Toll-like receptor 4 polymorphism influences susceptibility to but not severity and outcome of rheumatoid arthritis

Introduction

Toll-like receptors (TLRs) play an important role in the innate and adaptive immune response. TLR4 is the most thoroughly studied member of this receptor family and interacts with endogenous ligands, which are abundantly present in the synovial joint during rheumatoid arthritis (RA).

Objective

The aim of the present study was to analyze the relationship between the TLR4 Asp299Gly (896A>G) polymorphism and RA susceptibility, disease phenotype and outcome over a 6-year period of the disease.

Methods

Genotyping was performed on RA patients from an early RA inception cohort. Healthy controls consisted of healthy blood donors. To assess the influence of the TLR4 variant on disease phenotype, course and outcome, we compared prospectively collected disease activity and outcome parameters of patients with and without the variant TLR4 allele. TLR4 genotyping of the A>G polymorphism at position 896 of the TLR4 gene was performed using RFLP.

Results

In 282 RA patients and 314 healthy individuals we found that the frequency of the TLR4 Asp299Gly polymorphism was significantly lower among RA patients (10.6%) than among controls (17.2%; P = 0.02). To analyze potential differences in disease phenotype, severity and outcome 30 RA patients heterozygous for the TLR4 variant were compared with 252 RA patients possessing two wild-type alleles. Apart from the higher DAS at baseline (6.1 versus 5.4; P = 0.01), no other differences in phenotype, severity or outcome of RA were detected between both groups.

Discussion

Here we demonstrate a link between RA disease susceptibility and the TLR4 polymorphism in a large set of RA patients and healthy individuals. Furthermore, we show that the TLR4 polymorphism might be important in the onset of disease but does not seem to play a role in disease outcome.