Background/Purpose: Previous epigenetic studies of rheumatoid arthritis (RA) using prevalent cases and unrelated controls have indicated that DNA methylation is altered in patients with RA. However case control studies of unrelated individuals do not allow matching for important confounders such as the underlying genetic variability and environmental exposures, which may influence disease development and the epigenome. By investigating DNA methylation differences in disease discordant monozygotic (MZ) twins, such confounding effects may be mitigated, increasing the power to detect alterations to the methylome which might be associated with RA.

Objectives: To identify a DNA methylation signature in RA using disease discordant monozygotic twins.

Methods: Twin subjects were recruited from the Rheumatoid Arthritis Twin Study (Manchester) and TwinsUK (London). Each twin pair included one twin classified as having RA according to established classification criteria (n=63) while the other was classified as not having RA (n=63) at the time samples were collected. Whole blood DNA was bisulfite converted and an epigenome-wide association study was performed using the HumanMethylation450 BeadChip (Illumina). A detection threshold was applied and probes with a detection-p value >0.01 were removed. Differentially methylated positions (DMPs) were identified using linear regression following quantile normalisation.

Results: 30 CpG sites were differentially methylated at a false discovery rate of 10%. One of the most significant DMPs, cg07693617 (p=1.05×10^-6) lies in the PRKCZ gene which contains 22 differentially methylated CpG sites in the gene body and 5’ UTR. Interestingly this gene was found to be hypermethylated in RA fibroblast-like synoviocytes in a previous epigenome-wide association study.

Conclusion: This is the largest study to date of DNA methylation in RA discordant MZ twin pairs. We have identified 30 CpG sites with a potential role in RA development and added to the evidence for an association at PRKCZ. While further validation and replication studies are required, these preliminary data support the hypothesis that DNA methylation is altered in patients with RA and provides a plausible biological mechanism to account for the observed twin discordance in RA.

Acknowledgements: This work was supported by the innovative medicines initiative joint undertaking (IMI JU) funded project BeTheCure, (contract number 115142-2). The work was supported by the NIHR Manchester Musculoskeletal Biomedical Research Unit. We also acknowledge support from Arthritis Research UK. TwinsUK. The study was funded by the Wellcome Trust; European Community’s Seventh Framework Programme (FP7/2007-2013) and also received support from the National Institute for Health Research (NIHR)- funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. The Chronic Disease Research Foundation also supported this work.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/differential-dna-methylation-associated-with-rheumatoid-arthritis-in-disease-discordant-monozygotic-twins/