Plasticity of Individual Lung Function States from Childhood to Adulthood.

Rationale: Recent evidence highlights the importance of optimal lung development during childhood for health throughout life. Objectives: To explore the plasticity of individual lung function states during childhood. Methods: Prebronchodilator FEV1 z-scores determined at age 8, 16, and 24 years in the Swedish population-based birth cohort BAMSE (Swedish abbreviation for Child [Barn], Allergy, Milieu, Stockholm, Epidemiological study) (N = 3,069) were used. An unbiased, data-driven dependent mixture model was applied to explore lung function states and individual state chains. Lung function catch-up was defined as participants moving from low or very low states to normal or high or very high states, and growth failure as moving from normal or high or very high states to low or very low states. At 24 years, we compared respiratory symptoms, small airway function (multiple-breath washout), and circulating inflammatory protein levels, by using proteomics, across states. Models were replicated in the independent Dutch population-based PIAMA (Prevention and Incidence of Asthma and Mite Allergy) cohort. Measurements and Main Results: Five lung function states were identified in BAMSE. Lung function catch-up and growth failure were observed in 74 (14.5%) BAMSE participants with low or very low states and 36 (2.4%) participants with normal or high or very high states, respectively. The occurrence of catch-up and growth failure was replicated in PIAMA. Early-life risk factors were cumulatively associated with the very low state, as well as with catch-up (inverse association) and growth failure. The very low state as well as growth failure were associated with respiratory symptoms, airflow limitation, and small airway dysfunction at adulthood. Proteomics identified IL-6 and CXCL10 (C-X-C motif chemokine 10) as potential biomarkers of impaired lung function development. Conclusions: Individual lung function states during childhood are plastic, including catch-up and growth failure.

Associations of improved air quality with lung function growth from childhood to adulthood: the BAMSE study.

BACKGROUND: The beneficial effect of improving air quality on lung function development remains understudied. We assessed associations of changes in ambient air pollution levels with lung function growth from childhood until young adulthood in a Swedish cohort study. METHODS: In the prospective birth cohort BAMSE (Children, Allergy, Environment, Stockholm, Epidemiology (in Swedish)), spirometry was conducted at the 8-year (2002-2004), 16-year (2011-2013) and 24-year (2016-2019) follow-ups. Participants with spirometry data at 8 years and at least one other measurement in subsequent follow-ups were included (1509 participants with 3837 spirometry measurements). Ambient air pollution levels (particulate matter with diameter ≤2.5 µm (PM2.5), particulate matter with diameter ≤10 µm (PM10), black carbon (BC) and nitrogen oxides (NO x )) at residential addresses were estimated using dispersion modelling. Linear mixed effect models were used to estimate associations between air pollution exposure change and lung function development. RESULTS: Overall, air pollution levels decreased progressively during the study period. For example, the median (interquartile range (IQR)) level of PM2.5 decreased from 8.24 (0.92) µg·m-3 during 2002-2004 to 5.21 (0.67) µg·m-3 during 2016-2019. At the individual level, for each IQR reduction of PM2.5 the lung function growth rate increased by 4.63 (95% CI 1.64-7.61) mL per year (p<0.001) for forced expiratory volume in 1 s and 9.38 (95% CI 4.76-14.00) mL per year (p<0.001) for forced vital capacity. Similar associations were also observed for reductions of BC and NO x . Associations persisted after adjustment for potential confounders and were not modified by asthma, allergic sensitisation, overweight, early-life air pollution exposure or dietary antioxidant intake. CONCLUSIONS: Long-term reduction of air pollution is associated with positive lung function development from childhood to young adulthood.

Toxicity and health effects of ultrafine particles: Towards an understanding of the relative impacts of different transport modes.

