OP0016 IDENTIFICATION OF FUNCTIONAL VARIANTS IN THE RHEUMATOID ARTHRITIS ASSOCIATED JAZF1 LOCUS IN SYNOVIAL FIBROBLASTS

Background: Over the past decade, genome wide association studies (GWAS) have identified JAZF1 locus as a risk for several autoimmune diseases, including rheumatoid arthritis (RA) 1 . However, exact causal variants in and their underlying regulatory events contributing to RA are still not known. Here, we focus on effect of these gene expression synovial fibroblasts (SF). Objectives: To characterize functional consequences RA-causal SF. Methods: Genetic fine-mapping loci was conducted by computing sets credible driving GWAS signals. These variant were integrated with DNA architecture (ChIP-seq), 3D chromatin interactions (3C, HiC capture HiC), accessibility (ATAC-seq) (RNA-seq CAGE-seq) datasets select putative Selected tested function luciferase reporter assays electrophoretic mobility shift (EMSA) fibrosarcoma cell line HT1080. The JASPAR2020 database used identify transcription factors (TF) binding selected variants. HOTTIP measured quantitative PCR hand SF (n=23). Genotyping done pyrosequencing. Results: fine mapping revealed 47 locus. Integration prioritized rs2158624, rs57585717 rs186735625 top candidates (posterior probability causality >0.1) We found that rs2158624 located vicinity enhancer elements determined ATAC-seq. In addition, region exhibited strong genomic HOXA13 Both transcripts previously shown be specifically expressed isolated from hands feet 2 Based this, most promising candidate rs2158624-C allele (risk) is associated lower HOTTIP, but , compared rs2158624-T (non-risk) ( p =0.02). Luciferase HT1080 cells demonstrated activity both =0.006) T =0.04), no significant difference between allele. EMSAs stronger specific HT1080-cell nuclear extract than C (risk). database, NFAT5 potential TF can bind may regulate Conclusion: able substantially narrow down using our data integration approach assays. suggest influences TFs controlling long non-coding RNA SF, which might confer develop hands. References: [1]Okada Y et al. contributes biology drug discovery. Nature 2014;506:376. [2]Frank-Bertoncelj M Epigenetically-driven anatomical diversity guides joint-specific fibroblast functions. Nat Commun 2017;8:14852. Disclosure Interests: Miranda Houtman: None declared, Xiangyu Ge: Amanda McGovern: Kerstin Klein: Gisela Orozco: Mojca Frank Bertoncelj: Miriam Marks: Oliver Distler Speakers bureau: Bayer, Boehringer Ingelheim, iQone, Medscape, MSD, Novartis, Pfizer Roche, Consultant of: Abbvie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Boehringer, CSL Behring, ChemomAb, Corbus Pharmaceuticals, Galapagos NV, GSK, Glenmark Horizon Inventiva, Italfarmaco, iQvia, Kymera, Lilly, Medac, Mitsubishi Tanabe Pfizer, Roivant Sciences, Sanofi UCB, Grant/research support from: Kymera Therapeutics Tanabe, Paul Martin: Stephen Eyre: Caroline Ospelt: declared