Journal of Orthopaedic Science

, Volume 11, Issue 6, pp 592–600 | Cite as

Single nucleotide polymorphisms in the interleukin-6 gene promoter, tumor necrosis factor-α gene promoter, and transforming growth factor-β1 gene signal sequence as predictors of time to onset of aseptic loosening after total hip arthroplasty: preliminary study

  • Robert Kolundžić
  • Dubravko Orlić
  • Vladimir Trkulja
  • Krešimir Pavelić
  • Koraljka Gall Trošelj
Original article



Aseptic loosening resulting from inflammatory response to the implant wear debris is the major cause of late total hip arthroplasty (THA) failure. We examined single nucleotide polymorphisms in genes encoding for three involved cytokines — interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and transforming growth factor-β1 (TGF-β1) — as potential predictors of time to onset of aseptic instability.


A total of 41 patients/45 total hip endoprostheses (same type, same surgeon) were followed up for as long as 18 years. They were genotyped for the IL-6 promoter (-597G→A) and (-572G→C), TNF-α promoter (-308G→A), and TGF-β1 signal sequence (29T→C) transitions. Cox regression was performed on the prosthesis survival.


Overall, 22 of 45 prostheses developed aseptic instability. Cumulative survivals at 10 and 15 years after THA were 95.6% and 66.6%, respectively. The effect of a particular polymorphic site was estimated with adjustment for sex, age at THA, reason for THA, and the effects of other analyzed sites. The hazard ratio (HR) for genotype T/T versus “C-allele carriage”) at the TGF-β1 site was 8.23 [95% confidence interval (CI) 1.45–46.8] (P = 0.017) or 5.70 (1.39-23.4) (P = 0.016) when the IL-6 promoter sites were considered as a “combination of genotypes (-597) | (-572). “The most prevalent combination of genotypes at IL-6 sites was G/A (-597) | C/C (-572). HR for this combination (versus other combinations) was 5.43 (1.73-17.0) (P = 0.004) when “TGF-β1 (29T→C)” was considered as a three-level factor (three possible genotypes), and 4.92 (1.71-14.1) (P = 0.003) when TGF-β1 site was considered as a two-level factor (T/T and “C-allele carriage”. The HR for the “A-allele carriage” at TNF-α (-308G→A) could not be determined (only two patients had the G/G genotype).


This preliminary study is the first to suggest that the TGF-β1 signal sequence (29T→C) and IL-6 promoter (-597G→A) | (-572G→C) transitions are predictive for the time to onset of aseptic instability after THA.


