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ATP-binding cassette (ABC) transporters are proteins responsible for active transport of various compounds, from small ions to macromolecules, across membranes. Proteins from this superfamily also pump drugs out of the cell resulting in multidrug resistance. Based on the cellular functions of ABC-transporters they are commonly associated with diseases like cancer and cystic fibrosis. To understand the molecular mechanism of this critical family of integral membrane proteins, structural characterization is a powerful tool which in turn requires successful recombinant production of stable and functional protein in good yields. In this review we have used high resolution structures of ABC transporters as a measure of successful protein production and summarized strategies for prokaryotic and eukaryotic proteins, respectively. In general, Escherichia coli is the most frequently used host for production of prokaryotic ABC transporters while human embryonic kidney 293 (HEK293) cells are the preferred host system for eukaryotic proteins. Independent of origin, at least two-steps of purification were required after solubilization in the most used detergent DDM. The purification tag was frequently cleaved off before structural characterization using cryogenic electron microscopy, or crystallization and X-ray analysis for prokaryotic proteins., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Lung development starts in utero and continues during childhood through to adolescence, reaching its peak in early adulthood. This growth is followed by gradual decline due to physiological lung ageing. Lung-function development can be altered by several host and environmental factors during the life course. As a result, a range of lung-function trajectories exist in the population. Below average trajectories are associated with respiratory, cardiovascular, metabolic, and mental health comorbidities, as well as with premature death. This Review presents progressive research into lung-function trajectories and assists the implementation of this knowledge in clinical practice as an innovative approach to detect poor lung health early, monitor respiratory disease progression, and promote lung health. Specifically, we propose that, similar to paediatric height and weight charts used globally to monitor children's growth, lung-function charts could be used for both children and adults to monitor lung health status across the life course. To achieve this proposal, we introduce our free online Lung Function Tracker tool. Finally, we discuss challenges and opportunities for effective implementation of the trajectory concept at population level and outline an agenda for crucial research needed to support such implementation., Competing Interests: Declaration of interests LL has given lectures sponsored by Chiesi, a non-profit organisation facilitating lifelong learning for health-care providers, and received consulting fees from AstraZeneca, all paid to Ghent University. EM has received lecture fees from Airsonett, ALK, AstraZeneca, Chiesi, and Sanofi. AA has received lecture fees from AstraZeneca, Chiesi, GSK, Menarini, MSD, Sanofi, and Zambon; and research grants from AstraZeneca, GSK, Menarini, and Sanofi. SS has received lecture fees from Vyaire Medical, and consulting fees from Chiasi and NDD. JG-A's institution has received consulting and lecture fees from AstraZeneca (not related to this study); JGA has received lecture fees from Esteve and Chiesi (not related to this study). SCD has received investigator-initiated grants from GlaxoSmithKline and AstraZeneca. HP has received lecture fees (not related to this review) from Teva and Sandoz. AC reports personal fees from Novartis, Sanofi, Stallergenes Greer, AstraZeneca, GlaxoSmithKline, and La Roche-Posay, outside the submitted work. LEGWV has received lecture fees and advisory board fees from GlaxoSmithKline, AstraZeneca, Chiesi, Boehringer, Pulmonx, and Menarini. RF has received lecture fees Chiesi, AstraZeneca, and Zambon, advisory board fees from AstraZeneca, and research grants from AstraZeneca, GSK, Menarini, and Sanofi. JPA has received lecture fees from AstraZeneca. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Competing Interests: PEM declares no conflicts of interest. EM is supported by grants from the Swedish Research Council, Swedish Heart-Lung Foundation and Region Stockholm (ALF). EM has received advisory board or lecture fees from Airsonett, ALK, AstraZeneca, Chiesi, Novartis, and Sanofi outside of the study. GHK is supported by a ZON-MW VICI grant, and reports receiving research grants from Netherlands Lung Foundation, Ubbo Emmius Foundation, Health Holland, EU, GSK, Vertex, and TEVA the Netherlands outside of the submitted work. GHK received advisory board or lecture fees from Astra Zeneca, PURE-IMS, Sanofi, and Boehringer-Ingelheim. JCC is supported by grants HL152475, HL168539 and HL150431 from the US National Institutes of Health. JCC has received research materials (inhaled corticosteroids) from Merck to provide medications free of cost to participants in an NIH-funded study.

