title: DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases.
abstract: 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.
  
  
  
  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.
  
  
  
  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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authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
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authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
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authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.|Division of Depression & Anxiety Disorders, McLean Hospital, Belmont, MA, USA.|Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
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authors.affiliation: Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, Ulm, Germany.|Deutsches Herzzentrum München, Technische Universität München, Munich, Germany.|DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
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authors.affiliation: University of Kentucky, College of Public Health, Lexington, KY, USA.
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authors.affiliation: Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
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authors.initials: AA
authors.lastname: Baccarelli
authors.affiliation: Boston University School of Medicine, Boston, MA, USA.|Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.|Boston University and the NHLBI's Framingham Heart Study, Boston, MA, USA.
authors.forename: Emelia J
authors.initials: EJ
authors.lastname: Benjamin
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands. a.dehghan@erasmusmc.nl.|Department of Biostatistics and Epidemiology, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK. a.dehghan@erasmusmc.nl.
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authors.lastname: Dehghan
mesh_terms: D001741:Black or African American; D002097:C-Reactive Protein / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D015870:Gene Expression; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000235:genetics*; D008297:Male; D059372:Nucleotide Motifs / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*; D044465:White People
chemical_list: D002097:C-Reactive Protein
keywords: Body mass index; C-reactive protein; Coronary heart disease; DNA methylation; Diabetes; Epigenome-wide association study; Inflammation