Elucidation of the role of obesity and air pollution in the asthma etiology in adults

Non-communicable disease (NCD) epidemic threatens public health in all regions of the world. Asthma is one of the major NCDs along with cardiovascular diseases, cancer, diabetes, and other chronic respiratory diseases. Asthma etiology is poorly understood, hindering the efficient primary prevention. Recent findings indicate that asthma is a mixture of various phenotypes with potentially different mechanism. While obesity and air pollution have been indicated as risk factors for asthma, it is not clear yet whether they contribute to the development of asthma rather than exacerbation of already existing disease and through which mechanisms they exert the effects on asthma development. Elucidation of such mechanism, especially if it is shared by multiple exposures and/or multiple diseases, will critically benefit primary prevention. The research efforts for mechanistic understanding can be contextualized as part of exposome — the entirety of the exposures an individual experiences throughout the life course — and aging phenome — the diseases and morbidities often accompanied with aging — research, where systems approach e.g. omics analysis finds a critical usage. The Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) is an on-going population cohort since 1991. With its detailed information on the participants' health, life style, and exposure, SAPALDIA offers a unique opportunity to investigate the NCD etiology. This PhD project aimed to contribute to better understanding the role of obesity and air pollution exposure in asthma etiology, taking the heterogeneity of the disease phenotype into account. We identified four asthma phenotypes using latent class analysis, which showed heterogeneity in the association with obesity. We conducted epigenomics — assessments of genome-wide DNA methylation — and metabolomics — assessments of the entirety ofsmall molecules — on the blood samples taken from the adult-onset asthma cases and controls. Epigenomics pathway analysis revealed that DNA methylation on the inflammation-related genes modifies the effect of BMI on non-atopic adult-onset asthma. This pathway analysis also provided evidence that the NLRP3-IL1B-IL17 axis, a component of innate immunity, plays a role in the asthma etiology in humans, confirming the previous research findings in mice experiments. Metabolomics pathway analysis pointed to the perturbation of inflammatory pathways as a potentially shared mechanism through which long-term air pollution exposure affects adult-onset asthma and cardio- and cerebrovascular diseases. Despite the cross-sectional study design and the limited statistical power, this PhD project achieved to demonstrate the importance of distinguishing asthma phenotypes to study etiology; to exemplify the usefulness of cohort studies with biobanks in exposome research and the applicability of systems approach in cohort studies; and to provide a proof-of-concept evidence of the disease mechanism shared by multiple NCDs. Our findings can be considered as the first step of the translational approach — innovation, validation, and application. Once validated by future research including replication in other populations and consolidation of causality using Mendelian randomization, the pursuit of mechanistic understanding can guide prevention strategies to efficiently tackle the NCD epidemic

Heterogeneity of obesity-asthma association disentangled by latent class analysis, the SAPALDIA cohort

Abstract Although evidence for the heterogeneity of asthma accumulated, consensus for definitions of asthma phenotypes is still lacking. Obesity may have heterogeneous effects on various asthma phenotypes. We aimed to distinguish asthma phenotypes by latent class analysis and to investigate their associations with different obesity parameters in adults using a population-based Swiss cohort (SAPALDIA). We applied latent class analysis to 959 self-reported asthmatics using information on disease activity, atopy, and age of onset. Associations with obesity were examined by multinomial logistic regression, after adjustments for age, sex, smoking status, educational level, and study centre. Body mass index, percent body fat, waist hip ratio, waist height ratio, and waist circumference were used as obesity measure. Four asthma classes were identified, including persistent multiple symptom-presenting asthma (n = 122), symptom-presenting asthma (n = 290), symptom-free atopic asthma (n = 294), and symptom-free non-atopic asthma (n = 253). Obesity was positively associated with symptom-presenting asthma classes but not with symptom-free ones. Percent body fat showed the strongest association with the persistent multiple symptom-presenting asthma. We observed heterogeneity of associations with obesity across asthma classes, indicating different asthma aetiologies

SPHN - The Swiss Aging Citizen Reference (SACR)

In Switzerland by 2045, we expect 2.7 Mio citizens aged 65+ of whom 1.0 Mio. aged 80+. A priority and focus of personalized health research is therefore aging biology to extend healthy life expectancy. Novel molecular and imaging features will emerge as candidate targets for risk prediction and screening of chronic diseases. It is of utmost importance to test the clinical and public health utility of candidate biomarkers evolving from this research in citizen reference cohorts. We will build a Swiss Aging Citizen Reference (SACR), a testable and scalable reference cohort offering interoperable, searchable, and accessible data. 1000 participants from existing Swiss citizen cohorts will be combined and analyzed for DNA methylation and MRI brain imaging. SACR will serve as a testbed for clinical and public health utility of candidate biomarkers. As for a proof-of-concept study, we will conduct an agnostic search for structural and functional brain features associated with epigenetic aging acceleration to examine the potential of epigenetic age acceleration as the intermediate aging biomarker and to better understand the aging mechanism in brain