Asthma is one of the most common chronic non-communicable diseases worldwide and is characterised by variable airflow obstruction, causing dyspnoea and wheezing. Highly effective therapies are available; asthma morbidity and mortality have vastly improved in the past 15 years, and most patients can attain good asthma control. However, undertreatment is still common, and improving patient and health-care provider understanding of when and how to adjust treatment is crucial. Asthma management consists of a cycle of assessment of asthma control and risk factors and adjustment of medications accordingly. With the introduction of biological therapies, management of severe asthma has entered the precision medicine era-a shift that is driving clinical ambitions towards disease remission. Patients with severe asthma often have co-existing conditions contributing to their symptoms, mandating a multidimensional management approach. In this Seminar, we provide a clinically focused overview of asthma; epidemiology, pathophysiology, diagnosis, and management in children and adults., Competing Interests: Declaration of interests CP declares research grants from AstraZeneca, GSK, Novartis, Teva Pharmaceuticals, Sanofi, Chiesi Farmaceutici, and ALK-Abelló; consulting fees from AstraZeneca, GSK, Novartis, Teva Pharmaceuticals, Sanofi, Chiesi Farmaceutici, and ALK-Abelló; honoraria for lectures from AstraZeneca, GSK, Novartis, Teva Pharmaceuticals, Sanofi, Chiesi Farmaceutici, and ALK-Abelló; and fees for being on the advisory board for AstraZeneca, Novartis, Teva Pharmaceuticals, Sanofi, and ALK-Abelló. EM declares consulting fees from ALK-Abelló, AstraZeneca, Chiesi Farmaceutici, Novartis, and Sanofi. EM is a member of the European Respiratory Society Environmental Health Committee. LL declares consulting fees from ALK-Abelló, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Circassia Group, GSK, Menarini, Novartis, Orion, and Sanofi; honoraria for lectures from ALK-Abelló, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Circassia Group, GSK, Menarini, Novartis, Orion, and Sanofi; and fees for being on the advisory board for ALK-Abelló, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Circassia Group, GSK, Menarini, Novartis, Orion, and Sanofi. LL owns shares of Ausculthing OY. DS declares consulting fees from GSK and Novartis; honoraria for lectures from Teva Pharmaceuticals and Chiesi; and travel fees from Chiesi., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background and Aim: Experimental studies show that short-term exposure to air pollution may alter cytokine concentrations. There is, however, a lack of epidemiological studies evaluating the association between long-term air pollution exposure and inflammation-related proteins in young children. Our objective was to examine whether air pollution exposure is associated with inflammation-related proteins during the first 2 years of life., Methods: In a pooled analysis of two birth cohorts from Stockholm County (n = 158), plasma levels of 92 systemic inflammation-related proteins were measured by Olink Proseek Multiplex Inflammation panel at 6 months, 1 year and 2 years of age. Time-weighted average exposure to particles with an aerodynamic diameter of <10 μm (PM 10 ), <2.5 μm (PM 2.5 ), and nitrogen dioxide (NO 2 ) at residential addresses from birth and onwards was estimated via validated dispersion models. Stratified by sex, longitudinal cross-referenced mixed effect models were applied to estimate the overall effect of preceding air pollution exposure on combined protein levels, "inflammatory proteome", over the first 2 years of life, followed by cross-sectional protein-specific bootstrapped quantile regression analysis., Results: We identified significant longitudinal associations of inflammatory proteome during the first 2 years of life with preceding PM 2.5 exposure, while consistent associations with PM 10 and NO 2 across ages were only observed among girls. Subsequent protein-specific analyses revealed significant associations of PM 10 exposure with an increase in IFN-gamma and IL-12B in boys, and a decrease in IL-8 in girls at different percentiles of proteins levels, at age 6 months. Several inflammation-related proteins were also significantly associated with preceding PM 10 , PM 2.5 and NO 2 exposures, at ages 1 and 2 years, in a sex-specific manner., Conclusions: Ambient air pollution exposure influences inflammation-related protein levels already during early childhood. Our results also suggest age- and sex-specific differences in the impact of air pollution on children's inflammatory profiles., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Despite the growing popularity of electronic cigarettes (e-cigarettes) over the last decade, few epidemiological studies have examined the influence on respiratory health in young adulthood. The aim of this study was to identify factors associated with e-cigarette use in young adulthood in Sweden, and to examine associations between e-cigarette use and lung function, respiratory symptoms, and obesity. This cross-sectional study included 3055 young adults from Sweden and used questionnaire and clinical data obtained at age 22-25 years. The prevalence of current e-cigarette use was 3.9% (n = 120). Few participants reported daily (0.4%) or exclusive (0.8%) use of e-cigarettes. In a multivariable adjusted logistic regression model, e-cigarette use was significantly associated with male gender (OR:3.2; 95% CI:1.5-6.7) and cigarette smoking (OR:14.7; 95% CI:5.5-39.0 for daily smoking). Prevalence of cough (15.0% vs. 8.5%) and mucus production (22.3% vs. 14.8%) was significantly higher among e-cigarette users compared to non-users, while no difference in lung function was observed. In addition, the prevalence of overweight/obesity was higher among e-cigarette users compared to non-users (36.7% vs. 22.3% with BMI≥25 kg/m 2 ). In conclusion, cigarette smokers and males used e-cigarette more often compared to females and non-cigarette smokers. Attention should be given to respiratory symptoms among e-cigarette users, although our results may be explained by the concurrent use of conventional cigarettes, as the group of exclusive e-cigarette users were too small to allow firm conclusions., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The traditional view of chronic obstructive pulmonary disease (COPD) as a self-inflicted disease caused by tobacco smoking in genetically susceptible individuals has been challenged by recent research findings. COPD can instead be understood as the potential end result of the accumulation of gene-environment interactions encountered by an individual over the life course. Integration of a time axis in pathogenic models of COPD is necessary because the biological responses to and clinical consequences of different exposures might vary according to both the age of an individual at which a given gene-environment interaction occurs and the cumulative history of previous gene-environment interactions. Future research should aim to understand the effects of dynamic interactions between genes (G) and the environment (E) by integrating information from basic omics (eg, genomics, epigenomics, proteomics) and clinical omics (eg, phenomics, physiomics, radiomics) with exposures (the exposome) over time (T)-an approach that we refer to as GETomics. In the context of this approach, we argue that COPD should be viewed not as a single disease, but as a clinical syndrome characterised by a recognisable pattern of chronic symptoms and structural or functional impairments due to gene-environment interactions across the lifespan that influence normal lung development and ageing., Competing Interests: Declaration of interests AA has received research funds and honoraria as a speaker and consultant from AstraZeneca, GlaxoSmithKline, Chiesi, and Menarini for initiatives related to chronic obstructive pulmonary disease (COPD), outside of the submitted work. EM has received advisory board reimbursements and fees as a speaker from AstraZeneca, Chiesi, Novartis, and Sanofi, outside of the submitted work. DLD has received research funds from the National Institutes of Health, Alpha-1 Foundation, and Bayer, and honoraria from Novartis. RB-K has received honoraria as a speaker from AstraZeneca, GlaxoSmithKline, Menarini, and Novartis. RF has received research funds from AstraZeneca, GlaxoSmithKline, and Menarini, honoraria as a speaker from Chiesi, and consultancy fees from GlaxoSmithKline for COPD-related initiatives outside of the submitted work., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: PUFAs may influence the risk of asthma; however, long-term prospective studies including objective biomarkers of PUFA intake are lacking., Objectives: The objective was to investigate the role of dietary intake and plasma concentrations of n-3 and n-6 (ω-3 and ω-6) PUFAs in childhood and adolescence for the development of asthma and lung function up to young adulthood., Methods: The study included participants from the Swedish prospective birth cohort BAMSE. Dietary intake of PUFAs was calculated from FFQs (n = 1992) and plasma proportions of PUFAs were measured in phospholipids (n = 831). We analyzed the n-3 PUFA α-linolenic acid (ALA; 18:3n-3); the sum of very-long-chain (VLC) n-3 PUFAs: EPA (20:5n-3), DHA (22:6n-3), and docosapentaenoic acid (22:5n-3); and the n-6 PUFAs linoleic acid (LA; 18:2n-6) and arachidonic acid (AA; 20:4n-6). Asthma was assessed by questionnaires at 8, 16, and 24 y and lung function was measured by spirometry at 24 y., Results: A high (≥median) self-reported dietary intake of LA at 8 y and AA at 16 y was associated with increased risk of prevalent asthma at 24 y (OR: 1.41; 95% CI: 1.10, 1.82 and OR: 1.32; 95% CI: 1.02, 1.70, respectively). In contrast, plasma proportions of ALA, ∑VLC n-3 PUFAs, and AA at 8 y, as well as LA at 16 y, were inversely associated with prevalent asthma at 24 y (e.g., OR: 0.55; 95% CI: 0.38, 0.81 for ∑VLC n-3 PUFAs). No consistent associations were observed with lung function., Conclusions: High dietary intake of certain n-6 PUFAs in childhood or adolescence may be associated with increased risk of asthma up to young adulthood, whereas dietary biomarkers of certain n-3 and n-6 PUFAs in plasma may be associated with decreased risk. Thus, the role of diet compared with altered metabolism of PUFAs needs further investigation to improve dietary preventive strategies for asthma., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Spirometric restriction, defined as a reduced forced vital capacity (FVC) with a preserved FEV 1 /FVC ratio, is associated with increased respiratory and non-respiratory comorbidities and all-cause mortality in adulthood. Little is known about the early origins of this condition. We sought to identify early-life risk factors for spirometric restriction in adult life., Methods: In this longitudinal, multicohort, population-based study, we used data from the Tucson Children's Respiratory Study (TCRS), which recruited 1246 healthy infants at birth between April 1980, and October 1984, in Tucson, AZ, USA. Questionnaires were answered by the primary caregiver at enrolment, immediately after the child's birth, and multiple follow-up questionnaires were completed through childhood and adulthood. At the age of 22, 26, 32, and 36 years, lung function was measured with spirometry. At each survey, three mutually exclusive spirometric patterns were defined: (1) normal (FEV 1 /FVC ≥10th percentile and FVC ≥10th percentile); (2) restrictive (FEV 1 /FVC ≥10th percentile and FVC <10th percentile); and (3) obstructive (FEV 1 /FVC <10th percentile, independent of FVC). Data on demographic features and parental health factors were collected from questionnaires; pregnancy and perinatal data (including nutritional problems) and birth measurements were obtained from medical records; and weight, height, and body-mass index (BMI) during