Primary osteoarthritis (OA) is the most common type of a joint disease. It has a polygenic risk inheritance pattern and affects older people. The etiology of this disease is not fully understood. The aim of this study was to investigate the associations between polymorphisms in pro-inflammatory interleukin-17 (IL17A and IL17F) and anti-inflammatory Toll-like Receptor 10 (TLR10) genes with the risk for development of advanced stage hip and knee primary OA in the Croatian population. A total of 500 OA patients and 597 controls were genotyped for IL17A SNP (rs2275913), IL17F SNPs (rs763780 and rs1889570), and TLR10 (rs11096957) genes. The allelic and genotypic frequencies of IL17F SNP (rs763780) showed statistically significant differences in comparisons of controls with hip-but not knee-OA patients. The major allele (T) of rs763780 was associated with the lower risk for developing hip OA (p = 7.9 × 10 , OR = 0.45, 95%CI = 0.27-0.74), whereas the minor allele (C) was associated with susceptibility to hip OA (p = 7.9 × 10 , OR = 2.24, 95%CI = 1.35-3.72). The genotype T/T was associated with the protection to hip OA (p = 3.9 × 10 , OR = 0.41, 95%CI = 0.24-0.70), and, lastly, the genotype T/C was associated with the higher risk to acquiring hip OA (p = 2.6 × 10 , OR = 2.50, 95%CI = 1.47-4.25). TLR10 SNP rs11096957 was found significantly associated with predisposition to hip OA (p = 0.04, OR = 1.41, 95%CI = 1.02-1.94) but not knee OA. Our findings suggest that hip OA in Croatian population might have a different genetic risk regarding the IL17 and TLR10 gene locus than knee OA. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1684-1693, 2018.

We studied the genetic epidemiology of primary large-joint (hip and knee) osteoarthritis (OA), in order to find disease risk factors by a candidate-gene approach. We used case-control study in the Croatian Caucasian population. We genotyped 500 OA patients (260 hip, 240 knee; both with total joint replacements) and 597 healthy individuals for single-nucleotide polymorphisms (SNPs) in interleukin 17A (IL17A) (rs2275913) and IL17F (rs763780 and rs1889570) genes. On the basis of our population and allelic and genotypic frequencies haplotypes were predicted by PHASE software and compared between patients and controls. The three-SNP haplotype (rs2275913-rs763780-rs1889570) G-C-A confers predisposition to hip (p < 0.005) but not knee OA. The three-SNP haplotype having opposed nucleotides A-T-G was found significantly associated with 2.6 times higher risk for developing knee (p < 0.02) but not hip OA. The haplotype G-T (IL17A-IL17F; rs2275913-rs763780) is associated with protection to the disease in hip OA (p < 0.01). Our analyses show that two disparate haplotypes within the IL17A-F gene locus are associated with higher risk to developing hip and knee OA in the Croatian population. The data might suggest a difference in the etiology of hip OA from that of the knee OA, perhaps due to an unknown dissimilarity in vulnerability of these joints to the actions of IL17. Alternatively, other differences in genetic factors like the long nonprotein coding region LINCMD1 and/or microRNA species like miR133b and miR206 found in the vicinity of the IL17 locus might be involved in the observed risk.

Regarding genetic predisposition to tuberculosis, we suggest that the maximal risk for clinical manifestation requires complementation of sub-risks divided among the hallmarks of the disease. Clinical tuberculosis would only be revealed if at least one from each group of the genes encoding putative 5 (perhaps 7) hallmarks of the disease are mutated or changed epigenetically. These mutations/changes could be either sporadic (usually by the influence of the environment like other infection [HIV], nutrition, smoking, radiation etc.) or inherited. Avoidance of the immune attack is one of the hallmarks for TB that is shared with cancer. Perhaps, a similar immunotherapy as the recent one used in treating immunogenic types of cancer (anti-PD1, or/and anti-CTLA4) could be also successful in therapy of (multi-drug) resistant TB.