Exposure to particulate matter (PM) has been associated with a wide range of adverse health effects, but it is still unclear how particles from various transport modes differ in terms of toxicity and associations with different human health outcomes. This literature review aims to summarize toxicological and epidemiological studies of the effect of ultrafine particles (UFPs), also called nanoparticles (NPs, <100 nm), from different transport modes with a focus on vehicle exhaust (particularly comparing diesel and biodiesel) and non-exhaust as well as particles from shipping (harbor), aviation (airport) and rail (mainly subway/underground). The review includes both particles collected in laboratory tests and the field (intense traffic environments or collected close to harbor, airport, and in subway). In addition, epidemiological studies on UFPs are reviewed with special attention to studies aimed at distinguishing the effects of different transport modes. Results from toxicological studies indicate that both fossil and biodiesel NPs show toxic effects. Several in vivo studies show that inhalation of NPs collected in traffic environments not only impacts the lung, but also triggers cardiovascular effects as well as negative impacts on the brain, although few studies compared NPs from different sources. Few studies were found on aviation (airport) NPs, but the available results suggest similar toxic effects as traffic-related particles. There is still little data related to the toxic effects linked to several sources (shipping, road and tire wear, subway NPs), but in vitro results highlighted the role of metals in the toxicity of subway and brake wear particles. Finally, the epidemiological studies emphasized the current limited knowledge of the health impacts of source-specific UFPs related to different transport modes. This review discusses the necessity of future research for a better understanding of the relative potencies of NPs from different transport modes and their use in health risk assessment.

Ambient air pollution and inflammation-related proteins during early childhood.

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 (PM10), <2.5 µm (PM2.5), and nitrogen dioxide (NO2) 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 PM2.5 exposure, while consistent associations with PM10 and NO2 across ages were only observed among girls. Subsequent protein-specific analyses revealed significant associations of PM10 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 PM10, PM2.5 and NO2 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.

Air pollution exposure impairs lung function in infants.

AIM: To assess associations between air pollution exposure and infant lung function. METHODS: Healthy infants from Stockholm were recruited to two cohorts (n = 99 and n = 78). Infant spirometry included plethysmography and raised volume forced expiratory flows. In pooled analyses, lung function at ~6 months of age was related to time-weighted average air pollution levels at residential addresses from birth until the lung function test. The pollutants included particulate matter with an aerodynamic diameter < 10 µm (PM10 ) or <2.5 µm and nitrogen dioxide. RESULTS: There were significant inverse relations between air pollution exposure during infancy and forced expiratory volume at 0.5 s (FEV0.5 ) as well as forced vital capacity (FVC) for all pollutants. For example, the decline was 10.1 ml (95% confidence interval 1.3-18.8) and 10.3 ml (0.5-20.1) in FEV0.5 and FVC, respectively, for an interquartile increment of 5.3 µg/m3 in PM10 . Corresponding associations for minute ventilation and functional residual capacity were 43.3 ml/min (-9.75-96.3) and 0.84 ml (-4.14-5.82). CONCLUSIONS: Air pollution exposure was associated with impaired infant lung function measures related to airway calibre and lung volume, suggesting that comparatively low levels of air pollution negatively affect lung function in early life.

Air pollution and IgE sensitization in 4 European birth cohorts-the MeDALL project.

BACKGROUND: Whether long-term exposure air to pollution has effects on allergic sensitization is controversial. OBJECTIVE: Our aim was to investigate associations of air pollution exposure at birth and at the time of later biosampling with IgE sensitization against common food and inhalant allergens, or specific allergen molecules, in children aged up to 16 years. METHODS: A total of 6163 children from 4 European birth cohorts participating in the Mechanisms of the Development of ALLergy [MeDALL] consortium were included in this meta-analysis of the following studies: Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE) (Sweden), Influences of Lifestyle-Related Factors on the Human Immune System and Development of Allergies in Childhood (LISA)/German Infant Study on the Influence of Nutrition Intervention PLUS Environmental and Genetic Influences on Allergy Development (GINIplus) (Germany), and Prevention and Incidence of Asthma and Mite Allergy (PIAMA) (The Netherlands). The following indicators were modeled by land use regression: individual residential outdoor levels of particulate matter with aerodynamic diameters less than 2.5 µm, less than 10 µm, and between 2.5 and 10 µm; PM2.5 absorbance (a measurement of the blackness of PM2.5 filters); and nitrogen oxides levels. Blood samples drawn at ages 4 to 6 (n = 5989), 8 to 10 (n = 6603), and 15 to 16 (n = 5825) years were analyzed for IgE sensitization to allergen extracts by ImmunoCAP. Additionally, IgE against 132 allergen molecules was measured by using the MedALL microarray chip (n = 1021). RESULTS: Air pollution was not consistently associated with IgE sensitization to any common allergen extract up to age 16 years. However, allergen-specific analyses suggested increased risks of sensitization to birch (odds ratio [OR] = 1.12 [95% CI = 1.01-1.25] per 10-µg/m3 increase in NO2 exposure). In a subpopulation with microarray data, IgE to the major timothy grass allergen Phleum pratense 1 (Phl p 1) and the cat allergen Felis domesticus 1 (Fel d 1) greater than 3.5 Immuno Solid-phase Allergen Chip standardized units for detection of IgE antibodies were related to PM2.5 exposure at birth (OR = 3.33 [95% CI = 1.40-7.94] and OR = 4.98 [95% CI = 1.59-15.60], respectively, per 5-µg/m3 increase in exposure). CONCLUSION: Air pollution exposure does not seem to increase the overall risk of allergic sensitization; however, sensitization to birch as well as grass pollen Phl p 1 and cat Fel d 1 allergen molecules may be related to specific pollutants.

