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Arthritis Research & Therapy

Open Access

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

  • TRDJ Radstake1,
  • B Franke2,
  • S Hanssen2,
  • P Welsing1,
  • LAB Joosten1,
  • PLCM van Riel1,
  • P Barrera1 and
  • WB van den Berg1
Arthritis Res Ther20046(Suppl 1):75

Received: 16 January 2004

Published: 24 February 2004


Rheumatoid ArthritisRheumatoid Arthritis PatientDisease PhenotypeEarly Rheumatoid ArthritisHealthy Blood Donor


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).


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.


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.


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.


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.

Authors’ Affiliations

Department of Rheumatology, University Medical Center Nijmegen, The Netherlands
Department of Genetics, University Medical Center Nijmegen, The Netherlands


© The Author(s) 2004