Genetically distinct subsets within ANCA-associated vasculitis

Abstract

Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a severe condition encompassing two major syndromes: granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis) and microscopic polyangiitis. Its cause is unknown, and there is debate about whether it is a single disease entity and what role ANCA plays in its pathogenesis. We investigated its genetic basis.

Methods: A genomewide association study was performed in a discovery cohort of 1233 U.K. patients with ANCA-associated vasculitis and 5884 controls and was replicated in 1454 Northern European case patients and 1666 controls. Quality control, population stratification, and statistical analyses were performed according to standard criteria.

Results: We found both major-histocompatibility-complex (MHC) and non-MHC associations with ANCA-associated vasculitis and also that granulomatosis with polyangiitis and microscopic polyangiitis were genetically distinct. The strongest genetic associations were with the antigenic specificity of ANCA, not with the clinical syndrome. Anti-proteinase 3 ANCA was associated with HLA-DP and the genes encoding α(1)-antitrypsin (SERPINA1) and proteinase 3 (PRTN3) (P=6.2×10(-89), P=5.6×10(-12,) and P=2.6×10(-7), respectively). Anti-myeloperoxidase ANCA was associated with HLA-DQ (P=2.1×10(-8)).

Conclusions: This study confirms that the pathogenesis of ANCA-associated vasculitis has a genetic component, shows genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis that are associated with ANCA specificity, and suggests that the response against the autoantigen proteinase 3 is a central pathogenic feature of proteinase 3 ANCA-associated vasculitis. These data provide preliminary support for the concept that proteinase 3 ANCA-associated vasculitis and myeloperoxidase ANCA-associated vasculitis are distinct autoimmune syndromes. (Funded by the British Heart Foundation and others.).

Figure 1. Associations of MHC and Non-MHC Loci with Antineutrophil Cytoplasmic Antibody (ANCA)–Associated Vasculitis

Panel A shows quantile–quantile plots of the results of the association test for all single-nucleotide polymorphisms (SNPs) with data of sufficient quality from the discovery cohort (left) and replication cohort (right). Triangles at the upper right of each graph indicate SNPs with −log₁₀ P values exceeding 30. The red symbols indicate SNPs other than those mapping to the major histocompatibility complex (MHC) for the discovery cohort and the three MHC SNPs specifically chosen for investigation in the replication cohort. The interrupted line indicates the estimated dispersion factor, lambda, and is estimated according to the ratio of the observed trimmed mean (calculated from the leftmost, linear half of the graph) to its expected value under the chi-square assumption. The shaded area indicates the concentration band for the plot and is defined by 95% probability bounds for each order statistic. Panel B shows the −log₁₀ P values for each SNP plotted against its chromosomal location in the discovery cohort. The red points indicate in the discovery cohort SNPs with a P value of less than 1×10⁻⁵ and a minor allele frequency of greater than 5%.

Figure 2. Relationships between Clinical Subtype and ANCA Specificity in ANCA-Associated Vasculitis and Associations of the MHC Locus with Proteinase 3 ANCA and Myeloperoxidase ANCA

A Venn diagram shows the overlap between clinical diagnosis (granulomatosis with polyangiitis [GPA] or microscopic polyangiitis [MPA]) and ANCA specificity (proteinase 3 [PR3] or myeloperoxidase [MPO]) in the combined cohort (Panel A). Also shown are the −log₁₀ P values for the association of SNPs at the MHC locus in all case patients with ANCA-associated vasculitis (AAV) (Panel B), case patients with PR3 ANCA only (Panel C), and case patients with MPO ANCA only (Panel D). The gray vertical line (Panels B, C, and D) indicates the genomic location of the most associated SNP. The arrow (Panel D) indicates the position of rs5000634 (HLA-DQ). The genomic architecture of the MHC locus (Panel E) shows the recombination rates along the sequence, as well.