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Open Access Highly Accessed Open Badges Research article

Lack of validation of genetic variants associated with anti–tumor necrosis factor therapy response in rheumatoid arthritis: a genome-wide association study replication and meta-analysis

Ana Márquez1*, Aida Ferreiro-Iglesias2, Cristina L Dávila-Fajardo13, Ariana Montes2, Dora Pascual-Salcedo4, Eva Perez-Pampin2, Manuel J Moreno-Ramos5, Rosa García-Portales6, Federico Navarro7, Virginia Moreira7, César Magro8, Rafael Caliz9, Miguel Angel Ferrer9, Juan José Alegre-Sancho10, Beatriz Joven11, Patricia Carreira11, Alejandro Balsa12, Yiannis Vasilopoulos13, Theologia Sarafidou13, José Cabeza-Barrera3, Javier Narvaez14, Enrique Raya8, Juan D Cañete15, Antonio Fernández-Nebro16, María del Carmen Ordóñez16, Arturo R de la Serna17, Berta Magallares17, Juan J Gomez-Reino182, Antonio González2 and Javier Martín1

Author Affiliations

1 Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas (CSIC), Avenida del Conocimiento s/n, 18016-Armilla, Granada, Spain

2 Laboratorio Investigación 10 and Rheumatology Unit, Instituto de Investigación Sanitaria-Hospital Clínico Universitario de Santiago, Travesia Choupana s/n 15706-Santiago de Compostela, Spain

3 Department of Clinical Pharmacy, Hospital Universitario San Cecilio, Instituto de Investigación Biosanitaria de Granada (IBIG), Avenida Doctor Oloriz 16, 18012-Granada, Spain

4 Department of Immunology, Instituto de Investigación Sanitaria del Hospital Universitario La Paz (IdiPAZ), Research Network in Inflammation and Rheumatic Diseases (RIER), Hospital La Paz, Paseo de la Castellana, 261, 28046-Madrid, Spain

5 Department of Rheumatology, Hospital Virgen de la Arrixaca, Ctra. Madrid-Cartagena s/n, 30120-El Palmar Murcia, Spain

6 Department of Rheumatology, Hospital Virgen de la Victoria, Campus de Teatinos s/n, 29010-Málaga, Spain

7 Rheumatology Unit, Hospital Universitario Virgen Macarena, Avenida Dr. Fedriani 3, 41007-Sevilla, Spain

8 Department of Rheumatology, Hospital Clínico San Cecilio, Avenida Doctor Oloriz 16, 18012-Granada, Spain

9 Rheumatology Unit, Hospital Universitario Virgen de las Nieves, Avenida de las Fuerzas Armadas 2, 18014-Granada, Spain

10 Department of Rheumatology, Hospital Doctor Peset, Avenida de Gaspar Aguilar 90, 46017-Valencia, Spain

11 Department of Rheumatology, Instituto de Investigación I+12, Research Network in Inflammation and Rheumatic Diseases (RIER), Hospital Universitario 12 de Octubre, Avenida de Córdoba s/n, 28041-Madrid, Spain

12 Department of Rheumatology, Instituto de Investigación Sanitaria del Hospital Universitario La Paz (IdiPAZ), Research Network in Inflammation and Rheumatic Diseases (RIER), Paseo de la Castellana, 261, 28046-Madrid, Spain

13 Department of Biochemistry and Biotechnology, University of Thessaly, 26 Ploutonos & Aiolou Str., 41221-Larissa, Greece

14 Rheumatology Department, Hospital Universitario de Bellvitge, Feixa Llarga s/n, 08907-L'Hospitalet de Llobregat, Barcelona, Spain

15 Rheumatology Department, Hospital Clinic and Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Calle Villarroel 170, 08036-Barcelona, Spain

16 Unidad de Gestión Clínica (UGC) Rheumatology, Hospital Regional Universitario de Málaga, Instituto de Investigación Biomédica de Málaga (IBIMA), Avenida Carlos Haya s/n, 29010-Málaga, Spain

17 Rheumatology Unit, Hospital Santa Creu e San Pau, Carrer de Sant Quintí 89, 08026-Barcelona, Spain

18 Department of Medicine, University of Santiago de Compostela, Rúa de San Francisco s/n, 15782-Santiago de Compostela, Spain

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Arthritis Research & Therapy 2014, 16:R66  doi:10.1186/ar4504

Published: 11 March 2014



In this study, our aim was to elucidate the role of four polymorphisms identified in a prior large genome-wide association study (GWAS) in which the investigators analyzed the responses of patients with rheumatoid arthritis (RA) to treatment with tumor necrosis factor inhibitors (TNFi). The authors of that study reported that the four genetic variants were significantly associated. However, none of the associations reached GWAS significance, and two subsequent studies failed to replicate these associations.


The four polymorphisms (rs12081765, rs1532269, rs17301249 and rs7305646) were genotyped in a total of 634 TNFi-treated RA patients of Spanish Caucasian origin. Four outcomes were evaluated: changes in the Disease Activity Score in 28 joints (DAS28) after 6 and 12 months of treatment and classification according to the European League Against Rheumatism (EULAR) response criteria at the same time points. Association with DAS28 changes was assessed by linear regression using an additive genetic model. Contingency tables of genotype and allele frequencies between EULAR responder and nonresponder patients were compared. In addition, we combined our data with those of previously reported studies in a meta-analysis including 2,998 RA patients.


None of the four genetic variants showed an association with response to TNFi in any of the four outcomes analyzed in our Spanish patients. In addition, only rs1532269 yielded a suggestive association (P = 0.0033) with the response to TNFi when available data from previous studies were combined in the meta-analysis.


Our data suggest that the rs12081765, rs1532269, rs17301249 and rs7305646 genetic variants do not have a role as genetic predictors of TNFi treatment outcomes.