Aseptic Loosening Cumulative Hazard Prosthesis Survival Norwegian Arthroplasty Register Kidney Allograft Survival 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Archibeck, MJ, Jacobs, JJ, Roebuck, K, Glant, TT 2001The basic science of periprosthetic osteolysisInstr Course Lect5018595PubMedGoogle Scholar
  2. 2.
    Havelin, LI, Vollset, SE, Engesaeter, LB 1995Revision for aseptic loosening of uncemented cups in 4,352 primary total hip prostheses: a report from the Norwegian Arthroplasty RegisterActa Orthop Scand66494500PubMedCrossRefGoogle Scholar
  3. 3.
    Havelin, LI, Espehaug, B, Vollset, SE, Engesaeter, LB 1995Early aseptic loosening of uncemented femoral components in primary total hip replacement: a review based on the Norwegian Arthroplasty RegisterJ Bone Joint Surg Br771117PubMedGoogle Scholar
  4. 4.
    Eskelinen, A, Remes, V, Helenius, I, Pulkkinen, P, Nevalainen, J, Paavolainen, P 2005Total hip arthroplasty for primary osteoarthrosis in younger patients in the Finnish Arthroplasty Register: 4,661 primary replacements followed for 0–22 yearsActa Orthop762841CrossRefPubMedGoogle Scholar
  5. 5.
    Smabrekke, A, Espehaug, B, Havelin, LI, Furnes, O 2004Operating time and survival of primary total hip replacements: an analysis of 34,745 primary cemented and uncemented total hip replacements from local hospitals reported to the Norwegian Arthroplasty Register 1987–2001Acta Orthop Scand7552432PubMedCrossRefGoogle Scholar
  6. 6.
    Losina, E, Barrett, J, Mahomed, NN, Baron, JA, Katz, JN 2004Early failures of total hip replacement: effect of surgeon volumeArthritis Rheum50133843CrossRefPubMedGoogle Scholar
  7. 7.
    Furnes, O, Lie, SA, Espehaug, B, Vollset, SE, Engesaeter, LB, Havelin, LI 2001Hip disease and the prognosis of total hip replacements: a review of 53,698 primary total hip replacements reported to the Norwegian Arthroplasty Register 1987–99J Bone Joint Surg Br8357986CrossRefPubMedGoogle Scholar
  8. 8.
    Mabry, TM, Prpa, B, Haidukewych, GJ, Harmsen, WS, Berry, DJ 2004Long-term results of total hip arthroplasty for femoral neck fracture non-unionJ Bone Joint Surg Am8622637PubMedGoogle Scholar
  9. 9.
    Malchau, H, Herberts, P, Ahnfelt, L 1993Prognosis of total hip replacement in Sweden: follow-up of 92,675 operations performed 1978–1990Acta Orthop Scand64497506PubMedGoogle Scholar
  10. 10.
    Wilkinson, JM, Wilson, AG, Stockley, I, Scott, IR, Macdonald, DA, Hamer, AJ,  et al. 2003Variation in the TNF gene promoter and risk of osteolysis after total hip arthroplastyJ Bone Miner Res1819952001CrossRefPubMedGoogle Scholar
  11. 11.
    Derynck, R, Jarrett, JA, Chen, EY, Eaton, DH, Bell, JR, Assoian, RK,  et al. 1985Human transforming growth factor-beta complementary DNA sequence and expression in normal and transformed cellsNature3167015CrossRefPubMedGoogle Scholar
  12. 12.
    Derynck, R, Rhee, L, Chen, EY, Van Tilburg, A 1987Intron-exon structure of the human transforming growth factor-beta precursor geneNucleic Acids Res1531889CrossRefPubMedGoogle Scholar
  13. 13.
    Hinke, V, Seck, T, Clanget, C, Scheidt-Nave, C, Ziegler, R, Pfeilschifter, J 2001Association of transforming growth factor-beta 1 (TGF beta 1) T29→C gene polymorphism with bone mineral density (BMD), changes in BMD, and serum concentrations of TGF-β1 in a population-based sample of postmenopausal German womenCalcif Tissue Int6931520CrossRefPubMedGoogle Scholar
  14. 14.
    Bowcock, AM, Kidd, JR, Lathrop, GM, Daneshvar, L, May, LT, Ray, A,  et al. 1988The human interferon-β2/hepatocyte stimulating factor/interleukin-6 gene: DNA polymorphism studies and localization to chromosome 7p21Genomics3816CrossRefPubMedGoogle Scholar
  15. 15.
    Terry, CF, Loukaci, V, Green, FR 2000Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulationJ Biol Chem2751813844CrossRefPubMedGoogle Scholar
  16. 16.
    Brull, DJ, Montgomery, HE, Sanders, J, Dhamrait, S, Luong, L, Rumley, A,  et al. 2001Interleukin-6 gene -174G > C and -572G > C promoter polymorphisms are strong predictors of plasma interleukin-6 levels after coronary artery bypass surgeryArterioscler Thromb Vasc Biol21145863CrossRefPubMedGoogle Scholar
  17. 17.
    Udalova, IA, Nedospasov, SA, Webb, GC, Chaplin, DD, Turetskaya, RL 1993Highly informative typing of the human TNF locus using six adjacent polymorphic markersGenomics161806CrossRefPubMedGoogle Scholar
  18. 18.
    Abraham, LJ, Kroeger, KM 1999Impact of the -308 TNF promoter polymorphism on the transcriptional regulation of the TNF gene: relevance to diseaseJ Leukoc Biol665626PubMedGoogle Scholar
  19. 19.
    Kolundzic, R, Sulentic, M, Smerdelj, M, Orlic, D, Trkulja, V 2005Stability of Endler cementless polyethylene acetabular cup: long-term follow-upCroat Med J462617PubMedGoogle Scholar
  20. 20.
    DeLee, JG, Charnley, J 1976Radiological demarcation of cemented sockets in total hip replacementClin Orthop1212032PubMedGoogle Scholar
  21. 21.
    Krugluger, J, Eyb, R 1993Bone reaction to uncemented threaded polyethylene acetabular componentsInt Orthop1725965CrossRefPubMedGoogle Scholar
  22. 22.
    Um, JY, Park, JH, Kim, HM 2003Gene polymorphisms in tumor necrosis factor locus and waist-hip ratio in obese KoreansClin Chim Acta33811722CrossRefPubMedGoogle Scholar
  23. 23.
    Schwarzer, G, Schumacher, M, Maurer, TB, Ochsner, PE 2001Statistical analysis of failure times in total joint replacementJ Clin Epidemiol549971003CrossRefPubMedGoogle Scholar
  24. 24.
    Gordon, D, Finch, SJ 2005Factors affecting statistical power in the detection of genetic associationJ Clin Invest115140818CrossRefPubMedGoogle Scholar
  25. 25.
    Villuendas, G, San Millan, JL, Sancho, J, Escobar-Morreale, HF 2002The -597G→A and -174G→C polymorphisms in the promoter of the IL-6 gene are associated with hyperandrogenismJ Clin Endorinol Metab87113441CrossRefGoogle Scholar
  26. 26.
    Hamid, Yh, Rose, CS, Urhammer, SA, Glumer, C, Nolsoe, R, Kristiansen, OP,  et al. 2005Variations of the interleukin-6 promoter are associated with features of the metabolic syndrome in Caucasian DanesDiabetologia4825160CrossRefPubMedGoogle Scholar
  27. 27.
    Georges, JL, Loukaci, V, Poirier, O, Evans, A, Luc, G, Arveiler, D,  et al. 2001Interleukin-6 gene polymorphisms and susceptibility to myocardial infarction: the ECTIM studyJ Mol Med793005CrossRefPubMedGoogle Scholar
  28. 28.
    Muller-Steinhardt, M, Fricke, L, Muller, B, Ebel, B, Kirchner, H, Harter, C 2004Cooperative influence of the interleukin-6 promoter polymorphisms -597, -572 and -174 on long-term kidney allograft survivalAm J Transplant44026CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Orthopaedic Association 2006

Authors and Affiliations

  • Robert Kolundžić
    • 1
  • Dubravko Orlić
    • 1
  • Vladimir Trkulja
    • 2
  • Krešimir Pavelić
    • 3
  • Koraljka Gall Trošelj
    • 3
  1. 1.Department of Orthopaedic SurgeryClinical Hospital Center Zagreb and University School of MedicineZagrebCroatia
  2. 2.Department of PharmacologyZagreb University School of MedicineZagrebCroatia
  3. 3.Laboratory of Molecular PathologyRudjer Bošković InstituteZagrebCroatia

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