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

Symen Ligthart, Carola Marzi, Stella Aslibekyan, Michael M. Mendelson, Karen N. Conneely, Toshiko Tanaka, Elena Colicino, Lindsay L. Waite, Roby Joehanes, Weihua Guan, Jennifer A. Brody, Cathy Elks, Riccardo Marioni, Min A. Jhun, Golareh Agha, Jan Bressler, Cavin K. Ward-Caviness, Brian H. Chen, Tianxiao Huan, Kelly BakulskiElias L. Salfati, Giovanni Fiorito, Simone Wahl, Katharina Schramm, Jin Sha, Dena G. Hernandez, Allan C. Just, Jennifer A. Smith, Nona Sotoodehnia, Luke C. Pilling, James S. Pankow, Phil S. Tsao, Chunyu Liu, Wei Zhao, Simonetta Guarrera, Vasiliki J. Michopoulos, Alicia K. Smith, Marjolein J. Peters, David Melzer, Pantel Vokonas, Myriam Fornage, Holger Prokisch, Joshua C. Bis, Audrey Y. Chu, Christian Herder, Harald Grallert, Chen Yao, Sonia Shah, Allan F. McRae, Honghuang Lin, Steve Horvath, Daniele Fallin, Albert Hofman, Nicholas J. Wareham, Kerri L. Wiggins, Andrew P. Feinberg, John M. Starr, Peter M. Visscher, Joanne M. Murabito, Sharon L.R. Kardia, Devin M. Absher, Elisabeth B. Binder, Andrew B. Singleton, Stefania Bandinelli, Annette Peters, Melanie Waldenberger, Giuseppe Matullo, Joel D. Schwartz, Ellen W. Demerath, André G. Uitterlinden, Joyce B.J. Meurs, Oscar H. Franco, Yii Der Ida Chen, Daniel Levy, Stephen T. Turner, Ian J. Deary, Kerry J. Ressler, Josée Dupuis, Luigi Ferrucci, Ken K. Ong, Themistocles L. Assimes, Eric Boerwinkle, Wolfgang Koenig, Donna K. Arnett, Andrea A. Baccarelli, Emelia J. Benjamin, Abbas Dehghan

Research output: Contribution to journalArticlepeer-review

216 Scopus citations


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.

Original languageEnglish
Article number255
JournalGenome Biology
Issue number1
StatePublished - Dec 12 2016

Bibliographical note

Publisher Copyright:
© 2016 The Author(s).


  • Body mass index
  • C-reactive protein
  • Coronary heart disease
  • DNA methylation
  • Diabetes
  • Epigenome-wide association study
  • Inflammation

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Genetics
  • Cell Biology


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