Shared DNA methylation signatures in childhood allergy: The MeDALL study.

BACKGROUND: Differential DNA methylation associated with allergy might provide novel insights into the shared or unique etiology of asthma, rhinitis, and eczema. OBJECTIVE: We sought to identify DNA methylation profiles associated with childhood allergy. METHODS: Within the European Mechanisms of the Development of Allergy (MeDALL) consortium, we performed an epigenome-wide association study of whole blood DNA methylation by using a cross-sectional design. Allergy was defined as having symptoms from at least 1 allergic disease (asthma, rhinitis, or eczema) and positive serum-specific IgE to common aeroallergens. The discovery study included 219 case patients and 417 controls at age 4 years and 228 case patients and 593 controls at age 8 years from 3 birth cohorts, with replication analyses in 325 case patients and 1111 controls. We performed additional analyses on 21 replicated sites in 785 case patients and 2124 controls by allergic symptoms only from 8 cohorts, 3 of which were not previously included in analyses. RESULTS: We identified 80 differentially methylated CpG sites that showed a 1% to 3% methylation difference in the discovery phase, of which 21 (including 5 novel CpG sites) passed genome-wide significance after meta-analysis. All 21 CpG sites were also significantly differentially methylated with allergic symptoms and shared between asthma, rhinitis, and eczema. The 21 CpG sites mapped to relevant genes, including ACOT7, LMAN3, and CLDN23. All 21 CpG sties were differently methylated in asthma in isolated eosinophils, and 10 were replicated in respiratory epithelium. CONCLUSION: Reduced whole blood DNA methylation at 21 CpG sites was significantly associated with childhood allergy. The findings provide novel insights into the shared molecular mechanisms underlying asthma, rhinitis, and eczema.

Early-life risk factors for reversible and irreversible airflow limitation in young adults: findings from the BAMSE birth cohort.

We aimed to determine prevalence and early-life risk factors for reversible and irreversible airflow limitation in young adults from the general population. Among young adults in their 20s, the prevalence was 5.3% for reversible airflow limitation and 2.0% for irreversible airflow limitation. While parental asthma was the only risk factor for development of reversible airflow limitation, the risk factors for development of irreversible airflow limitation were current asthma, childhood respiratory tract infections and asthma, and exposure to air pollution.

Assessment of chronic bronchitis and risk factors in young adults: results from BAMSE.

