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.

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Published in Genome Biology, v. 17, 255, p. 1-15.

© The Author(s). 2016

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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.

Due to the large number of funding sources, only the first few are listed in this section. For the complete list of funding sources, please download this article.

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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).

Due to the large number of funding resources, only the first section of funding information is listed in the section above. For the complete list of funding resources, please download this article.

Related Content

The DNA methylation datasets analyzed during the current study are available at the following public repositories: dbGAP (FHS: phs000724.v5.p10; GOLDN: phs000741.v1.p1; NAS: phs000853.v1.p1; WHI: phs000200.v10.p3), GEO (GTP: GSE72680), and EGA (LBC: EGAS00001000910). The DNA methylation dataset from ARIC is available on request at https://www2.cscc.unc.edu/aric/distribution-agreements; the CHS data can be requested at https://chs-nhlbi.org/node/6222; for the EPIC data contact Ken K. Ong (Ken.Ong@mrc-epid.cam.ac.uk); EPICOR data are available upon request from HuGeF (http://www.hugef-torino.org/) by means of a project agreement. Requests should be sent to info@hugef-torino.org; for the GENOA data contact Sharon L.R. Kardia (skardia@umich.edu) and Jennifer A. Smith (smjenn@umich.edu); the InCHIANTI data are available on request at http://inchiantistudy.net/wp/inchianti-dataset/; the KORA data can be requested at KORA-gen (http://www.helmholtz-muenchen.de/kora-gen); for the RS data, request at http://www.epib.nl/research/ergo.htm or contact M. Arfan Ikram (m.a.ikram@erasmusmc.nl). The genotype and expression datasets from the FHS are available in the dbGAP repository (phs000724.v5.p10, phs000363.v15.p10). The gene expression dataset from the GTP, InCHIANTI, and RS are available in the GEO repository (GSE58137, GSE48152, and GSE33828). The source codes used for the analysis are available to download from https://github.com/sligthart/EWAS-CRP and deposited at Zenodo.org under doi:10.5281/zenodo.166797.

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