Suchergebnisse

Background: 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. Methods: 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 FEV1, FVC, and FEV1/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. Results: 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. Conclusions: 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. ; This work was conducted within the Ageing Lungs in European Cohorts (ALEC) project and received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 633212. The funders of this study had no role in study design, data analysis and interpretation of results, or writing of the manuscript. The ECRHS was supported by a contract from the European Commission (018996), Fondo de Investigación Sanitaria (91/0016–060-05/E, 92/0319, 93/0393, 97/0035–01, 99/0034–01 and 99/0034–02), Hospital General de Albacete, Hospital General Ramón Jiménez, Consejería de Sanidad del Principado de Asturias, CIRIT (1997SGR 00079, 1999SGR 00241), and Servicio Andaluz de Salud, SEPAR, Public Health Service (R01 HL62633–01), RCESP (C03/09), Red RESPIRA (C03/011), Basque Health Department, Swiss National Science Foundation, Swiss Federal Office for Education and Science, Swiss National Accident Insurance Fund (SUVA), GSF-National Research Centre for Environment and Health, Deutsche Forschungsgemeinschaft (DFG) (FR 1526/1–1, MA 711/4–1), Programme Hospitalier de Recherche Clinique-DRC de Grenoble 2000 no. 2610, Ministry of Health, Direction de la Recherche Clinique, Ministere de l'Emploi et de la Solidarite, Direction Generale de la Sante, CHU de Grenoble, Comite des Maladies Respiratoires de l'Isere. UCB-Pharma (France), Aventis (France), Glaxo France. Estonian Science Foundation, and Asthma UK (formerly known as National Asthma Campaign UK). The NFBC resource has been supported by grants from the Academy of Finland (project grants 104781, 120315, 129269, 1114194, 24300796, Center of Excellence in Complex Disease Genetics and SALVE), University Hospital Oulu, Biocenter, University of Oulu, Finland (75617), NHLBI grant 5R01HL087679–02 (1RL1MH083268–01), NIH/NIMH (5R01MH63706:02), ENGAGE project and grant agreement HEALTH-F4–2007-201413, EU FP7 EurHEALTHAgeing − 277849, the Medical Research Council, UK (G0500539, G0600705, G1002319, PrevMetSyn/SALVE) and the MRC, Centenary Early Career Award. H2020 DynaHEALTH (European Union's Horizon 2020 research and innovation programme under grant agreement No 633595); Exposomic, Genomic and Epigenomic Approach to Prediction of Metabolic and Cardiorespiratory function and Ill-Health (EGEA), Academy of Finland, Grant No 285547; ALEC Study (funded by the European Union's Horizon 2020 Research and Innovation programme under grant agreement No. 633212); H2020 / Marie Skłodowska-Curie Actions, CAPICE (Marie Curie Grant agreement Number 721567); National Public Health Institute, Biomedicum Helsinki, Finland. The SAPALDIA study was funded by the Swiss National Science Foundation (grants no 33CS30–148470/1&2, 33CSCO-134276/1, 33CSCO-108796, 324730_135673, 3247BO-104283, 3247BO-104288, 3247BO-104284, 3247–065896, 3100–059302, 3200–052720, 3200–042532, 4026–028099, PMPDP3_129021/1, PMPDP3_141671/1), the Federal Office for the Environment, the Federal Office of Public Health, the Federal Office of Roads and Transport, the canton's government of Aargau, Basel-Stadt, Basel-Land, Geneva, Luzern, Ticino, Valais, and Zürich, the Swiss Lung League, the canton's Lung League of Basel Stadt/ Basel Landschaft, Geneva, Ticino, Valais, Graubünden and Zurich, Stiftung ehemals Bündner Heilstätten, SUVA, Freiwillige Akademische Gesellschaft, UBS Wealth Foundation, Talecris Biotherapeutics GmbH, Abbott Diagnostics, European Commission 018996 (GABRIEL), Wellcome Trust WT 084703MA, Exposomics EC FP7 grant (Grant agreement No: 308610).