BACKGROUND: Chronic bronchitis is associated with substantial morbidity among elderly adults, but little is known about its prevalence and risk factors in young adults. Our aim was to assess the prevalence and early-life risk factors for chronic bronchitis in young adults. METHODS: Questionnaire data and clinical measures from the 24-year follow-up of the Swedish BAMSE (Child (Barn), Allergy, Milieu, Stockholm, Epidemiological) cohort were used. We assessed chronic bronchitis (CB) as the combination of cough and mucus production in the morning during winter. Environmental and clinical data from birth and onwards were used for analyses of risk factors. RESULTS: At the 24-year follow-up, 75% (n=3064) participants completed the questionnaire and 2030 performed spirometry. The overall prevalence of CB was 5.5% (n=158) with similar estimates in males and females. 49% of CB cases experienced more than three self-reported respiratory infections in the past year compared to 18% in non-CB subjects (p<0.001), and 37% of cases were current smokers (versus 19% of non-CB cases). Statistically significant lower post-bronchodilator forced expiratory volume in 1 s/forced vital capacity were observed in CB compared to non-CB subjects (mean z-score -0.06 versus 0.13, p=0.027). Daily smoking (adjusted (a)OR 3.85, p<0.001), air pollution exposure (black carbon at ages 1-4 years aOR 1.71 per 1 µg·m-3 increase, p=0.009) and exclusive breastfeeding for ≤4 months (aOR 0.66, p=0.044) were associated with CB. CONCLUSION: Chronic bronchitis in young adults is associated with recurrent respiratory infections. Besides smoking, our results support the role of early-life exposures, such as air pollution and exclusive breastfeeding, for respiratory health later in life.

A novel whole blood gene expression signature for asthma, dermatitis, and rhinitis multimorbidity in children and adolescents.

BACKGROUND: Allergic diseases often occur in combination (multimorbidity). Human blood transcriptome studies have not addressed multimorbidity. Large-scale gene expression data were combined to retrieve biomarkers and signaling pathways to disentangle allergic multimorbidity phenotypes. METHODS: Integrated transcriptomic analysis was conducted in 1233 participants with a discovery phase using gene expression data (Human Transcriptome Array 2.0) from whole blood of 786 children from three European birth cohorts (MeDALL), and a replication phase using RNA Sequencing data from an independent cohort (EVA-PR, n = 447). Allergic diseases (asthma, atopic dermatitis, rhinitis) were considered as single disease or multimorbidity (at least two diseases), and compared with no disease. RESULTS: Fifty genes were differentially expressed in allergic diseases. Thirty-two were not previously described in allergy. Eight genes were consistently overexpressed in all types of multimorbidity for asthma, dermatitis, and rhinitis (CLC, EMR4P, IL5RA, FRRS1, HRH4, SLC29A1, SIGLEC8, IL1RL1). All genes were replicated the in EVA-PR cohort. RT-qPCR validated the overexpression of selected genes. In MeDALL, 27 genes were differentially expressed in rhinitis alone, but none was significant for asthma or dermatitis alone. The multimorbidity signature was enriched in eosinophil-associated immune response and signal transduction. Protein-protein interaction network analysis identified IL5/JAK/STAT and IL33/ST2/IRAK/TRAF as key signaling pathways in multimorbid diseases. Synergistic effect of multimorbidity on gene expression levels was found. CONCLUSION: A signature of eight genes identifies multimorbidity for asthma, rhinitis, and dermatitis. Our results have clinical and mechanistic implications, and suggest that multimorbidity should be considered differently than allergic diseases occurring alone.

Noise exposure and childhood asthma up to adolescence.

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 dBLden (adjusted OR = 1.22; 95% CI 0.90-1.65), as well as prenatal occupational noise exposure ≥80 dBLAeq,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.

Epigenome-wide meta-analysis of DNA methylation and childhood asthma.

BACKGROUND: Epigenetic mechanisms, including methylation, can contribute to childhood asthma. Identifying DNA methylation profiles in asthmatic patients can inform disease pathogenesis. OBJECTIVE: We sought to identify differential DNA methylation in newborns and children related to childhood asthma. METHODS: Within the Pregnancy And Childhood Epigenetics consortium, we performed epigenome-wide meta-analyses of school-age asthma in relation to CpG methylation (Illumina450K) in blood measured either in newborns, in prospective analyses, or cross-sectionally in school-aged children. We also identified differentially methylated regions. RESULTS: In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, false discovery rate < 0.05) in relation to asthma development. In a cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (false discovery rate < 0.05) and 36 differentially methylated regions. In replication studies of methylation in other tissues, most of the 179 CpGs discovered in blood replicated, despite smaller sample sizes, in studies of nasal respiratory epithelium or eosinophils. Pathway analyses highlighted enrichment for asthma-relevant immune processes and overlap in pathways enriched both in newborns and children. Gene expression correlated with methylation at most loci. Functional annotation supports a regulatory effect on gene expression at many asthma-associated CpGs. Several implicated genes are targets for approved or experimental drugs, including IL5RA and KCNH2. CONCLUSION: Novel loci differentially methylated in newborns represent potential biomarkers of risk of asthma by school age. Cross-sectional associations in children can reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children was substantially replicated in eosinophils and respiratory epithelium.

DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis.

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.

Transcriptomics of atopy and atopic asthma in white blood cells from children and adolescents.

Early allergic sensitisation (atopy) is the first step in the development of allergic diseases such as atopic asthma later in life. Genes and pathways associated with atopy and atopic asthma in children and adolescents have not been well characterised.A transcriptome-wide association study (TWAS) of atopy and atopic asthma in white blood cells (WBCs) or whole blood was conducted in a cohort of 460 Puerto Ricans aged 9-20 years (EVA-PR study) and in a cohort of 250 Swedish adolescents (BAMSE study). Pathway enrichment and network analyses were conducted to further assess top findings, and classification models of atopy and atopic asthma were built using expression levels for the top differentially expressed genes (DEGs).In a meta-analysis of the study cohorts, both previously implicated genes (e.g. IL5RA and IL1RL1) and genes not previously reported in TWASs (novel) were significantly associated with atopy and/or atopic asthma. Top novel genes for atopy included SIGLEC8 (p=8.07×10-13), SLC29A1 (p=7.07×10-12) and SMPD3 (p=1.48×10-11). Expression quantitative trait locus analyses identified multiple asthma-relevant genotype-expression pairs, such as rs2255888/ALOX15 Pathway enrichment analysis uncovered 16 significantly enriched pathways at adjusted p<0.01, including those relevant to T-helper cell type 1 (Th1) and Th2 immune responses. Classification models built using the top DEGs and a few demographic/parental history variables accurately differentiated subjects with atopic asthma from nonatopic control subjects (area under the curve 0.84).We have identified genes and pathways for atopy and atopic asthma in children and adolescents, using transcriptome-wide data from WBCs and whole blood samples.

DNA methylation is associated with inhaled corticosteroid response in persistent childhood asthmatics.

BACKGROUND: Response to inhaled corticosteroids is highly variable, and the association between DNA methylation and treatment response is not known. OBJECTIVE: To examine the association between peripheral blood DNA methylation and inhaled corticosteroid response in children with persistent asthma. METHODS: Epigenome-wide DNA methylation was analysed in individuals on inhaled corticosteroids in three independent and ethnically diverse cohorts-Childhood Asthma Management Program (CAMP); Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE); and Genetic Epidemiology of Asthma in Costa Rica Study (GACRS). Treatment response was evaluated using two definitions, the absence of emergency department visits and/or hospitalizations and the absence oral corticosteroid use while on inhaled corticosteroid therapy. CpG sites meeting nominal significance (P < 0.05) for each outcome were combined in a three-cohort meta-analysis with adjustment for multiple testing. DNA methylation was correlated with gene expression using Pearson and partial correlations. RESULTS: In 154 subjects from CAMP, 72 from BAMSE, and 168 from GACRS, relative hypomethylation of cg00066816 (171 bases upstream of IL12B) was associated with the absence of emergency department visits and/or hospitalizations (Q = 0.03) in all cohorts and lower IL12B expression (ρ = 0.34, P = 0.01) in BAMSE. Relative hypermethylation of cg04256470 (688 bases upstream of CORT) was associated with the absence of oral corticosteroid use (Q = 0.04) in all cohorts and higher CORT expression (ρ = 0.20, P = 0.045) in CAMP. CONCLUSION AND CLINICAL RELEVANCE: Differential DNA methylation of IL12B and CORT are associated with inhaled corticosteroid treatment response in persistent childhood asthmatics. Pharmaco-methylation can identify novel markers of treatment sensitivity in asthma.

Traffic noise exposure in relation to adverse birth outcomes and body mass between birth and adolescence.

