Novel Insights into Rheumatoid Arthritis Through Characterisation of Concordant Changes in DNA Methylation and Gene Expression in Synovial Biopsies of Patients with Differing Numbers of Swollen Joints

Abstract

In this study, we sought to characterize synovial tissue obtained from individuals with arthralgia and disease-specific auto-antibodies, and patients with established rheumatoid arthritis (RA) by applying an integrative multi-omics approach where we investigated changes at the level of DNA methylation and gene expression and its relation to disease pathogenesis. We performed genome-wide DNA methylation and gene expression profiling of synovial tissue obtained from the knee and ankle from 4 auto-antibody positive arthralgia patients and thirteen RA patients. Through multi-omics factor analysis we observed that the latent factor explaining the variance in gene expression and DNA methylation was associated with Swollen Joint Count 66 (SJC66) where patients with SJC66 of 9 or more displayed reasonable separation from the rest. Specifically, combined DNA methylation and gene expression patterns of patients with SJC66 ≥ 9 displayed activation of the immune response as well as dysregulation of cell adhesion pathways. Through an integrative analysis framework, we reveal differences in both methylation and expression at 59 genes associated with the difference between SJC66 ≥ 9 and 0 < SJC66 ≤ 8, for which we identify specific transcripts correlated with differential methylation. Our results highlight the utility of genome-wide multi-omics profiling of synovial samples for improved understanding of the changes associated with an increasing number of swollen joints in RA patients, and point to novel candidate targets for the treatment of the disease. Funding Statement: AYFLY was funded by the European Union’s Horizon 2020 research and innovation program under Grant Agreement No. ITN-2014-EID-641665. Declaration of Interests: AYFLY, KM, GR, EC, HDL, DFT, CL, DG, and RB are employees of GSK. EF and PPT are employees of Novartis and Kintai Therapeutics, respectively. WJJ is financially supported by GSK and Mead Johnson. All declarations are correct for the time of writing and/or conducting this study. Ethics Approval Statement: All subjects provided written informed consent and the collection and use of the samples received Institutional Review Board review and approval. Characteristics of patients included in this study are listed in Table S1.