1. Epigenome-wide association study of adiposity and future risk of obesity-related diseases
- Author
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Gianluca Campanella, Rosario Tumino, Marc Chadeau-Hyam, Jos C. S. Kleinjans, Nicolle A. Mode, Robert Murray, Paolo Vineis, Per Lenner, Anne M. May, Theo M. de Kok, Karen A. Lillycrop, H. Bas Bueno-de-Mesquita, Morena Trevisan, Salvatore Panico, Paul Elliott, Silvia Polidoro, Philippe Froguel, Giuseppe Matullo, Soterios A. Kyrtopoulos, Licia Iacoviello, N. Charlotte Onland-Moret, Domenico Palli, Torkjel M. Sandanger, Valentina Fiano, Giovanni Fiorito, Marc J. Gunter, Ingvar A. Bergdahl, Monique Verschuren, Elio Riboli, Simonetta Guarrera, Panagiotis Georgiadis, Vittorio Krogh, Eiliv Lund, Carlotta Sacerdote, Beatrice Melin, Commission of the European Communities, Imperial College Healthcare NHS Trust- BRC Funding, National Institute for Health Research, Medical Research Council (MRC), Campanella, Gianluca, Gunter, Marc J, Polidoro, Silvia, Krogh, Vittorio, Palli, Domenico, Panico, Salvatore, Sacerdote, Carlotta, Tumino, Rosario, Fiorito, Giovanni, Guarrera, Simonetta, Iacoviello, Licia, Bergdahl, Ingvar A, Melin, Beatrice, Lenner, Per, de Kok, Theo M C M, Georgiadis, Panagioti, Kleinjans, Jos C S, Kyrtopoulos, Soterios A, Bueno-de-Mesquita, H Ba, Lillycrop, Karen A, May, Anne M, Onland-Moret, N Charlotte, Murray, Robert, Riboli, Elio, Verschuren, Monique, Lund, Eiliv, Mode, Nicolle, Sandanger, Torkjel M, Fiano, Valentina, Trevisan, Morena, Matullo, Giuseppe, Froguel, Philippe, Elliott, Paul, Vineis, Paolo, Chadeau-Hyam, Marc, Toxicogenomics, RS: FSE MaCSBio, RS: FPN MaCSBio, RS: FHML MaCSBio, RS: MHeNs - R3 - Neuroscience, and RS: GROW - R1 - Prevention
- Subjects
0301 basic medicine ,Epigenomics ,Genetic Markers ,Colorectal cancer ,Endocrinology, Diabetes and Metabolism ,Myocardial Infarction ,Medicine (miscellaneous) ,Genome-wide association study ,macromolecular substances ,PERIPHERAL-BLOOD ,Bioinformatics ,03 medical and health sciences ,Endocrinology & Metabolism ,0302 clinical medicine ,Endocrinology ,Neoplasms ,medicine ,Humans ,CPT1A LOCUS ,Obesity ,Risk factor ,11 Medical and Health Sciences ,Adiposity ,INSULIN-RESISTANCE ,Nutrition and Dietetics ,business.industry ,CHOLESTEROL ,Cancer ,Epigenome ,DNA Methylation ,medicine.disease ,CANCER ,GENE ,Diabetes and Metabolism ,BODY-MASS INDEX ,030104 developmental biology ,030220 oncology & carcinogenesis ,HIGH-DENSITY-LIPOPROTEINS ,Leukocytes, Mononuclear ,3-BETA-HYDROXYSTEROID-DELTA-24 REDUCTASE ,business ,Body mass index ,13 Education ,Genome-Wide Association Study - Abstract
BackgroundObesity 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.MethodsDNA 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.ResultsWe 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 P ConclusionOur 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.
- Published
- 2018