childhood (age 6-16 years) were measured by study nurses. The associations between early-life risk factors and spirometric patterns were assessed by multivariate multinomial logistic regression analysis, adjusted for survey year, sex, and race-ethnicity. Significant risk factors were further tested for replication in the Swedish Child (Barn), Allergy, Milieu, Stockholm, Epidemiological (BAMSE; n=1817; spirometry surveys were done at age 24 years) survey and the UK Manchester Asthma and Allergy Study (MAAS; n=411; spirometry surveys were done at age 18 years) birth cohorts, and fixed-effect meta-analyses of relative risk ratios (RRRs) from multinomial logistic regression models were done to generate a pooled estimate of the effect across the three cohorts. Measurements of body composition (MAAS; n=365) and total lung capacity (TCRS; n=173 and MAAS; n=407) were also available for a subset of participants., Findings: Of 1246 healthy infants included in TCRS, for the present study we included data for 652 participants who had at least one set of spirometry data, contributing up to 1668 observations. In the TCRS cohort, results from the multivariate models showed that maternal nutritional problems during pregnancy (RRR 2·48 [95% CI 1·30-4·76]; p=0·0062), being born small for gestational age (birthweight <10th percentile; 3·26 [1·34-7·93]; p=0·0093), and being underweight in childhood (BMI-for-age <5th percentile; 3·54 [1·35-9·26]; p=0·010) were independent predictors of spirometric restriction in adult life. Associations between being small for gestational age (p=0·0028) and underweight in childhood (p<0·0001) with adult spirometric restriction were supported by the results of meta-analysis of data from all three cohorts. In the MAAS cohort, having a low lean BMI (ie, <10th percentile) at age 11 years predicted adult (age 18 years) spirometric restriction (RRR 3·66 [1·48-9·02]; p=0·0048). These associations of spirometric restriction with small for gestational age, childhood underweight, and low lean BMI in childhood were verified in participants with spirometric restriction who had diminished total lung capacity, indicating that these factors specifically increase the risk of lung restriction., Interpretation: Poor growth and nutritional deficits in utero and throughout childhood precede and predict the development of spirometric restriction in adult life. Strategies to improve prenatal and childhood growth trajectories could help to prevent spirometric restriction and its associated morbidity and mortality burden., Funding: National Institutes of Health., Competing Interests: Declaration of interests WJM has received grant funding for this work from the National Institutes of Health; funding from the National Institutes of Health and the Cystic Fibrosis Foundation outside of the submitted work; and personal fees from the Cystic Fibrosis Foundation, the American Thoracic Society, and the American College of Chest Physicians outside of the submitted work. AC has received personal fees from Novartis, Thermo Fisher Scientific, Philips, Sanofi, Stallergenes Greer, and AstraZeneca outside of the submitted work. AS and CSM are supported by the NIHR Manchester Biomedical Research Centre. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Exposure to polycyclic aromatic hydrocarbons (PAHs) has been linked to adverse pulmonary effects. However, the impact of low-level environmental PAH exposure on lung function in early adulthood remains uncertain., Objectives: To evaluate the associations between urinary PAH metabolites and lung function parameters in young adults., Methods: Urinary metabolites of pyrene, phenanthrene, and fluorene were analysed in 1000 young adults from Sweden (age 22-25 years) using LC-MS/MS. Lung function and eosinophilic airway inflammation were measured by spirometry and exhaled nitric oxide fraction (FeNO), respectively. Linear regression analysis was used to evaluate associations between PAH metabolites and the outcomes., Results: Median urinary concentrations of 1-OH-pyrene, ∑OH-phenanthrene, and ∑OH-fluorene were 0.066, 0.36, 0.22 μg/L, respectively. We found inverse associations of ∑OH-phenanthrene and ∑OH-fluorene with FEV1 and FVC, as well as between 1-OH-pyrene and FEV1/FVC ratio (adjusted P < 0.05; all participants). An increase of 1% in ∑OH-fluorene was associated with a decrease of 73 mL in FEV1 and 59 mL in FVC. In addition, ∑OH-phenanthrene concentrations were, in a dose-response manner, inversely associated with FEV1 (B from -109 to -48 compared with the lowest quartile of ∑OH-phenanthrene; p trend 0.004) and FVC (B from -159 to -102 compared with lowest quartile; p-trend <0.001). Similar dose-response associations were also observed between ∑OH-fluorene and FEV1 and FVC, as well as between 1-OH-pyrene and FEV1/FVC (p-trend <0.05). There was no association between PAH exposure and FeNO, nor was there an interaction with smoking, sex, or asthma., Conclusion: Low-level PAH exposure was, in a dose-response manner, associated with reduced lung function in young adults. Our findings have public health implications due to i) the widespread occurrence of PAHs in the environment and ii) the clinical relevance of lung function in predicting all-cause and cardiovascular disease mortality., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Obesity rates are increasing globally, and recent theories suggest that phthalates may contribute to obesity development. This longitudinal study aimed to investigate associations between environmental phthalate exposure during childhood and obesity, utilizing data from 100 participants from a Swedish birth cohort. The participants were followed repeatedly from birth and provided spot urine samples at 4 years. Weight and height were measured at ages 4, 8, 16 and 24 years, as well as additional anthropometric indices at 24 years. Urine samples were analysed for 10 phthalate metabolites using liquid chromatography tandem mass spectrometry. Generalized