Avila-Pedretti, GabrielaTornero, JesúsFernández-Nebro, AntonioBlanco, FranciscoGonzález-Alvaro, IsidoroCañete, Juan DMaymó, JoanAlperiz, MercedesFernández-Gutiérrez, BenjamínOlivé, AlexCorominas, HéctorErra, AlbaAterido, AdriàLópez Lasanta, MaríaTortosa, RaülJulià, AntonioMarsal, Sara2016-07-132016-07-132015-04-07Avila-Pedretti G, Tornero J, Fernández-Nebro A, Blanco F, González-Alvaro I, Cañete JD, et al. Variation at FCGR2A and functionally related genes is associated with the response to anti-TNF therapy in rheumatoid arthritis. PLoS ONE. 2015; 10(4):e0122088http://hdl.handle.net/10668/2268Journal Article; Research Support, Non-U.S. Gov't;OBJECTIVE Anti-TNF therapies have been highly efficacious in the management of rheumatoid arthritis (RA), but 25-30% of patients do not show a significant clinical response. There is increasing evidence that genetic variation at the Fc receptor FCGR2A is associated with the response to anti-TNF therapy. We aimed to validate this genetic association in a patient cohort from the Spanish population, and also to identify new genes functionally related to FCGR2A that are also associated with anti-TNF response. METHODS A total of 348 RA patients treated with an anti-TNF therapy were included and genotyped for FCGR2A polymorphism rs1081274. Response to therapy was determined at 12 weeks, and was tested for association globally and independently for each anti-TNF drug (infliximab, etanercept and adalimumab). Using gene expression profiles from macrophages obtained from synovial fluid of RA patients, we searched for genes highly correlated with FCGR2A expression. Tag SNPs were selected from each candidate gene and tested for association with the response to therapy. RESULTS We found a significant association between FCGR2A and the response to adalimumab (P=0.022). Analyzing the subset of anti-CCP positive RA patients (78%), we also found a significant association between FCGR2A and the response to infliximab (P=0.035). DHX32 and RGS12 were the most consistently correlated genes with FCGR2A expression in RA synovial fluid macrophages (P<0.001). We found a significant association between the genetic variation at DHX32 (rs12356233, corrected P=0.019) and a nominally significant association between RGS12 and the response to adalimumab (rs4690093, uncorrected P=0.040). In the anti-CCP positive group of patients, we also found a nominally significant association between RGS12 and the response to infliximab (rs2857859, uncorrected P=0.042). CONCLUSIONS In the present study we have validated the FCGR2A association in an independent population, and we have identified new genes associated with the response to anti-TNF therapy in RA.enAntirreumáticosMacrófagosPolimorfismo de nucleótido únicoArtritis reumatoideReceptores de IgGLíquido sinovialResultado del tratamientoFactor de necrosis tumoral alfaMedical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antirheumatic AgentsMedical Subject Headings::Diseases::Musculoskeletal Diseases::Rheumatic Diseases::Arthritis, RheumatoidMedical Subject Headings::Check Tags::FemaleMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Anatomy::Cells::Phagocytes::MacrophagesMedical Subject Headings::Check Tags::MaleMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Variation::Polymorphism, Genetic::Polymorphism, Single NucleotideMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, Immunologic::Receptors, Fc::Receptors, IgGMedical Subject Headings::Anatomy::Musculoskeletal System::Skeleton::Joints::Joint Capsule::Synovial Membrane::Synovial FluidMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Prognosis::Treatment OutcomeMedical Subject Headings::Chemicals and Drugs::Biological Factors::Intercellular Signaling Peptides and Proteins::Tumor Necrosis Factors::Tumor Necrosis Factor-alphaMedical Subject Headings::Named Groups::Persons::Age Groups::Adultresearch article25848939open access10.1371/journal.pone.01220881932-6203PMC4388501