Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide ...association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (P
= 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications.
Air pollution is a known risk factor for several diseases, but the extent to which it influences COVID-19 compared to other respiratory diseases remains unclear. We performed a test-negative ...case-control study among people with COVID-19-compatible symptoms who were tested for SARS-CoV-2 infection, to assess whether their long- and short-term exposure to ambient air pollution (AAP) was associated with testing positive (vs. negative) for SARS-CoV-2. We used individual-level data for all adult residents in the Netherlands who were tested for SARS-CoV-2 between June and November 2020, when only symptomatic people were tested, and modeled ambient concentrations of PM10, PM2.5, NO2 and O3 at geocoded residential addresses. In long-term exposure analysis, we selected individuals who did not change residential address in 2017–2019 (1.7 million tests) and considered the average concentrations of PM10, PM2.5 and NO2 in that period, and different sources of PM (industry, livestock, other agricultural activities, road traffic, other Dutch sources, foreign sources). In short-term exposure analysis, individuals not changing residential address in the two weeks before testing day (2.7 million tests) were included in the analyses, thus considering 1- and 2-week average concentrations of PM10, PM2.5, NO2 and O3 before testing day as exposure. Mixed-effects logistic regression analysis with adjustment for several confounders, including municipality and testing week to account for spatiotemporal variation in viral circulation, was used. Overall, there was no statistically significant effect of long-term exposure to the studied pollutants on the odds of testing positive vs. negative for SARS-CoV-2. However, significant positive associations of long-term exposure to PM10 and PM2.5 from specifically foreign and livestock sources, and to PM10 from other agricultural sources, were observed. Short-term exposure to PM10 (adjusting for NO2) and PM2.5 were also positively associated with increased odds of testing positive for SARS-CoV-2. While these exposures seemed to increase COVID-19 risk relative to other respiratory diseases, the underlying biological mechanisms remain unclear. This study reinforces the need to continue to strive for better air quality to support public health.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Introduction Occupational risk reduction strategies are informed by existing scientific evidence on single exposure-single outcome associations, limiting their applicability. Within the EU ...EPHOR project (2020-2025), we aim to apply the exposome concept to working life health for developing new knowledge and methods on e.g. combined exposures and vulnerability that will enable more effective risk reduction strategies and policies. Methods Within EPHOR, we investigate the effects of the working-life exposome through combining large-scale meta analyses of existing cohorts with the collection of new external and internal exposome data in case studies. Methods for characterizing the exposome and for investigating its complex associations (multiple exposures, timing of exposures, early health effects and vulnerability) with health are being developed. Results The methods and results of the project are being made available to scientists, policy makers and occupational health practitioners via the WE-EXPOSE Toolbox. Example tools include methods to collect and interpret the external (e.g. with sensors) and internal (e.g. with noninvasive sampling) exposome, methods and tools to characterize (EuroJEM) and study effects of the exposome in multiple cohorts (Mega Cohort) in a harmonized way, and an online tool for visualizing occupational risk factors including levels, population sizes and related health effects across Europe. Discussion and conclusion An overview of the (planned) tools in the WE-EXPOSE Toolbox as well as the cocreation process for enhancing the usability of specific tools will be given. By providing a knowledge base for evidence-based prevention, the Toolbox will contribute to reducing the burden of occupational disease.
Abstract Introduction Exposure to diesel engine exhaust (DEE) is associated with increased lung cancer risk; however, underlying molecular mechanisms remain unclear. We apply an exposome approach to ...characterize early biological effects of occupational DEE exposure. Methods Plasma samples from 54 diesel engine factory workers and 55 non-exposed control workers were characterized using an integrated exposome platform that combines untargeted gas chromatography (GC-) and liquid chromatography (LC-) with high-resolution mass spectrometry (HRMS). Exposome profiles were evaluated by metabolome-wide association study (MWAS) for molecular features associated with DEE exposure and elemental carbon. Potential molecular mechanisms underlying DEE were further evaluated by integrating exposome profiles with plasma proteomics, urine aminopyrenes and mutagenicity, and buccal gene expression analysis. Results GC- and LC-HRMS untargeted analysis detected 68,285 metabolic features. Comparison of DEE-exposed and non-exposed workers identified 772 molecular features associated with exposure at a FDR <5%, including 102 detected using GC-HRMS and 670 detected using LC-HRMS. Molecular networking and annotation identified compounds consistent with DEE exposure, while metabolic pathway enrichment suggest alterations in oxidative stress and endothelial pathways. We conducted a secondary MWAS to link urinary mutagenicity, reflecting systemic exposure to genotoxic/carcinogenic agents, and associated with tumor development and identified 90 molecular features positively associated with urine mutagenicity at FDR<5%. Discussion Integration of exposome profiles with protein and genome-wide gene expression identified biological alterations consistent with many of the key characteristics of carcinogens. Conclusion Integrated exposome characterization of DEE exposure identified novel DEE biomarkers and biological response profiles in a high exposure setting.