BACKGROUND: There is growing evidence that traffic noise exposure is associated with adiposity among adults but data in children are limited. OBJECTIVE: This longitudinal study examined whether pre- and postnatal noise exposure is associated with body mass index (BMI) between birth and adolescence or with adverse birth outcomes. METHODS: The study was conducted using data from the BAMSE birth cohort, which included 4089 children born in Stockholm County, Sweden. Data on BMI from birth to adolescence were collected via questionnaires, clinical examinations and health care records. A national register provided information on birth outcomes. Road traffic noise levels at the most exposed façade were estimated for all residences of the children during follow-up, as well as of their mothers during pregnancy, and time-weighted average exposure was calculated for different time windows. Maternal occupational noise exposure was obtained from a job-exposure-matrix. Logistic- and quantile regression models were used to estimate associations between noise exposure and health outcomes. RESULTS: We found residential road traffic noise exposure to be associated with increases in BMI from school age to adolescence, but not at earlier ages. In the age groups 8-11 years and 12-16 years the BMI increments were 0.11 kg/m2 per 10 dB Lden (95% CI 0.08-0.13) and 0.20 kg/m2 per 10 dB Lden (95% CI 0.17-0.22), respectively. Maternal noise exposure during pregnancy was generally unrelated to adverse birth outcomes and BMI from birth to adolescence in the children, however, traffic noise exposure was associated with a decreased risk of preterm birth CONCLUSION: Residential road traffic noise exposure was associated with BMI increases from school age to adolescence, but not at earlier ages. Maternal occupational noise exposure or exposure from road traffic during pregnancy were not consistently related to birth outcomes or BMI from birth to adolescence.

Genetic regulation of IL1RL1 methylation and IL1RL1-a protein levels in asthma.

Interleukin-1 receptor-like 1 (IL1RL1) is an important asthma gene. (Epi)genetic regulation of IL1RL1 protein expression has not been established. We assessed the association between IL1RL1 single nucleotide polymorphisms (SNPs), IL1RL1 methylation and serum IL1RL1-a protein levels, and aimed to identify causal pathways in asthma.Associations of IL1RL1 SNPs 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 DNA IL1RL1 methylation 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 of IL1RL1 CpG 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).IL1RL1 asthma-risk SNPs strongly associated with IL1RL1 methylation (rs1420101; p=3.7×10-16) and serum IL1RL1-a levels (p=2.8×10-56). IL1RL1 methylation 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-associated IL1RL1 SNPs strongly regulate IL1RL1 methylation and serum IL1RL1-a levels, yet neither these IL1RL1-methylation CpG sites nor IL1RL1-a levels are associated with asthma.

Urban upbringing and childhood respiratory and allergic conditions: A multi-country holistic study.

OBJECTIVE: We integratively assessed the effect of different indoor and outdoor environmental exposures early in life on respiratory and allergic health conditions among children from (sub-) urban areas. METHODS: This study included children participating in four ongoing European birth cohorts located in three different geographical regions: INMA (Spain), LISAplus (Germany), GINIplus (Germany) and BAMSE (Sweden). Wheezing, bronchitis, asthma and allergic rhinitis throughout childhood were assessed using parental-completed questionnaires. We designed "environmental scores" corresponding to different indoor, green- and grey-related exposures (main analysis, a-priori-approach). Cohort-specific associations between these environmental scores and the respiratory health outcomes were assessed using random-effects meta-analyses. In addition, a factor analysis was performed based on the same exposure information used to develop the environmental scores (confirmatory analysis, data-driven-approach). RESULTS: A higher early exposure to the indoor environmental score increased the risk for wheezing and bronchitis within the first year of life (combined adjusted odds ratio: 1.20 [95% confidence interval: 1.13-1.27] and 1.28 [1.18-1.39], respectively). In contrast, there was an inverse association with allergic rhinitis between 6 and 8 years (0.85 [0.79-0.92]). There were no statistically significant associations for the outdoor related environmental scores in relation to any of the health outcomes tested. The factor analysis conducted confirmed these trends. CONCLUSION: Although a higher exposure to indoor related exposure through occupants was associated with an increased risk for wheezing and bronchitis within the 1st year, it might serve as a preventive mechanism against later childhood allergic respiratory outcomes in urbanized environments through enhanced shared contact with microbial agents.

Genome-Wide Interaction Analysis of Air Pollution Exposure and Childhood Asthma with Functional Follow-up.

RATIONALE: The evidence supporting an association between traffic-related air pollution exposure and incident childhood asthma is inconsistent and may depend on genetic factors. OBJECTIVES: To identify gene-environment interaction effects on childhood asthma using genome-wide single-nucleotide polymorphism (SNP) data and air pollution exposure. Identified loci were further analyzed at epigenetic and transcriptomic levels. METHODS: We used land use regression models to estimate individual air pollution exposure (represented by outdoor NO2 levels) at the birth address and performed a genome-wide interaction study for doctors' diagnoses of asthma up to 8 years in three European birth cohorts (n = 1,534) with look-up for interaction in two separate North American cohorts, CHS (Children's Health Study) and CAPPS/SAGE (Canadian Asthma Primary Prevention Study/Study of Asthma, Genetics and Environment) (n = 1,602 and 186 subjects, respectively). We assessed expression quantitative trait locus effects in human lung specimens and blood, as well as associations among air pollution exposure, methylation, and transcriptomic patterns. MEASUREMENTS AND MAIN RESULTS: In the European cohorts, 186 SNPs had an interaction P < 1 × 10-4 and a look-up evaluation of these disclosed 8 SNPs in 4 loci, with an interaction P < 0.05 in the large CHS study, but not in CAPPS/SAGE. Three SNPs within adenylate cyclase 2 (ADCY2) showed the same direction of the interaction effect and were found to influence ADCY2 gene expression in peripheral blood (P = 4.50 × 10-4). One other SNP with P < 0.05 for interaction in CHS, rs686237, strongly influenced UDP-Gal:betaGlcNAc ß-1,4-galactosyltransferase, polypeptide 5 (B4GALT5) expression in lung tissue (P = 1.18 × 10-17). Air pollution exposure was associated with differential discs, large homolog 2 (DLG2) methylation and expression. CONCLUSIONS: Our results indicated that gene-environment interactions are important for asthma development and provided supportive evidence for interaction with air pollution for ADCY2, B4GALT5, and DLG2.

Long-term exposure to ambient air pollution and traffic noise and incident hypertension in seven cohorts of the European study of cohorts for air pollution effects (ESCAPE).

Aims: We investigated whether traffic-related air pollution and noise are associated with incident hypertension in European cohorts. Methods and results: We included seven cohorts of the European study of cohorts for air pollution effects (ESCAPE). We modelled concentrations of particulate matter with aerodynamic diameter ≤2.5 µm (PM2.5), ≤10 µm (PM10), >2.5, and ≤10 µm (PMcoarse), soot (PM2.5 absorbance), and nitrogen oxides at the addresses of participants with land use regression. Residential exposure to traffic noise was modelled at the facade according to the EU Directive 2002/49/EC. We assessed hypertension as (i) self-reported and (ii) measured (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg or intake of BP lowering medication (BPLM). We used Poisson regression with robust variance estimation to analyse associations of traffic-related exposures with incidence of hypertension, controlling for relevant confounders, and combined the results from individual studies with random-effects meta-analysis. Among 41 072 participants free of self-reported hypertension at baseline, 6207 (15.1%) incident cases occurred within 5-9 years of follow-up. Incidence of self-reported hypertension was positively associated with PM2.5 (relative risk (RR) 1.22 [95%-confidence interval (CI):1.08; 1.37] per 5 µg/m³) and PM2.5 absorbance (RR 1.13 [95% CI:1.02; 1.24] per 10 - 5m - 1). These estimates decreased slightly upon adjustment for road traffic noise. Road traffic noise was weakly positively associated with the incidence of self-reported hypertension. Among 10 896 participants at risk, 3549 new cases of measured hypertension occurred. We found no clear associations with measured hypertension. Conclusion: Long-term residential exposures to air pollution and noise are associated with increased incidence of self-reported hypertension.