Gender differences in the association between life history of body silhouettes and asthma incidence : results from the SAPALDIA cohort study

Background: The association of obesity and asthma has been described in children and adults. However, whether a different life course of weight in men and women may explain gender differences in asthma incidence, has not been addressed. Objectives: Using data from the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults, we investigated the role of overweight/obesity as measured by body silhouettes at different life stages in men and women for asthma incidence. Methods: Our analysis included 5417 subjects who were asthma free at age 8, followed up to 2011, and had complete covariate information. The main predictor of interest was self-reported body silhouettes at age 8, menarche, 30, 45, menopause, and 60, and additionally changes in body silhouette number across these different time points. Asthma incidence was defined as newly reported doctor-diagnosed asthma after the body silhouette time point. Asthma incidence and its association with body silhouettes was analysed using sex stratified logistic regression, adjusting for age, atopy, urbanity, smoking, parental asthma, education and study area. Results: Men at age 60 had an increased risk of asthma incidence per unit increase in body silhouette number (OR 1.93, 95% CI 1.13–3.30). This association was stronger in women at age 60 (OR 2.78, 95% CI 1.49–5.18) and observed also at menopause (OR 1.35, 95% CI 1.03–1.78), as well as per unit change in body silhouette number between age 45 – menopause (OR 1.74, 95% CI 1.15–2.63). Conclusion: In this longitudinal study, the risk of incident asthma increased in men and women with a larger body silhouette in late adulthood. In women, this risk appeared present between age 45 and menopause. At age 60, both men and women were at higher risk of asthma incidence per unit increase in body silhouette, the risk being more pronounced in women. The age-related increase of obesity may underlie gender differences in asthma incidence at higher ages

The mediating effect of immune markers on the association between ambient air pollution and adult-onset asthma

We aim to investigate to what extent a set of immune markers mediate the association between air pollution and adult-onset asthma. We considered long-term exposure to multiple air pollution markers and a panel of 13 immune markers in peripheral blood samples collected from 140 adult cases and 199 controls using a nested-case control design. We tested associations between air pollutants and immune markers and adult-onset asthma using mixed-effects (logistic) regression models, adjusted for confounding variables. In order to evaluate a possible mediating effect of the full set of immune markers, we modelled the relationship between asthma and air pollution with a partial least square path model. We observed a strong positive association of IL-1RA [OR 1.37; 95% CI (1.09, 1.73)] with adult-onset asthma. Univariate models did not yield any association between air pollution and immune markers. However, mediation analyses indicated that 15% of the effect of air pollution on risk of adult-onset asthma was mediated through the immune system when considering all immune markers as a latent variable (path coefficient (β) = 0.09; 95% CI: (-0.02, 0.20)). This effect appeared to be stronger for allergic asthma (22%; β = 0.12; 95% CI: (-0.03, 0.27)) and overweight subjects (27%; β = 0.19; 95% CI: (-0.004, 0.38)). Our results provides supportive evidence for a mediating effect of the immune system in the association between air pollution and adult-onset asthma

Role of DNA methylation in the association of lung function with body mass index: a two-step epigenetic Mendelian randomisation study

Low lung function has been associated with increased body mass index (BMI). The aim of this study was to investigate whether the effect of BMI on lung function is mediated by DNA methylation.; We used individual data from 285,495 participants in four population-based cohorts: the European Community Respiratory Health Survey, the Northern Finland Birth Cohort 1966, the Swiss Study on Air Pollution and Lung Disease in Adults, and the UK Biobank. We carried out Mendelian randomisation (MR) analyses in two steps using a two-sample approach with SNPs as instrumental variables (IVs) in each step. In step 1 MR, we estimated the causal effect of BMI on peripheral blood DNA methylation (measured at genome-wide level) using 95 BMI-associated SNPs as IVs. In step 2 MR, we estimated the causal effect of DNA methylation on FEV; 1; , FVC, and FEV; 1; /FVC using two SNPs acting as methQTLs occurring close (in cis) to CpGs identified in the first step. These analyses were conducted after exclusion of weak IVs (F statistic < 10) and MR estimates were derived using the Wald ratio, with standard error from the delta method. Individuals whose data were used in step 1 were not included in step 2.; In step 1, we found that BMI might have a small causal effect on DNA methylation levels (less than 1% change in methylation per 1 kg/m2 increase in BMI) at two CpGs (cg09046979 and cg12580248). In step 2, we found no evidence of a causal effect of DNA methylation at cg09046979 on lung function. We could not estimate the causal effect of DNA methylation at cg12580248 on lung function as we could not find publicly available data on the association of this CpG with SNPs.; To our knowledge, this is the first paper to report the use of a two-step MR approach to assess the role of DNA methylation in mediating the effect of a non-genetic factor on lung function. Our findings do not support a mediating effect of DNA methylation in the association of lung function with BMI

