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.
To investigate the role of TLR4 G299D and Mal S180L variants in RA.
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 chi(2) 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.
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.
The Mal S180L and TLR4 G299D polymorphisms do not contribute to RA susceptibility or severity either individually or in combination.