title: Interleukin-4 promoter polymorphisms: a genetic prognostic factor for survival in metastatic renal cell carcinoma.
abstract: OBJECTIVE
  Renal cell carcinoma (RCC) is considered a cytokine-responsive tumor. The clinical course of a patient may thus be influenced by the patient's capacity to produce distinct cytokines. Therefore, cytokine gene polymorphisms in RCC patients were analyzed to determine haplotype combinations with prognostic significance.
  
  
  METHODS
  A selection of 21 single nucleotide polymorphisms within the promoter regions of 13 cytokine genes were analyzed in a cross-sectional single-center study of 80 metastatic RCC patients. Univariate and multivariate analyses and the Cox forward-stepwise regression model were chosen to assess genetic risk factors.
  
  
  RESULTS
  Multivariate Cox regression analysis confirmed by a bootstrap technique identified the heterozygous IL4 genotype -589T-33T/-589C-33C as an independent prognostic risk factor (risk ratio, 3.1; P < .01; 95% CI, 1.4 to 6.9; adjusted for age, sex, and nuclear grading) in metastatic RCC patients. IL4 haplotype -589T-33T and -589C-33C were found with a frequency of 0.069 and 0.925, respectively, which represents a two-fold decrease of IL4 haplotype -589T-33T (P < .01) and an increase of IL4 haplotype -589C-33C frequency (P < .05) in metastatic RCC compared with other white reference study populations. The median overall survival was decreased 3.5-fold (P < .05) in heterozygote patients carrying IL4 haplotype -589T-33T and -589C-33C (3.78 months) compared with patients homozygote for IL4 haplotype -589C-33C (13.44 months). In addition, a linkage disequilibrium between the IL4 gene and the KIF3A gene was detected.
  
  
  CONCLUSIONS
  Our findings indicate that IL4 promoter variants influence prognosis in patients with metastatic RCC and suggest that genetically determined interleukin-4 (IL-4) production affects the clinical course of the disease possibly through regulation of immune surveillance.
authors.affiliation: Central Institute for Blood Transfusion and Immunological Department, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kleinrath
authors.forename: Christoph
authors.initials: C
authors.lastname: Gassner
authors.forename: Peter
authors.initials: P
authors.lastname: Lackner
authors.forename: Martin
authors.initials: M
authors.lastname: Thurnher
authors.forename: Reinhold
authors.initials: R
authors.lastname: Ramoner
mesh_terms: D002292:Carcinoma, Renal Cell / Q000235:genetics*; D005260:Female; D006239:Haplotypes; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics*; D007680:Kidney Neoplasms / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D053773:Transforming Growth Factor beta1 / Q000235:genetics
chemical_list: D053773:Transforming Growth Factor beta1; D016753:Interleukin-10; D015847:Interleukin-4