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

Abstract

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.

Association of HLA Genes with Clinical Outcomes of ANCA-Associated Vasculitis

“…ANCA antigens are mainly located in azurophilic granules of polymorphonuclear granulocytes; after being primed by TNFa, there are more ANCA antigens expressed on the membrane of polymorphonuclear granulocytes (29,30). Over-representation of TNFa 2a/DRB1*04 might contribute to the severe courses of GPA (11). We speculated that the mechanism of HLA-DRB1*0405 contributing to the outcome of AAV is possibly through the over-representation of TNFa, resulting in poor prognosis of renal function.…”

Association of HLA-DRB1*0901-DQB1*0303 haplotype with microscopic polyangiitis in Japanese

“…1 Although the etiology of AAV is poorly understood, substantial difference in the incidence among populations 2 and sporadic reports of multiplex families 3 suggest a role of genetic predisposition. With respect to MPO-ANCA associated vasculitis, previous studies reported association of HLA [4][5][6] and non-HLA genes, 7-10 although many of them have not been confirmed by independent studies.…”

The cytokine gene polymorphisms (TNF- and #945;, IL-10 And IFN- and #947;) and the role of inflammatory cytokines in diabetic neuropathy

“…36 However, it has been shown to be nonsignificant in many other inflammatory diseases. [37][38][39] Our study also, could not find any association of TNF-α -308 gene polymorphism with diabetic peripheral neuropathy. Similarly, a study in South Indian population also could not find any association of TNF-α with diabetic peripheral neuropathy.…”