BACKGROUND: The differences in total hip arthroplasty (THA) survivorship may be influenced by individual susceptibility to periprosthetic osteolysis. This may be driven by functional polymorphisms in the genes for cytokines and cytokine receptors involved in the development of osteolysis in THA, thereby having an effect on the individual's phenotype. METHODS: We performed a study on 22 single-nucleotide polymorphisms (SNPs) for 11 cytokines and two cytokine receptor candidate genes for association with severity of acetabular osteolysis and risk to failure in THA. Samples from 205 unrelated Caucasian patients with cementless type THA (ABG 1) were investigated. Distribution of investigated SNP variants between the groups of mild and severe acetabular osteolysis was determined by univariate and multivariate analysis. Time-dependent output variables were analyzed by the Cox hazards model. RESULTS: Univariate analysis showed: 1) TNF-238*A allele was associated with severe osteolysis (odds ratio, OR = 6.59, p = 0.005, population attributable risk, PAR 5.2%); 2) carriers of the IL6-174*G allele were 2.5 times more prone to develop severe osteolysis than non-carriers (OR = 2.51, p = 0.007, PAR = 31.5%); 3) the carriage of IL2-330*G allele was associated with protection from severe osteolysis (OR = 0.55, p = 0.043). Based on logistic regression, the alleles TNF-238*A and IL6-174*G were independent predictors for the development of severe acetabular osteolysis. Carriers of TNF-238*A had increased cumulative hazard of THA failure according to Cox model (p = 0.024). In contrast, IL2-330*G allele predicted lower cumulative hazard of THA failure (p = 0.019). CONCLUSION: Genetic variants of proinflammatory cytokines TNF-alpha and IL-6 confer susceptibility to severe OL. In this way, presence of the minor TNF allele could increase the cumulative risk of THA failure. Conversely, SNP in the IL2 gene may protect carriers from the above THA complications.

Department of Orthopaedics Teaching Hospital and Faculty of Medicine and Dentistry Palacky University 1 P Pavlova 6 Olomouc775 20 Czech Republic; Laboratory of Immunogenomics Faculty of Medicine and Dentistry Palacky University 1 P Pavlova 6 Olomouc 775 20 Czech Republic

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Learmonth ID, Young C, Rorabeck C. The operation of the century: total hip replacement. Lancet. 2007;370:1508–1519. doi: 10.1016/S0140-6736(07)60457-7. PubMed DOI

Tuan RS, Lee FY, Y TK, Wilkinson JM, Smith RL. What are the local and systemic biologic reactions and mediators to wear debris, and what host factors determine or modulate the biologic response to wear particles? J Am Acad Orthop Surg. 2008;16:S42–48. PubMed PMC

Konttinen YT, Zhao D, Beklen A, Ma G, Takagi M, Kivela-Rajamaki M, Ashammakhi N, Santavirta S. The microenvironment around total hip replacement prostheses. Clin Orthop Relat Res. 2005:28–38. doi: 10.1097/01.blo.0000150451.50452.da. PubMed DOI

Vermes C, Chandrasekaran R, Jacobs JJ, Galante JO, Roebuck KA, Glant TT. The effects of particulate wear debris, cytokines, and growth factors on the functions of MG-63 osteoblasts. J Bone Joint Surg Am. 2001;83-A:201–211. PubMed

Koulouvaris P, Ly K, Ivashkiv LB, Bostrom MP, Nestor BJ, Sculco TP, Purdue PE. Expression profiling reveals alternative macrophage activation and impaired osteogenesis in periprosthetic osteolysis. J Orthop Res. 2008;26:106–116. doi: 10.1002/jor.20486. PubMed DOI

Shanbhag AS, Kaufman AM, Hayata K, Rubash HE. Assessing osteolysis with use of high-throughput protein chips. J Bone Joint Surg Am. 2007;89:1081–1089. doi: 10.2106/JBJS.F.00330. PubMed DOI

Sabokbar A, Itonaga I, Sun SG, Kudo O, Athanasou NA. Arthroplasty membrane-derived fibroblasts directly induce osteoclast formation and osteolysis in aseptic loosening. J Orthop Res. 2005;23:511–519. doi: 10.1016/j.orthres.2004.10.006. PubMed DOI