Long-term exposure to transportation noise and its association with adiposity markers and development of obesity

The contribution of different transportation noise sources to metabolic disorders such as obesity remains understudied. We evaluated the associations of long-term exposure to road, railway and aircraft noise with measures of obesity and its subphenotypes using cross-sectional and longitudinal designs. We assessed 3796 participants from the population-based Swiss Cohort Study on Air Pollution and Lung and Heart Diseases (SAPALDIA), who attended the visits in 2001 (SAP2) and 2010/2011 (SAP3) and who were aged 29-72 at SAP2. At SAP2 we measured body mass index (BMI, kg/m; 2; ). At SAP3 we measured BMI, waist circumference (centimetres) and Kyle body Fat Index (%) and derived overweight, central and general obesity. Longitudinally for BMI, we derived change in BMI, incidence of overweight and obesity and a 3-category outcome combining the latter two. We assigned source-specific 5-year mean noise levels before visits and during follow-up at the most exposed dwelling façade (Lden, dB), using Swiss noise models for 2001 and 2011 and participants' residential history. Models were adjusted for relevant confounders, including traffic-related air pollution. Exposure to road traffic noise was significantly associated with all adiposity subphenotypes, cross-sectionally (at SAP3) [e.g. beta (95% CI) per 10 dB, BMI: 0.39 (0.18; 0.59); waist circumference: 0.93 (0.37; 1.50)], and with increased risk of obesity, longitudinally (e.g. RR = 1.25, 95% CI: 1.04; 1.51, per 10 dB in 5-year mean). Railway noise was significantly related to increased risk of overweight. In cross-sectional analyses, we further identified a stronger association between road traffic noise and BMI among participants with cardiovascular disease and an association between railway noise and BMI among participants reporting bad sleep. Associations were independent of the other noise sources, air pollution and robust to all adjustment sets. No associations were observed for aircraft noise. Long-term exposure to transportation noise, particularly road traffic noise, may increase the risk of obesity and could constitute a pathway towards cardiometabolic and other diseases

Genome-wide DNA methylation in peripheral blood and long-term exposure to source-specific transportation noise and air pollution: The SAPALDIA Study

Background: Few epigenome-wide association studies (EWAS) on air pollutants exist, and none have been done on transportation noise exposures, which also contribute to environmental burden of disease. Objective: We performed mutually independent EWAS on transportation noise and air pollution exposures. Methods: We used data from two time points of the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) from 1,389 participants contributing 2,542 observations. We applied multiexposure linear mixed-effects regressions with participant-level random intercept to identify significant Cytosine-phosphate-Guanine (CpG) sites and differentially methylated regions (DMRs) in relation to 1-y average aircraft, railway, and road traffic day-evening-night noise (Lden); nitrogen dioxide (NO2); and particulate matter (PM) with aerodynamic diameter <2.5μm (PM2.5). We performed candidate (CpG-based; cross-systemic phenotypes, combined into “allostatic load”) and agnostic (DMR-based) pathway enrichment tests, and replicated previously reported air pollution EWAS signals. Results: We found no statistically significant CpGs at false discovery rate <0.05. However, 14, 48, 183, 8, and 71 DMRs independently associated with aircraft, railway, and road traffic Lden; NO2; and PM2.5, respectively, with minimally overlapping signals. Transportation Lden and air pollutants tendentially associated with decreased and increased methylation, respectively. We observed significant enrichment of candidate DNA methylation related to C-reactive protein and body mass index (aircraft, road traffic Lden, and PM2.5), renal function and “allostatic load” (all exposures). Agnostic functional networks related to cellular immunity, gene expression, cell growth/proliferation, cardiovascular, auditory, embryonic, and neurological systems development were enriched. We replicated increased methylation in cg08500171 (NO2) and decreased methylation in cg17629796 (PM2.5). Conclusions: Mutually independent DNA methylation was associated with source-specific transportation noise and air pollution exposures, with distinct and shared enrichments for pathways related to inflammation, cellular development, and immune responses. These findings contribute in clarifying the pathways linking these exposures and age-related diseases but need further confirmation in the context of mediation analyses. https://doi.org/10.1289/EHP617