in lung function. We used 12,772 observations from 2,527 participants in the Vlagtwedde-Vlaardingen Study, a general-population-based cohort study that followed subjects for 25 years, from 1965 to the last survey in 1989/1990. Job-specific exposure was estimated with the ALOHA+ job exposure matrix. Associations between exposures and annual changes in forced expiratory volume in 1 second (FEV1) and FEV1 as a percentage of inspiratory vital capacity (FEV1%VC) were assessed with linear mixed-effect models including sex, age, and level of lung function at the first measurement and pack-years of smoking at the last measurement. We tested for interaction between smoking and occupational exposure and assessed associations separately for never smokers and ever smokers. Exposure to VGDF was not associated with accelerated lung function decline after adjustment for co-exposure to pesticides. Exposure to pesticides, both in the last-held job and as a cumulative measure, was associated with accelerated decline in FEV1 and FEV1%VC, especially among ever smokers, where we found an excess change in FEV1 of -6.9 mL/year (95% confidence interval: -10.2, -3.7) associated with high pesticide exposure.

The Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort was set up in The Netherlands with two main aims: to investigate the effect of mite-allergen avoidance on the incidence of childhood asthma (Intervention study) and to assess lifestyle and environmental risk factors for childhood asthma (Natural History study). The baseline study population consisted of 3963 children born in 1996– 1997. Questionnaires were completed by parents during pregnancy, when the child was 3 months old, then annually from 1 up to 8 years and by parents as well as children at 11 and 14 years. Data were obtained on child and family characteristics, a wide range of environmental and lifestyle exposures and on asthma and other allergic and respiratory outcomes. Home visits and clinical examinations were conducted in sub-groups at the ages of 1, 4, 8 and 12 years to obtain objective measures. These included anthropometric measures, measurements of lung function, bronchial hyper-responsiveness and blood pressure, house dust and blood samples, which were used to determine total and specific IgEs, cholesterol and HbA1c and to extract DNA.

Rationale: Genetic polymorphisms in the asthma susceptibility gene, urokinase plasminogen activator receptor (uPAR/PLAUR) have been associated with lung function decline and uPAR blood levels in asthma subjects. Preliminary studieshave identified uPAR elevation in asthma; however, a definitive study regarding which clinical features of asthma uPAR may be driving is currently lacking. Objectives: We aimed to comprehensively determine the uPAR expression profilein asthma and control subjects utilizing bronchial biopsies and serum, and to relate uPAR expression to asthma clinical features. Methods: uPAR levels were determined in control (n = 9) and asthmatic (n = 27)bronchial biopsies using immunohistochemistry, with a semi-quantitative score defining intensity in multiple cell types. Soluble-cleaved (sc) uPAR levels weredetermined in serum through ELISA in UK (cases n = 129; controls n = 39) and Dutch (cases n = 514; controls n = 96) cohorts.Measurements and main results: In bronchial tissue, uPAR was elevated ininflammatory cells in the lamina propria (P = 0.0019), bronchial epithelial(P = 0.0002) and airway smooth muscle cells (P = 0.0352) of patients with asthma, with uPAR levels correlated between the cell types. No correlation with disease severity or asthma clinical features was identified. scuPAR serum levels were elevated in patients with asthma (1.5-f old; P = 0.0008), and we identified an association between high uPAR serum levels and severe, nonatopic disease. Conclusions: This study provides novel data that elevated airway and blood uPAR is a feature of asthma and that blood uPAR is particularly related to severe, nonatopic asthma. The findings warrant further investigation and may provide a therapeutic opportunity for this refractory population.

Probe sets replicated in both replication sets (UBC and Groningen) in the lung eQTL analyses. A table of replicated probe sets in the lung eQTL analysis. (DOCX 38 kb)

Background: Chronic obstructive pulmonary disease (COPD) is a complex disease characterized by impaired lung function and airway obstruction resulting from interactions between multiple genes and multiple environmental exposures. Thus far, genome-wide association studies have largely disregarded environmental factors that might trigger the development of lung function impairment and COPD, such as occupational exposures, which are thought to contribute to 15% to 20% of the COPD prevalence.Objectives: We performed a genome-wide interaction study to identify novel susceptibility loci for occupational exposure to biological dust, mineral dust, and gases and fumes in relation to FEV1 levels.Methods: We performed an identification analysis in 12,400 subjects from the LifeLines cohort study and verified our findings in 1436 subjects from a second independent cohort, the Vlagtwedde-Vlaardingen cohort. Additionally, we assessed whether replicated single nucleotide polymorphisms (SNPs) were cis-acting expression (mRNA) quantitative trait loci in lung tissue.Results: Of the 7 replicated SNPs that interacted with one of the occupational exposures, several identified loci were plausible candidates that might be involved in biological pathways leading to lung function impairment, such as PCDH9 and GALNT13. Two of the 7 replicated SNPs were cis-acting expression quantitative trait loci associated with gene expression of PDE4D and TMEM176A in lung tissue.Conclusion: This genome-wide interaction study on occupational exposures in relation to the level of lung function identified several novel genes. Further research should determine whether the identified genes are true susceptibility loci for occupational exposures and whether these SNP-by-exposure interactions consequently contribute to the development of COPD.

