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Interleukin-4 Promoter Polymorphisms: A Genetic Prognostic Factor for Survival in Metastatic Renal Cell Carcinoma

Thomas Kleinrath, Christoph Gassner, Peter Lackner, Martin Thurnher, Reinhold Ramoner

From the Central Institute for Blood Transfusion and Immunological Department, Department of Neurology, and Department of Urology, Innsbruck Medical University, Innsbruck, Austria

Address reprint requests to Reinhold Ramoner, PhD, Department of Urology, Innsbruck Medical University, Anichstr 35, Innsbruck, Ty, Austria; e-mail: reinhold.ramoner{at}i-med.ac.at; cc: martin.thurnher{at}i-med.ac.at

Purpose 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.

Patients and 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.

Conclusion 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.

Supported by Grant No. 03a of the Kompetenzzentrum Medizin Tirol (to M.T., work was performed in the Department of Urology).

All institutions are certified according to International Standards Organization 9001:2000.

Both T.K. and C.G. contributed equally to this work.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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