estimating equation models were performed to assess overall and age-specific associations between urinary phthalate concentrations and BMI groups; thin/normal weight vs overweight/obese. After adjustment for potential confounders, overall associations were observed for diisononyl phthalate (DiNP) metabolites mono(oxo-isononyl) phthalate (MOiNP) (OR per increase ng/ml: 1.18; 95% CI: 1.05, 1.33), mono(carboxy-isooctyl) phthalate (MCiOP) (OR: 1.06; 95% CI: 1.01, 1.11) and ∑DiNP (OR: 1.02; 95% CI:1.00, 1.04) and development of overweight/obesity up to age 24 years. Age-specific associations were observed for the same metabolites at 8, 16 and 24 years. Furthermore, linear regression analysis revealed associations between increased body fat % at age 24 years and MHiNP (β: 2.42; 95% CI: 0.44, 4.39), MOiNP (β: 2.32; 95% CI: 0.46, 4.18), MCiOP (β: 2.65; 95% CI: 0.41, 4.89) and ∑DiNP (β: 2.65; 95% CI: 0.52, 4.77). These findings suggest that DiNP exposure during preschool age may be associated with subsequent obesity, however these findings need to be corroborated by further research., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Increasing evidence indicates aggravation of immune-mediated diseases due to physiological and psychological stress. Noise is a stressor, however, little is known about its effects on children's respiratory health. This study investigates the association between pre- or postnatal road traffic or occupational noise exposure and asthma as well as related symptoms from infancy to adolescence., Methods: The study was conducted in the Swedish birth cohort BAMSE, including over 4000 participants followed with repeated questionnaires and clinical tests until 16 years of age. Pre- and postnatal residential road traffic noise was assessed by estimating time-weighted average noise levels at the most exposed façade. Maternal occupational noise exposure during pregnancy was evaluated using a job-exposure-matrix. The associations between noise exposure and asthma-related outcomes were explored using logistic regression and generalised estimating equations., Results: We observed non-significant associations for asthma ever up to 16 years with residential road traffic noise exposure in infancy ≥55 dB Lden (adjusted OR = 1.22; 95% CI 0.90-1.65), as well as prenatal occupational noise exposure ≥80 dB LAeq,8h (1.18, 0.85-1.62). In longitudinal analyses, however, no clear associations between pre- or postnatal exposure to residential road traffic noise, or average exposure to noise since birth, were detected in relation to asthma or wheeze until 16 years., Conclusion: We did not find a clear overall association between exposure to noise during different time periods and asthma or wheeze up to adolescence., Competing Interests: Declaration of competing interest All authors declare no competing financial interests., (Copyright © 2020. Published by Elsevier Inc.)

Rationale: Little is known about how perinatal and childhood factors influence lung function change between childhood and adolescence., Objectives: To investigate possible early life predictors of change in FEV 1 between age 8 and 16 years. In addition, to investigate possible predictors of having persistently low lung function (FEV 1 <25th percentiles both at age 8 and 16) up to adolescence., Methods: The BAMSE birth cohort study collected data throughout childhood on environmental factors, individual characteristics, and spirometric measures at 8 and 16 years (n = 1425). Associations between early life predictors (n = 31) and FEV 1 increase between 8 and 16 years were assessed with linear regression. Predictors of having persistently low lung function were examined., Results: Few factors were consistently associated with altered lung function growth, although low birth weight, asthma heredity (paternal), secondhand smoke in infancy, and season of birth had a significant impact (p-value ≤0.01). The majority of subjects stayed however within the same category of lung function between ages 8 and 16 years (in total 821/1425 = 58%). Predictors associated with having persistently low lung function were gestational age, secondhand smoke (at 2 and 8 years of age), and factors related to lower respiratory tract infections in infancy., Conclusions: In summary, rather few exposures in childhood were identified to have a significant impact on lung function growth between childhood and adolescence. Our data support previous study findings indicating that lung function development is influenced by factors before birth and in infancy, including second hand tobacco smoke., (Copyright © 2018. Published by Elsevier Ltd.)

Background: DNA methylation profiles associated with childhood asthma might provide novel insights into disease pathogenesis. We did an epigenome-wide association study to assess methylation profiles associated with childhood asthma., Methods: We did a large-scale epigenome-wide association study (EWAS) within the Mechanisms of the Development of ALLergy (MeDALL) project. We examined epigenome-wide methylation using Illumina Infinium Human Methylation450 BeadChips (450K) in whole blood in 207 children with asthma and 610 controls at age 4-5 years, and 185 children with asthma and 546 controls at age 8 years using a cross-sectional case-control design. After identification of differentially methylated CpG sites in the discovery analysis, we did a validation study in children (4-16 years; 247 cases and 2949 controls) from six additional European cohorts and meta-analysed the results. We next investigated whether replicated CpG sites in cord blood predict later asthma in 1316 children. We subsequently investigated cell-type-specific methylation of the identified CpG sites in eosinophils and respiratory epithelial cells and their related gene-expression signatures. We studied cell-type specificity of the asthma association of the replicated CpG sites in 455 respiratory epithelial cell samples, collected by nasal brushing of 16-year-old children as well as in DNA isolated from blood eosinophils (16 with asthma, eight controls [age 2-56 years]) and compared this with whole-blood DNA samples of 74 individuals with asthma and 93 controls (age 1-79 years). Whole-blood transcriptional profiles associated with replicated CpG sites were annotated using RNA-seq data of subsets of peripheral blood mononuclear cells sorted by fluorescence-activated cell sorting., Findings: 27 methylated CpG sites were identified in the discovery analysis. 