Genetic Variants in Toll-Like Receptors Are Not Associated with Rheumatoid Arthritis Susceptibility or Anti-Tumour Necrosis Factor Treatment Outcome

Marieke J H Coenen,Alf Kastbom,Leonid Padyukov,Tim L Jansen,Christian Enevold,Piet L C M Van Riel,Klaus Bendtzen,Erik J M Toonen,Mascha M V A P Schijvenaars,Barbara Franke,Wietske Kievit,Dorine Swinkels,Anne Barton,Timothy R D J Radstake,Pilar Barrera,Hans Scheffer,Lars Klareskog,Maarten J Rood

doi:10.1371/journal.pone.0014326

Abstract

BackgroundSeveral studies point to a role of Toll-like receptors (TLRs) in the development of rheumatoid arthritis (RA). We investigated if genetic variants in TLR genes are associated with RA and response to tumour necrosis factor blocking (anti-TNF) medication.Methodology and Principal Findings22 single nucleotide polymorphisms (SNPs) in seven TLR genes were genotyped in a Dutch cohort consisting of 378 RA patients and 294 controls. Significantly associated variants were investigated in replication cohorts from The Netherlands, United Kingdom and Sweden (2877 RA patients and 2025 controls). 182 of the Dutch patients were treated with anti-TNF medication. Using these patients and a replication cohort (269 Swedish patients) we analysed if genetic variants in TLR genes were associated with anti-TNF outcome. In the discovery phase of the study we found a significant association of SNPs rs2072493 in TLR5 and rs3853839 in TLR7 with RA disease susceptibility. Meta-analysis of discovery and replication cohorts did not confirm these findings. SNP rs2072493 in TLR5 was associated with anti-TNF outcome in the Dutch but not in the Swedish population.ConclusionWe conclude that genetic variants in TLRs do not play a major role in susceptibility for developing RA nor in anti-TNF treatment outcome in a Caucasian population.

Highlights

Rheumatoid arthritis (RA) is a severe chronic inflammatory disorder leading to joint damage
We conclude that genetic variants in Toll-like receptors (TLRs) do not play a major role in susceptibility for developing rheumatoid arthritis (RA) nor in anti-tumour necrosis factor (TNF) treatment outcome in a Caucasian population
The minor allele of both SNPs conferred a protective effect for the development of RA

Summary

Introduction

Rheumatoid arthritis (RA) is a severe chronic inflammatory disorder leading to joint damage. The causes of RA are largely unknown, the role of genetic factors is evident, with the MHC region as the major contributor [1]. More than 20 non-MHC regions explaining approximately one third of the genetic contribution to RA have been identified [2]. The role of Toll-like receptors (TLRs) in the development of RA is supported by several studies. Since TLRs are potent activators of proinflammatory cytokines, including tumour necrosis factor (TNF). Several studies point to a role of Toll-like receptors (TLRs) in the development of rheumatoid arthritis (RA). We investigated if genetic variants in TLR genes are associated with RA and response to tumour necrosis factor blocking (antiTNF) medication

Methods

Results

Conclusion