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

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Title: Epigenome-wide association study of adiposity and future risk of obesity-related diseases
Authors: Chadeau, M
Campanella, G
Gunter, MJ
Polidoro, S
Krogh, V
Palli, D
Panico, S
Sacerdote, C
Tumino, R
Fiorito, G
Guarrera, S
Iacovello, L
Bergdahl, I
Melin, B
Lenner, P
De Kok, T
Georgiadis, P
Kleinjans, J
Kyrtopoulos, S
Bueno-de-Mesquita, B
Lillycrop, K
May, A
Onland-Moret, C
Murray, R
Riboli, E
Verschuren, M
Lund, E
Mode, N
Sandanger, TM
Fiano, V
Trevisan, M
Matullo, G
Froguel, P
Elliott, P
Vineis, P
Item Type: Journal Article
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.
Issue Date: 1-Dec-2018
Date of Acceptance: 13-Feb-2018
URI: http://hdl.handle.net/10044/1/57102
DOI: https://doi.org/10.1038/s41366-018-0064-7
ISSN: 0307-0565
Publisher: Nature Publishing Group
Start Page: 2022
End Page: 2035
Journal / Book Title: International Journal of Obesity
Volume: 42
Issue: 12
Copyright Statement: © 2018 Macmillan Publishers Limited, part of Springer Nature.
Sponsor/Funder: Commission of the European Communities
Imperial College Healthcare NHS Trust- BRC Funding
National Institute for Health Research
National Institute for Health Research
Medical Research Council (MRC)
Funder's Grant Number: 308610
RDF03
RTJ6219303-1
NF-SI-0611-10136
MR/L01341X/1
Keywords: Adiposity
DNA Methylation
Epigenomics
Genetic Markers
Genome-Wide Association Study
Humans
Leukocytes, Mononuclear
Myocardial Infarction
Neoplasms
Obesity
Leukocytes, Mononuclear
Humans
Neoplasms
Myocardial Infarction
Obesity
Genetic Markers
DNA Methylation
Adiposity
Genome-Wide Association Study
Epigenomics
11 Medical and Health Sciences
13 Education
Endocrinology & Metabolism
Publication Status: Published
Online Publication Date: 2018-05-01
Appears in Collections:Faculty of Medicine
Epidemiology, Public Health and Primary Care



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