Association between PM2.5 from a coal mine fire and FeNO concentration 7.5 years later.

BACKGROUND AND AIM: There are few long-term studies of respiratory health effects of landscape fires, despite increasing frequency and intensity due to climate change. We investigated the association between exposure to coal mine fire PM2.5 and fractional exhaled nitric oxide (FeNO) concentration 7.5 years later. METHODS: Adult residents of Morwell, who were exposed to the 2014 Hazelwood mine fire over 6 weeks, and unexposed residents of Sale, participated in the Hazelwood Health Study Respiratory Stream in 2021, including measurements of FeNO concentration, a marker of eosinophilic airway inflammation. Individual exposure to coal mine fire PM2.5 was modelled and mapped to time-location diaries. The effect of exposure to PM2.5 on log-transformed FeNO in exhaled breath was investigated using multivariate linear regression models in the entire sample and stratified by potentially vulnerable subgroups. RESULTS: A total of 326 adults (mean age: 57 years) had FeNO measured. The median FeNO level (interquartile range [IQR]) was 17.5 [15.0] ppb, and individual daily exposure to coal mine fire PM2.5 was 7.2 [13.8] µg/m3. We did not identify evidence of association between coal mine fire PM2.5 exposure and FeNO in the general adult sample, nor in various potentially vulnerable subgroups. The point estimates were consistently close to zero in the total sample and subgroups. CONCLUSION: Despite previous short-term impacts on FeNO and respiratory health outcomes in the medium term, we found no evidence that PM2.5 from the Hazelwood coal mine fire was associated with any long-term impact on eosinophilic airway inflammation measured by FeNO levels.

Sex-specific associations between air pollutants and asthma prevalence in Japanese adults: a population-based study.

This study investigated the association between air pollutants and asthma prevalence in male and female Japanese adults. In this retrospective cross-sectional analysis, annual mean exposure levels of air pollutants, specifically nitrogen dioxide (NO2) and particulate matter with a median aerodynamic diameter ≤2.5 µm (PM2.5), were assessed at a local monitoring site. Multivariable logistic regression models, adjusted for genetic and/or lifestyle factors, were used to explore the association between air pollutants and asthma, with stratification by sex. A total of 1,497 participants aged ≥40 years were included. Their mean age was 65.9 ± 12.4 years, with 847 being women. Overall, 91 participants were diagnosed with asthma. In the multivariable model, ambient exposure levels of NO2 and PM2.5 were significantly associated with asthma in women but not in men. This study highlights sex as a significant determinant of the link between air pollutants and asthma exacerbation, particularly among female Japanese adults.

Allergic disease trajectories up to adolescence: Characteristics, early-life, and genetic determinants.

BACKGROUND: Allergic diseases often develop jointly during early childhood but differ in timing of onset, remission, and progression. Their disease course over time is often difficult to predict and determinants are not well understood. OBJECTIVES: We aimed to identify trajectories of allergic diseases up to adolescence and to investigate their association with early-life and genetic determinants and clinical characteristics. METHODS: Longitudinal k-means clustering was used to derive trajectories of allergic diseases (asthma, atopic dermatitis, and rhinitis) in two German birth cohorts (GINIplus/LISA). Associations with early-life determinants, polygenic risk scores, food and aeroallergen sensitization, and lung function were estimated by multinomial models. The results were replicated in the independent Swedish BAMSE cohort. RESULTS: Seven allergic disease trajectories were identified: "Intermittently allergic," "rhinitis," "early-resolving dermatitis," "mid-persisting dermatitis," "multimorbid," "persisting dermatitis plus rhinitis," and "early-transient asthma." Family history of allergies was more prevalent in all allergic disease trajectories compared the non-allergic controls with stronger effect sizes for clusters comprising more than one allergic disease (e.g., RRR = 5.0, 95% CI = [3.1-8.0] in the multimorbid versus 1.8 [1.4-2.4] in the mild intermittently allergic cluster). Specific polygenic risk scores for single allergic diseases were significantly associated with their relevant trajectories. The derived trajectories and their association with genetic effects and clinical characteristics showed similar results in BAMSE. CONCLUSION: Seven robust allergic clusters were identified and showed associations with early life and genetic factors as well as clinical characteristics.

