Objectives: Toll-like receptors (TLRs) including TLR4 have been implicated in the pathogenesis of RA. Signalling by these receptors involves interations 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 disease and inhibits pro-inflammatory 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. The aim of this study was 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 (HWE) was tested for each SNP in cases and controls separately using a x2 test with a threshold of a p<0.05. The odd ratios (OR) were calculated with asymptotic 95% confidence intervals (CI) and p-values less than 0.05 were considered significant. Epistasis was assessed using both stratified analysis and the linkage disequilibrium (LD)-based statistic.
Results: MAL S180L genotypes were similar in cases and controls (OR: 0.9, 95% CI: 0.7-1.0, p=0.2). Similarly no difference for TLR4 G299D genotypes was observed (OR: 1.7, 95% CI: 0.3-11.1, p=0.5). No association with either rheumatoid factor (RF) or anti-cyclic citrullinated peptide (anti-CCP) 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.
- innate immunity
- rheumatoid arthritis
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