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

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

0307-0565
1-14
Campanella, Gianluca
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Gunter, Marc J.
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Polidoro, Silvia
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Krogh, Vittorio
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Palli, Domenico
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Panico, Salvatore
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Sacerdote, Carlotta
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Tumino, Rosario
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Fiorito, Giovanni
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Guarrera, Simonetta
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Iacoviello, Licia
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Bergdahl, Ingvar A.
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Melin, Beatrice
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Lenner, Per
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de Kok, Theo M.C.M.
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Georgiadis, Panagiotis
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Kleinjans, Jos C.S.
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Kyrtopoulos, Soterios A.
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Bueno-de-Mesquita, H. Bas
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Lillycrop, Karen A.
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May, Anne M.
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Onland-Moret, N. Charlotte
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Murray, Robert
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Riboli, Elio
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Verschuren, Monique
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Lund, Eiliv
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Mode, Nicolle
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Sandanger, Torkjel M.
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Fiano, Valentina
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Matullo, Giuseppe
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Froguel, Philippe
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Vineis, Paolo
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Chadeau-Hyam, Marc
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Campanella, Gianluca
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Gunter, Marc J.
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Polidoro, Silvia
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Krogh, Vittorio
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Palli, Domenico
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Panico, Salvatore
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Sacerdote, Carlotta
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Tumino, Rosario
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Fiorito, Giovanni
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Guarrera, Simonetta
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Bueno-de-Mesquita, H. Bas
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Lillycrop, Karen A.
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May, Anne M.
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Onland-Moret, N. Charlotte
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Murray, Robert
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Mode, Nicolle
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Fiano, Valentina
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Vineis, Paolo
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Chadeau-Hyam, Marc
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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, Panagiotis, Kleinjans, Jos C.S., Kyrtopoulos, Soterios A., Bueno-de-Mesquita, H. Bas, 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 and Chadeau-Hyam, Marc (2018) Epigenome-wide association study of adiposity and future risk of obesity-related diseases. International Journal of Obesity, 1-14. (doi:10.1038/s41366-018-0064-7).

Record type: 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.

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34501_2_merged_1517388057_1 - Accepted Manuscript
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Accepted/In Press date: 13 February 2018
e-pub ahead of print date: 1 May 2018

Identifiers

Local EPrints ID: 421868
URI: https://eprints.soton.ac.uk/id/eprint/421868
ISSN: 0307-0565
PURE UUID: 08f7a143-f1ce-4e71-ab78-e3d0384c34cd
ORCID for Karen A. Lillycrop: ORCID iD orcid.org/0000-0001-7350-5489

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Date deposited: 03 Jul 2018 16:30
Last modified: 14 Mar 2019 05:07

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Contributors

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

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