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Distinct tumour necrosis factor , interferon , interleukin 10, and cytotoxic T cell antigen 4 gene polymorphisms in disease occurrence and end stage renal disease in Wegener’s granulomatosis

B M Spriewald¹, O Witzke², R Wassmuth³, R R Wenzel², M-L Arnold¹, T Philipp², J R Kalden¹

¹ Institute for Clinical Immunology, Department of Medicine III, University Erlangen-Nürnberg, Erlangen, Germany
² Department of Nephrology, University Hospital Essen, Essen, Germany
³ Institute for Transplantation Diagnostics and Cell Therapeutics, University Medical Centre, Düsseldorf, Germany

Correspondence to:
Correspondence to:
Dr Bernd M Spriewald
Institute for Clinical Immunology, Department of Medicine III, Glückstrasse 4a, 91054 Erlangen, Germany; bernd.spriewald{at}med3.imed.uni-erlangen.de

Background: Cytokines and T cell regulatory proteins play an important role in the pathogenesis of Wegener’s granulomatosis (WG).

Objective: To investigate cytokine and cytotoxic T cell antigen-4 (CTLA4) gene polymorphisms and HLA class II alleles in generalised WG.

Methods: The distribution of cytokine and cytotoxic T cell antigen 4 (CTLA4) gene polymorphisms and HLA class II alleles was analysed in 32 patients with generalised WG and 91 healthy controls. Genotyping was carried out for HLA-DRB1 and HLA-DQB1 and for polymorphism of the genes encoding TNF (–238, –308, –376), TGFß (codon 10 and 25), IFN (+874), IL6 (–174), IL10 (–592, –819, –1082), CTLA4 (–318, +49), and the (AT)_n repeats of the CTLA4 gene. In addition, stratification analysis was carried out according to the presence (n = 15) or absence (n = 17) of end stage renal disease.

Results: An increase in the IFN +874 T/T (odds ratio (OR) = 3.14) and TNF –238 G/A (OR = 5.01) genotypes was found in WG patients. When ESRD positive and negative patients were compared, the IFN +874 A/A and the CTLA4 –318 C/C genotypes were found more often in the ESRD subgroup (OR = 10.6 and OR = 2.25). WG patients without ESRD had a higher frequency of the IL10 GCC/ACC promotor genotype (OR = 0.13) and long CTLA4 (AT)_n repeats (OR = 0.4). No effect was seen for HLA-DR and –DQ markers.

Conclusions: Disease susceptibility and clinical course in WG may be associated with distinct polymorphisms of cytokine and CTLA4 genes.

Abbreviations: ANCA, antineutrophil cytoplasmic autoantibodies; ESRD, end stage renal disease; IFN, interferon ; IL, interleukin; TGFß, transforming growth factor ß; TNF, tumour necrosis factor ; WG, Wegener’s granulomatosis

Keywords: Wegener’s granulomatosis; polymorphism; TNF; CTLA4

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