Immunogenetic risk factors for anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis

Wegener's granulomatosis (WG) and microscopic polyangiitis are systemic aut oimmune diseases characterized by the presence of ANCA in the sera of patie nts. Little is known about the aetiologic factors and genetic predispositio n as well as the pathogenesis of these disease entities. A slightly decreas ed representation of HLA-DRB1*13 and HLA-DQB 1*0603 individuals was observe d in our cohort of ANCA-associated systemic vasculitis (AASV) patients comp ared with controls. In addition, HLA-DRB1*04 individuals were over-represen ted in a subgroup of patients with WG in end-stage renal disease as a resul t of renal vasculitis. In order to identify other genes relevant for these diseases, we investigated highly polymorphic markers in the vicinity of sev eral 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 compar ed the representation with controls. Furthermore, functional polymorphisms were directly analysed in the promotor region of TNF alpha as well as in th e coding region of the Fc gamma IIRA genes. Polymorphisms of the TNF alpha promotor (TNF-308) as well as in the Fc gamma IIRA gene were excluded as ri sk factors for the disease in our cohort. No major phenotype distribution d ifferences 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 a (PR3)-ANCA(+) AASV. Thus, as in other autoimmune diseases, different predisposing factors play differen tial aetiopathogenic roles in various groups of AASV patients.