Evaluation of tree-based statistical learning methods for constructing genetic risk scores.

BACKGROUND: Genetic risk scores (GRS) summarize genetic features such as single nucleotide polymorphisms (SNPs) in a single statistic with respect to a given trait. So far, GRS are typically built using generalized linear models or regularized extensions. However, these linear methods are usually not able to incorporate gene-gene interactions or non-linear SNP-response relationships. Tree-based statistical learning methods such as random forests and logic regression may be an alternative to such regularized-regression-based methods and are investigated in this article. Moreover, we consider modifications of random forests and logic regression for the construction of GRS. RESULTS: In an extensive simulation study and an application to a real data set from a German cohort study, we show that both tree-based approaches can outperform elastic net when constructing GRS for binary traits. Especially a modification of logic regression called logic bagging could induce comparatively high predictive power as measured by the area under the curve and the statistical power. Even when considering no epistatic interaction effects but only marginal genetic effects, the regularized regression method lead in most cases to inferior results. CONCLUSIONS: When constructing GRS, we recommend taking random forests and logic bagging into account, in particular, if it can be assumed that possibly unknown epistasis between SNPs is present. To develop the best possible prediction models, extensive joint hyperparameter optimizations should be conducted.

Chronic air pollution-induced subclinical airway inflammation and polygenic susceptibility.

BACKGROUND: Air pollutants can activate low-grade subclinical inflammation which further impairs respiratory health. We aimed to investigate the role of polygenic susceptibility to chronic air pollution-induced subclinical airway inflammation. METHODS: We used data from 296 women (69-79 years) enrolled in the population-based SALIA cohort (Study on the influence of Air pollution on Lung function, Inflammation and Aging). Biomarkers of airway inflammation were measured in induced-sputum samples at follow-up investigation in 2007-2010. Chronic air pollution exposures at residential addresses within 15 years prior to the biomarker assessments were used to estimate main environmental effects on subclinical airway inflammation. Furthermore, we calculated internally weighted polygenic risk scores based on genome-wide derived single nucleotide polymorphisms. Polygenic main and gene-environment interaction (GxE) effects were investigated by adjusted linear regression models. RESULTS: Higher exposures to nitrogen dioxide (NO2), nitrogen oxides (NOx), particulate matter with aerodynamic diameters of ≤ 2.5 µm, ≤ 10 µm, and 2.5-10 µm significantly increased the levels of leukotriene (LT)B4 by 19.7% (p-value = 0.005), 20.9% (p = 0.002), 22.1% (p = 0.004), 17.4% (p = 0.004), and 23.4% (p = 0.001), respectively. We found significant effects of NO2 (25.9%, p = 0.008) and NOx (25.9%, p-value = 0.004) on the total number of cells. No significant GxE effects were observed. The trends were mostly robust in sensitivity analyses. CONCLUSIONS: While this study confirms that higher chronic exposures to air pollution increase the risk of subclinical airway inflammation in elderly women, we could not demonstrate a significant role of polygenic susceptibility on this pathway. Further studies are required to investigate the role of polygenic susceptibility.

Does social cohesion mediate neighbourhood effects on mental and physical health? Longitudinal analysis using German Socio-Economic Panel data.