We assessed the association between occupational exposures and symptoms of chronic bronchitis and pulmonary ventilatory defects in a general population-based study of five areas in Spain. This study ...forms part of the European Community Respiratory Health Study (ECRHS). Subjects (n = 1,735; age range, 20-44 yr; 52.4% of those initially selected) completed a respiratory questionnaire on symptoms and occupation and underwent baseline spirometry. Occupation was translated with an ad hoc developed job-exposure matrix (JEM) into none, low, and high exposure to biological dust, mineral dust, and gases and fumes. Exposure to high levels of biological dust was associated with cough for more than 3 mo (odds ratio OR, 1.9; p = 0.07), a reduction in FEF sub(25-75) to 478 ml/s (SD 178), and a reduction in FEV sub(1) to 151 mL (SD 71). These associations remained after excluding subjects with asthma symptoms or bronchial responsiveness. Smokers tended to have a higher risk for respiratory symptoms, but smoking did not modify the association of occupation with pulmonary function. Exposure to mineral dust and gases/fumes with less consistently related to pulmonary function or to respiratory symptoms and this association further decreased after excluding subjects with asthma. In conclusion, exposure to high levels of biological dust in young adults is associated with symptoms of chronic bronchitis and pulmonary ventilatory defects, independently of asthma and smoking.
Abstract
Background
The relation between blood pressure and kidney cancer risk is well established but complex and different study designs have reported discrepant findings on the relative importance ...of diastolic blood pressure (DBP) and systolic blood pressure (SBP). In this study, we sought to describe the temporal relation between diastolic and SBP with renal cell carcinoma (RCC) risk in detail.
Methods
Our study involved two prospective cohorts: the European Prospective Investigation into Cancer and Nutrition study and UK Biobank, including >700 000 participants and 1692 incident RCC cases. Risk analyses were conducted using flexible parametric survival models for DBP and SBP both separately as well as with mutuality adjustment and then adjustment for extended risk factors. We also carried out univariable and multivariable Mendelian randomization (MR) analyses (DBP: ninstruments = 251, SBP: ninstruments = 213) to complement the analyses of measured DBP and SBP.
Results
In the univariable analysis, we observed clear positive associations with RCC risk for both diastolic and SBP when measured ≥5 years before diagnosis and suggestive evidence for a stronger risk association in the year leading up to diagnosis. In mutually adjusted analysis, the long-term risk association of DBP remained, with a hazard ratio (HR) per standard deviation increment 10 years before diagnosis (HR10y) of 1.20 (95% CI: 1.10–1.30), whereas the association of SBP was attenuated (HR10y: 1.00, 95% CI: 0.91–1.10). In the complementary multivariable MR analysis, we observed an odds ratio for a 1-SD increment (ORsd) of 1.34 (95% CI: 1.08–1.67) for genetically predicted DBP and 0.70 (95% CI: 0.56–0.88) for genetically predicted SBP.
Conclusion
The results of this observational and MR study are consistent with an important role of DBP in RCC aetiology. The relation between SBP and RCC risk was less clear but does not appear to be independent of DBP.