BackgroundUnderstanding the genetic basis of airflow obstruction and smoking behaviour is key to determining the pathophysiology of chronic obstructive pulmonary disease (COPD). We used UK Biobank data to study the genetic causes of smoking behaviour and lung health.MethodsWe sampled individuals of European ancestry from UK Biobank, from the middle and extremes of the forced expiratory volume in 1 s (FEV1) distribution among heavy smokers (mean 35 pack-years) and never smokers. We developed a custom array for UK Biobank to provide optimum genome-wide coverage of common and low-frequency variants, dense coverage of genomic regions already implicated in lung health and disease, and to assay rare coding variants relevant to the UK population. We investigated whether there were shared genetic causes between different phenotypes defined by extremes of FEV1. We also looked for novel variants associated with extremes of FEV1 and smoking behaviour and assessed regions of the genome that had already shown evidence for a role in lung health and disease. We set genome-wide significance at p

BACKGROUND: Childhood wheeze is an important, well-known risk factor for asthma, yet little is known about the contribution of nocturnal dry cough. We investigated the association of nocturnal dry cough at ages 1-7 years with doctor-diagnosed asthma at 8 years of age, both in the presence and absence of wheeze. METHODS: Data of 3,252 children from the PIAMA birth cohort were studied. Parents reported the presence of nocturnal dry cough, wheeze, and doctor-diagnosed asthma in the past 12 months yearly, from birth up to the age of 8 years. RESULTS: Nocturnal dry cough without wheeze was significantly associated with doctor-diagnosed asthma at age 8, except for age 1 (range of Relative Risks (RR) at ages 2-7: 1.8 (age 5) - 7.1 (age 7), all P-values

Background and objectiveSmall airway dysfunction is associated with asthma severity and control, but its association with airway inflammation is unknown. The aim was to determine the association between sputum inflammatory cells and the site of small airway dysfunction, measured by multiple breath nitrogen washout in convection-dependent (Scond) and more peripheral diffusion-dependent (Sacin) airways. MethodsFifty-three (20-67 years) subjects with asthma on inhaled corticosteroid (ICS) treatment were characterized by spirometry, Scond, Sacin and induced sputum differential counts. %Predicted values for Scond and Sacin were calculated from published reference equations to adjust for the effects of age. Univariate correlations were assessed using the Spearman test. Multivariate linear regressions were performed to account for potential confounders, including age, gender, disease duration, body mass index and ICS dose. ResultsSacin (%predicted) correlated significantly with neutrophil% (r(s)=0.33, P=0.02), ICS dose (r(s)=-0.28, P=0.04) and age (r(s)=0.27, P=0.05). In multivariate analysis, Sacin related only to neutrophil% (adjusted R-2=0.18, P=0.001). Scond (%predicted) correlated significantly only with eosinophil% (r(s)=0.39, P=0.004). There was a trend for a negative relationship with ICS dose (r(s)=-0.26, P=0.06). In multivariate analysis, Scond related to eosinophil% and ICS dose independently (adjusted R-2=0.12, P=0.02). ConclusionsAcinar and conductive airway dysfunction is associated with different inflammatory profiles in asthmatic airways, independently of the effects of age and disease duration. The association between acinar airway dysfunction and neutrophilic airway inflammation may have implications for asthma treatment. The aim of this cross-sectional study was to determine the association between sputum inflammatory cells and small airway dysfunction in asthma. This is the first report of an association between small airway dysfunction and neutrophilic airway inflammation. The results may have implications for asthma treatment.

