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

Author

Listed:
  • Aida Ferreiro-Iglesias
  • Ariana Montes
  • Eva Perez-Pampin
  • Juan D Cañete
  • Enrique Raya
  • Cesar Magro-Checa
  • Yiannis Vasilopoulos
  • Rafael Caliz
  • Miguel Angel Ferrer
  • Beatriz Joven
  • Patricia Carreira
  • Alejandro Balsa
  • Dora Pascual-Salcedo
  • Francisco J Blanco
  • Manuel J Moreno-Ramos
  • Sara Manrique-Arija
  • María del Carmen Ordoñez
  • Juan Jose Alegre-Sancho
  • Javier Narvaez
  • Federico Navarro-Sarabia
  • Virginia Moreira
  • Lara Valor
  • Rosa Garcia-Portales
  • Ana Marquez
  • Juan J Gomez-Reino
  • Javier Martin
  • Antonio Gonzalez

Abstract

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.

Suggested Citation

  • Aida Ferreiro-Iglesias & Ariana Montes & Eva Perez-Pampin & Juan D Cañete & Enrique Raya & Cesar Magro-Checa & Yiannis Vasilopoulos & Rafael Caliz & Miguel Angel Ferrer & Beatriz Joven & Patricia Carr, 2019. "Evaluation of 12 GWAS-drawn SNPs as biomarkers of rheumatoid arthritis response to TNF inhibitors. A potential SNP association with response to etanercept," PLOS ONE, Public Library of Science, vol. 14(2), pages 1-14, February.
    • Handle: RePEc:plo:pone00:0213073
    DOI: 10.1371/journal.pone.0213073
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    1. Viechtbauer, Wolfgang, 2010. "Conducting Meta-Analyses in R with the metafor Package," Journal of Statistical Software, Foundation for Open Access Statistics, vol. 36(i03).
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