Abstract

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 non-protein 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. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1972-1978, 2019.

Highlights

  • Primary osteoarthritis (OA) is a complex genetic disease of unknown origin that has close to 100 genetic loci associated with the onset of disease

  • Because T‐cell reactivity against chondrocyte surface antigens was detected in patients with OA,[9] it has been surmised that interleukin 17A (IL17A) plays an important role in pathogenesis of OA

  • Haplotype Analysis of Two single‐nucleotide polymorphisms (SNPs): IL17A–IL17F The frequency and number of estimated IL17A–IL17F haplotypes are listed in Table 1 (HOA vs. controls) and Table 2 (KOA vs. controls)

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Summary

Introduction

Primary osteoarthritis (OA) is a complex genetic disease of unknown origin that has close to 100 genetic loci associated with the onset of disease. Each of these might contribute by a minute part of the risk. The IL17 gene locus, whose products could increase predisposition to primary OA, is located on chromosome 6 (6p12.3‐q13), in the area found previously to harbor such genetic risk in the UK population.[4] The genes at this locus encode interleukin 17A (IL17A) and IL17F cytokines,[5] which are involved in the innate and adaptive immune responses. The case complicates when many of these genetic susceptibilities are found specific for a certain population or even subpopulation

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