Smoking is a notorious risk factor for chronic mucus hypersecretion (CMH). CMH frequently occurs in chronic obstructive pulmonary disease (COPD). The question arises whether the same single-nucleotide polymorphisms (SNPs) are related to CMH in smokers with and without COPD.We performed two genome-wide association studies of CMH under an additive genetic model in male heavy smokers (≥20 pack-years) with COPD (n=849, 39.9% CMH) and without COPD (n=1348, 25.4% CMH), followed by replication and meta-analysis in comparable populations, and assessment of the functional relevance of significantly associated SNPs.Genome-wide association analysis of CMH in COPD and non-COPD subjects yielded no genome-wide significance after replication. In COPD, our top SNP (rs10461985, p=5.43×10−5) was located in the GDNF-AS1 gene that is functionally associated with the GDNF gene. Expression of GDNF in bronchial biopsies of COPD patients was significantly associated with CMH (p=0.007). In non-COPD subjects, four SNPs had a p-value −5 in the meta-analysis, including a SNP (rs4863687) in the MAML3 gene, the T-allele showing modest association with CMH (p=7.57×10−6, OR 1.48) and with significantly increased MAML3 expression in lung tissue (p=2.59×10−12).Our data suggest the potential for differential genetic backgrounds of CMH in individuals with and without COPD.

Lung function measures reflect the physiological state of the lung, and are essential to the diagnosis of chronic obstructive pulmonary disease (COPD). The SpiroMeta-CHARGE consortium undertook the largest genome-wide association study (GWAS) so far (n=48 201) for forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FEV1/FVC) in the general population. The lung expression quantitative trait loci (eQTLs) study mapped the genetic architecture of gene expression in lung tissue from 1111 individuals. We used a systems genetics approach to identify single nucleotide polymorphisms (SNPs) associated with lung function that act as eQTLs and change the level of expression of their target genes in lung tissue; termed eSNPs.

Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10-8) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.© 2014 Nature America, Inc. All rights reserved.

Background There is limited knowledge about the extent to which estimates of air pollution effects on health are affected by the choice for a specific exposure model. Objectives We aimed to evaluate the correlation between long-term air pollution exposure estimates using two commonly used exposure modeling techniques [dispersion and land use regression (LUR) models] and, in addition, to compare the estimates of the association between long-term exposure to air pollution and lung function in children using these exposure modeling techniques. Methods We used data of 1,058 participants of a Dutch birth cohort study with measured forced expiratory volume in 1 sec (FEV1), forced vital capacity (FVC), and peak expiratory flow (PEF) measurements at 8 years of age. For each child, annual average outdoor air pollution exposure [nitrogen dioxide (NO2), mass concentration of particulate matter with diameters ≤ 2.5 and ≤ 10 μm (PM2.5, PM10), and PM2.5 soot] was estimated for the current addresses of the participants by a dispersion and a LUR model. Associations between exposures to air pollution and lung function parameters were estimated using linear regression analysis with confounder adjustment. Results Correlations between LUR- and dispersion-modeled pollution concentrations were high for NO2, PM2.5, and PM2.5 soot (R = 0.86–0.90) but low for PM10 (R = 0.57). Associations with lung function were similar for air pollutant exposures estimated using LUR and dispersion modeling, except for associations of PM2.5 with FEV1 and FVC, which were stronger but less precise for exposures based on LUR compared with dispersion model. Conclusions Predictions from LUR and dispersion models correlated very well for PM2.5, NO2, and PM2.5 soot but not for PM10. Health effect estimates did not depend on the type of model used to estimate exposure in a population of Dutch children. Citation Wang M, Gehring U, Hoek G, Keuken M, Jonkers S, Beelen R, Eeftens M, Postma DS, Brunekreef B. 2015. Air pollution and lung function in Dutch children: a comparison of exposure estimates and associations based on land use regression and dispersion exposure modeling approaches. Environ Health Perspect 123:847–851; http://dx.doi.org/10.1289/ehp.1408541

Asthma and CORD are both heterogeneous lung diseases including many different phenotypes. The classical asthma and CORD phenotypes are easy to discern because they reflect extremes of a phenotypical spectrum. Thus asthma in childhood and CORD in smokers have their own phenotypic expression with underlying pathophysiological mechanisms that differ importantly. In older adults, asthma and CORD are more difficult to differentiate and there exists a bronchodilator response in most but not all patients with asthma and persistent airway obstruction in most but not all patients with CORD where even up to 50% have been reported to have some bronchodilator response as assessed with FEVi. Airway obstruction is generated in the large and small airways both in asthma and CORD, and this small airway obstruction is located more proximally in asthma, yet is found more distally in severe and older individuals with asthma, comparable to CORD. Though the underlying inflammation and remodelling processes in asthma and COPD are different in their extreme phenotypes, there are overlap phenotypes with eosinophilic inflammation even in stable COPD and neutrophilic inflammation in longstanding and severe asthma.

