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

• 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; Giovanni Fiorito, Human Genetics Foundation; CHARGE epigenetics of Coronary Heart Disease; Simone Wahl, Helmholtz Zentrum München; Katharina Schramm, German Research Center for Environmental Health; Jin Sha, University of Alabama at Birmingham; Dena G. Hernandez, National Institute on Aging; Allan C. Just, Harvard University; Jennifer A. Smith, University of Michigan; Nona Sotoodehnia, University of Washington; Luke C. Pilling, University of Exeter; James S. Pankow, University of Minnesota; Phil S. Tsao, Stanford University; Chunyu Liu, National Heart, Lung, and Blood Institute; Wei Zhao, University of Michigan; Simonetta Guarrera, Human Genetics Foundation; Vasiliki Michopoulos, Emory University; Alicia Smith, Emory University; Marjolein J. Peters, Erasmus University; David Melzer, University of Exeter; Pantel Vokonas, VA Boston Healthcare System; Myriam Fornage, University of Texas; Holger Prokisch, German Research Center for Environmental Health; Joshua C. Bis, University of Washington; Audrey Y. Chu, National Heart, Lung, and Blood Institute; Christian Herder, University of Düsseldorf; Harald Grallert, Helmholtz Zentrum München; Chen Yao, National Heart, Lung, and Blood Institute; Sonia Shah, University of Queensland; Allan F. McRae, University of Queensland; Honghuang Lin, Boston University; Steve Horvath, University of California Los Angeles; Daniele Fallin, Johns Hopkins University; Albert Hofman, Erasmus University; Nicholas J. Wareham, University of Cambridge; Kerri L. Wiggins, University of Washington; Andrew P. Feinberg, Johns Hopkins University; John M. Starr, University of Edinburgh; Peter M. Visscher, University of Edinburgh; Joanne M. Murabito, Boston University; Sharon L.R. Kardia, University of Michigan; Devin M. Absher, HudsonAlpha Institute for Biotechnology; Elisabeth Binder, Emory University; Andrew B. Singleton, National Institute on Aging; Stefania Bandinelli, Azienda Sanitaria Firenze (ASF); Annette Peters, Helmholtz Zentrum München; Melanie Waldenberger, Helmholtz Zentrum München; Giuseppe Matullo, Human Genetics Foundation; Joel D. Schwartz, Harvard University; Ellen W. Demerath, University of Minnesota; André G. Uitterlinden, Erasmus University; Joyce B.J. van Meurs, Erasmus University; Oscar H. Franco, Erasmus University; Yii-Der Ida Chen, Harbor-UCLA Medical Center; Daniel Levy, Boston University; Stephen T. Turner, Mayo Clinic; Ian J. Deary, University of Edinburgh; Kerry Ressler, Emory University; Josée Dupuis, Boston University; Luigi Ferrucci, National Institute on Aging; Ken K. Ong, University of Cambridge; Themistocles L. Assimes, Stanford University; Eric Boerwinkle, University of Texas; Wolfgang Koenig, University of Ulm; Donna K. Arnett, University of Kentucky; Andrea A. Baccarelli, Harvard University; Emilia J. Benjamin, Boston University; Abbas Dehghan, Erasmus University
• Journal Title: Genome Biology
• Volume: Volume 17, Number 1
• Publisher: BioMed Central | 2016-12-12, Pages 255-255
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1186/s13059-016-1119-5
• Subjects: Biology, Genetics; Biology, Microbiology; Health Sciences, Epidemiology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Biotechnology & Applied Microbiology; Genetics & Heredity; Inflammation; DNA methylation; Epigenome-wide association study; C-reactive protein; Body mass index; Diabetes; Coronary heart disease

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.