14 of these CpG sites were replicated and passed genome-wide significance (p<1·14 × 10 -7 ) after meta-analysis. Consistently lower methylation levels were observed at all associated loci across childhood from age 4 to 16 years in participants with asthma, but not in cord blood at birth. All 14 CpG sites were significantly associated with asthma in the second replication study using whole-blood DNA, and were strongly associated with asthma in purified eosinophils. Whole-blood transcriptional signatures associated with these CpG sites indicated increased activation of eosinophils, effector and memory CD8 T cells and natural killer cells, and reduced number of naive T cells. Five of the 14 CpG sites were associated with asthma in respiratory epithelial cells, indicating cross-tissue epigenetic effects., Interpretation: Reduced whole-blood DNA methylation at 14 CpG sites acquired after birth was strongly associated with childhood asthma. These CpG sites and their associated transcriptional profiles indicate activation of eosinophils and cytotoxic T cells in childhood asthma. Our findings merit further investigations of the role of epigenetics in a clinical context., Funding: EU and the Seventh Framework Programme (the MeDALL project)., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Little is known about synergistic effects of several risk factors on asthma. We developed a risk score in Puerto Rican children, and then used this score to estimate the combined effects of multiple risk factors on asthma at school age in Puerto Rican and Swedish children., Methods: Case-control study in 609 Puerto Rican children (aged 6-14 years) and longitudinal birth cohort study of 2290 Swedish children followed up to age 12 years (The Children, Allergy, Milieu, Stockholm, Epidemiological Survey [BAMSE] Study). In both cohorts, there was data on parental asthma, sex, obesity, allergic rhinitis, and early-life second-hand smoke (SHS); data on diet and (in children ≥9 years) lifetime exposure to gun violence were also available in the Puerto Rico study. Asthma was defined as physician-diagnosed asthma and ≥1 episode of wheeze in the previous year., Results: In a multivariable analysis in Puerto Rican children, male sex, parental asthma, allergic rhinitis, early-life SHS, an unhealthy diet and (in children ≥9 years) gun violence were each significantly associated with asthma. We next created a risk score using these variables (range, 0 to 5-6 in Puerto Rico and 0 to 4 in BAMSE). Compared with Puerto Rican children without any risk factors (i.e. a score of 0), Puerto Rican children with 2, 3, and at least 4 risk factors had 3.6 times (95% CI = 1.4-9.2), 10.4 times (95% CI = 4.0-27.0), and 21.6 times (95% CI = 7.2-64.9) significantly higher odds of asthma, respectively. In BAMSE, the presence of 2, 3, and at least 4 risk factors was significantly associated with 4.1 times (95% CI = 2.3-7.4), 6.3 times (95% CI = 3.0-13.3), and 17.2 times (95% CI = 4.1-73.2) increased odds of asthma at age 12 years., Conclusions: Our findings emphasize the multifactorial etiology of asthma, and suggest that concurrent eradication or reduction of several modifiable risk factors may better prevent or reduce the burden of childhood asthma., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Previous published analyses have focused on the effect of air pollution on asthma and rhinoconjunctivitis throughout early and middle childhood. However, the role of exposure to air pollution in the development of childhood and adolescent asthma and rhinoconjunctivitis remains unclear. We aimed to assess the longitudinal associations between exposure to air pollution and development of asthma and rhinoconjunctivitis throughout childhood and adolescence., Methods: We did a population-based birth cohort study of 14 126 participants from four prospective birth cohort studies from Germany, Sweden, and the Netherlands with 14–16 years of follow-up. We linked repeated questionnaire reports of asthma and rhinoconjunctivitis with annual average air pollution concentrations (nitrogen dioxide [NO2], particulate matter [PM] with a diameter of less than 2·5 μm [PM2·5], less than 10 μm [PM10], and between 2·5 μm and 10 μm [PMcoarse], and PM2·5 absorbance [indicator of soot]) at the participants' home addresses. We analysed longitudinal associations of air pollution exposure at participants' birth addresses and addresses at the time of follow-up with asthma and rhinoconjunctivitis incidence and prevalence in cohort-specific analyses, with subsequent meta-analysis and pooled analyses., Findings: Overall, the risk of incident asthma up to age 14–16 years increased with increasing exposure to NO2 (adjusted meta-analysis odds ratio [OR] 1·13 per 10 μg/m3 [95% CI 1·02–1·25]) and PM2·5 absorbance (1·29 per 1 unit [1·00–1·66]) at the birth address. A similar, albeit non-significant, trend was shown for PM2·5 and incident asthma (meta-analysis OR 1·25 per 5 μg/m3 [95% CI 0·94–1·66]). These associations with asthma were more consistent after age 4 years than before that age. There was no indication of an adverse effect of air pollution on rhinoconjunctivitis., Interpretation: Exposure to air pollution early in life might contribute to the development of asthma throughout childhood and adolescence, particularly after age 4 years, when asthma can be more reliably diagnosed. Reductions in levels of air pollution could help to prevent the development of asthma in children., Funding: The European Union.