Microfluidics-based nanoLC-MS/MS (chipLC-MS/MS) was used to identify and quantify proteins in epithelial lining fluid (ELF), collected during bronchoscopy from the main bronchi of chronic obstructive pulmonary disease (COPD) patients and healthy controls using microprobes. ELF is a biofluid that is well suited to study pathophysiological processes in the lung, because it contains high concentrations of biologically active molecules. 1D-PAGE followed by in-gel tryptic digestion and chipLC-MS/MS resulted in identification of approximately 300 proteins. A comparative study of ELF from COPD patients and non-COPD controls using chemical stable isotope labeling (iTRAQ (R)-8Plex) showed that the levels of lactotransferrin, high-mobility group protein B1 (HMGB 1), alpha 1-antichymotrypsin and cofilin-1 differed significantly in ELF from COPD patients and non-COPD controls (p-values

Background Body mass index (BMI) and waist circumference (WC) may be associated with lung function in children, as observed in adults. Methods Height, weight, waist circumference, and lung function (FVC and FEV1) were measured during a medical examination in 1,058 eight-year-old children participating in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort study. Results After adjusting for height, age and other potential confounders large WC or high BMI (>90th percentile) were not associated with forced expiratory volume in 1sec (FEV1) or forced vital capacity (FVC). In girls only, large WC was, independently of BMI, associated with 3.5% (95% confidence interval (CI): -6.4, -0.6) lower FEV1/FVC ratio in the model including WC and BMI. Girls with low BMI (

Background and objective We assessed whether co-deposition of a long-acting β2-agonist and a corticosteroid affects their respective transport rates across epithelial cells. Methods Drug particles were deposited on the air-interface culture of Calu-3 cells using a twin-stage impinger. We compared the transport rate of salmeterol and fluticasone across the epithelial cells using commercially available formulations (Serevent, Flixotide and Seretide). The transepithelial resistance of Calu-3 cells was measured before and after each deposition to monitor epithelial resistance. Results The codeposition of salmeterol and fluticasone had no significant effect on transport of salmeterol through the cell layer. In contrast, the rate of fluticasone propionate transport in presence of salmeterol xinofoate was significantly lower (0.53 ± 0.20%) compared with the single fluticasone formulation (2.36 ± 0.97%). Furthermore, the resistance of the epithelial cells was significantly increased after salmeterol deposition from both single and combination products. Conclusions Our data demonstrate that salmeterol may decrease the permeability of epithelial cells, resulting in slower fluticasone transport across Calu-3 epithelial monolayers. The subsequent increased residence time of fluticasone in the airways could prolong its anti-inflammatory effects. This study shows for the first time that salmeterol prolongs the transport of fluticasone across the epithelial cell layer following codeposition of salmeterol and fluticasone particles on epithelial cell cultures. This may increase residence time of fluticasone in the airways and result in prolonged anti-inflammatory effects of this corticosteroid. See Editorial, page 1165 © 2013 The Authors. Respirology © 2013 Asian Pacific Society of Respirology.

To cite this article: Vijverberg SJH, Koster ES, Koenderman L, Arets HGM, van der Ent CK, Postma DS, Koppelman GH, Raaijmakers JAM, Maitland-van der Zee A-H. Exhaled NO is a poor marker of asthma control in children with a reported use of asthma medication: a pharmacy-based study. Pediatr Allergy Immunol 2012: 23: 529536. Abstract Background: A high fraction of nitric oxide in exhaled breath (FeNO) has been suggested to be a marker of ongoing airway inflammation and poorly controlled disease in asthma. The usefulness of FeNO to monitor asthma control is still debated today. Aim: To assess the validity of FeNO as a marker of asthma control in children with reported use of asthma medication. Methods: Fraction of nitric oxide in exhaled breath was measured in 601 children (aged 412 yr) with reported use of asthma medication in the past 6 months and in 63 healthy non-asthmatic children (aged 512). Asthma control was assessed by the Asthma Control Questionnaire (ACQ). A receiver-operator characteristics (ROC) curve was generated to assess the accuracy of FeNO as a marker for asthma control. Logistic regression analysis was used to study whether clinical, healthcare, medication, and environmental factors are associated with high FeNO levels (>25 ppb). Results: Fraction of nitric oxide in exhaled breath had a poor accuracy to discriminate well-controlled from not well-controlled asthma [area under the ROC curve: 0.56 (95% CI: 0.520.61, p = 0.008)]. In addition, high FeNO (>25 ppb) was associated with lower medication adherence rates (OR: 0.4; 95% CI 0.30.6), fewer antibiotic courses in the past year (OR: 0.6; 95% CI: 0.40.9), fewer leukotriene antagonists use in the past year (OR: 0.4; 95% CI: 0.20.9), and fewer visits to a (pulmonary) pediatrician (OR: 0.6; 95% CI: 0.40.9). Children living in a non-urban environment had more often high FeNO levels (OR: 1.7; 95% CI: 1.12.6). Conclusion: High FeNO is a poor marker of asthma control in children with reported use of asthma medication. Various other factors, including medication adherence and medication use, are associated with increased FeNO levels.

