title: 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.
abstract: BACKGROUND
  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-alpha (TNF-alpha), and transforming growth factor-beta1 (TGF-beta1)--as potential predictors of time to onset of aseptic instability.
  
  
  METHODS
  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-alpha promoter (-308G-->A), and TGF-beta1 signal sequence (29T-->C) transitions. Cox regression was performed on the prosthesis survival.
  
  
  RESULTS
  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-beta1 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-beta1 (29T-->C)" was considered as a three-level factor (three possible genotypes), and 4.92 (1.71-14.1) (P=0.003) when TGF-beta1 site was considered as a two-level factor (T/T and "C-allele carriage"). The HR for the "A-allele carriage" at TNF-alpha (-308G-->A) could not be determined (only two patients had the G/G genotype).
  
  
  CONCLUSIONS
  This preliminary study is the first to suggest that the TGF-beta1 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.
authors.affiliation: Department of Orthopaedic Surgery, Clinical Hospital Center Zagreb and University School of Medicine, Salata 3, 10000, Zagreb, Croatia.
authors.forename: Robert
authors.initials: R
authors.lastname: Kolundzić
authors.forename: Dubravko
authors.initials: D
authors.lastname: Orlić
authors.forename: Vladimir
authors.initials: V
authors.lastname: Trkulja
authors.forename: Kresimir
authors.initials: K
authors.lastname: Pavelić
authors.forename: Koraljka Gall
authors.initials: KG
authors.lastname: Troselj
mesh_terms: D000328:Adult; D019644:Arthroplasty, Replacement, Hip; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006622:Hip Prosthesis; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D011475:Prosthesis Failure; D053773:Transforming Growth Factor beta1 / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D015850:Interleukin-6; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha