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.