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Atmospheric pollutants and meteorological conditions are suspected to be causes of preterm birth. We aimed to characterize their possible association with the risk of preterm birth (defined as birth occurring before 37 completed gestational weeks). We pooled individual data from 13 birth cohorts in 11 European countries (71,493 births from the period 1994-2011, European Study of Cohorts for Air Pollution Effects (ESCAPE)). City-specific meteorological data from routine monitors were averaged over time windows spanning from 1 week to the whole pregnancy. Atmospheric pollution measurements (nitrogen oxides and particulate matter) were combined with data from permanent monitors and land-use data into seasonally adjusted land-use regression models. Preterm birth risks associated with air pollution and meteorological factors were estimated using adjusted discrete-time Cox models. The frequency of preterm birth was 5.0%. Preterm birth risk tended to increase with first-trimester average atmospheric pressure (odds ratio per 5-mbar increase = 1.06, 95% confidence interval: 1.01, 1.11), which could not be distinguished from altitude. There was also some evidence of an increase in preterm birth risk with first-trimester average temperature in the-5 degrees C to 15 degrees C range, with a plateau afterwards (spline coding, P = 0.08). No evidence of adverse association with atmospheric pollutants was observed. Our study lends support for an increase in preterm birth risk with atmospheric pressure.

Supplementary methods, tables and figures. (DOCX 1790 kb)

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)

BACKGROUND: Long-term air pollution exposure is negatively associated with lung function, yet the mechanisms underlying this association are not fully clear. Differential DNA methylation may explain this association. OBJECTIVES: Our main aim was to study the association between long-term air pollution exposure and DNA methylation. METHODS: We performed a genome-wide methylation study using robust linear regression models in 1,017 subjects from the LifeLines cohort study to analyze the association between exposure to nitrogen dioxide (NO 2 ) and particulate matter (PM 2.5 , fine particulate matter with aerodynamic diameter ≤2.5 lm; PM 10 , particulate matter with aerodynamic diameter ≤10 lm) and PM 2.5absorbance , indicator of elemental carbon content (estimated with land-use-regression models) with DNA methylation in whole blood (Illumina® HumanMethylation450K BeadChip). Replication of the top hits was attempted in two independent samples from the population-based Cooperative Health Research in the Region of Augsburg studies (KORA). RESULTS: Depending on the p-value threshold used, we found significant associations between NO 2 exposure and DNA methylation for seven CpG sites (Bonferroni corrected threshold p < 1.19 × 10 −7 ) or for 4,980 CpG sites (False Discovery Rate < 0.05). The top associated CpG site was annotated to the PSMB9 gene (i.e., cg04908668). None of the seven Bonferroni significant CpG-sites were significantly replicated in the two KORA-cohorts. No associations were found for PM exposure. CONCLUSIONS: Long-term NO 2 exposure was genome-wide significantly associated with DNA methylation in the identification cohort but not in the replication cohort. Future studies are needed to further elucidate the potential mechanisms underlying NO 2 -exposure–related respiratory disease.

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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)

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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)

Supplement details on study design and additional results. (PDF 1068Â 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)

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.

Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2× 10(-16)). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure.

Supplementary methods. Sputum induction, bronchial biopsies, skin auto-fluorescence. Supplementary Table 1. AGE and RAGE expression in young and old never-smokers and smokers, and COPD GOLD stages. Supplementary Table 2. Correlations of AGEs and RAGE between different compartments. Supplementary Table 3. Expression QTL analysis of AGER. Supplementary Table 4. SNP association with AGE levels detected in the skin. Supplementary Figure 1. Quantitative analyses of AGEs (left panel) and RAGE (right panel) expression in A) intact epithelium, B) basal epithelium, C) smooth muscle, D) connective tissue of bronchial biopsies. Intensity of staining was scored by a 4-points scale: 0=negative staining, 1=weak positive, 2=positive, and 3=strong positive. Horizontal bars represent median values. Supplementary Figure 2. Representative immunohistological staining of AGEs (AGE 1/750, Cosmo Bio Clone 6D12) and RAGE (RAGE 1/1500, Abcam, ab7764) in young healthy controls, old healthy controls and COPD patients. Pictures are shown as 40x magnification, scans taken using the Hamamatsu Slide Scanner (Hamamatsu Photonics, Hamamatsu City, Japan). Supplementary Figure 3. Quantitative analyses of AGEs (left panel) and RAGE (right panel) expression in A) epithelium and B) smooth muscle of the peripheral airways. Intensity of staining was scored by a 4-points scale: 0=negative staining, 1=weak positive, 2=positive, and 3=strong positive. Horizontal bars represent median values.

