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Genome Biology

, 17:255

The Biology of Human Diseases, as Revealed Through Genomics

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 in the discovery panel of European ancestry and replicated P < 2.29 × 10 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, ten 17% CpG sites were associated with a nearby genetic variant P < 2.50 × 10, and 51 88% were also associated with at least one related cardiometabolic entity P < 9.58 × 10. 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.

KeywordsInflammation DNA methylation Epigenome-wide association study C-reactive protein Body mass index Diabetes Coronary heart disease AbbreviationsBMIBody mass index

CHDCoronary heart disease

CpGCytosine-phosphate-guanine

CRPC-reactive protein

DNADeoxyribonucleic acid

eQTLExpression quantitative trait locus

EWASEpigenome-wide association study

GWASGenome-wide association study

HDL-cholesterolHigh-density lipoprotein cholesterol

mQTLMethylation quantitative trait locus

NHGRINational Human Genome Research Institute

SNPSingle nucleotide polymorphism

SVSurrogate variable

Electronic supplementary materialThe online version of this article doi:10.1186-s13059-016-1119-5 contains supplementary material, which is available to authorized users.

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Author: Symen Ligthart - Carola Marzi - Stella Aslibekyan - Michael M. Mendelson - Karen N. Conneely - Toshiko Tanaka - Elena Col

Source: https://link.springer.com/



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