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

197 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

Funding Information:
OHF works in ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec Ltd.), Metagenics Inc., and AXA. Nestlé Nutrition (Nestec Ltd.), Metagenics Inc., and AXA had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review or approval of the manuscript.

Funding Information:
The Atherosclerosis Risk in Communities (ARIC) study is carried out as a collaborative study supported by the National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). Funding support for “Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium” was provided by the National Institutes of Health (NIH) through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419). CHS: Infrastructure for the CHARGE Consortium is supported in part by the NHLBI grant R01HL105756. The CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL092111, R01HL105756, R01HL103612, R01HL111089, R01HL116747, and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA) as well as the Laughlin Family, Alpha Phi Foundation, and Locke Charitable Foundation. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. EPIC-Norfolk is supported by programme grants from the Medical Research Council (MRC) (G9502233; G0401527) and Cancer Research UK (C864/A8257). The generation and management of the Illumina 450 K methylation array data in this cohort is supported through the MRC Cambridge initiative in metabolomic science (MR/L00002/1). CEE, KKO, and NJW are supported by MRC programme grants (MC_UU_12015/1 and MC_UU_12015/2). FHS is funded by the U.S. NIH contract N01-HC-25195 and HHSN268201500001I. The laboratory work for this investigation was funded by the Division of Intramural Research, NHLBI, NIH, and by a Director’s Challenge Award, NIH (DL). The analytical component of this project was funded by the Division of Intramural Research, NHLBI, and the Center for Information Technology, NIH, Bethesda, MD. This study utilized the computational resources of the Biowulf system at the NIH, Bethesda, MD (https://hpc.nih.gov/docs/user_guides.html). MMM is partly supported by the Tommy Kaplan Fund, Boston Children’s Hospital. EJB was supported by 1RO1 HL64753, R01 HL076784, 1R01 AG028321, and 1P50HL120163. Support for the Genetic Epidemiology Network of Arteriopathy (GENOA) was provided by the NHLBI (HL054457, HL100185, and HL119443) of the NIH. GOLDN is supported by NIH grant R01HL104135. Methylation and expression work for GTP was primarily supported by the National Institute of Mental Health (MH096764 and MH071537 to KJR). Support was also received from Emory and Grady Memorial Hospital General Clinical Research Center, the Max Planck Society, the Behrens-Weise Foundation, NIH National Centers for Research Resources (M01RR00039), and the National Center for Advancing Translational Sciences of the NIH (UL1TR000454). The KORA study was initiated and financed by the Helmholtz Zentrum München – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. The research leading to these results has received funding from the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 603288 (SysVasc) and HEALTH-F2-2013-602736 (PAIN-OMICS) and BMBF e:Med project: e:AtheroSysMed - Systems medicine of myocardial infarction and stroke. Furthermore, this study was supported in part by a grant from the BMBF to the German Center for Diabetes Research (DZD). In addition, part of this work was financed by the German National Genome Research Network (NGFNplus, project no. 01GS0834) and through additional funds from the University of Ulm. The present work on the US Department of Veterans Affairs (VA) Normative Aging Study has been supported by funding from the U.S. National Institute of Environmental Health Sciences (NIEHS) (R01ES015172, R01ES021733). The VA Normative Aging Study is supported by the Cooperative Studies Program/ERIC, US Department of Veterans Affairs, and is a research component of the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC). Additional support to the VA Normative Aging Study was provided by the US Department of Agriculture, Agricultural Research Service (contract 53-K06-510). The views expressed in this paper are those of the authors and do not necessarily represent the views of the US Department of Veterans Affairs. The generation and management of the Illumina 450 K methylation array data (EWAS data) for the Rotterdam Study was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Netherlands. The EWAS data were funded by the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, and by the Netherlands Organization for Scientific Research (NWO; project number 184021007). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam.

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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