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Genetics of ANCA-associated vasculitis: role in pathogenesis, classification and management

Abstract

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), that share features of pauci-immune small-vessel vasculitis and the positivity of ANCA targeting proteinase-3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA). AAV syndromes are rare, complex diseases and their aetio-pathogenesis is mainly driven by the interaction between environmental and genetic factors. In patients with GPA and MPA, the genetic associations are stronger with ANCA specificity (PR3- versus MPO-ANCA) than with the clinical diagnosis, which, in keeping with the known clinical and prognostic differences between PR3-ANCA-positive and MPO-ANCA-positive patients, supports an ANCA-based re-classification of these disorders. EGPA is also made up of genetically distinct subsets, which can be stratified on ANCA-status (MPO ANCA-positive versus ANCA-negative); these subsets differ in clinical phenotype and possibly in their response to treatment. Interestingly, MPO-ANCA-positive patients with either MPA or EGPA have overlapping genetic determinants, thus strengthening the concept that this EGPA subset is closely related to the other AAV syndromes. The genetics of AAV provides us with essential information to understand its varied phenotype. This Review discusses the main findings of genetic association studies in AAV, their pathogenic implications and their potential effect on classification, management and prognosis.

Key points

  • ANCA-associated vasculitides (AAV) are classified according to clinico-pathological features as granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), and have complex aetio-pathogenetic mechanisms.

  • In GPA and MPA, genetic associations are stronger with ANCA specificity (PR3- or MPO-ANCA) than with the clinical diagnosis.

  • Evidence of a distinct genetic background between PR3-ANCA-positive and MPO-ANCA-positive vasculitis is coherent with the demographic, clinical and prognostic data, and supports a re-classification of AAV according to ANCA specificity.

  • In EGPA, MPO-ANCA-positive and ANCA-negative subsets share associations with loci involved in eosinophilia and asthma, and differ for associations with HLA-DQ, IL-5 and GPA33.

  • The genetic differences between the two EGPA subsets support the ANCA-based dichotomy of this syndrome.

  • ANCA-positive disease, which often displays vasculitic features, is closely related to MPO-ANCA-positive vasculitis, whereas ANCA-negative disease, which shows a higher prevalence of eosinophilic manifestations, may be associated with mucosal barrier dysfunction.

  • Future studies focusing on genotype–phenotype, genotype–prognosis and pharmacogenomics are likely to improve our understanding of AAV and refine our approaches to patient management.

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Fig. 1: Main clinical, imaging and histopathological features of the three AAV syndromes.
Fig. 2: Immunopathogenesis of PR3-ANCA-positive and MPO-ANCA-positive vasculitis.
Fig. 3: Immunopathogenesis of MPO-ANCA-positive and ANCA-negative EGPA.
Fig. 4: Genetic associations in AAV.
Fig. 5: Main demographic and clinical features as well as outcomes in AAV subsets based on their ANCA status along with their genetic associations.

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Acknowledgements

We gratefully thank Dr. Giovanni M. Rossi for providing the histological images included in Fig. 1.

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All authors researched data for the article. A.V., G.T., D.M., M.T. and A.K. contributed substantially to discussion of the content. A.V., G.T., A.M., D.M., A.K. and P.A.L. wrote the article. G.T., A.M., M.T., A.K. and P.A.L. reviewed and/or edited the manuscript before submission.

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Correspondence to Augusto Vaglio.

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Related links

Abatacept for the Treatment of Relapsing, Non-Severe, Granulomatosis With Polyangiitis (Wegener’s) : https://clinicaltrials.gov/ct2/show/NCT02108860

Rituximab and Belimumab Combination Therapy in PR3 Vasculitis (COMBIVAS) : https://clinicaltrials.gov/ct2/show/NCT03967925

Supplementary information

Glossary

DNA methylation

An epigenetic mechanism involved in the regulation of gene expression through the transfer of a methyl group to the 5′-carbon of a cytosine.

Histone marks

Covalent post-translational modifications of histone proteins that affect chromatin structure and, consequently, gene expression.

Linkage disequilibrium

Non-random association of alleles at different loci because of their physical proximity on a chromosome.

Luciferase reporter assay

An assay used to determine the allele-specific effects of a genetic variant on the expression of a target gene by measuring luminescence emitted by a reporter gene.

Pleiotropy-informed conditional false discovery rate

A method of exploiting the shared similarities between two diseases to detect additional genetic loci common to both.

Mendelian randomization

An approach that uses genetic variation as an instrumental variable to explore the causal relationship between risk factors and clinical traits.

BOLT-REML

A computationally efficient method for carrying out variance component analyses of large GWAS data sets. Such an approach allows an estimation of the variance of a trait that is explained by aggregated sets of SNPs rather than simply testing the significance of individual loci.

Whole-genome/-exome sequencing

The analysis of either the entire genomic sequence of an individual or, in the case of exome sequencing, the protein-coding regions of the genome.

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Trivioli, G., Marquez, A., Martorana, D. et al. Genetics of ANCA-associated vasculitis: role in pathogenesis, classification and management. Nat Rev Rheumatol 18, 559–574 (2022). https://doi.org/10.1038/s41584-022-00819-y

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