FRI0100 Multi-omics analysis identifies a gene signature associated with the clinical response to anti-tnf therapy in rheumatoid arthritis

Background Tumour Necrosis Factor (TNF) inhibitors have improved the management of many patients with rheumatoid arthritis (RA). However,~30% of anti-TNF treated patients do not show a significant clinical improvement. To date, little is known on the biological mechanisms underlying the differential response to anti-TNF agents. Objectives We sought to identify genetic variation associated with the anti-TNF response in RA using a sequential multi-omics approach. Methods First, we aimed to identify gene coexpression modules (GCMs) associated with anti-TNF response. For this objective, we extracted the RNA from synovial biopsies of 13 RA patients starting anti-TNF therapy and determined the expression profiles using Illumina microarrays. GCMs were identified using the WGCNA approach. The association between GCMs and anti-TNF response was performed using the eigengene of each GCM. Clinical response was defined using the EULAR criteria at week 14. To analyse the association of GCMs with anti-TNF response at the genetic level, we used 348 anti-TNF treated RA patients from Spain. The statistical analysis was performed using GWAS data and the set-based test in PLINK. The GCMs that were significantly associated with anti-TNF response were subsequently tested for validation in an independent cohort of 2706 anti-TNF treated RA patients. The functional implication of the validated GCMs was studied via pathway and cell type epigenetic enrichment analyses. Results We identified 148 GCMs in the RA synovium. From these, 15 GCMs were found to be associated with anti-TNF response (p Conclusions Our study shows the existence of a drug-specific genetic basis for the anti-TNF response. Therefore, this molecular diversity should be considered for biomarker research in RA. Disclosure of Interest None declared