Tunyogi-Csapo M, Kis-Toth K, Radacs M, Farkas B, Jacobs JJ, Finnegan A, Mikecz K, Glant TT. Cytokine-controlled RANKL and osteoprotegerin expression by human and mouse synovial fibroblasts: Fibroblast-mediated pathologic bone resorption. Arthritis Rheum. 2008;58:2397–2408. doi: 10.1002/art.23653. PubMed DOI

Ramage SC, Urban NH, Jiranek WA, Maiti A, Beckman MJ. Expression of RANKL in osteolytic membranes: association with fibroblastic cell markers. J Bone Joint Surg Am. 2007;89:841–848. doi: 10.2106/JBJS.F.00655. PubMed DOI

Wilkinson JM, Hamer AJ, Stockley I, Eastell R. Polyethylene wear rate and osteolysis: critical threshold versus continuous dose-response relationship. J Orthop Res. 2005;23:520–525. doi: 10.1016/j.orthres.2004.11.005. PubMed DOI

Goodman SB. Wear particles, periprosthetic osteolysis and the immune system. Biomaterials. 2007;28:5044–5048. doi: 10.1016/j.biomaterials.2007.06.035. PubMed DOI PMC

Granchi D, Cenni E, Trisolino G, Giunti A, Baldini N. Sensitivity to implant materials in patients undergoing total hip replacement. J Biomed Mater Res B Appl Biomater. 2006;77:257–264. PubMed

Ollier WE. Cytokine genes and disease susceptibility. Cytokine. 2004;28:174–178. doi: 10.1016/j.cyto.2004.07.014. PubMed DOI

Wilkinson JM, Wilson AG, Stockley I, Scott IR, Macdonald DA, Hamer AJ, Duff GW, Eastell R. Variation in the TNF gene promoter and risk of osteolysis after total hip arthroplasty. J Bone Miner Res. 2003;18:1995–2001. doi: 10.1359/jbmr.2003.18.11.1995. PubMed DOI

Malik MH, Bayat A, Jury F, Kay PR, Ollier WE. Genetic susceptibility to total hip arthroplasty failure--positive association with mannose-binding lectin. J Arthroplasty. 2007;22:265–270. doi: 10.1016/j.arth.2006.02.163. PubMed DOI

Malik MH, Jury F, Bayat A, Ollier WE, Kay PR. Genetic susceptibility to total hip arthroplasty failure: a preliminary study on the influence of matrix metalloproteinase 1, interleukin 6 polymorphisms and vitamin D receptor. Ann Rheum Dis. 2007;66:1116–1120. doi: 10.1136/ard.2006.062018. PubMed DOI PMC

Kolundzic R, Orlic D, Trkulja V, Pavelic K, Troselj KG. Single nucleotide polymorphisms in the interleukin-6 gene promoter, tumor necrosis factor-alpha gene promoter, and transforming growth factor-beta1 gene signal sequence as predictors of time to onset of aseptic loosening after total hip arthroplasty: preliminary study. J Orthop Sci. 2006;11:592–600. doi: 10.1007/s00776-006-1069-y. PubMed DOI

Malik MH, Bayat A, Jury F, Ollier WE, Kay PR. Genetic susceptibility to hip arthroplasty failure--association with the RANK/OPG pathway. Int Orthop. 2006;30:177–181. doi: 10.1007/s00264-006-0074-2. PubMed DOI PMC

Gordon A, Southam L, Loughlin J, Wilson AG, Stockley I, Hamer AJ, Eastell R, Wilkinson JM. Variation in the secreted frizzled-related protein-3 gene and risk of osteolysis and heterotopic ossification after total hip arthroplasty. J Orthop Res. 2007;25:1665–1670. doi: 10.1002/jor.20446. PubMed DOI

Gordon A, Kiss-Toth E, Stockley I, Eastell R, Wilkinson JM. Polymorphisms in the interleukin-1 receptor antagonist and interleukin-6 genes affect risk of osteolysis in patients with total hip arthroplasty. Arthritis Rheum. 2008;58:3157–3165. doi: 10.1002/art.23863. PubMed DOI

