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

• Type of Material: Article
• Authors: Symen Ligthart, Erasmus University; Carola Marzi, Helmholtz Zentrum München; Stella Aslibekyan, University of Alabama at Birmingham; Michael M. Mendelson, Boston University; Karen Conneely, Emory University; Toshiko Tanaka, National Institute on Aging; Elena Colicino, Harvard University; Lindsay L. Waite, HudsonAlpha Institute for Biotechnology; Roby Joehanes, Harvard University; Weihua Guan, University of Minnesota; Jennifer A. Brody, University of Washington; Cathy Elks, University of Cambridge; Riccardo Marioni, University of Edinburgh; Min A. Jhun, University of Michigan; Golareh Agha, Harvard University; Jan Bressler, University of Texas; Cavin K. Ward-Caviness, Helmholtz Zentrum München; Brian H. Chen, National Institute on Aging; Tianxiao Huan, National Heart, Lung, and Blood Institute; Kelly Bakulski, Johns Hopkins University; Elias L. Salfati, Stanford University; WHI-EMPC Investigators, Human Genetics Foundation; Giovanni Fiorito, Helmholtz Zentrum München; CHARGE epigenetics of Coronary Heart Disease, German Research Center for Environmental Health; Simone Wahl, University of Alabama at Birmingham; Katharina Schramm, National Institute on Aging; Jin Sha, Harvard University; Dena G. Hernandez, University of Michigan; Allan C. Just, University of Washington; Jennifer A. Smith, University of Exeter; Nona Sotoodehnia, University of Minnesota; Luke C. Pilling, Stanford University; James S. Pankow, National Heart, Lung, and Blood Institute; Phil S. Tsao, University of Michigan; Chunyu Liu, Human Genetics Foundation; Wei Zhao, Emory University; Simonetta Guarrera, Emory University; Vasiliki Michopoulos, Erasmus University; Alicia Smith, University of Exeter; Marjolein J. Peters, VA Boston Healthcare System; David Melzer, University of Texas; Pantel Vokonas, German Research Center for Environmental Health; Myriam Fornage, University of Washington; Holger Prokisch, National Heart, Lung, and Blood Institute; Joshua C. Bis, University of Düsseldorf; Audrey Y. Chu, Helmholtz Zentrum München; Christian Herder, National Heart, Lung, and Blood Institute; Harald Grallert, University of Queensland; Chen Yao, University of Queensland; Sonia Shah, Boston University; Allan F. McRae, University of California Los Angeles; Honghuang Lin, Johns Hopkins University; Steve Horvath, Erasmus University; Daniele Fallin, University of Cambridge; Albert Hofman, University of Washington; Nicholas J. Wareham, Johns Hopkins University; Kerri L. Wiggins, University of Edinburgh; Andrew P. Feinberg, University of Edinburgh; John M. Starr, Boston University; Peter M. Visscher, University of Michigan; Joanne M. Murabito, HudsonAlpha Institute for Biotechnology; Sharon L.R. Kardia, Emory University; Devin M. Absher, National Institute on Aging; Elisabeth Binder, Azienda Sanitaria Firenze (ASF); Andrew B. Singleton, Helmholtz Zentrum München; Stefania Bandinelli, Helmholtz Zentrum München; Annette Peters, Human Genetics Foundation; Melanie Waldenberger, Harvard University; Giuseppe Matullo, University of Minnesota; Joel D. Schwartz, Erasmus University; Ellen W. Demerath, Erasmus University; André G. Uitterlinden, Erasmus University; Joyce B.J. van Meurs, Harbor-UCLA Medical Center; Oscar H. Franco, Boston University; Yii-Der Ida Chen, Mayo Clinic; Daniel Levy, University of Edinburgh; Stephen T. Turner, Emory University; Ian J. Deary, Boston University; Kerry Ressler, National Institute on Aging; Josée Dupuis, University of Cambridge; Luigi Ferrucci, Stanford University; Ken K. Ong, University of Texas; Themistocles L. Assimes, University of Ulm; Eric Boerwinkle, University of Kentucky; Wolfgang Koenig, Harvard University; Donna K. Arnett, Boston University; Andrea A. Baccarelli, Erasmus University; Emilia J. Benjamin; Abbas Dehghan
• Language: English
• Date: 2016-12-12
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © 2016 The Author(s). The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s13059-016-1119-5
• Title of Journal or Parent Work: Genome Biology
• ISSN: 1465-6906
• Volume: 17
• Issue: 1
• Start Page: 255
• End Page: 255
• Grant/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).; For additional funding information, please see the full article.
• Keywords: Genetics & Heredity; Inflammation; C-reactive protein; Epigenome-wide association study; Body mass index; Biotechnology & Applied Microbiology; DNA methylation; Science & Technology; Life Sciences & Biomedicine; Coronary heart disease; Diabetes
• Research Categories: Biology, Microbiology; Biology, Genetics; Health Sciences, Epidemiology

Abstract

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.