Oxidative potential (OP) of particulate matter (PM) is proposed as a biologically-relevant exposure metric for studies of air pollution and health. We aimed to evaluate the spatial variability of the ...OP of measured PM2.5 using ascorbate (AA) and (reduced) glutathione (GSH), and develop land use regression (LUR) models to explain this spatial variability. We estimated annual average values (m−3) of OPAA and OPGSH for five areas (Basel, CH; Catalonia, ES; London-Oxford, UK (no OPGSH); the Netherlands; and Turin, IT) using PM2.5 filters. OPAA and OPGSH LUR models were developed using all monitoring sites, separately for each area and combined-areas. The same variables were then used in repeated sub-sampling of monitoring sites to test sensitivity of variable selection; new variables were offered where variables were excluded (p > .1). On average, measurements of OPAA and OPGSH were moderately correlated (maximum Pearson's maximum Pearson's R = = .7) with PM2.5 and other metrics (PM2.5absorbance, NO2, Cu, Fe). HOV (hold-out validation) R2 for OPAA models was .21, .58, .45, .53, and .13 for Basel, Catalonia, London-Oxford, the Netherlands and Turin respectively. For OPGSH, the only model achieving at least moderate performance was for the Netherlands (R2 = .31). Combined models for OPAA and OPGSH were largely explained by study area with weak local predictors of intra-area contrasts; we therefore do not endorse them for use in epidemiologic studies. Given the moderate correlation of OPAA with other pollutants, the three reasonably performing LUR models for OPAA could be used independently of other pollutant metrics in epidemiological studies.
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•OP moderately correlated (r ~.6) with PM2.5 mass, NO2, and elemental constituents.•OPAA and OPGSH LUR models were developed and evaluated for five areas.•Three reasonably performing (R2: .45–.58) OPAA LUR models in hold-out validation.•OPGSH models were not robust to new coefficients derived against sub-samples of sites.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
► To describe levels of PFCs in serum among Inuits from Greenland. ► To describe levels among inhabitants from Warsaw, Poland and Kharkiv, Ukraine. ► To define social- and lifestyle related ...determinants of exposure. ► Levels of PFCs in the serum of Inuits on Greenland were among the highest described. ► Determinants for PFOS on Greenland were seafood and tea intake, age and area of living.
Perfluorinated compounds (PFCs), such as perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), are used in large quantities. They are persistent and found in measurable levels in human serum around the world. They have been associated with developmental, hepatic, and carcinogenic effects in animal studies. The aim of the present study was to describe levels of PFCs in serum among Inuits from Greenland and inhabitants from Warsaw, Poland and Kharkiv, Ukraine. Furthermore, the aim was to define social- and lifestyle related determinants of exposure for these compounds. Serum levels of seven PFCs were analyzed by liquid chromatography/tandem mass spectrometry (LC/MS/MS). The concentrations of PFOS and PFOA were the highest of all PFCs in all three populations with a total amount of almost 90% of the PFCs. The mean levels of PFOS and PFOA were in the Greenlandic Inuits 52 and 4.8ngmL−1, in Poland 19 and 5.2ngmL−1, and in Ukraine 8.1 and 1.9ngmL−1, respectively. Thus, levels of PFCs in the serum of Inuits on Greenland were among the highest described in a general population whereas the levels in Poland were similar to other industrialized countries. The exposure in Ukraine was rather low. In the Greenlandic Inuit population, intake of seafood, tea, age and area of living were significant determinants of PFOS concentrations and explained about 22% of the variation. For the other populations no strong determinants were found.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
ObjectivesRetrospective exposure assessment remains a problematic aspect of population-based case–control studies. Different methods have been developed, including case-by-case expert assessment and ...job–exposure matrices (JEM). The present analyses compare exposure prevalence and risk estimates derived by different exposure assessment methods.MethodsIn the context of a case–control study conducted in seven European countries, exposure was estimated for asbestos, diesel motor emissions (DME) and crystalline silica, using three different assessment methods. First, experts assigned exposures to all reported jobs on a case-by-case basis. Second, a population-specific JEM (PSJEM) was developed using the expert assessments of controls only, and re-applied to all study subjects. Third, an independent general population JEM (GPJEM) was created by occupational exposure experts not involved in the original study, and applied to study subjects. Results from these methods were compared.ResultsThere was poor to fair agreement in assigned exposure between expert assessment and the GPJEM (kappas: asbestos 0.17; DME 0.48; silica 0.38). Exposure prevalence was significantly heterogeneous (p<0.01) between countries for all three agents and assessment methods. For asbestos and DME, significant country heterogeneity in risk estimates was observed when using expert assessment. When applying the GPJEM, the heterogeneity in risk estimates for asbestos and, to some extent, silica diminished.ConclusionsIt has been previously advocated that the expert assessment approach to assign exposures based on detailed questionnaire responses provides more accurate exposure estimates than JEM-based results. However, current results demonstrated little, if any, advantage of case-by-case assessment when compared to a JEM approach.
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BFBNIB, CMK, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
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