DRB1*15 Allele Is a Risk Factor for PR3-ANCA Disease in African Americans

Abstract

Anti-neutrophil cytoplasmic autoantibody (ANCA) disease rarely occurs in African Americans and risk factors for the disease in this population are unknown. Here, we genotyped MHC class II alleles and found that, among African Americans, those with proteinase 3-ANCA (PR3-ANCA) had 73.3-fold higher odds of having HLA-DRB1*15 alleles than community-based controls (OR 73.3; 95% CI 9.1 to 591). In addition, a disproportionate number of African American patients carried the DRB1*1501 allelic variant of Caucasian descent rather than the DRB1*1503 allelic variant of African descent. Among Caucasians, those with PR3-ANCA had 2.2-fold higher odds of carrying DRB1*1501 than controls (OR 2.2; 95% CI 1.2 to 4.0). A validation study supported by the Vasculitis Clinical Research Consortium confirmed the strong association between the DRB1*15 allele and PR3-ANCA disease, among African Americans. Furthermore, we found that DRB1*1501 protein binds with high affinity to amino acid sequences of sense-PR3, purportedly an antigenic epitope, and to the amino acid sequence complementary to this epitope in vitro. Peptides of sense-PR3 and complementary-PR3 also bound to TNF-␣-induced surface expression of DRB1*1501 on peripheral neutrophils. Taken together, these data suggest HLA-DRB1*15 alleles contribute to the pathogenesis of PR3-ANCA disease.

Proteinase 3-ANCA Vasculitis versus Myeloperoxidase-ANCA Vasculitis

“…43 Interestingly, the allele HLA-DRB1*15 has been associated with PR3-AAV in African Americans, but not with MPO-AAV in these patients or with Caucasian patients in general. 44 Such findings further support a strong genetic background of AAV, which may support categorization of patients based on ANCA serotypes rather than on clinical diagnosis.…”

ANCA Glomerulonephritis and Vasculitis

“…ANCA vasculitis prevalence in France is higher in people with European lineage compared with non-European lineage (105 per million versus 53 per million). In North America, ANCA vasculitis incidence is greater in whites than in blacks, which may be caused by HLA differences (14). ANCA vasculitis is less common in blacks, occurs at a younger age (mean 52 versus 57 years), and is more often MPO-ANCA positive compared with whites (71% versus 54%) (15).…”

“…In China, GPA patients more often have MPO-ANCA than PR3-ANCA. Geographic and racial differences in serotypes and clinicopathologic phenotypes may be determined by HLA differences (14,16,17).…”

Basic and Translational Concepts of Immune-Mediated Glomerular Diseases

“…122,[124][125][126][127][128] There also have been significant but low-level associations with potential susceptibility genes and their polymorphisms, including ANCA antigens, HLA, immune response proteins, Fc receptors, cytokines and others, but no high-level associations have been described, 163 other than DRB1*15 in African Americans. 164 The relatively frequent observation of ANCA antibodies in other autoimmune glomerular diseases including anti-GBM disease, lupus, and membranous nephropathy suggests that common etiologic or susceptibility factors may be present (Table 1). [165][166][167] Lupus Nephritis In lupus nephritis, IgG, IgM, IgA (full house), and C3 deposits are localized primarily in the mesangium in mild disease (mesangial lupus nephritis, class I and II), along the subendothelial aspect of the capillary wall with increasing proliferative/inflammatory lesions (focal or diffuse proliferative lupus nephritis, class III and IV), or in the subepithelial space with membranous lupus nephritis (class V).…”