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The Mal/TIRAP S180L and TLR4 G299D polymorphisms are not associated with susceptibility to, or severity of, rheumatoid arthritis
  1. F J Sheedy1,
  2. I Marinou2,
  3. L A J O’Neill1,
  4. A G Wilson2
  1. 1
    School of Biochemistry and Immunology, Trinity College Dublin, Ireland
  2. 2
    School of Medicine and Biomedical Sciences, The University of Sheffield, Royal Hallamshire Hospital, Sheffield, UK
  1. Dr A G Wilson, Section of Musculoskeletal Sciences, School of Medicine and Biomedical Sciences, The University of Sheffield, Royal Hallamshire Hospital, Sheffield S10 2RX, UK; a.g.wilson{at}shef.ac.uk

Abstract

Background: Toll-like receptors (TLRs), including TLR4, have been implicated in the pathogenesis of rheumatoid arthritis (RA). Signalling by these receptors involves interactions with intracellular proteins, including the MyD88 adapter-like (Mal) protein. Recently, a polymorphism (Mal S180L) has been described which contributes to susceptibility to common infectious diseases and inhibits proinflammatory cytokine production. A non-synonymous variant in the extracellular domain of TLR4 (G299D) has been shown to interrupt TLR4-mediated signalling, resulting in endotoxin hyporesponsiveness.

Objective: To investigate the role of TLR4 G299D and Mal S180L variants in RA.

Methods: A total of 964 Caucasians with RA and 965 controls were genotyped. Deviation from Hardy–Weinberg equilibrium was tested for each single nucleotide polymorphism in cases and controls separately using a χ2 test with a threshold of p<0.05. The odd ratios were calculated with asymptotic 95% confidence intervals, and p values <0.05 were considered significant. Epistasis was assessed using both stratified analysis and the linkage disequilibrium-based statistic.

Results: Mal S180L genotypes were similar in cases and controls (OR = 0.9, 95% CI 0.7 to 1.0, p = 0.2). Similarly, no difference for TLR4 G299D genotypes was seen (OR = 1.7, 95% CI 0.3 to 11.1, p = 0.5). No association with either rheumatoid factor or anti-cyclic citrullinated peptide status or with radiological damage was detected. Finally, no evidence of epistasis was detected between Mal S180L and TLR4 G299D and RA susceptibility.

Conclusions: The Mal S180L and TLR4 G299D polymorphisms do not contribute to RA susceptibility or severity either individually or in combination.

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Footnotes

  • Funding: This work was funded by the Science Foundation Ireland.

  • Competing interests: None.

  • Ethics approval: Ethics committee approval was obtained.

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