BACKGROUND: Neighbourhood has risen as a relevant determinant of health. While there is substantial evidence that environmental factors affect health, far less evidence of the role of social mechanisms in the causal chain between neighbourhood characteristics and health is available. METHOD: To evaluate the role of social cohesion as a mediator between four different neighbourhood characteristics and health using data from German Socio-Economic-Panel (SOEP), a longitudinal mediation analysis was performed. Multilevel linear regression models adjusted for socio-economic variables involved three time points and two measures of physical and mental health (physical and mental component scores (PCS and MCS) of the SF12 Questionnaire. Participants were followed-up for 4 and 10 year starting in 2004. RESULTS: A total of 15,518 measures of MCS and PCS on 10,013 participants living in 4985 households were included. After adjusting for values of MCS and PCS at baseline and demographic/socio-economic variables, social cohesion was a significant positive predictor of both MCS and PCS (ß-coefficient MCS: 1.57 (0.27); PCS: 1.50 (0.24)). Interaction between social cohesion and follow-up were significant for PCS. The effect of environmental and built characteristics on health was consistently mediated by social cohesion with proportion varying between 10 and 23%. DISCUSSION: We show that social cohesion is part of the causal chain between environmental and built characteristics of a neighbourhood and health, with increasing mediation effect over time for physical health. Social mechanisms should be considered when studying the effect of neighbourhood characteristics on health inequalities making social cohesion as a legitimate target of public health interventions at neighbourhood level.

Efficient gene-environment interaction testing through bootstrap aggregating.

Gene-environment (GxE) interactions are an important and sophisticated component in the manifestation of complex phenotypes. Simple univariate tests lack statistical power due to the need for multiple testing adjustment and not incorporating potential interplay between several genetic loci. Approaches based on internally constructed genetic risk scores (GRS) require the partitioning of the available sample into training and testing data sets, thus, lowering the effective sample size for testing the GxE interaction itself. To overcome these issues, we propose a statistical test that employs bagging (bootstrap aggregating) in the GRS construction step and utilizes its out-of-bag prediction mechanism. This approach has the key advantage that the full available data set can be used for both constructing the GRS and testing the GxE interaction. To also incorporate interactions between genetic loci, we, furthermore, investigate if using random forests as the GRS construction method in GxE interaction testing further increases the statistical power. In a simulation study, we show that both novel procedures lead to a higher statistical power for detecting GxE interactions, while still controlling the type I error. The random-forests-based test outperforms a bagging-based test that uses the elastic net as its base learner in most scenarios. An application of the testing procedures to a real data set from a German cohort study suggests that there might be a GxE interaction involving exposure to air pollution regarding rheumatoid arthritis.

Changes in sleep duration and sleep difficulties from adolescence to young adulthood and the risk of obesity: Bidirectional evidence in the GINIplus and LISA studies.

OBJECTIVE: This study aimed to assess the association of changes in sleep behaviors from adolescence to young adulthood with the risk of overweight/obesity, and the reverse relationship. METHODS: Data of 1978 participants was obtained from the 15- and 20-year follow-ups of the GINIplus and LISA birth cohorts. Insufficient sleep was defined as reported sleep duration <8 h for adolescents, <7 h for adults, and sleep difficulties as reported having sleeping difficulties. Logistic regression models were used to assess bidirectional associations of changes in insufficient sleep and sleep difficulties with overweight/obesity. The polygenic risk scores (PRS) for body mass index (BMI) was tested in a sub-sample (n = 918). RESULTS: Compared with sufficient sleep in both adolescence and young adulthood, insufficient sleep only in young adulthood was associated with an increased risk of overweight/obesity (odds ratio = 1.85, 95%confidence interval = [1.27-2.69]). Compared with no sleep difficulties at both time-points, only persistent sleep difficulties was associated with a higher risk of overweight/obesity (2.15 [1.22-3.77]). The PRS for BMI was associated with overweight/obesity (1.41 [1.17-1.70]), but no significant gene-sleep interaction effect was observed. Reversely, only persistent overweight/obesity was associated with increased risks of insufficient sleep (1.81 [1.21-2.70]), and sleep difficulties (1.77 [1.18-2.66]), respectively. CONCLUSIONS: Insufficient sleep only presented a cross-sectional association with overweight/obesity in young adulthood, while long-term sleep difficulties from adolescence to young adulthood was associated with young adult overweight/obesity. Reversely, long-term overweight/obesity from adolescence to young adulthood was associated with insufficient sleep and sleep difficulties in young adulthood.

Gene-environment interaction in the association of residential greenness and 25(OH) vitamin D.

