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

Aida Ferreiro-Iglesias,Beatriz Joven,Enrique Raya,Ariana Montes,Yiannis Vasilopoulos,Juan D Cañete,Lara Valor,Alejandro Balsa,Francisco J Blanco,Sara Manrique‐Arija ,Veridiana Mota Moreira ,César Magro-Checa ,Juan J Gómez-Reino ,Rafael Cáliz ,María Del Carmen Fernández Ordóñez ,Manuel José Moreno‐Ramos ,Javier Martín ,Federico Navarro‐Sarabia ,Eva Pérez‐Pampín ,Miguel Ferrer ,Javier Narváez ,Ana Márquez ,Rosa García-Portales ,Juan José Alegre-Sancho ,Patrícia Carreira ,Dora Pascual‐Salcedo ,Antonio González

doi:10.1371/journal.pone.0213073

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.

Highlights

Rheumatoid arthritis (RA) is a systemic autoimmune disease that until the late 1990s led to permanent disability, low life quality and increased mortality [1]
One of these areas has been genetics, where candidate-gene and genomewide studies (GWAS) have been performed [5,6]. They have been primarily concentrated on the response to three TNF inhibitors (TNFi): infliximab, adalimumab, and etanercept, as the most widely used biologic Disease Modifying Anti-Rheumatic Drug
Some appeared in candidate-gene studies, as the PTPRC rs10919563 SNP, which approached the genome-wide association studies (GWAS)-level of significance combining three large studies [15,16,17]

Summary

Introduction

Rheumatoid arthritis (RA) is a systemic autoimmune disease that until the late 1990s led to permanent disability, low life quality and increased mortality [1]. The goal of predicting the response to treatment in RA patients has been pursued in many research areas [3,4] One of these areas has been genetics, where candidate-gene and genomewide studies (GWAS) have been performed [5,6]. They have been primarily concentrated on the response to three TNFi: infliximab, adalimumab, and etanercept, as the most widely used biologic Disease Modifying Anti-Rheumatic Drug (bDMARD). The initial studies were focused on candidate genes, with many addressing the TNFα gene [7,8] These studies were small, probably expecting polymorphisms with an important influence in the drug effect [6,9]. Others have been highlighted in GWAS [11,12,13,14,18,19], like the four SNPs we attempted to validate in a previous work [20], and the 12 SNPs that we have selected

Methods

Results

Conclusion