Distinct tumour necrosis factor alpha, interferon gamma, 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 TNF alpha (-238, -308, -376), TGF beta (codon 10 and 25), IFN gamma (+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 gamma +874 T/T (odds ratio (OR) = 3.14) and TNF alpha -238 G/A (OR = 5.01) genotypes was found in WG patients. When ESRD positive and negative patients were compared, the IFN gamma +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.
Spriewald
B M
BM
Institute for Clinical Immunology, Department of Medicine III, University Erlangen-Nürnberg, 91054 Erlangen, Germany. bernd.spriewald@med3.imed.uni-erlangen.de
Witzke
O
O
Wassmuth
R
R
Wenzel
R R
RR
Arnold
M-L
ML
Philipp
T
T
Kalden
J R
JR
D000328:Adult; D000368:Aged; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D060908:CTLA-4 Antigen; D016207:Cytokines / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D014890:Granulomatosis with Polyangiitis / Q000235:genetics* / Q000276:immunology; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics; D007676:Kidney Failure, Chronic / Q000235:genetics* / Q000276:immunology; D008875:Middle Aged; D011110:Polymorphism, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D016207:Cytokines; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma