Epigenome-wide association study of adiposity and future risk of obesity-related diseases

Gianluca Campanella, Marc J. Gunter, Silvia Polidoro, Vittorio Krogh, Domenico Palli, Salvatore Panico, Carlotta Sacerdote, Rosario Tumino, Giovanni Fiorito, Simonetta Guarrera, Licia Iacoviello, Ingvar A. Bergdahl, Beatrice Melin, Per Lenner, Theo M.C.M. de Kok, Panagiotis Georgiadis, Jos C.S. Kleinjans, Soterios A. Kyrtopoulos, H. Bas Bueno-de-Mesquita, Karen A. LillycropAnne M. May, N. Charlotte Onland-Moret, Robert Murray, Elio Riboli, Monique Verschuren, Eiliv Lund, Nicolle Mode, Torkjel M. Sandanger, Valentina Fiano, Morena Trevisan, Giuseppe Matullo, Philippe Froguel, Paul Elliott, Paolo Vineis, Marc Chadeau-Hyam

Research output: Contribution to journalArticle

Abstract

Background: 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. Methods: 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. Results: 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)2022-2035
Number of pages14
JournalInternational Journal of Obesity
Volume42
Issue number12
DOIs
Publication statusPublished - Dec 1 2018

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Endocrinology, Diabetes and Metabolism
  • Nutrition and Dietetics

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    Campanella, G., Gunter, M. J., Polidoro, S., Krogh, V., Palli, D., Panico, S., Sacerdote, C., Tumino, R., Fiorito, G., Guarrera, S., Iacoviello, L., Bergdahl, I. A., Melin, B., Lenner, P., de Kok, T. M. C. M., Georgiadis, P., Kleinjans, J. C. S., Kyrtopoulos, S. A., Bueno-de-Mesquita, H. B., ... Chadeau-Hyam, M. (2018). Epigenome-wide association study of adiposity and future risk of obesity-related diseases. International Journal of Obesity, 42(12), 2022-2035. https://doi.org/10.1038/s41366-018-0064-7