Background: 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., Methods: 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<5 × 10(-8)., Findings: UK Biobank participants were recruited from March 15, 2006, to July 7, 2010. Sample selection for the UK BiLEVE study started on Nov 22, 2012, and was completed on Dec 20, 2012. We selected 50,008 unique samples: 10,002 individuals with low FEV1, 10,000 with average FEV1, and 5002 with high FEV1 from each of the heavy smoker and never smoker groups. We noted a substantial sharing of genetic causes of low FEV1 between heavy smokers and never smokers (p=2.29 × 10(-16)) and between individuals with and without doctor-diagnosed asthma (p=6.06 × 10(-11)). We discovered six novel genome-wide significant signals of association with extremes of FEV1, including signals at four novel loci (KANSL1, TSEN54, TET2, and RBM19/TBX5) and independent signals at two previously reported loci (NPNT and HLA-DQB1/HLA-DQA2). These variants also showed association with COPD, including in individuals with no history of smoking. The number of copies of a 150 kb region containing the 5' end of KANSL1, a gene that is important for epigenetic gene regulation, was associated with extremes of FEV1. We also discovered five new genome-wide significant signals for smoking behaviour, including a variant in NCAM1 (chromosome 11) and a variant on chromosome 2 (between TEX41 and PABPC1P2) that has a trans effect on expression of NCAM1 in brain tissue., Interpretation: By sampling from the extremes of the lung function distribution in UK Biobank, we identified novel genetic causes of lung function and smoking behaviour. These results provide new insight into the specific mechanisms underlying airflow obstruction, COPD, and tobacco addiction, and show substantial shared genetic architecture underlying airflow obstruction across individuals, irrespective of smoking behaviour and other airway disease., Funding: Medical Research Council., (Copyright © 2015 Wain et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.)

Background: Low concentrations of the anti-inflammatory protein CC16 (approved symbol SCGB1A1) in serum have been associated with accelerated decline in forced expiratory volume in 1 s (FEV1) in patients with chronic obstructive pulmonary disease (COPD). We investigated whether low circulating CC16 concentrations precede lung function deficits and incidence of COPD in the general population., Methods: We assessed longitudinal data on CC16 concentrations in serum and associations with decline in FEV1 and incidence of airflow limitation for adults who were free from COPD at baseline in the population-based Tucson Epidemiological Study of Airway Obstructive Disease ([TESAOD] n=960, mean follow-up 14 years), European Community Respiratory Health Survey ([ECRHS-Sp] n=514, 11 years), and Swiss Cohort Study on Air Pollution and Lung Diseases in Adults ([SAPALDIA] n=167, 8 years) studies. Additionally, we measured circulating CC16 concentrations in samples from children aged 4-6 years in the Tucson Children's Respiratory Study (n=427), UK Manchester Asthma and Allergy Study (n=481), and the Swedish Barn/children, Allergy, Milieu, Stockholm, Epidemiological survey (n=231) birth cohorts to assess whether low CC16 concentrations in childhood were predictive for subsequent lung function., Findings: After adjustment for sex, age, height, smoking status and intensity, pack-years, asthma, and FEV1 at baseline, we found an inverse association between CC16 concentration and decline in FEV1 in adults in TESAOD (4·4 mL/year additional FEV1 decline for each SD decrease in baseline CC16 concentration, p=0·0014) and ECRHS-Sp (2·4 mL/year, p=0·023); the effect in SAPALDIA was marginal (4·5 mL/year, p=0·052). Low CC16 concentration at baseline was also associated with increased risk of incident stage 2 airflow limitation (ratio of FEV1 to forced expiratory volume [FEV1/FVC] less than 70% plus FEV1 % predicted less than 80%) in TESAOD and ECRHS-Sp. In children, the lowest tertile of CC16 concentrations was associated with a subsequent FEV1 deficit of 68 mL up to age 16 years (p=0·0001), which was confirmed in children who had never smoked by age 16 years (-71 mL, p<0·0001)., Interpretation: Low concentrations of CC16 in serum are associated with reduced lung function in childhood, accelerated lung function decline in adulthood, and development of moderate airflow limitation in the general adult population., Funding: National Heart, Lung, and Blood Institute and European Union Seventh Framework Programme., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: The World Health Organization (WHO) recently proposed a new definition of severe asthma to facilitate standardized characterization of patients, and enable more accurate estimations of the prevalence of severe asthma. The aim of this study was to estimate the prevalence of severe asthma according to the WHO definition in children aged 12 years, in Stockholm, Sweden., Methods: The birth cohort BAMSE enrolled 4089 children during 1994-96. Parental questionnaires provided information on asthma-related symptoms, diagnosis and medication from 3015 enrolled children at the age of 12 years. Severe asthma was defined as the presence of asthma, as well as continuous treatment with inhaled corticosteroids and long-acting beta-2 agonists, based on information from the Swedish prescribed drug register demonstrating prescriptions of at least 800 μg budesonide daily (or equivalent)., Results: The prevalence of asthma was 11% among 12-year-olds (n = 329). Based on information from the Swedish prescribed drug register, seven children with asthma fulfilled the definition of severe asthma. The estimated prevalence corresponds to 0.23% (95% CI, 0.06-0.4) of the population, or 2.1% (95% CI, 0.5-3.7) of children with asthma. Based on assessed markers of asthma control, 3/7 with severe asthma were considered to have controlled asthma and 4/7 had partly or uncontrolled asthma., Conclusion: Severe asthma appears rare both among 12-year-old schoolchildren with asthma and in the general population. Combining self-reported information from a population-based birth cohort with data from a drug