Toll-like receptors (TLRs) participate in the defence against bacterial infections that are common in patients with Chronic Obstructive Pulmonary Disease (COPD). We studied all tagging SNPs in TLR2 and TLR4 and their associations with the level and change over time of both FEV1 and sputum inflammatory cells in moderate-to-severe COPD. Nine TLR2 SNPs and 17 TLR4 SNPs were genotyped in 110 COPD patients. Associations of SNPs with lung function and inflammatory cells in induced sputum were analyzed cross-sectionally with linear regression and longitudinally with linear mixed-effect models. Two SNPs in TLR2 (rs1898830 and rs11938228) were associated with a lower level of FEV1 and accelerated decline of FEV1 and higher numbers of sputum inflammatory cells. None of the TLR4 SNPs was associated with FEV1 level. Eleven out of 17 SNPs were associated with FEV1 decline, including rs12377632 and rs10759931, which were additionally associated with higher numbers of sputum inflammatory cells at baseline and with increase over time. This is the first longitudinal study showing that tagging SNPs in TLR2 and TLR4 are associated with the level and decline of lung function as well as with inflammatory cell numbers in induced sputum in COPD patients, suggesting a role in the severity and progression of COPD.

Background: Genome-wide association studies have identified determinants of chronic obstructive pulmonary disease, asthma, and lung function level; however, none have addressed decline in lung function. Objective: We conducted the first genome-wide association study on the age-related decrease in FEV1 and its ratio to forced vital capacity (FVC) stratified a priori by asthma status. Methods: Discovery cohorts included adults of European ancestry (1,441 asthmatic and 2,677 nonasthmatic participants: the Epidemiological Study on the Genetics and Environment of Asthma, the Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults, and the European Community Respiratory Health Survey). The associations of FEV1 and FEV1/FVC ratio decrease with 2.5 million single nucleotide polymorphisms (SNPs) were estimated. Thirty loci were followed up by in silico replication (1,160 asthmatic and 10,858 nonasthmatic participants: Atherosclerosis Risk in Communities, the Framingham Heart Study, the British 1958 Birth Cohort, and the Dutch Asthma Study). Results: Main signals identified differed between asthmatic and nonasthmatic participants. None of the SNPs reached genome-wide significance. The association between the height-related gene DLEU7 and FEV1 decrease suggested for nonasthmatic participants in the discovery phase was replicated (discovery, P = 4.8 x 10(-6); replication, P = .03), and additional sensitivity analyses point to a relation to growth. The top ranking signal, TUSC3, which is associated with FEV1/FVC ratio decrease in asthmatic participants (P = 5.3 x 10(-8)), did not replicate. SNPs previously associated with cross-sectional lung function were not prominently associated with decline. Conclusions: Genetic heterogeneity of lung function might be extensive. Our results suggest that genetic determinants of longitudinal and cross-sectional lung function differ and vary by asthma status. (J Allergy Clin Immunol 2012;129:1218-28.)

Genome-wide association studies (GWAS) have identified determinants of chronic obstructive pulmonary disease, asthma and lung function level, however none addressed decline in lung function.

Background: Several studies have shown that predictors of asthma treatment outcomes differ depending on the definition of the outcome chosen. This provides evidence that different outcomes studied may reflect distinct aspects of asthma control. To assess predictors of asthma control, we need firm outcome phenotypes. The aim of this study was to investigate the association between measurements of current and long-term asthma control. Methods: We included 527 children using inhaled corticosteroids participating in the Pharmacogenetics of Asthma medication in Children: Medication with ANti-inflammatory effects cohort. Current asthma control (previous week) was defined using the Asthma Control Questionnaire. Long-term asthma control was based on Global Initiative for Asthma guidelines. Not well-controlled asthma in a season was defined as =3 of the following items present in a season: (i) day-time or (ii) night-time symptoms, (iii) limitations in activities, and (iv) rescue medication use. Asthma control during (i) the previous season and (ii) the year preceding the pharmacy visit was used as long-term asthma control definitions. Current and long-term asthma control were compared to investigate agreement. Results: Long-term uncontrolled asthma rates were highest in autumn and winter (50%) and lowest in summer (32%) (p

Asthma and COPD have a high personal, societal, and economic impact. Both diseases are characterized by airway obstruction and an inflammatory process. The inflammatory process affects the whole respiratory tract, from central to peripheral airways that are

