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 = 9.07×108 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 = 5.37×109) 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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Author contributions

Samples from EPIC-Italy were provided by Vittorio Krogh, Domenico Palli, Salvatore Panico, Carlotta Sacerdote, and Rosario Tumino. Samples from EPIC-Netherlands were provided by H. Bas Bueno-de-Mesquita, Anne M. May, N. Charlotte Onland-Moret, Elio Riboli, and W. M. Monique Verschuren. Samples and data from NOWAC were provided by Eiliv Lund, Nicolle Mode, and Torkjel M. Sandanger. Samples and data from NSHDS were provided by Ingvar A. Bergdahl, Beatrice Melin, and Per Lenner. Giuseppe Matullo provided DNA methylation profiles, and Giovanni Fiorito performed management and data quality assurance for the EPICOR study. Soterios A. Kyrtopoulos provided DNA methylation profiles from the EnviroGenoMarkers project. Laboratory analyses were performed by Silvia Polidoro (EPIC-Italy and NOWAC), Simonetta Guarrera (EPIC-Italy), Panagiotis Georgiadis (DNA methylation in EnviroGenoMarkers), Theo M. C. M. de Kok and Jos C. S. Kleinjans (gene expression in EnviroGenoMarkers), and Karen A. Lillycrop and Robert Murray (EPIC-Netherlands). Measurements of blood lipids, glucose, and insulin for EPIC-Italy samples were provided by Licia Iacoviello. Bisulphite pyrosequencing of the Italian replication samples was conducted by Valentina Fiano and Morena Trevisan. Marc Chadeau-Hyam supervised the statistical analyses; Gianluca Campanella compiled the data, reviewed its quality, devised and carried out all statistical analyses. Gianluca Campanella, Marc Gunter and Silvia Polidoro drafted the manuscript. Philippe Froguel provided critical comments and contributed to the manuscript preparation. Paul Elliott, Paolo Vineis, and Marc Chadeau-Hyam coordinated the work and contributed to writing the manuscript. All authors approved the final version of this article.

Funding

EPIC-Italy was financially supported by the Italian Association for Cancer Research (AIRC). Genome-wide DNA methylation profiling and bisulphite pyrosequencing of EPIC-Italy samples was financially supported by the Human Genetics Foundation (HuGeF) and Compagnia di San Paolo. The EnviroGenoMarkers project was financially supported by the European Union (grant agreement 226756 to Soterios A. Kyrtopoulos). EPIC-Netherlands was financially supported by the Dutch Ministry of Public Health, Welfare, and Sports (VWS), by the Netherlands Cancer Registry, by LK Research Funds, by Dutch Prevention Funds, by the Netherlands Organisation for Health Research and Development (ZON), and by the World Cancer Research Fund (WCRF). Genome-wide DNA methylation profiling of EPIC-Netherlands samples was financially supported by internal Imperial College funds. Genome-wide DNA methylation and gene expression profiling of NOWAC samples was financially supported by the European Research Council for frontier research, Advanced Grant TICE—Transcriptomics in Cancer Epidemiology (number 232997, period 2009–2014). Gianluca Campanella received a Doctoral Prize studentship awarded by the Engineering and Physical Sciences Research Council (EPSRC). Paul Elliott is a National Institute for Health Research (NIHR) senior investigator and acknowledges support from the NIHR Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London, and the NIHR Health Protection Unit on Health Impact of Environmental Hazards. He is supported by the Medical Research Council and Public Health England as part of joint funding for the MRC-PHE Centre for Environment and Health.

Author information

Author notes

  1. Joint first authors: Gianluca Campanella, Marc J. Gunter, Silvia Polidoro.

  2. Joint last authors: Paul Elliott, Paolo Vineis, Marc Chadeau-Hyam.

Affiliations

  1. Department of Epidemiology and Biostatistics, Imperial College London, London, UK

    • Gianluca Campanella
    • , H. Bas Bueno-de-Mesquita
    • , Elio Riboli
    • , Paul Elliott
    • , Paolo Vineis
    •  & Marc Chadeau-Hyam
  2. Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC), Lyon, France

    • Marc J. Gunter
  3. Italian Institute for Genomic Medicine (IIGM), Turin, Italy

    • Silvia Polidoro
    • , Carlotta Sacerdote
    • , Giovanni Fiorito
    • , Simonetta Guarrera
    • , Giuseppe Matullo
    •  & Paolo Vineis
  4. Fondazione IRCCS—Istituto Nazionale dei Tumori, Milan, Italy

    • Vittorio Krogh
  5. Istituto per lo Studio e la Prevenzione Oncologica (ISPO Toscana), Florence, Italy

    • Domenico Palli
  6. Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

    • Salvatore Panico
  7. Piedmont Reference Centre for Epidemiology and Cancer Prevention (CPO Piemonte), Turin, Italy

    • Carlotta Sacerdote
  8. Cancer Registry and Histopathology Unit, Azienda Ospedaliera “Civile—M.P. Arezzo”, Ragusa, Italy

    • Rosario Tumino
  9. Department of Medical Sciences, University of Turin, Turin, Italy

    • Giovanni Fiorito
    • , Simonetta Guarrera
    •  & Giuseppe Matullo
  10. Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli (IS), Italy

    • Licia Iacoviello
  11. Department of Biobank Research, Umeå University, Umeå, Sweden

    • Ingvar A. Bergdahl
  12. Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden

    • Beatrice Melin
    •  & Per Lenner
  13. Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands

    • Theo M. C. M. de Kok
    •  & Jos C. S. Kleinjans
  14. Institute of Biology, Medicinal Chemistry, and Biotechnology, National Hellenic Research Foundation, Athens, Greece

    • Panagiotis Georgiadis
    •  & Soterios A. Kyrtopoulos
  15. Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands

    • H. Bas Bueno-de-Mesquita
  16. Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands

    • H. Bas Bueno-de-Mesquita
  17. Department of Social and Preventive Medicine, University of Malaya, Kuala Lumpur, Malaysia

    • H. Bas Bueno-de-Mesquita
  18. Centre for Biological Sciences, University of Southampton, Southampton, UK

    • Karen A. Lillycrop
    •  & Robert Murray
  19. Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht, The Netherlands

    • Anne M. May
    •  & N. Charlotte Onland-Moret
  20. MRC-PHE Centre for Environment and Health, Imperial College London, London, UK

    • Elio Riboli
    • , Paul Elliott
    • , Paolo Vineis
    •  & Marc Chadeau-Hyam
  21. Centre for Prevention and Health Services Research, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands

    • Monique Verschuren
  22. Department of Community Medicine, University of Tromsø (UiT)—The Artic University of Norway, Tromsø, Norway

    • Eiliv Lund
    • , Nicolle Mode
    •  & Torkjel M. Sandanger
  23. Department of Medical Sciences, Unit of Cancer Epidemiology–CERMS, University of Turin, Turin, Italy

    • Valentina Fiano
    •  & Morena Trevisan
  24. CNRS UMR8199, Pasteur Institute of Lille, Lille University, Lille, France

    • Philippe Froguel
  25. Department of Genomics of Common Disease, Imperial College London, London, UK

    • Philippe Froguel

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Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Marc Chadeau-Hyam.

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