Genetic and Epigenetic Mapping of Very Early RA Synovial Fibroblasts

Emmanuel Karouzakis¹, Andrew Filer², Stephen Eyre³, Karim Raza⁴, Christoph Kolling⁵, Renate E. Gay¹, Beat A. Michel¹, Jane Worthington³, Christopher Buckley⁶, Steffen Gay¹, Michel Neidhart¹ and Caroline Ospelt¹, ¹University Hospital Zurich, Center of Experimental Rheumatology, Switzerland, Zurich, Switzerland, ²University of Birmingham, Birmingham, United Kingdom, ³University of Manchester,Institute of Inflammation and Repair, United Kingdom, Manchester, United Kingdom, ⁴University of Birmingham, Rheumatology Research Group, Institute of Inflammation and Ageing, United Kingdom, Birmingham, United Kingdom, ⁵Upper Extremity Dept., Schulthess Clinic Zurich, Zurich, Switzerland, ⁶University of Birmingham, Rheumatology Research Group, Birmingham, United Kingdom

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: epigenetics and synovial cells, Genetic Biomarkers, synovial fluid, WNT Signaling

Session Information

Date: Monday, November 9, 2015

Title: Genetics, Genomics and Proteomics Poster II

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose:

Genome wide association studies (GWAS) studies from rheumatoid arthritis patients have identified SNPs, which are associated with changes in gene expression levels. Recent studies revealed epigenetic changes in DNA methylation associated with rheumatoid arthritis synovial fibroblasts (RASF). Now, we want to identify genetic variations in RASF that are associated with quantitative changes in DNA methylation at very early disease state of RA.

Methods:

SF were obtained from patients with undifferentiated arthritis (symptom duration <3 months). Patients were classified as resolving arthritis or very early RA (VeRA) depending on whether they fulfilled the ACR criteria for classification within the subsequent 18 months. Methylation immunoprecipitation (MeDIP) and high throughput sequencing was used for the analysis of differentially methylated regions (DMRs) between resolving and very early RA (n=2). The DMRs were visualized with Integrative genome viewer (IGV) and biological pathway analysis was performed by DAVID bioinformatics tools. Rheumatoid arthritis single nucleotide polymorphisms (SNPs) associated with CpG sites were mapped together with the DMRs sequencing data.

Results:

The high throughput methylome sequencing of samples from VeRA versus resolving arthritis revealed >1000 DMRs that are associated with nearby gene promoters or introns. The gene ontology analysis of the DMRs showed significant enrichment of extracellular matrix, cell adhesion and joint development pathways. Genomic loci of WNT6, WNT8A and WNT1 secreted proteins were found to be altered by DNA methylation in very early RA disease. Next, we mapped genotypic data from RA associated CpGs SNPs with the DMRs sequences of very early RASF. Thereby, we found that the region containing the IL6R introning SNPs rs4576655 and rs4537645 were hypomethylated in VeRASF versus resolving arthritis SF.

Conclusion:

In this study, we clearly show that changes in DNA methylation in RASF occur even before diagnosis and differ between RA and resolving arthritis. The overlap of DMR with RA risk SNPs suggests that genetic/epigenetic interactions play a role in disease development.

Disclosure: E. Karouzakis, None; A. Filer, None; S. Eyre, None; K. Raza, None; C. Kolling, None; R. E. Gay, None; B. A. Michel, None; J. Worthington, None; C. Buckley, None; S. Gay, None; M. Neidhart, None; C. Ospelt, None.

To cite this abstract in AMA style:

Karouzakis E, Filer A, Eyre S, Raza K, Kolling C, Gay RE, Michel BA, Worthington J, Buckley C, Gay S, Neidhart M, Ospelt C. Genetic and Epigenetic Mapping of Very Early RA Synovial Fibroblasts [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/genetic-and-epigenetic-mapping-of-very-early-ra-synovial-fibroblasts/. Accessed .

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