Item does not contain fulltext BACKGROUND: Despite existing effective treatment options, asthma is uncontrolled in a considerable proportion of patients. The aim of this study was to identify determinants of uncontrolled asthma at age 8 in children participating in the PIAMA birth cohort study. METHODS: One hundred seventy children using inhaled corticosteroids in the previous 12 months at age 8 were included. Uncontrolled asthma was defined as: >/=3 items present in the past month: (1) day-time or (2) night-time asthma symptoms, (3) limitations in activities, (4) rescue medication use, (5) FEV(1)

Background Chronic Obstructive Pulmonary Disease (COPD) is associated with bronchial epithelial changes, including squamous cell metaplasia and goblet cell hyperplasia. These features are partially attributed to activation of the epidermal growth factor receptor (EGFR). Whereas smoking cessation reduces respiratory symptoms and lung function decline in COPD, inflammation persists. We determined epithelial proliferation and composition in bronchial biopsies from current and ex-smokers with COPD, and its relation to duration of smoking cessation. Methods 114 COPD patients were studied cross-sectionally: 99 males/15 females, age 62 ± 8 years, median 42 pack-years, no corticosteroids, current (n = 72) or ex-smokers (n = 42, median cessation duration 3.5 years), postbronchodilator FEV1 63 ± 9% predicted. Squamous cell metaplasia (%), goblet cell (PAS/Alcian Blue+) area (%), proliferating (Ki-67+) cell numbers (/mm basement membrane), and EGFR expression (%) were measured in intact epithelium of bronchial biopsies. Results Ex-smokers with COPD had significantly less epithelial squamous cell metaplasia, proliferating cell numbers, and a trend towards reduced goblet cell area than current smokers with COPD (p = 0.025, p = 0.001, p = 0.081, respectively), but no significant difference in EGFR expression. Epithelial features were not different between short-term quitters ( Conclusion Ex-smokers with COPD had less bronchial epithelial remodelling than current smokers, which was only observed after long-term smoking cessation (>3.5 years). Trial registration NCT00158847

Background: The ratio of FVC to slow inspiratory vital capacity (SVC) has been reported to reflect small airways obstruction, but its validity as such is still unclear. The aim of this study was to assess the applicability of the FVC/SVC ratio as a marker of small airways function in patients with bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTX), which is a disorder in which predominantly small airways obstruction causes progressive airflow limitation. Methods: The FVC/SVC ratio was analyzed both cross-sectionally and longitudinally in 39 patients (26 men) with BOS after bilateral LTX (median age, 47 years; interquartile range [IQR], 35 to 54 years), and 36 bilateral lung transplant recipients without BOS (14 men; median age, 46 years; IQR, 41 to 53 years). Results: The FVC/SVC ratio decreased significantly during follow-up in patients with BOS stages I and 2, by 2.2% and 4.4%, respectively, from baseline (p

Background New evidence has suggested that people with asthma who are homozygous for arginine at aminoacid 16 of the beta(2)-adrenergic receptor (ADRB2) might not benefit from longacting beta(2)-agonist therapy. We, therefore, investigated whether ADRB2 polymorphisms affect response to longacting beta(2)-agonists in combination with inhaled corticosteroids. Methods Asthmatics were stratified by ADRB2 genotype in two studies to assess the effects of inhaled corticosteroids plus longacting beta(2)-agonists on asthma exacerbations. In study 1 (double-blind), 2250 asthmatics were randomly assigned to budesonide plus formoterol maintenance and reliever therapy, fixed-dose budesonide plus formoterol, or fixed-dose fluticasone plus salmeterol for 6 months. Study 2 (open-label) consisted of 405 asthmatics and compared an adjustable regimen of budesonide plus formoterol with fixed-dose budesonide plus formoterol and fixed-dose fluticasone plus salmeterol for 7 months. The relation between ADRB2 polymorphism, severe asthma exacerbations, and other asthma outcomes was analysed. Primary endpoints for studies 1 and 2 were severe asthma exacerbation and asthma control as assessed by measures of exacerbations, respectively. Findings In study 1, Gly16Arg genotype had no effect on the percentage of participants with severe exacerbations across all treatment groups (99 [12%] of 833 Gly/Gly, 110 [11%] of 1028 Gly/Arg, and 32 [9%] of 361 Arg/Arg participants). Secondary endpoints, including forced expiratory volume in 1 s, peak expiratory flow, use of as-needed medication, and number of nights with awakenings were similar between genotype groups. No relation was recorded between ADRB2 haplotype and primary and secondary endpoints. In study 2, the frequency of asthma exacerbations (15 [9%] of 168 Gly/Gly, 13 [8%] of 169 Gly/Arg, and 6 [9%] of 67 Arg/Arg participants) and other study endpoints were closely similar for all ADRB2 genotypes. Interpretation Since we showed no pharmacogenetic effect of ADRB2 variation on therapeutic response in asthma, patients, irrespective of their genotype, can continue to receive inhaled corticosteroids plus longacting beta(2)-agonists.

