Genes play a key role in the pathogenesis of antineutrophil cytoplasmic antibody-associated vasculitis, and genetic distinctions exist between two of the condition’s main clinical syndromes: granulomatosis with polyangiitis and microscopic polyangiitis, judging from data from a genomewide association study.
The findings also support the concept that proteinase 3 ANCA-associated vasculitis and myeloperoxidase ANCA-associated vasculitis are distinct autoimmune syndromes. If true, those findings could have both immunopathogenic and therapeutic implications, according to Paul A. Lyons, Ph.D., of the Cambridge (England) Institute for Medical Research, and his colleagues in their online report in the July 19 issue of the New England Journal of Medicine.
"There is debate as to whether the clinical syndromes of granulomatosis with polyangiitis and microscopic polyangiitis represent distinct diseases or are part of a single disease spectrum," the investigators wrote. The concept of a single disease spectrum has resulted in similar treatment strategies being used in trials regardless of which of these two clinical syndromes are present, and also in the suggestion that genetic studies should consider the two syndromes together, they explained.
"Clear evidence that these clinical syndromes are etiologically distinct might provide a rationale for devising syndrome-specific therapeutic strategies," the investigators noted (N. Engl. J. Med. 2012 July 19 [doi: 10.1056/NEJMoa1108735]).
To identify genetic risk factors and evaluate whether a common or distinct genetic background exists for granulomatosis with polyangiitis and microscopic polyangiitis, they performed genotyping in a discovery cohort of 1,233 patients with ANCA-associated vasculitis from the United Kingdom and 5,884 controls, as well as in a replication cohort of 1,454 Northern European case patients and 1,666 controls.
Combined analysis of the discovery and replication cohorts demonstrated that four single nucleotide polymorphisms (SNPs) exceeded the significance threshold for genomewide association, including three from the major histocompatibility complex (MHC). The most significant of these three was within the gene encoding HLA-DPB1. The fourth was in the SERPINA1 locus at 14q32.
Another SNP in PRTN3, which was added to the replication analysis on the bases of a priori hypotheses, was also found to be significantly associated with disease.
"Together, these data provide evidence of a genetic base of ANCA-associated vasculitis that extends beyond the MHC," the investigators said.
Additional analysis of the discovery cohort after subdivision on the basis of whether patients were diagnosed with granulomatosis with polyangiitis or with microscopic polyangiitis showed that all three MHC-associated SNPs differed between the two groups, with "essentially all of the association" found in those with granulomatosis with polyangiitis.
"This was also true of SERPINA1 – while it did not show a significant difference when granulomatosis with polyangiitis and microscopic polyangiitis were compared directly, perhaps owing to small numbers of patients and thus reduced power, it was associated with granulomatosis with polyangiitis, but not microscopic polyangiitis, when each subtype was compared with controls," they added.
There also was a suggestion of an association between PRTN3 and granulomatosis with polyangiitis rather than with microscopic polyangiitis, and also between some less significant SNPs and granulomatosis with polyangiitis, they said.
"Overall, there was evidence that granulomatosis with polyangiitis had genetic associations distinct from microscopic polyangiitis at both the MHC and SERPIN loci," they said.
Additional subgroup analysis based on proteinase 3 and myeloperoxidase ANCA specificity showed significant differences at the MHC, SERPINA1, and PRTN3 loci, all of which included a genetic association with proteinase 3 ANCA but not with myeloperoxidase ANCA. Further analysis demonstrated associations of HLA-DP and the related SNPs SERPINA1 and PRTN3 in patients with proteinase 3 ANCA associated with granulomatosis with polyangiitis but not myeloperoxidase ANCA. The findings were the same in the microscopic polyangiitis group, showing an association of proteinase 3 ANCA and the HLA-DP SNP and SERPINA1. The converse was true for the HLA-DQ SNP, which was associated with myeloperoxidase ANCA rather than proteinase 3 ANCA in patients with microscopic polyangiitis.
The clear association of genetic background with autoantibody specificity suggests that it might contribute to the clinical classifications of granulomatosis with polyangiitis and microscopic polyangiitis, the investigators said.
"The genetic difference between proteinase 3 ANCA and myeloperoxidase ANCA polyangiitis could have immunopathogenic and therapeutic implications, ... and will require future genetic studies powered to detect associations with these conditions rather than with ANCA-associated vasculitis as a whole," they said.
The investigators concluded that this study "provides clear evidence of a genetic contribution to disease susceptibility, which differs between granulomatosis with polyangiitis and microscopic polyangiitis."
Further, "associations with HLA, SERPINA1, and PRTN3 are primarily aligned with ANCA specificity rather than with the clinically defined syndromes granulomatosis with polyangiitis and microscopic polyangiitis, making it logical to consider including ANCA specificity in the diagnostic criteria for ANCA-associated vasculitis," they argued.