register seems trustworthy in estimating severe asthma as defined by the WHO., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Eczema, rhinitis, and asthma often coexist (comorbidity) in children, but the proportion of comorbidity not attributable to either chance or the role of IgE sensitisation is unknown. We assessed these factors in children aged 4-8 years., Methods: In this prospective cohort study, we assessed children from 12 ongoing European birth cohort studies participating in MeDALL (Mechanisms of the Development of ALLergy). We recorded current eczema, rhinitis, and asthma from questionnaires and serum-specific IgE to six allergens. Comorbidity of eczema, rhinitis, and asthma was defined as coexistence of two or three diseases in the same child. We estimated relative and absolute excess comorbidity by comparing observed and expected occurrence of diseases at 4 years and 8 years. We did a longitudinal analysis using log-linear models of the relation between disease at age 4 years and comorbidity at age 8 years., Findings: We assessed 16 147 children aged 4 years and 11 080 aged 8 years in cross-sectional analyses. The absolute excess of any comorbidity was 1·6% for children aged 4 years and 2·2% for children aged 8 years; 44% of the observed comorbidity at age 4 years and 50·0% at age 8 years was not a result of chance. Children with comorbidities at 4 years had an increased risk of having comorbidity at 8 years. The relative risk of any cormorbidity at age 8 years ranged from 36·2 (95% CI 26·8-48·8) for children with rhinitis and eczema at age 4 years to 63·5 (95% CI 51·7-78·1) for children with asthma, rhinitis, and eczema at age 4 years. We did longitudinal assessment of 10 107 children with data at both ages. Children with comorbidities at 4 years without IgE sensitisation had higher relative risks of comorbidity at 8 years than did children who were sensitised to IgE. For children without comorbidity at age 4 years, 38% of the comorbidity at age 8 years was attributable to the presence of IgE sensitisation at age 4 years., Interpretation: Coexistence of eczema, rhinitis, and asthma in the same child is more common than expected by chance alone-both in the presence and absence of IgE sensitisation-suggesting that these diseases share causal mechanisms. Although IgE sensitisation is independently associated with excess comorbidity of eczema, rhinitis, and asthma, its presence accounted only for 38% of comorbidity, suggesting that IgE sensitisation can no longer be considered the dominant causal mechanism of comorbidity for these diseases., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Fish intake in infancy has been associated with reduced risk of allergic disease in early childhood, but it is unknown whether this effect remains as children grow older., Objective: We studied the possible effect of fish consumption in infancy on prevalent and incident allergic disease up to the age of 12 y., Design: A total of 3285 children from a prospective Swedish birth cohort (Children, Asthma, Milieu, Stockholm, Epidemiology) were included in the current analyses. At 1, 2, 4, 8, and 12 y, parental questionnaires were used to obtain information on lifestyle factors, environmental exposures, and symptoms of allergic disease. The frequency of fish intake in infancy was assessed in the 1-y questionnaire. Serum immunoglobulin (Ig) E concentrations associated with common allergens were obtained at age 8 y. Generalized estimating equations and multivariate logistic regression were used to examine associations between fish consumption in infancy and prevalent and incident allergic disease at ages 1-12 y, including sensitization and IgE-associated disease at age 8 y., Results: At 1 y of age, 80% of the children consumed fish regularly (ie, ≥2 times/mo). From 1 to 12 y of age, regular fish consumption in infancy reduced overall risks of prevalent and incident allergic disease [adjusted OR (95% CI) after restriction to children without early symptoms of allergic disease was 0.74 (0.60, 0.90) (P = 0.003) for prevalent rhinitis and 0.78 (0.63, 0.97) (P = 0.028) for prevalent eczema., Conclusion: Regular fish consumption in infancy may reduce risk of allergic disease up to age 12 y.

Background: The G protein-coupled receptor neuropeptide S receptor 1 (NPSR1) and its ligand neuropeptide S (NPS) form a signaling system mainly implicated in susceptibility to asthma and inflammatory disorders in humans and regulation of anxiety and arousal in rodents. We addressed here the role of NPS and NPSR1 as susceptibility genes for human anxiety disorders., Methods: We performed comprehensive association analysis of genetic variants in NPS and NPSR1 in three independent study samples. We first studied a population-based sample (Health 2000, Finland) of 321 anxiety disorder patients and 1317 control subjects and subsequently a Spanish clinical panic disorder sample consisting of 188 cases and 315 control subjects. In addition, we examined a birth cohort of 2020 children (Barn Allergi Miljö Stockholm Epidemiologi [BAMSE], Sweden). We then tested whether alleles of the most significantly associated single nucleotide polymorphisms alter DNA-protein complex formation in electrophoretic mobility shift assays. Finally, we compared acute stress responses on the gene expression level in wild-type and Npsr1(-/-) mice., Results: We confirmed previously observed epidemiological association between anxiety and asthma in two population-based cohorts. Single nucleotide polymorphisms within NPS and NPSR1 associated with panic disorder diagnosis in the Finnish and Spanish samples and with parent-reported anxiety/depression in the BAMSE sample. Moreover, some of the implicated single nucleotide polymorphisms potentially affect transcription factor binding. Expression of neurotrophin-3, a neurotrophic factor connected to stress and panic reaction, was significantly downregulated in brain regions of stressed Npsr1(-/-) mice, whereas interleukin-1 beta, an active stress-related immunotransmitter, was upregulated., Conclusions: Our results suggest that NPS-NPSR1 signaling is likely involved in anxiety., (Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)