Associations of toll-like receptor (TLR)-4 single nucleotide polymorphisms and rheumatoid arthritis disease progression: An observational cohort study

•This study examines the association of select toll-like receptor (TLR)4 polymorphisms with rheumatoid arthritis (RA) disease progression over time.•These results demonstrate an independent association between the TLR4 rs1927911 polymorphism and RA disease progression over time.•These findings support an important role of TLR4 in the natural course of RA and suggest that TLR4 could represent a viable target in RA treatment.

ObjectiveTo examine the associations of toll-like receptor (TLR)-4 single nucleotide polymorphisms (SNPs) with disease progression in rheumatoid arthritis (RA).MethodsA total of 1188 RA patients were genotyped for TLR4 SNPs (rs1927911, rs11536878, and rs4986790). Measures of disease activity were examined, including Disease Activity Score-28 (DAS28), Multidimensional Health Assessment Questionnaire (MD-HAQ), Clinical Disease Activity Index (CDAI), and Simplified Disease Activity Index (SDAI). Genetic associations with these longitudinal measures were examined using generalized estimating equations in both univariate and multivariate analyses. Analyses were then stratified by antigen specific anti-citrullinated peptide antibody (ACPA) status including antibody to citrullinated fibrinogen and citrullinated histone H2B.ResultsDisease activity measures progressed less over time in the homozygous minor allele group of rs1927911 including DAS28 (p < 0.001), CDAI (p = 0.008), and MD-HAQ (p = 0.015) in univariate analysis and DAS28, CDAI and SDAI in multivariate analysis. Disease activity progression among those homozygous for the minor allele tended to be lower in the groups with positive ACPA though major differences by autoantibody status were not identified. There were no associations of TLR4 rs11536878 and rs4986790 SNPs with RA disease activity progression.ConclusionsIn this population, TLR4 rs1927911 genotypes are associated with disease activity independent of other covariates.