There is increasing awareness for beneficial health effects of green space surrounding the home, but the underlying mechanisms are not yet fully understood and challenging to study given the correlation with other exposures. Here, the association of residential greenness and vitamin D including a gene-environment interaction is investigated. 25-hydroxyvitamin D (25(OH)D) was measured by electrochemiluminescence at ages 10 and 15 years in participants of two German birth cohorts GINIplus and LISA. Greenness was measured using the Landsat-derived Normalized Difference Vegetation Index (NDVI) in a 500 m buffer surrounding the home. Linear and logistic regression models were applied at both time points adjusted for several covariates (N10Y = 2,504, N15Y = 2,613). In additional analyses vitamin D-related genes, physical activity, time spent outdoors, supplements, and measurement season were investigated as potential confounders or effect modifiers. A 1.5-SD increase in NDVI was significantly associated with increased 25(OH)D values at ages 10 and 15 years (ß10y = 2.41 nmol/l, p=<0.01; ß15y = 2.03 nmol/l, p = 0.02). In stratified analyses, the associations were not seen in participants spending more than 5 h/day outside in summer, having a high physical activity level, taking supplements, or being examined during the winter season. In a subset (n = 1,732) with genetic data, a significant gene-environment interaction of NDVI with CYP2R1, an upstream gene in 25(OH)D synthesis, was observed at age 10 years. When investigating 25(OH)D sufficiency, defined as values above 50 nmol/l, a 1.5-SD increase in NDVI was associated with significantly higher odds of having sufficient 25 (OH)D levels at age 10 years (OR = 1.48, 1.19-1.83). In conclusion, robust associations between residential greenness and 25 (OH)D levels were observed in children and adolescents independent of other confounders and additionally supported by the presence of a gene-environment interaction. Effects of NDVI were stronger in those having lower vitamin D levels at age 10 years due to their covariate profile or genetically lower 25(OH)D synthesis.

European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation.

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.

Airway inflammation in adolescents and elderly women: Chronic air pollution exposure and polygenic susceptibility.

BACKGROUND AND AIM: The fractional exhaled nitric oxide (FeNO) concentration in the exhaled breath is a biomarker for eosinophilic airway inflammation. We explored the interplay between chronic air pollution exposure and polygenic susceptibility to airway inflammation at different critical age stages. METHODS: Adolescents (15 yr) enrolled in the GINIplus/LISA birth cohorts (n = 2434) and 220 elderly women (75 yr on average) enrolled in the SALIA cohort with FeNO measurements available were investigated. Environmental main effects of the mean of ESCAPE land-use regression air pollutant concentrations within a time window of 15 years and main effects of the polygenic risk scores (PRS) using internal weights from elastic net regression of genome-wide derived single nucleotide polymorphisms were investigated. Furthermore, we examined gene-environment interaction (GxE) effects on natural log-transformed FeNO levels by adjusted linear regression models. RESULTS: While we observed no significant environmental and polygenic main effects on airway inflammation in either age group, we found robust harmful effects of chronic nitrogen dioxide (NO2) exposure in the GxE models for elderly women (16.2 % increase in FeNO, p-value = 0.027). Stratified analyses found GxE effects between the PRS and chronic NO2 exposure in never-smoker elderly women and in adolescents without any inflammatory respiratory conditions. CONCLUSIONS: FeNO measurement is a useful biomarker to detect higher risk of NO2-induced eosinophilic airway inflammation in the elderly. There was limited evidence for GxE effects on airway inflammation in adolescents or the elderly. Further GxE studies in subpopulations should be conducted to investigate the assumption that susceptibility to airway inflammation differs between age stages.

The Role of Polygenic Susceptibility on Air Pollution-Associated Asthma between German and Japanese Elderly Women.

