Abstract
BackgroundChronic 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.ResultsWe 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.ConclusionWe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-1119-5) contains supplementary material, which is available to authorized users.
Highlights
Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases
Genetic correlates of Deoxyribonucleic acid (DNA) methylation in cis In the Rotterdam Study (RS), we identified 20 cis-Methylation quantitative trait locus (mQTL) pairs (19 unique Single nucleotide polymorphism (SNP) and 20 unique CpG sites) for the replicated CpG sites, ten of these cis-mQTL pairs could be replicated in the Framingham Heart Study (FHS) (P < 2.5 × 10−3) (Additional file 10: Table S9)
We performed the first meta-analysis of epigenome-wide association studies (EWAS) of C-reactive protein (CRP), a sensitive marker of low-grade inflammation
Summary
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. Several pathways have been identified for chronic low-grade inflammation [1, 5] and genetic studies have found candidate loci through discovery of genetic sequence determinants of circulating CRP levels [6]. Most of the molecular mechanisms underlying interindividual variation in inflammation in the general population and the inter-relation with complex diseases remain to be elucidated. Epigenetic modifications comprise biochemical alterations to the genome that leave the underlying nucleic acid sequence unchanged but can affect phenotypic expression. Investigating DNA methylation in chronic low-grade inflammation may point to functional epigenetic changes that occur in the context of inflammation
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