Obesity is an established risk factor for several common chronic diseases such as breast and colorectal cancer, metabolic and cardiovascular diseases; however, the biological basis for these relationships is not fully understood. To explore the association of obesity with these conditions, we investigated peripheral blood leucocyte (PBL) DNA methylation markers for adiposity and their contribution to risk of incident breast and colorectal cancer and myocardial infarction.
DNA methylation profiles (Illumina Infinium® HumanMethylation450 BeadChip) from 1941 individuals from four population-based European cohorts were analysed in relation to body mass index, waist circumference, waist-hip and waist-height ratio within a meta-analytical framework. In a subset of these individuals, data on genome-wide gene expression level, biomarkers of glucose and lipid metabolism were also available. Validation of methylation markers associated with all adiposity measures was performed in 358 individuals. Finally, we investigated the association of obesity-related methylation marks with breast, colorectal cancer and myocardial infarction within relevant subsets of the discovery population.
We identified 40 CpG loci with methylation levels associated with at least one adiposity measure. Of these, one CpG locus (cg06500161) in ABCG1 was associated with all four adiposity measures (P = 9.07×10−8 to 3.27×10−18) and lower transcriptional activity of the full-length isoform of ABCG1 (P = 6.00×10−7), higher triglyceride levels (P = 5.37×10−9) and higher triglycerides-to-HDL cholesterol ratio (P = 1.03×10−10). Of the 40 informative and obesity-related CpG loci, two (in IL2RB and FGF18) were significantly associated with colorectal cancer (inversely, P < 1.6×10−3) and one intergenic locus on chromosome 1 was inversely associated with myocardial infarction (P < 1.25×10−3), independently of obesity and established risk factors.
Our results suggest that epigenetic changes, in particular altered DNA methylation patterns, may be an intermediate biomarker at the intersection of obesity and obesity-related diseases, and could offer clues as to underlying biological mechanisms.
Samples from EPIC-Italy were provided by Vittorio Krogh, Domenico Palli, Salvatore Panico, Carlotta Sacerdote, and Rosario Tumino. Samples from EPIC-Netherlands were provided by H. Bas Bueno-de-Mesquita, Anne M. May, N. Charlotte Onland-Moret, Elio Riboli, and W. M. Monique Verschuren. Samples and data from NOWAC were provided by Eiliv Lund, Nicolle Mode, and Torkjel M. Sandanger. Samples and data from NSHDS were provided by Ingvar A. Bergdahl, Beatrice Melin, and Per Lenner. Giuseppe Matullo provided DNA methylation profiles, and Giovanni Fiorito performed management and data quality assurance for the EPICOR study. Soterios A. Kyrtopoulos provided DNA methylation profiles from the EnviroGenoMarkers project. Laboratory analyses were performed by Silvia Polidoro (EPIC-Italy and NOWAC), Simonetta Guarrera (EPIC-Italy), Panagiotis Georgiadis (DNA methylation in EnviroGenoMarkers), Theo M. C. M. de Kok and Jos C. S. Kleinjans (gene expression in EnviroGenoMarkers), and Karen A. Lillycrop and Robert Murray (EPIC-Netherlands). Measurements of blood lipids, glucose, and insulin for EPIC-Italy samples were provided by Licia Iacoviello. Bisulphite pyrosequencing of the Italian replication samples was conducted by Valentina Fiano and Morena Trevisan. Marc Chadeau-Hyam supervised the statistical analyses; Gianluca Campanella compiled the data, reviewed its quality, devised and carried out all statistical analyses. Gianluca Campanella, Marc Gunter and Silvia Polidoro drafted the manuscript. Philippe Froguel provided critical comments and contributed to the manuscript preparation. Paul Elliott, Paolo Vineis, and Marc Chadeau-Hyam coordinated the work and contributed to writing the manuscript. All authors approved the final version of this article.Funding
EPIC-Italy was financially supported by the Italian Association for Cancer Research (AIRC). Genome-wide DNA methylation profiling and bisulphite pyrosequencing of EPIC-Italy samples was financially supported by the Human Genetics Foundation (HuGeF) and Compagnia di San Paolo. The EnviroGenoMarkers project was financially supported by the European Union (grant agreement 226756 to Soterios A. Kyrtopoulos). EPIC-Netherlands was financially supported by the Dutch Ministry of Public Health, Welfare, and Sports (VWS), by the Netherlands Cancer Registry, by LK Research Funds, by Dutch Prevention Funds, by the Netherlands Organisation for Health Research and Development (ZON), and by the World Cancer Research Fund (WCRF). Genome-wide DNA methylation profiling of EPIC-Netherlands samples was financially supported by internal Imperial College funds. Genome-wide DNA methylation and gene expression profiling of NOWAC samples was financially supported by the European Research Council for frontier research, Advanced Grant TICE—Transcriptomics in Cancer Epidemiology (number 232997, period 2009–2014). Gianluca Campanella received a Doctoral Prize studentship awarded by the Engineering and Physical Sciences Research Council (EPSRC). Paul Elliott is a National Institute for Health Research (NIHR) senior investigator and acknowledges support from the NIHR Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London, and the NIHR Health Protection Unit on Health Impact of Environmental Hazards. He is supported by the Medical Research Council and Public Health England as part of joint funding for the MRC-PHE Centre for Environment and Health.