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Published December 12, 2016 | Version v1
Journal article Open

DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases

Creators

  • 1. Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands
  • 2. Institute of Epidemiology II, Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherber, Germany
  • 3. Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA
  • 4. Boston University School of Medicine, Boston, MA, USA
  • 5. Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
  • 6. Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA
  • 7. Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA
  • 8. HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
  • 9. Hebrew SeniorLife, Harvard Medical School, Boston, MA, USA
  • 10. Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA
  • 11. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
  • 12. MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK
  • 13. Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
  • 14. Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA
  • 15. Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA
  • 16. Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherber, Germany
  • 17. Longitudinal Studies Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
  • 18. Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
  • 19. Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
  • 20. Department of Medicine - Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA
  • 21. Human Genetics Foundation, Torino, Italy
  • 22. Institute of Human Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
  • 23. Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA
  • 24. Epidemiology and Public Health, University of Exeter Medical School, RILD Building Level 3 Research, Exeter, UK
  • 25. Division of Epidemiology & Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA
  • 26. Stanford University School of Medicine, Palo Alto, CA, USA
  • 27. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA
  • 28. Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
  • 29. VA Boston Healthcare System and Boston University Schools of Public Health and Medicine, Jamaica Plain, Boston, MA, USA
  • 30. Institute of Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
  • 31. Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia
  • 32. Department of Biostatistics, Boston University School of Public Health, Boston, MA, 02118, USA
  • 33. UCLA, Department of Human Genetics, Gonda Research Center, David Geffen School of Medicine, Los Angeles, CA, USA
  • 34. Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy
  • 35. Department of Environmental Health and Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
  • 36. Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, USA
  • 37. Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
  • 38. Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
  • 39. Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, Ulm, Germany
  • 40. University of Kentucky, College of Public Health, Lexington, KY, USA

Description

Background: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation.

Results: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10–7) in the discovery panel of European ancestry and replicated (P < 2.29 × 10–4) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10–5), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10–3), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10–5). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants.

Conclusion: We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.

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