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PLoS One. 2019 Feb 28;14(2):e0213073. doi: 10.1371/journal.pone.0213073. eCollection 2019.

Evaluation of 12 GWAS-drawn SNPs as biomarkers of rheumatoid arthritis response to TNF inhibitors. A potential SNP association with response to etanercept.

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Experimental and Observational Rheumatology and Rheumatology Unit, Instituto de Investigacion Sanitaria-Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain.
Arthritis Unit, Rheumatology Dpt, Hospital Clinic and IDIBAPS, Barcelona, Spain.
Department of Rheumatology, Hospital Clínico San Cecilio, Granada, Spain.
Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
Department of Biochemistry and Biotechnology, University of Thessaly, Larissa, Greece.
Rheumatology Unit, Hospital Universitario Virgen de las Nieves, Granada, Spain.
Reumatology Department, Hospital 12 de Octubre, Madrid, Spain.
Department of Rheumatology, Instituto de Investigación Hospital Universitario La Paz, Hospital Universitario La Paz, Madrid, Spain.
Department of Immunology, Instituto de Investigación Hospital Universitario La Paz, Madrid, Spain.
Rheumatology Department, Instituto de Investigacion Biomedica-Complejo Hospitalario Universitario A Coruna, A Coruna, Spain.
Department of Rheumatology, Hospital Virgen de la Arrixaca, Murcia, Spain.
Servicio de Reumatología, HRU Carlos Haya, Universidad de Málaga, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain.
Department of Rheumatology, Hospital Doctor Peset, Valencia, Spain.
Department of Rheumatology, Hospital Universitario de Bellvitge, Barcelona, Spain.
Rheumatology Unit, Hospital Universitario Virgen Macarena, Sevilla, Spain.
Rheumatology Unit, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
Department of Rheumatology, Hospital Virgen de la Victoria, Málaga, Spain.
Instituto de Parasitología y Biomedicina López-Neyra, CSIC, Granada, Spain.


Research in rheumatoid arthritis (RA) is increasingly focused on the discovery of biomarkers that could enable personalized treatments. The genetic biomarkers associated with the response to TNF inhibitors (TNFi) are among the most studied. They include 12 SNPs exhibiting promising results in the three largest genome-wide association studies (GWAS). However, they still require further validation. With this aim, we assessed their association with response to TNFi in a replication study, and a meta-analysis summarizing all non-redundant data. The replication involved 755 patients with RA that were treated for the first time with a biologic drug, which was either infliximab (n = 397), etanercept (n = 155) or adalimumab (n = 203). Their DNA samples were successfully genotyped with a single-base extension multiplex method. Lamentably, none of the 12 SNPs was associated with response to the TNFi in the replication study (p > 0.05). However, a drug-stratified exploratory analysis revealed a significant association of the NUBPL rs2378945 SNP with a poor response to etanercept (B = -0.50, 95% CI = -0.82, -0.17, p = 0.003). In addition, the meta-analysis reinforced the previous association of three SNPs: rs2378945, rs12142623, and rs4651370. In contrast, five of the remaining SNPs were less associated than before, and the other four SNPs were no longer associated with the response to treatment. In summary, our results highlight the complexity of the pharmacogenetics of TNFi in RA showing that it could involve a drug-specific component and clarifying the status of the 12 GWAS-drawn SNPs.

Conflict of interest statement

The authors have declared that no competing interests exist.

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