Chanock SJ, Manolio T, Boehnke M, Boerwinkle E, Hunter DJ, Thomas G, Hirschhorn JN, Abecasis G, Altshuler D, Bailey-Wilson JE, et al. Replicating genotype-phenotype associations. Nature. 2007;447:655–660. doi: 10.1038/447655a. PubMed DOI

Saleh KJ, Holtzman J, Gafni A, Saleh L, Davis A, Resig S, Gross AE. Reliability and intraoperative validity of preoperative assessment of standardized plain radiographs in predicting bone loss at revision hip surgery. J Bone Joint Surg Am. 2001;83-A:1040–1046. PubMed

Gallo J, Langova K, Havranek V, Cechova I. Poor survival of ABG I hip prosthesis in younger patients. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2008;152:163–168. PubMed

Engh CA, Massin P, Suthers KE. Roentgenographic assessment of the biologic fixation of porous-surfaced femoral components. Clin Orthop Relat Res. 1990:107–128. PubMed

Udomkiat P, Wan Z, Dorr LD. Comparison of preoperative radiographs and intraoperative findings of fixation of hemispheric porous-coated sockets. J Bone Joint Surg Am. 2001;83-A:1865–1870. PubMed

Gallo J, Havranek V, Zapletalova J, Mandat D. Measurement of acetabular polyethylene wear of total hip replacement, using a universal measuring microscope. Characteristics of measurements. Acta Chir Orthop Traumatol Cech. 2006;73:28–33. In Czech. PubMed

Gallo J, Havranek V, Cechova I, Zapletalova J. Wear measurement of retrieved polyethylene ABG 1 cups by universal-type measuring microscope and X-ray methods. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2006;150:321–326. PubMed

Javor J, Bucova M, Ferencik S, Grosse-Wilde H, Buc M. Single nucleotide polymorphisms of cytokine genes in the healthy Slovak population. Int J Immunogenet. 2007;34:273–280. doi: 10.1111/j.1744-313X.2007.00693.x. PubMed DOI

Kubistova Z, Mrazek F, Tudos Z, Kriegova E, Ambruzova Z, Mytilineos J, Petrek M. Distribution of 22 cytokine gene polymorphisms in the healthy Czech population. Int J Immunogenet. 2006;33:261–267. doi: 10.1111/j.1744-313X.2006.00609.x. PubMed DOI

Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215. doi: 10.1093/nar/16.3.1215. PubMed DOI PMC

Hansen JA, (Ed) Proceedings of the 13th International Histocompatibility Workshop and Conference. Vol. 1. Seattle: IHWG Press; 2007. Immunobiology of the human MHC.

Hutyrova B, Pantelidis P, Drabek J, Zurkova M, Kolek V, Lenhart K, Welsh KI, Du Bois RM, Petrek M. Interleukin-1 gene cluster polymorphisms in sarcoidosis and idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2002;165:148–151. PubMed

Mrazek F, Gallo J, Arakelyan A, Kubistova Z, Petrek M. Single nucleotide polymorphisms in genes for cytokines interleukin (IL)-2, IL-6 and TNFalpha influence severity of osteolysis after total hip arthroplasty. Tissue Antigens. 2008;71:331–332.

Wroblewski BM, Siney PD, Fleming PA. Charnley low-friction arthroplasty: survival patterns to 38 years. J Bone Joint Surg Br. 2007;89:1015–1018. doi: 10.1302/0301-620X.89B8.18387. PubMed DOI

Kurreeman FA, Padyukov L, Marques RB, Schrodi SJ, Seddighzadeh M, Stoeken-Rijsbergen G, Helm-van Mil AH van der, Allaart CF, Verduyn W, Houwing-Duistermaat J, et al. A candidate gene approach identifies the TRAF1/C5 region as a risk factor for rheumatoid arthritis. PLoS Med. 2007;4:e278. doi: 10.1371/journal.pmed.0040278. PubMed DOI PMC

DeLee JG, Charnley J. Radiological demarcation of cemented sockets in total hip replacement. Clin Orthop Relat Res. 1976:20–32. PubMed

Little J, Higgins JP, Ioannidis JP, Moher D, Gagnon F, von Elm E, Khoury MJ, Cohen B, Davey-Smith G, Grimshaw J, et al. Strengthening the reporting of genetic association studies (STREGA): an extension of the STROBE Statement. Hum Genet. 2009;125:131–151. doi: 10.1007/s00439-008-0592-7. PubMed DOI

