Association of a functional polymorphism in the promoter region of TLR-3 with osteoarthritis: A two-stage case-control study

Recent studies have suggested that polymorphisms in toll‐like receptor 9 (TLR‐9), an endosomal TLR, are associated with knee osteoarthritis (OA). TLR‐3, ‐7, and ‐8 are also found on the surface of endosomes and to investigate whether similar associations exist with polymorphisms in these TLR genes we performed a two‐stage case–control study and genotyped 11 TLR single nucleotide polymorphisms (SNPs) in 823 OA cases and 594 healthy controls by polymerase chain reaction restriction fragment length polymorphism assays. Real‐time PCR was performed to assess the functional expression of an identified promoter polymorphism in TLR‐3 following dexamethasone stimulation of articular chondrocytes. An association between TLR‐3 SNPs at rs3775296 and rs3775290 and OA was identified in both populations. In males the allelic frequencies of TLR‐7 rs179010 and TLR‐8 rs5744080 were significantly different between OA cases and healthy controls. The ATCA, CTCA, and CCTA haplotypes of TLR‐3 were associated with OA susceptibility. A significant difference in TLR‐3 gene expression following dexamethasone treatment was seen among the various genotypes of rs3775296 (p = 0.004). Our findings indicate that a SNP in the promoter region of TLR‐3 is associated with elevated TLR‐3 gene expression and susceptibility to knee OA in a Chinese Han population. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 680–685, 2013