title: Variation at FCGR2A and functionally related genes is associated with the response to anti-TNF therapy in rheumatoid arthritis.
abstract: 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.
authors.affiliation: Vall d'Hebron Hospital Research Institute, Rheumatology Research Group. Barcelona, Spain.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Avila-Pedretti
authors.affiliation: Hospital Universitario De Guadalajara, Rheumatology Department, Guadalajara, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Tornero
authors.affiliation: UGC Reumatología, Instituto de Investigación Biomédica en Málaga, Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Fernández-Nebro
authors.affiliation: INIBIC-Hospital Universitario A Coruña, Rheumatology Department, A Coruña, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Blanco
authors.affiliation: Hospital Universitario de La Princesa, IIS La Princesa, Rheumatology Department, Madrid, Spain.
authors.forename: Isidoro
authors.initials: I
authors.lastname: González-Alvaro
authors.affiliation: Hospital Clínic de Barcelona, Rheumatology Department, Barcelona, Spain.
authors.forename: Juan D
authors.initials: JD
authors.lastname: Cañete
authors.affiliation: Hospital del Mar, Barcelona, Rheumatology Department, Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Maymó
authors.affiliation: Hospital Universitario Central de Asturias, Rheumatology Department, Oviedo, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Alperiz
authors.affiliation: Hospital Clínico San Carlos, Madrid, Rheumatology Department, Madrid, Spain.
authors.forename: Benjamín
authors.initials: B
authors.lastname: Fernández-Gutiérrez
authors.affiliation: Hospital Universitari Germans Trias i Pujol, Rheumatology Department, Barcelona, Spain.
authors.forename: Alex
authors.initials: A
authors.lastname: Olivé
authors.affiliation: Hospital Moisès Broggi, Rheumatology Department, Barcelona, Spain.
authors.forename: Héctor
authors.initials: H
authors.lastname: Corominas
authors.affiliation: Hospital Sant Rafael, Rheumatology Department, Barcelona, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Erra
authors.affiliation: Vall d'Hebron Hospital Research Institute, Rheumatology Research Group. Barcelona, Spain.
authors.forename: Adrià
authors.initials: A
authors.lastname: Aterido
authors.affiliation: Vall d'Hebron Hospital Research Institute, Rheumatology Research Group. Barcelona, Spain.
authors.forename: María
authors.initials: M
authors.lastname: López Lasanta
authors.affiliation: Vall d'Hebron Hospital Research Institute, Rheumatology Research Group. Barcelona, Spain.
authors.forename: Raül
authors.initials: R
authors.lastname: Tortosa
authors.affiliation: Vall d'Hebron Hospital Research Institute, Rheumatology Research Group. Barcelona, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Julià
authors.affiliation: Vall d'Hebron Hospital Research Institute, Rheumatology Research Group. Barcelona, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Marsal
mesh_terms: D000328:Adult; D018501:Antirheumatic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology; D005260:Female; D006801:Humans; D008264:Macrophages / Q000187:drug effects; D008297:Male; D020641:Polymorphism, Single Nucleotide; D017452:Receptors, IgG / Q000235:genetics*; D013582:Synovial Fluid / Q000187:drug effects / Q000276:immunology; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D018501:Antirheumatic Agents; C445323:FCGR2A protein, human; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha
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