Potential Impact of Polymorphisms in Toll-like Receptors 2, 3, 4, 7, 9, miR-146a, miR-155, and miR-196a Genes on Osteoarthritis Susceptibility

SIMPLE SUMMARY: Osteoarthritis (OA) is a progressive inflammatory disease and a leading cause of disability among elders. Accumulating evidence suggests that inflammation-related genes, including genes for Toll-like receptors (TLRs), could play an important role in the susceptibility to and pathogenesis of OA. Toll-like receptors are controlled by several microRNAs, which in addition to their role in the epigenetic regulation of gene expression on a post-transcriptional level, are ligands for TLR activation and downstream signaling. Thus, we evaluated the association between OA risk and genetic variants in TLR2, TLR3, TLR4, TLR7, TLR9, and microRNAs that regulate TLR signaling miR-146a, miR-155, and miR-196a2. Our findings indicate that polymorphisms in the TLR4 and TLR7 genes could increase OA risk, and shows a novel suggestive association of the miR-196a2 polymorphism rs11614913 variant allele with a decreased susceptibility to OA. The modulation of TLRs and miRNAs and their cross-talk might be an attractive target for a personalized approach to OA management. ABSTRACT: Osteoarthritis (OA) is a progressive inflammatory disease of synovial joints and a leading cause of disability among adults. Inflammation-related genes, including genes for Toll-like receptors (TLRs), are tightly controlled by several microRNAs that, in addition to their pivotal role in the epigenetic regulation of target genes, are ligands for TLR activation and downstream signaling. Thus, we evaluated the association between OA risk and genetic variants in TLR2, TLR3, TLR4, TLR7, TLR9, and microRNAs that regulate TLRs signaling miR146a, miR155, and miR196a2. Our study group consisted of 95 surgically treated OA patients and a control group of 104 healthy individuals. Genetic polymorphisms were determined using TaqMan real-time PCR assays (Applied Biosystems). Adjusted logistic regression analysis demonstrated that polymorphisms in TLR4 rs4986790 (OR = 2.964, p = 0.006), TLR4 rs4986791 (OR = 8.766, p = 0.00001), and TLR7 rs385389 (OR = 1.579, p = 0.012) increased OA risk, while miR-196a2 rs11614913 (OR = 0.619, p = 0.034) was significantly associated with decreased OA risk. Our findings indicate that polymorphisms in the TLR4 and TLR7 genes might increase OA risk and suggest a novel association of miR-196a2 polymorphism with decreased OA susceptibility. The modulation of TLRs and miRNAs and their cross-talk might be an attractive target for a personalized approach to OA management.