Immunogenetic risk factors for anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis.
Wegener's granulomatosis (WG) and microscopic polyangiitis are systemic autoimmune diseases characterized by the presence of ANCA in the sera of patients. Little is known about the aetiologic factors and genetic predisposition as well as the pathogenesis of these disease entities. A slightly decreased representation of HLA-DRB1*13 and HLA-DQB1*0603 individuals was observed in our cohort of ANCA-associated systemic vasculitis (AASV) patients compared with controls. In addition, HLA-DRB1*04 individuals were over-represented in a subgroup of patients with WG in end-stage renal disease as a result of renal vasculitis. In order to identify other genes relevant for these diseases, we investigated highly polymorphic markers in the vicinity of several immunorelevant genes, i.e. tumour necrosis factor (TNF)alpha, IL-2, IL-5 receptor alpha (IL-5RA), in a group of 102 patients with AASV and compared the representation with controls. Furthermore, functional polymorphisms were directly analysed in the promotor region of TNFalpha as well as in the coding region of the FcgammaIIRA genes. Polymorphisms of the TNFalpha promotor (TNF-308) as well as in the FcgammaIIRA gene were excluded as risk factors for the disease in our cohort. No major phenotype distribution differences were observed between patients and controls for the IL-2 and IL-5RA microsatellites. Most importantly, several haplotypes on chromosome 6p appeared strongly associated with proteinase 3 (PR3)-ANCA+ AASV. Thus, as in other autoimmune diseases, different predisposing factors play differential aetiopathogenic roles in various groups of AASV patients.
Gencik
M
M
Molekulare Humangenetik, Ruhr-Universität Bochum, Germany.
Borgmann
S
S
Zahn
R
R
Albert
E
E
Sitter
T
T
Epplen
J T
JT
Fricke
H
H
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000097:blood*; D005260:Female; D005819:Genetic Markers; D006683:HLA-DQ Antigens / Q000097:blood / Q000235:genetics; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000097:blood / Q000235:genetics; D059811:HLA-DRB1 Chains; D006650:Histocompatibility Testing; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics; D015848:Interleukin-5 / Q000235:genetics; D015810:Linkage Disequilibrium; D008297:Male; D018895:Microsatellite Repeats / Q000276:immunology; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000276:immunology; D017452:Receptors, IgG / Q000235:genetics; D018123:Receptors, Interleukin / Q000235:genetics; D053649:Receptors, Interleukin-5; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D014657:Vasculitis / Q000097:blood / Q000235:genetics* / Q000276:immunology*
D019268:Antibodies, Antineutrophil Cytoplasmic; D005819:Genetic Markers; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D007376:Interleukin-2; D015848:Interleukin-5; D017452:Receptors, IgG; D018123:Receptors, Interleukin; D053649:Receptors, Interleukin-5; D014409:Tumor Necrosis Factor-alpha