OP0337 DIFFERENTIAL METHYLATION OF PERIPHERAL BLOOD ADAPTIVE IMMUNE CELLS IN INDIVIDUALS AT HIGH RISK FOR RA AND WITH EARLY RA COMPARED WITH CONTROLS IDENTIFIES PATHWAYS IMPORTANT IN TRANSITION TO ARTHRITIS

• Published in: Annals of the Rheumatic Diseases
• Main Authors: Ai, R., Boyle, D., Hammaker, D., Deane, K., Holers, V. M., Matti, A., Robinson, W., Buckner, J., Rao, N., Baribaud, F., Johnsen, A., Nagpal, S., Wang, W., Firestein, G.
• Format: Article in Journal/Newspaper
• Language: English
• Published: BMJ 2020
• Subjects: General Biochemistry, Genetics and Molecular Biology; Immunology; Immunology and Allergy; Rheumatology; DML
• Online Access: http://dx.doi.org/10.1136/annrheumdis-2020-eular.2989; https://syndication.highwire.org/content/doi/10.1136/annrheumdis-2020-eular.2989

Background: The “Targeting Immune Responses for Prevention of RA” (TIP-RA) collaboration studies individuals at high risk for developing RA because of serum anti-citrullinated protein antibody positivity in absence of arthritis, and is focused on defining how they transition from at-risk to classifiable disease. One potential mechanism is through alterations in epigenetics patterns in adaptive immune cells. Objectives: Previous studies showed that DNA methylation patterns of early RA (ERA) synoviocytes differ from long-standing RA, suggesting that abnormal methylation occurs early in synovium and evolves over time. To extend these observations, we performed a cross-sectional analysis in TIP-RA of DNA methylation signatures in peripheral blood cells in ERA, at-risk anti-CCP3+ individuals and demographically matched CCP- controls. Methods: Genomic DNA was isolated from two independent cohorts of CCP- (cohorts 1 and 2, respectively: B cell: n = 17/34; memory T cell: n = 21/34; and naïve T cell: n = 21/33), CCP3+ (B cell: n = 18/37; memory T cell: n = 20/36; and naïve T cell: n = 20/35), and CCP3+ ERA (B cell: n = 4/18; memory T cell: n = 5/18; and naïve T cell: n = 5/18) after separating PBMCs using antibodies and magnetic beads. Methylation was measured by Illumina Infinium MethylationEPIC chip. Differentially methylated loci (DMLs) were identified using Welch’s t-test and mapped to gene promoter regions to define DM genes (DMGs). Principal component analysis (PCA) was used to represent relationship among groups. Pathway analysis was applied by Reactome. Results: For the initial cohort, 1494, 1097 and 1330 DMLs were identified among CCP+, CCP- and ERA in B cells, memory T cells and naïve T cells, respectively. For the confirmatory cohort, 523, 793 and 548 DMLs were found in corresponding cell populations. The DML overlap between the 2 cohorts was highly significant ( p = 2.48E-77). The DMLs were combined for both groups and corresponded to 411, 412, and 351 DMGs in B cells, memory T cells and naïve T cells. Of ...