Identification of Functional and Expression Polymorphisms Associated With Risk for Antineutrophil Cytoplasmic Autoantibody–Associated Vasculitis

Abstract

ObjectiveTo identify risk alleles relevant to the causal and biologic mechanisms of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV).MethodsA genome‐wide association study and subsequent replication study were conducted in a total cohort of 1,986 cases of AAV (patients with granulomatosis with polyangiitis [Wegener's] [GPA] or microscopic polyangiitis [MPA]) and 4,723 healthy controls. Meta‐analysis of these data sets and functional annotation of identified risk loci were performed, and candidate disease variants with unknown functional effects were investigated for their impact on gene expression and/or protein function.ResultsAmong the genome‐wide significant associations identified, the largest effect on risk of AAV came from the single‐nucleotide polymorphism variants rs141530233 and rs1042169 at the HLA–DPB1 locus (odds ratio [OR] 2.99 and OR 2.82, respectively) which, together with a third variant, rs386699872, constitute a triallelic risk haplotype associated with reduced expression of the HLA–DPB1 gene and HLA–DP protein in B cells and monocytes and with increased frequency of complementary proteinase 3 (PR3)–reactive T cells relative to that in carriers of the protective haplotype. Significant associations were also observed at the SERPINA1 and PTPN22 loci, the peak signals arising from functionally relevant missense variants, and at PRTN3, in which the top‐scoring variant correlated with increased PRTN3 expression in neutrophils. Effects of individual loci on AAV risk differed between patients with GPA and those with MPA or between patients with PR3‐ANCAs and those with myeloperoxidase‐ANCAs, but the collective population attributable fraction for these variants was substantive, at 77%.ConclusionThis study reveals the association of susceptibility to GPA and MPA with functional gene variants that explain much of the genetic etiology of AAV, could influence and possibly be predictors of the clinical presentation, and appear to alter immune cell proteins and responses likely to be key factors in the pathogenesis of AAV.

ANCA Glomerulonephritis and Vasculitis

“…This predicts that different HLA molecules would be involved in initiating the MPO-ANCA autoimmune response versus the PR3-ANCA autoimmune response. This was in fact observed in patients with ANCA vasculitis by genome-wide association studies that showed specific, and different, HLA associations with MPO-ANCA and PR3-ANCA vasculitis (16,17). Not surprisingly given their lineal role in immune responses, the HLA associations correlated better with ANCA specificity than with clinicopathologic phenotypes.…”

“…Both antibodies (34) and T cells (35) specific for complementary PR3 have been detected in patients with ANCA vasculitis. Evaluation of the functional significance of ANCA vasculitis genome-wide association study data also suggested a role for immune recognition of complementary peptides by T cells (17).…”

“…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).…”

Role of Macrophage Migration Inhibitory Factor in Granulomatosis With Polyangiitis

“…Recent genome-wide association studies have identified several gene polymorphisms that are associated with susceptibility to GPA. These analyses have been limited to the study of selected SNPs however, and have not examined potentially important structural variants such as promoter microsatellites (48, 49). While patients with GPA had a greater prevalence of high expression MIF genotypes when compared to healthy controls, healthy controls also had a fair percentage of high expression MIF genotypes.…”

Genetic Analyses of Blood Cell Structure for Biological and Pharmacological Inference

“…The PRTN3 colocalization illustrates how the genetic associations with cellular and molecular phenotypes can be combined to elucidate disease pathogenesis. rs138303849-C, a variant upstream of PRTN3 (encoding proteinase-3, PR3), is known to be associated with an increased risk of a vasculitis characterised by autoantibodies against PR3 (Merkel et al 2017) . This variant is an eQTL in whole blood (GTEx Consortium 2015) and we recently showed that the risk allele is associated with increased PR3 concentration in plasma .…”