Bayley JP, de Rooij H, Elsen PJ van den, Huizinga TW, Verweij CL. Functional analysis of linker-scan mutants spanning the -376, -308, -244, and -238 polymorphic sites of the TNF-alpha promoter. Cytokine. 2001;14:316–323. doi: 10.1006/cyto.2001.0902. PubMed DOI

Sharma S, Ghosh B, Sharma SK. Association of TNF polymorphisms with sarcoidosis, its prognosis and tumour necrosis factor (TNF)-alpha levels in Asian Indians. Clin Exp Immunol. 2008;151:251–259. PubMed PMC

Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin JS, Humphries S, Woo P. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest. 1998;102:1369–1376. doi: 10.1172/JCI2629. PubMed DOI PMC

Terry CF, Loukaci V, Green FR. Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation. J Biol Chem. 2000;275:18138–18144. doi: 10.1074/jbc.M000379200. PubMed DOI

Smith AJ, Humphries SE. Cytokine and cytokine receptor gene polymorphisms and their functionality. Cytokine Growth Factor Rev. 2009;20:43–59. doi: 10.1016/j.cytogfr.2008.11.006. PubMed DOI

Schluter B, Raufhake C, Erren M, Schotte H, Kipp F, Rust S, Van Aken H, Assmann G, Berendes E. Effect of the interleukin-6 promoter polymorphism (-174 G/C) on the incidence and outcome of sepsis. Crit Care Med. 2002;30:32–37. doi: 10.1097/00003246-200201000-00005. PubMed DOI

Michalek J, Svetlikova P, Fedora M, Klimovic M, Klapacova L, Bartosova D, Hrstkova H, Hubacek JA. Interleukin-6 gene variants and the risk of sepsis development in children. Hum Immunol. 2007;68:756–760. doi: 10.1016/j.humimm.2007.06.003. PubMed DOI

Campos MI, Godoy dos Santos MC, Trevilatto PC, Scarel-Caminaga RM, Bezerra FJ, Line SR. Interleukin-2 and interleukin-6 gene promoter polymorphisms, and early failure of dental implants. Implant Dent. 2005;14:391–396. PubMed

Zaiss MM, Axmann R, Zwerina J, Polzer K, Guckel E, Skapenko A, Schulze-Koops H, Horwood N, Cope A, Schett G. Treg cells suppress osteoclast formation: A new link between the immune system and bone. Arthritis Rheum. 2007;56:4104–4112. doi: 10.1002/art.23138. PubMed DOI

Matesanz F, Fedetz M, Leyva L, Delgado C, Fernandez O, Alcina A. Effects of the multiple sclerosis associated -330 promoter polymorphism in IL2 allelic expression. J Neuroimmunol. 2004;148:212–217. doi: 10.1016/j.jneuroim.2003.12.001. PubMed DOI

Hoffmann SC, Stanley EM, Darrin Cox E, Craighead N, DiMercurio BS, Koziol DE, Harlan DM, Kirk AD, Blair PJ. Association of cytokine polymorphic inheritance and in vitro cytokine production in anti-CD3/CD28-stimulated peripheral blood lymphocytes. Transplantation. 2001;72:1444–1450. doi: 10.1097/00007890-200110270-00019. PubMed DOI

Scola L, Candore G, Colonna-Romano G, Crivello A, Forte GI, Paolisso G, Franceschi C, Lio D, Caruso C. Study of the association with -330T/G IL-2 in a population of centenarians from centre and south Italy. Biogerontology. 2005;6:425–429. doi: 10.1007/s10522-005-4909-9. PubMed DOI

Dupuis J, O'Donnell CJ. Interpreting results of large-scale genetic association studies: separating gold from fool's gold. JAMA. 2007;297:529–531. doi: 10.1001/jama.297.5.529. PubMed DOI

Ioannidis JP. Why most published research findings are false. PLoS Med. 2005;2:e124. doi: 10.1371/journal.pmed.0020124. PubMed DOI PMC

Chougle A, Hemmady MV, Hodgkinson JP. Severity of hip dysplasia and loosening of the socket in cemented total hip replacement. A long-term follow-up. J Bone Joint Surg Br. 2005;87:16–20. PubMed

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