Variation at FCGR2A and functionally related genes is associated with the response to anti-TNF therapy in rheumatoid arthritis
Ávila, Gabriela (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Tornero, Jesús (Hospital Universitario de Guadalajara)
Fernández-Nebro, Antonio (Instituto de Investigación Biomédica de Málaga)
Blanco, Francisco (Instituto de Investigación Biomédica de A Coruña)
González-Alvaro, Isidoro (Hospital Universitario de la Princesa (Madrid))
Cañete, Juan D. (Hospital Clínic i Provincial de Barcelona)
Maymó, Joan (Hospital del Mar (Barcelona, Catalunya))
Alperiz, Mercedes (Hospital Universitario Central de Asturias)
Fernández-Gutiérrez, Benjamín (Hospital Clínico San Carlos (Madrid))
Olivé Marqués, Alejandro (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Corominas, Hèctor (Hospital de Sant Joan Despí Moisès Broggi)
Erra Duran, Alba (Hospital Sant Rafael (Barcelona))
Aterido, Adrià (Hospital Universitari Vall d'Hebron. Institut de Recerca)
López Lasanta, María (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Tortosa, Raül (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Julià Cano, Antonio (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Marsal Barril, Sara (Hospital Universitari Vall d'Hebron. Institut de Recerca)

Date:	2015
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.
Grants:	Ministerio de Economía y Competitividad PSE/010000-2006-6 Ministerio de Economía y Competitividad IPT/010000-2010-36
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Rheumatoid arthritis ; Macrophages ; Gene expression ; Human genetics ; Synovial fluid ; Antibody response ; Fc receptors ; Variant genotypes
Published in:	PloS one, Vol. 10, Núm. 4 (April 2015) , p. e0122088, ISSN 1932-6203

DOI: 10.1371/journal.pone.0122088
PMID: 25848939

12 p, 192.3 KB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
Articles > Research articles
Articles > Published articles