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

Authors: Gianluca Campanella; Marc J. Gunter; Silvia Polidoro; Vittorio Krogh; Domenico Palli; Salvatore Panico; Carlotta Sacerdote; +28 Authors

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

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 < 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.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.

Countries
Netherlands, United Kingdom, Italy, United Kingdom, Italy
Subjects by Vocabulary

Microsoft Academic Graph classification: Colorectal cancer Genome-wide association study Bioinformatics medicine Risk factor Epigenomics business.industry Cancer Epigenome medicine.disease Obesity business Body mass index

Keywords

Epigenomics, Genetic Markers, Endocrinology, Diabetes and Metabolism, Myocardial Infarction, Medicine (miscellaneous), PERIPHERAL-BLOOD, Endocrinology & Metabolism, Endocrinology, Neoplasms, Humans, Obesity, CPT1A LOCUS, DNA METHYLATION, 11 Medical and Health Sciences, Adiposity, INSULIN-RESISTANCE, Nutrition and Dietetics, CHOLESTEROL, CANCER, GENE, Diabetes and Metabolism, BODY-MASS INDEX, HIGH-DENSITY-LIPOPROTEINS, Leukocytes, Mononuclear, 3-BETA-HYDROXYSTEROID-DELTA-24 REDUCTASE, 13 Education, Genome-Wide Association Study

14 references, page 1 of 2

Stevens GA, Singh GM, Lu Y, Danaei G, Lin JK, Finucane MM et al. National, regional, and global trends in adult overweight and obesity prevalences. Population Health Metrics 2012; 10.

Arnold M, Pandeya N, Byrnes G, Renehan AG, Stevens GA, Ezzati M et al. Global burden of cancer attributable to high body-mass index in 2012: a population-based study. Lancet Oncol.

Bhaskaran K, Douglas I, Forbes H, dos-Santos-Silva I, Leon DA, Smeeth L. Body-mass index and risk of 22 specific cancers: a population-based cohort study of 5.24 million UK adults.

Lancet 2014; 384(9945): 755-765.

Samuel VT, Shulman GI. Mechanisms for Insulin Resistance: Common Threads and Missing Links. Cell 2012; 148(5): 852-871.

Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat. Genet. 2010; 42(11): 937-948.

Heid IM, Jackson AU, Randall JC, Winkler TW, Qi L, Steinthorsdottir V et al. Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nat. Genet. 2010; 42(11): 949-960.

Yang J, Loos RJF, Powell JE, Medland SE, Speliotes EK, Chasman DI et al. FTO genotype is associated with phenotypic variability of body mass index. Nature 2012; 490: 267-272.

Scott RA, Lagou V, Welch RP, Wheeler E, Montasser ME, Luan Ja et al. Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways. Nat. Genet. 2012; 44: 991-1005. [OpenAIRE]

Dick KJ, Nelson CP, Tsaprouni L, Sandling JK, Aissi D, Wahl S et al. DNA methylation and body-mass index: a genome-wide analysis. Lancet 2014; 383(9933): 1990-8.

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    This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
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    This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
    Top 10%
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    This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
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citations
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
views
OpenAIRE UsageCountsViews provided by UsageCounts
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45
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136
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Funded by
EC| TICE
Project
TICE
TRANSCRIPTOMICS IN CANCER EPIDEMIOLOGY
  • Funder: European Commission (EC)
  • Project Code: 232997
  • Funding stream: FP7 | SP2 | ERC
,
EC| ENVIROGENOMARKERS
Project
ENVIROGENOMARKERS
Genomics biomarkers of environmental health
  • Funder: European Commission (EC)
  • Project Code: 226756
  • Funding stream: FP7 | SP1 | ENV
iis
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Sustainable Development Solutions Network - Greece
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