Background/Purpose:

Toll-like receptor (TLR)-4 signaling pathways have been implicated in both the innate and adaptive immune responses that characterize rheumatoid arthritis (RA).  In this study, we examined the associations between TLR-4 single nucleotide polymorphisms (SNPs) and RA using a large well-characterized RA cohort.  

Methods:

A total of 1,559 patients were genotyped for three TLR4 SNPs (rs1927911, rs11536878, and rs4986790), which were selected using a haplotype tagging strategy. Measures of disease severity included the Disease Activity Score-28 (DAS28), Multidimensional Health Assessment Questionnaire (MD-HAQ), Clinical Disease Activity Index (CDAI), and Simplified Diseases Activity Index (SDAI). Associations of TLR4 SNPs with these measures were examined longitudinally (mean of 10 visits, range: 0-60) using generalized estimating equations in both univariate and multivariate analyses, adjusting for age, sex, race, comorbidity, body mass index, smoking, erythrocyte sedimentation rate (ESR), rheumatoid factor (RF) and anti-CCP positivity, methotrexate and anti-tumor necrosis factor use. Based on existing data showing that anti-citrullinated protein antibody (ACPA)-containing immune complexes may drive TLR4 signaling in RA, analyses were also stratified by ACPA positivity including antibody positivity to anti-CCP and anti-citrullinated fibrinogen (cFb) antibody.

Results:

RA patients homozygous for the minor allele of TLR4 rs1927911 demonstrated lower disease activity over follow-up including lower DAS28 (p<0.001), CDAI (p=0.002), and SDAI (p=0.010) in univariate analysis and lower DAS28 (p<0.001) and CDAI (p=0.007) in multivariate analysis (Table). Disease activity among those homozygous for the minor allele tended to be numerically lower in groups with elevated anti-CCP and anti-cFb antibody though no significant differences by ACPA status were identified.  There were no associations of TLR4 rs11536878 and rs4986790 SNPs with any of the RA disease activity measures.

Conclusion:

We found TLR4 rs1927911 genotypes are associated with the rate of disease progression over time independent of other factors. Although further studies are needed to identify mechanisms by which variation in rs1927911 impacts inflammatory burden, these data are consistent with reports in other disease states suggesting that this SNP is associated with a meaningful anti-inflammatory effect and support the concept of TLR4 as a potential therapeutic target in RA.

Table:  Associations of TLR-4 rs1927911 genotype with RA disease progression (DAS28, HAQ, CDAI, and SDAI differences per year of follow up); p-values < 0.0167 (Bonferroni correction) considered to be statistically significant