Polygenic susceptibility likely influences individual responses to air pollutants and the risk of asthma. We compared the role of polygenic susceptibility on air pollution-associated asthma between German and Japanese women. We investigated women that were enrolled in the German SALIA cohort (n = 771, mean age = 73 years) and the Japanese Shika cohort (n = 847, mean age = 67 years) with known asthma status. Adjusted logistic regression models were used to assess the associations between (1) particulate matter with a median aerodynamic diameter ≤ 2.5µm (PM2.5) and nitrogen dioxide (NO2), (2) polygenic risk scores (PRS), and (3) gene-environment interactions (G × E) with asthma. We found an increased risk of asthma in Japanese women after exposure to low pollutant levels (PM2.5: median = 12.7µg/m3, p-value < 0.001, NO2: median = 8.5µg/m3, p-value < 0.001) and in German women protective polygenic effects (p-value = 0.008). While we found no significant G × E effects, the direction in both groups was that the PRS increased the effect of PM2.5 and decreased the effect of NO2 on asthma. Our study confirms that exposure to low air pollution levels increases the risk of asthma in Japanese women and indicates polygenic effects in German women; however, there was no evidence of G × E effects. Future genome-wide G × E studies should further explore the role of ethnic-specific polygenic susceptibility to asthma.

Air pollution, metabolites and respiratory health across the life-course.

Previous studies have explored the relationships of air pollution and metabolic profiles with lung function. However, the metabolites linking air pollution and lung function and the associated mechanisms have not been reviewed from a life-course perspective. Here, we provide a narrative review summarising recent evidence on the associations of metabolic profiles with air pollution exposure and lung function in children and adults. Twenty-six studies identified through a systematic PubMed search were included with 10 studies analysing air pollution-related metabolic profiles and 16 studies analysing lung function-related metabolic profiles. A wide range of metabolites were associated with short- and long-term exposure, partly overlapping with those linked to lung function in the general population and with respiratory diseases such as asthma and COPD. The existing studies show that metabolomics offers the potential to identify biomarkers linked to both environmental exposures and respiratory outcomes, but many studies suffer from small sample sizes, cross-sectional designs, a preponderance on adult lung function, heterogeneity in exposure assessment, lack of confounding control and omics integration. The ongoing EXposome Powered tools for healthy living in urbAN Settings (EXPANSE) project aims to address some of these shortcomings by combining biospecimens from large European cohorts and harmonised air pollution exposure and exposome data.

The mediating role of lung function on air pollution-induced cardiopulmonary mortality in elderly women: The SALIA cohort study with 22-year mortality follow-up.

BACKGROUND: Air pollution exposure is associated with reduced lung function and increased cardio-pulmonary mortality (CPM). OBJECTIVES: We analyzed the potential mediating effect of reduced lung function on the association between air pollution exposure and CPM. METHODS: We used data from the German SALIA cohort including 2527 elderly women (aged 51-56 years at baseline 1985-1994) with 22-year follow-up to CPM. Exposures to PM10, PM2.5, PM2.5 absorbance, NO2 and NOx were assessed by land-use regression modelling and back-extrapolated to estimate exposures at baseline. Lung function (FVC, FEV1) was measured by spirometry and transformed to GLI z-scores. Adjusted Cox proportional hazards and causal proportional hazards mediation analysis models were fitted. RESULTS: The survival analysis showed that reduced lung function (z-scores of FVC or FEV1 below 5% predicted) reflected significantly lower survival probability from CPM (p < 0.0001). Longterm exposures to NOx and NO2 were associated with increased risks of CPM (eg. HR = 1.215; 95%CI: 1.017-1.452 for IQR increase in NOx and HR = 1.209; 95%CI: 1.011-1.445 for IQR increase in NO2) after adjusting for reduced lung function and additional covariates. The associations of PM2.5 absorbance and CPM remained significant in models adjusted for FEV1/FVC, but the associations with PM10 and PM2.5 were not significant. The mediation analysis showed significant indirect effects of NO2 and NOx on CPM mediated through reduced FEV1 and FVC. The largest indirect effects were found for exposures to NO2 (HR = 1.037; 95%CI: 1.005-1.070) and NOx (HR = 1.028; 95%CI: 1.004-1.052) mediated through reduced FVC. The mediated proportion effect ranged from 13.9% to 19.6% in fully adjusted models. DISCUSSION: This study provides insights into the mechanism of reduced lung function in association between long-term air pollution exposure and CPM. The mediated effect was substantial for exposure to nitrogen oxides (NOx and NO2), but less pronounced for PM10 and PM2.5.

