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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Ligthart, Symen 
Marzi, Carola 
Aslibekyan, Stella 
Mendelson, Michael M 
Conneely, Karen N 

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.

Description

Keywords

Body mass index, C-reactive protein, Coronary heart disease, DNA methylation, Diabetes, Epigenome-wide association study, Inflammation, Black or African American, C-Reactive Protein, CpG Islands, DNA Methylation, Epigenesis, Genetic, Female, Gene Expression, Genetic Variation, Genome-Wide Association Study, Humans, Inflammation, Male, Nucleotide Motifs, Quantitative Trait Loci, White People

Journal Title

Genome Biol

Conference Name

Journal ISSN

1474-7596
1474-760X

Volume Title

17

Publisher

Springer Science and Business Media LLC
Sponsorship
MRC (unknown)
Medical Research Council (MC_UU_12015/2)
MRC (MC_PC_13048)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0512-10135)
Medical Research Council (MC_UU_12015/1)
Medical Research Council (MR/M023095/1)
Medical Research Council (G0401527)
Medical Research Council (MC_EX_MR/L100002/1)
Medical Research Council (MC_U106179471)
Cancer Research Uk (None)
Medical Research Council (MC_U106179472)
Medical Research Council (G0401527/1)
Medical Research Council (MC_PC_13048)