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

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 TNFalpha (-238, -308, -376), TGFbeta (codon 10 and 25), IFNgamma (+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 IFNgamma +874 T/T (odds ratio (OR) = 3.14) and TNFalpha-238 G/A (OR = 5.01) genotypes was found in WG patients. When ESRD positive and negative patients were compared, the IFNgamma +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.