Long-term Air Pollution Exposure Under European Union Limits and Adolescents' Lung Function: Modifying Effect of Abnormal Weight in the GINIplus and LISA Birth Cohorts.

BACKGROUND: Abnormal weights, eg, obesity, has shown a strong modifying effect on the association between air pollution exposure and lung function impairment in adults. RESEARCH QUESTION: How might weight status modify the effects of long-term air pollution exposure on adolescents' lung function, particularly in areas with pollution levels much lower than the current European Union (EU) air quality standards? STUDY DESIGN AND METHODS: In this observational study, we investigated 2,224 adolescents from the German Infant Study on the Influence of Nutrition Intervention Plus Environmental and Genetic Influences on Allergy Development and the Influence of Life Style Factors on the Development of the Immune System and Allergies in East and West Germany birth cohorts. Lung function was measured at age 15 years. Underweight, normal weight, and overweight or obese were defined using percentiles of BMI. Average concentrations of air pollution were modelled at residential addresses at four exposure windows between 0 and 15 years. Multivariate linear regression models were fitted by weight group on lung function with exposure at each window or cumulative exposure since birth. RESULTS: The median air pollution concentrations were half to two-thirds of the EU standards. Significant associations were observed only for individuals who were underweight and overweight or obese. For example, per interquartile range increase in nitrogen dioxide at the 15-year exposure window, FEV1 declined by -2.9% (95% CI, -5.2% to -0.5%) for the underweight group and -3.4% (95% CI, -5.4% to -1.2%) for the overweight or obese group. Similarly, longer exposure to moderate-level air pollution since birth was associated significantly with lung function impairment for groups with abnormal weight. INTERPRETATION: Exposure to low to moderate levels of air pollution was associated with lung function impairment for adolescents with abnormal weight. Longer exposure aggravated the adverse effect. Whether a critical exposure window since birth exists warrants further exploration.

Air pollution during infancy and lung function development into adolescence: The GINIplus/LISA birth cohorts study.

BACKGROUND: Limited evidence exists on how air pollution exposure during infancy, i.e. the first year of life, may affect lung function development into adolescence. OBJECTIVES: To investigate the association between exposure to air pollution during the first-year of life and lung function development up to the age of 15 in Germany. METHODS: We investigated 915 children from the GINIplus and LISA birth cohorts from Munich (n = 181) and Wesel (n = 734), who had at least two spirometric measurements at ages 6, 10 and 15. Z-scores of forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were calculated. Annual average concentrations of nitrogen dioxide, particulate matter with diameters <2.5, <10 and 2.5-10 µm (PM2.5/10/coarse), and PM2.5 absorbance at home addresses during the first-year of life, were estimated by land-use regression models. Associations between infancy exposure and lung function changes were fitted using multivariable linear mixed models with adjustment for potential confounders. RESULTS: For per interquartile range increase in air pollutants during the first-year life, FEV1 z-scores declined annually by -0.012 (95% confidence interval (CI): -0.014, -0.009) for PM2.5 to -0.023 (95%CI: -0.028, -0.018) for PMcoarse. The declines in FVC were lower than FEV1 [-0.006 (95%CI: -0.008, -0.003) to -0.011 (95%CI: -0.019, -0.003)]. In Munich, the attenuations were only significant for FEV1. Effect estimates of infancy exposure for certain air pollutants were higher for groups with asthma, older maternal age, and breastfeeding <12 weeks than their counterparts. DISCUSSION: Infancy exposure to higher air pollution may reduce lung function development up to adolescence, with airway size more affected than lung volume restriction. The potential modifying effects of maternal age, asthmatic status of children and breastfeeding warrant further exploration.