Aterido, AdriàCañete, Juan DTornero, JesúsBlanco, FranciscoFernández-Gutierrez, BenjamínPérez, CarolinaAlperi-López, MercedesOlivè, AlexCorominas, HéctorMartínez-Taboada, VíctorGonzález, IsidoroFernández-Nebro, AntonioErra, AlbaLópez-Lasanta, MaríaLópez Corbeto, MireiaPalau, NúriaMarsal, SaraJulià, Antonio2024-02-102024-02-102019-07-02http://hdl.handle.net/10668/14246http://hdl.handle.net/20.500.12105/17885Background: Rheumatoid arthritis (RA) is the most frequent autoimmune disease involving the joints. Although anti-TNF therapies have proven effective in the management of RA, approximately one third of patients do not show a significant clinical response. The objective of this study was to identify new genetic variation associated with the clinical response to anti-TNF therapy in RA. Methods: We performed a sequential multi-omic analysis integrating different sources of molecular information. First, we extracted the RNA from synovial biopsies of 11 RA patients starting anti-TNF therapy to identify gene coexpression modules (GCMs) in the RA synovium. Second, we analyzed the transcriptomic association between each GCM and the clinical response to anti-TNF therapy. The clinical response was determined at week 14 using the EULAR criteria. Third, we analyzed the association between the GCMs and anti-TNF response at the genetic level. For this objective, we used genome-wide data from a cohort of 348 anti-TNF treated patients from Spain. The GCMs that were significantly associated with the anti-TNF response were then tested for validation in an independent cohort of 2,706 anti-TNF treated patients. Finally, the functional implication of the validated GCMs was evaluated via pathway and cell type epigenetic enrichment analyses. Results: A total of 149 GCMs were identified in the RA synovium. From these, 13 GCMs were found to be significantly associated with anti-TNF response (PengVoRhttp://creativecommons.org/licenses/by/4.0/anti-TNF therapyGenomicsMulti-omics association analysisRheumatoid arthritisTranscriptomicsAdalimumabAntirheumatic AgentsArthritis, RheumatoidBiopsyCohort StudiesFemaleGene Regulatory NetworksGenome-Wide Association StudyHumansInfliximabMalePolymorphism, Single NucleotideSynovial MembraneTranscriptomeTreatment OutcomeTumor Necrosis Factor-alphaAttribution 4.0 International3131220110145910.3389/fimmu.2019.014591664-3224Frontiers in immunologyopen access