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

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.

Indirect influence of microRNA‐146a on the association of IL‐6 and TNF‐α genetic polymorphisms with the increased risk of hip osteoarthritis

“…This means that there are different risk populations, and miR-146a is a significant modifying factor. So, our results regarding the role of the miR-146a gene in affecting the genetic risk of PHOA are in disagreement with the study by Stefik et al 19 We believe that these authors 19 have not found significance in their analyses due to the small sample size of the study and consequently being unable to stratify results.…”

“…Our study is the first of this type in the Croatian (Caucasian) population. Regarding the role of the miR-146a gene in affecting the genetic risk of PKOA, our results seem to be in agreement with studies by Papathanasiou et al, 17 Miranda-Duarte et al, 18 and Stefik et al, 19 and are in disagreement with studies by Liu and colleagues. 5,26 In our study with 609 patients with end-stage POA, it was investigated the association of the miR-146a SNP rs2910164 (G>C) with a predisposition to PHOA.…”

“…That led to the investigation of the association of the miR-146a SNP rs2910164 (G>C) with a predisposition to primary knee osteoarthritis (PKOA) in different populations (Greek, Mexican) without evidence of susceptibility to PKOA. 17,18 In a recently published article, Stefik et al 19 investigated 10 different SNPs in Toll-like receptors (TLRs) genes (TLR2, TLR3, TLR4, TLR7, TLR9), and miRNA genes that regulate TLR signaling (miR-146a, miR-155, and miR-196a2) and their association with advanced stage POA risk in 61 primary hip osteoarthritis (PHOA) patients and 34 PKOA patients. Although it was the first study that investigated the association of the miR-146a SNP rs2910164 with a predisposition to PHOA, the authors have not found the association of this SNP with PHOA susceptibility.…”

Impact of miR-155 rs767649 Polymorphism on Rheumatoid Arthritis Activity in Egyptian Patients

“…The intricate association observed between the rs767649 TA/AA genotype and an increased risk of RA in the multivariate analysis raises questions regarding the precise role of this genetic variant in RA pathogenesis. The miR-155 rs767649 polymorphism is known to influence key regulatory pathways within the immune system [16,17], potentially exacerbating the inflammatory responses characteristic of RA. This finding suggests a nuanced genetic landscape contributing to RA susceptibility, indicating the necessity for further investigations on the molecular mechanisms underlying the influence of this specific genotype on the complex interplay of immune dysregulations in RA.…”

Non-lipid genetic predictors of the development of coronary heart disease and myocardial infarction in patients with hypertension

“…Однако имеется ряд публикаций, оценивающих ассоциацию данного полиморфизма с негативным и протективным влиянием в отношении ряда других нозологий. В настоящее время показана ассоциация данного полиморфизма с некоторыми аутоиммунными и онкологическими заболеваниями [25][26][27][28]. Известно, что TLR3 связывают двухцепочечную рибонуклеиновую кислоту (РНК) вирусов, бактерий, грибов и матричную РНК, выделяемую из некротизированных клеток [29].…”