The Dutch hypothesis, formulated in the 1960s, holds that the various forms of airway obstruction are different expressions of a single disease entity. It suggests that genetic factors (eg, airway hyperresponsiveness [AHR] and atopy), endogenous factors (eg, sex and age), and exogenous factors (eg, allergens, infections, and smoking) all play a role in the pathogenesis of chronic nonspecific lung disease. This review finds evidence that AHR and smoking are common risk factors for asthma and COPD. To prove the Dutch hypothesis definitively, however, genetic studies, preferably longitudinal, must be performed. Such studies must include subjects who have airway obstruction that does not necessarily meet the current strict definitions of asthma or COPD (ie, the extremes of these conditions) that are used in clinical studies.

Background The new Global Obstructive Lung Disease (GOLD) guidelines advice to focus treatment in Chronic Obstructive Pulmonary Disease (COPD) on improvement of functional state, prevention of disease progression and minimization of symptoms. So far no validated questionnaires are available to measure symptom and functional state in daily clinical practice. The aim of this study was to develop and validate the Clinical COPD Questionnaire (CCQ). Methods Qualitative research with patients and clinicians was performed to generate possible items to evaluate clinical COPD control. Thereafter, an item reduction questionnaire was sent to 77 international experts. Sixty-seven experts responded and the 10 most important items, divided into 3 domains (symptoms, functional and mental state) were included in the CCQ (scale: 0 = best, 6 = worst). Results Cross-sectional data were collected from 119 subjects (57 COPD, GOLD stage I-III; 18 GOLD stage 0 and 44 (ex)smokers). Cronbach's α was high (0.91). The CCQ scores in patients (GOLD 0-III) were significantly higher than in healthy (ex)smokers. Furthermore, significant correlations were found between the CCQ total score and domains of the SF-36 (ρ = 0.48 to ρ = 0.69) and the SGRQ (ρ = 0.67 to ρ = 0.72). In patients with COPD, the correlation between the CCQ and FEV1%pred was ρ =-0.49. Test-retest reliability was determined in 20 subjects in a 2-week interval (Intra Class Coefficient = 0.94). Thirty-six smokers with and without COPD showed significant improvement in the CCQ after 2 months smoking cessation, indicating the responsiveness of the CCQ. Conclusion The CCQ is a self-administered questionnaire specially developed to measure clinical control in patients with COPD. Data support the validity, reliability and responsiveness of this short and easy to administer questionnaire.

This thesis deals with variations in airway diameter in patients with chronic, partly reversible airflow obstruction. The patients studied in this thesis have been addressed in the literature with terms as CAO, COPD, CNSLD. The confusion caused by combining patients in one descriptive term, e.g. Chronic Airflow Obstruction (CAO) has been discussed in the introduction. In the Netherlands the term Chronic A Specific Respiratory Disease (CARA) is used (1), which includes patients with asthma, chronic bronchitis, and emphyse¬ma. These three entities may be mixed in an individual patient. When used in the literature, the term CAO or CARA is, however, insufficient to describe the type of patients one is studying. It is therefore recommended to extend the term CARA or CAO with indicators of the factors which contribute to the dis¬ease: complaints, degree of reversibility of airflow obstruction, degree of a specific hyperreactivity, presence of allergy, and complicating diseases.

Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV1), and its ratio to forced vital capacity (FEV1/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV1 and FEV1/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest PJMA = 5.00×10−11), HLA-DQB1 and HLA-DQA2 (smallest PJMA = 4.35×10−9), and KCNJ2 and SOX9 (smallest PJMA = 1.28×10−8) were associated with FEV1/FVC or FEV1 in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.

Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease consisting of emphysema, small airway obstruction, and/or chronic bronchitis that results in significant loss of lung function over time. Methods: In order to gain insights into the molecular pathways underlying progression of emphysema and explore computational strategies for identifying COPD therapeutics, we profiled gene expression in lung tissue samples obtained from regions within the same lung with varying amounts of emphysematous destruction from smokers with COPD (8 regions × 8 lungs = 64 samples). Regional emphysema severity was quantified in each tissue sample using the mean linear intercept (Lm) between alveolar walls from micro-CT scans. Results: We identified 127 genes whose expression levels were significantly associated with regional emphysema severity while controlling for gene expression differences between individuals. Genes increasing in expression with increasing emphysematous destruction included those involved in inflammation, such as the B-cell receptor signaling pathway, while genes decreasing in expression were enriched in tissue repair processes, including the transforming growth factor beta (TGFβ) pathway, actin organization, and integrin signaling. We found concordant differential expression of these emphysema severity-associated genes in four cross-sectional studies of COPD. Using the Connectivity Map, we identified GHK as a compound that can reverse the gene-expression signature associated with emphysematous destruction and induce expression patterns consistent with TGFβ pathway activation. Treatment of human fibroblasts with GHK recapitulated TGFβ-induced gene-expression patterns, led to the organization of the actin cytoskeleton, and elevated the expression of integrin β1. Furthermore, addition of GHK or TGFβ restored collagen I contraction and remodeling by fibroblasts derived from COPD lungs compared to fibroblasts from former smokers without COPD. Conclusions: These results demonstrate that gene-expression changes associated with regional emphysema severity within an individual's lung can provide insights into emphysema pathogenesis and identify novel therapeutic opportunities for this deadly disease. They also suggest the need for additional studies to examine the mechanisms by which TGFβ and GHK each reverse the gene-expression signature of emphysematous destruction and the effects of this reversal on disease progression.

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10(-6)) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples, while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases.

Background: Reduced lung function in patients with chronic obstructive pulmonary disease (COPD) is likely due to both environmental and genetic factors. We report here a targeted high-throughput DNA sequencing approach to identify new and previously known genetic variants in a set of candidate genes for COPD. Methods: Exons in 22 genes implicated in lung development as well as 61 genes and 10 genomic regions previously associated with COPD were sequenced using individual DNA samples from 68 cases with moderate or severe COPD and 66 controls matched for age, gender and smoking. Cases and controls were selected from the Obstructive Lung Disease in Northern Sweden (OLIN) studies. Results: In total, 37 genetic variants showed association with COPD (p

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.

The aim of this thesis was to describe, investigate and compare the effects of smoking and atopy in asthma and COPD. A part of the research focused on asthmatic patients with ageing and smoking COPD phenotype, resulting in difficulties to discriminate between these two disorders. The following conclusions can be drawn: • Pathologists are able to differentiate between asthma and COPD, on condition they use a number of pathological criteria, and take the clinical setting into account, particularly the use of inhaled corticosteroids (ICS). • Prevalence of atopy is significantly higher in COPD patients who are males, have overweight and lower age. Atopy significantly associates with higher prevalence of respiratory symptoms and higher likelihood to lose cough upon treatment with busedonide.• Absence of atopy and non-ICS use contribute independently to higher numbers of IL-17 expressing cells. IL17-positive cells were found to be predominantly neutrophils. • CCL20 levels are higher in sputum of asthmatics who use ICS, whereas glucocorticoids increase the release of CCL20 by primary bronchial epithelial cells in vitro.• Smoking associates with higher epithelial HDAC-2 expression in airway biopsies from asthmatics, independent of ICS-use. • Increased Eosinophil Peroxidase (EPX) immunopositivity in airway biopsies from asthmatic subjects associates significantly with lower intact epithelium, particularly in uncontrolled asthma.In summary: heterogeneous populations of asthma and COPD patients determine the broad spectrum of obstructive airway diseases. Smoking and atopy may modulate the underlying inflammatory and clinical phenotype, and affect corticosteroid responsiveness. This heterogeneity should be taken into account when designing clinical studies.

Not being able to breathe, wheezing, coughing, feeling like you are suffocating… This is what happens during an asthma attack, which affects about 100,000 children in the Netherlands. Asthma is caused by a complex interaction between genetic and environmental factors. An important asthma gene is interleukin-1 receptor–like 1 (IL1RL1), which is expressed a.o. on inflammatory cells in the lungs. The gene encodes different proteins: IL1RL1-a and IL1RL1-b. Binding of the cytokine IL-33 to IL1RL1-b leads to an inflammatory response and, in contrast, binding of IL-33 to IL1RL1-a is thought to inhibit an inflammatory response. This study shows that the IL33-IL1RL1 pathway is associated with wheezing, especially after the age of 2 till 4 years old, and that it plays an important role in the development of childhood onset (eosinophilic, allergic) asthma. There are many gene variants that pose a risk of asthma. These variants may or may not encode a protein. A novel finding is that mostly non-coding gene variants are important regulators for IL1RL1 and the amount of IL1RL1 protein. In addition, we report that IL1RL1 variants that constitute a risk for asthma influence asthma treatment response in asthmatic children and that the amount of IL1RL1-a levels present in blood can be used to predict eosinophilic asthma at the age of 6 years. Finally, we show that genetic variants have no added value in predicting asthma at birth. The results of this study highly advanced our understanding of the (epi)genetic effects of IL1RL1 in relation to asthma. This contributes to better prediction of asthma and the development of new treatment options for specific asthma phenotypes.