Differentially Methylated DNA Regions in Monozygotic Twin Pairs Discordant for Rheumatoid Arthritis: An Epigenome-Wide Study

Anders J Svendsen, Kristina Gervin, Robert Lyle, Lene Christiansen, Kirsten Kyvik, Peter Junker, Christian Nielsen, Gunnar Houen, Qihua Tan

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OBJECTIVES: In an explorative epigenome-wide association study (EWAS) to search for gene independent, differentially methylated DNA positions and regions (DMRs) associated with rheumatoid arthritis (RA) by studying monozygotic (MZ) twin pairs discordant for RA.

METHODS: Genomic DNA was isolated from whole blood samples from 28 MZ twin pairs discordant for RA. DNA methylation was measured using the HumanMethylation450 BeadChips. Smoking, anti-cyclic citrullinated peptide antibodies, and immunosuppressive treatment were included as covariates. Pathway analysis was performed using GREAT.

RESULTS: Smoking was significantly associated with hypomethylation of a DMR overlapping the promoter region of the RNF5 and the AGPAT1, which are implicated in inflammation and autoimmunity, whereas DMARD treatment induced hypermethylation of the same region. Additionally, the promotor region of both S100A6 and EFCAB4B were hypomethylated, and both genes have previously been associated with RA. We replicated several candidate genes identified in a previous EWAS in treatment-naïve RA singletons. Gene-set analysis indicated the involvement of immunologic signatures and cancer-related pathways in RA.

CONCLUSION: We identified several differentially methylated regions associated with RA, which may represent environmental effects or consequences of the disease and plausible biological pathways pertinent to the pathogenesis of RA.

Original languageEnglish
Article number510
JournalFrontiers in Immunology
Issue numberNOV
Number of pages10
Publication statusPublished - 17. Nov 2016


  • DNA methylation
  • Epigenome-wide association study
  • Monozygotic twins
  • Pathway analysis
  • Rheumatoid arthritis


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