Supplementary methods. Detailed methods description regarding classification of COPD, sequencing protocol and linkage disequilibrium analysis. (DOCX 123 kb)

Targeted genes and variants for targeted high throughput sequencing. The table lists the selected genes and variants included in the study. (DOCX 79 kb)

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)

Pairwise linkage disequilibrium (LD) of associated variants. A list of detected genetic variants found to be in LD. (DOCX 46 kb)

A plot containing genomic positions and p-values of variants in the CHRNA3/CHRNA5 gene locus with rs8040869 and rs16969968 highlighted. (PDF 144 kb)

Gene burden analysis of common variants. The table present the SKAT analysis of gene burden of common variants. (DOCX 86 kb)

Number of rare variants found uniquely in cases and controls. The table present data of the UNIQ test of rare variants in cases versus controls. (DOCX 78 kb)

Objective: The study aims to elucidate the association of host-related factors on systemic inflammation in COPD patients. Methods: In 295 clinically stable and optimally treated COPD patients from 39 outpatient centers, age, gender, and body composition (body mass index, BMI; fat-free mass index, FFMI; fat mass index, FMI) were related to inflammatory biomarkers: CRP, fibrinogen, TNFα, and its soluble receptors (s)TNFαR1 and sTNFαR2. Furthermore, forced expiratory volume in the first second (FEV1), BMI, FFMI, and FMI were stratified by quartiles to elucidate the influence on inflammatory biomarkers. Monovariate and multivariate regression analyses were performed for associations between inflammatory biomarkers. Results: Positive correlations were found for FFMI with sTNFαR1, FMI with CRP and age with TNFα, sTNFαR1 and sTNFαR2 (p < 0.01). FEV1 was not correlated with body composition and inflammatory markers. Mono- and multivariate analysis showed weak correlations between the acute phase markers and the TNFα system after correcting for multiple co-variants. Conclusions: This study highlights the modest role of age and body composition on levels of systemic inflammatory biomarkers in COPD. Results show the degree of airflow limitation does not affect systemic inflammation. Last, a weak relationship between acute phase markers and markers of the TNFα system is present in COPD.

Background\ud \ud Understanding 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.\ud \ud Methods\ud \ud We 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

Rationale: Risk of subsequent asthma-like symptoms after early-life lower respiratory illness (LRI) caused by respiratory syncytial virus (RSV) is increased during the first decade of childhood and diminished thereafter by adolescence.

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

Background Genome-wide association studies identified IL33 and IL-1 receptor–like 1 ( IL1RL1 )/ IL18R1 as asthma susceptibility loci. IL33 and IL1RL1 constitute a single ligand-receptor pathway. Objective In 2 birth cohorts, the Prevalence and Incidence of Asthma and Mite Allergy (PIAMA) study and Avon Longitudinal Study of Parents and Children (ALSPAC), we analyzed associations of longitudinal wheezing phenotypes and asthma with single nucleotide polymorphisms (SNPs) of 8 genes encoding IL-33, IL1RL1, its coreceptor IL1RAcP, its adaptors myeloid differentiation primary response gene 88 (MyD88) and Toll–IL-11 receptor domain containing adaptor protein (TIRAP), and the downstream IL-1 receptor–associated kinase 1, IL-1 receptor–associated kinase 4, and TNF receptor–associated factor 6 (TRAF6). Furthermore, we investigated whether SNPs in this pathway show replicable evidence of gene-gene interaction. Methods Ninety-four SNPs were investigated in 2007 children in the PIAMA study and 7247 children in ALSPAC. Associations with wheezing phenotypes and asthma at 8 years of age were analyzed in each cohort and subsequently meta-analyzed. Gene-gene interactions were assessed through model-based multifactor dimensionality reduction in the PIAMA study, and gene-gene interactions of 10 SNP pairs were further evaluated. Results Intermediate-onset wheeze was associated with SNPs in several genes in the IL33-IL1RL1 pathway after applying multiple testing correction in the meta-analysis: 2 IL33 SNPs (rs4742170 and rs7037276), 1 IL-1 receptor accessory protein (IL1RAP) SNP (rs10513854), and 1 TRAF6 SNP (rs5030411). Late-onset wheeze was associated with 2 IL1RL1 SNPs (rs10208293 and rs13424006), and persistent wheeze was associated with 1 IL33 SNP (rs1342326) and 1 IL1RAP SNP (rs9290936). IL33 and IL1RL1 SNPs were nominally associated with asthma. Three SNP pairs showed interaction for asthma in the PIAMA study but not in ALSPAC. Conclusions IL33-IL1RL1 pathway polymorphisms are associated with asthma and specific wheezing phenotypes; that is, most SNPs are associated with intermediate-onset wheeze, a phenotype closely associated with sensitization. We speculate that IL33-IL1RL1 pathway polymorphisms affect development of wheeze and subsequent asthma through sensitization in early childhood.

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.

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 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.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

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.

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.