ANCA-Associated Vasculitis (AAV)

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disease. The disease causes inflammation of small and medium blood vessels, leading to vascular damage and tissue necrosis. Patients usually have circulating myeloperoxidase (MPO)-ANCAs or proteinase 3 (PR3)-ANCAs. The clinical syndromes within the AAV spectrum include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Although the pathogenesis of AAV is still unknown, environmental and genetic factors are thought to be involved.1,2 

Environmental components, such as exposure to silica, bacterial or viral infections, and medications, have suspected connections with the development and recurrence of AAV. Genetic association studies and familial studies have shown that there is a genetic predisposition to AAV. According to estimates, genetic factors account for 20% of AAV risk.2

Human leukocyte antigen (HLA), PTPN22, CTLA4, IL10, and TLR9 are believed to show associations with AAV.2 

HLA Genetic Associations 

HLA single-nucleotide polymorphisms (SNPs) have been linked with many human diseases, particularly autoimmune diseases. Candidate gene research on HLA regions in AAV has been performed in several populations, including in Germany, Sweden, Italy, China, and Japan. It was discovered that HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, and HLA-DRB1 were linked to AAV susceptibility.2 

Strong associations between retinoid X receptor beta (RXRB) and GPA were revealed through markers located in the HLA region and RXRB loci. As a result of the localization of RXRB to the HLA region near HLA-DPB1, the HLA-DPB1*0401/RXRB03 haplotype was discovered to be significantly associated with GPA.2

Ring finger protein 1 (RING1) is another HLA-region gene near HLA-DPB1. Three SNPs in the location near RING1 (rs213210, rs213209, and rs213208) have been linked with GPA in German patients. The HLA-DPB1/RING1 haplotype shows a strong association with GPA in ANCA-positive individuals.2 

Read more about AAV diagnosis

Non-HLA Genetic Associations

In addition to the HLA genes, non-HLA SNP markers linked to AAV may contribute to the overall variation in disease susceptibility.3 


The PTPN22 gene is found on chromosome 1p13.2. The encoded protein, lymphoid phosphatase (LYP), not only affects the threshold of T-cell receptor activation but is also linked to B-cell activation.4

The PTPN22 620W allele showed susceptibility to AAV in a German cohort, and the frequency of this allele was markedly high in ANCA-positive patients with GPA. Studies in Italian and British cohorts and a meta-analysis of 4 studies in patients of European descent also supported this finding.2


A regulatory molecule called cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), which is expressed on T cells, is crucial for peripheral tolerance and preventing T-cell activation.3 Results of various studies revealed associations between various CTLA4 SNPs and AAV, indicating that this molecule may play a part in the pathogenesis of AAV. CTLA4 has also been investigated as a possible therapeutic target in a pilot study involving patients with nonsevere GPA who were administered Orencia® (abatacept), a monoclonal antibody that contains the CTLA4 binding region, with positive outcomes for safety and disease response.4 

Read more about AAV clinical trials


There is increasing evidence that toll-like receptors (TLRs) play a part in the emergence of autoimmune diseases. The specificities of the TLR family of innate receptors are established in the germline.3 

Infection, especially Staphylococcus aureus infection, is considered a possible trigger of AAV, and TLR9 signaling may be implicated in disease pathogenesis, supporting models of infectious agents initiating AAV development. To examine the role of genetic TLR9 polymorphisms in disease susceptibility and clinical manifestations, SNPs in TLR9 were genotyped in a German cohort of 863 patients with AAV and 1344 healthy controls. TLR9 genotypes and haplotypes showed strong associations with GPA and MPA but no relationship with EGPA. The results were not reproduced in a group of 426 Dutch and British patients with AAV.2

Read more about AAV epidemiology


Interleukin-10 (IL-10) is an anti-inflammatory cytokine. One IL10 SNP was linked to an increased likelihood of developing GPA and MPA in 39 and 161 patients, respectively, by 2 comparatively small studies. A larger report, however, was unable to confirm this association in 403 GPA cases. The same study also found an association between an IL10 haplotype and the ANCA-negative subtype of EGPA in a cohort of 103 patients with EGPA, which is an intriguing finding but challenging due to the study’s sample size and absence of replication.4 


The SERPINA1 gene produces alpha1-antitrypsin, a neutral serine protease inhibitor. As the main inhibitor of PR3 action, alpha1-antitrypsin prevents widespread tissue damage. This process may be essential in AAV, because the diminished activity of alpha-1 antitrypsin can allow PR3 to persist in inflammatory tissue and ultimately lead to the production of ANCAs. Numerous studies examining the role of the Z allele in AAV revealed that heterozygous patients with the Z variant of the SERPINA1 gene had a higher risk of developing GPA than the general population.3 

Read more about AAV pathophysiology


In 79 patients with GPA and 129 healthy controls, the PRTN3 gene’s promoter and coding regions were sequenced to look for genetic variations. The researchers discovered 7 SNPs, one Val119Ile amino acid shift, one 84-bp insertion/deletion, and a microsatellite. The PRTN3 promoter’s A-564G polymorphism, which alters a potential transcription factor-binding site, has been shown to have an association with GPA. Overexpression of PRTN3 was thought to increase the risk of developing AAV.3 

Read more about AAV risk factors


  1. Rahmattulla C, Mooyaart AL, van Hooven D, et al. Genetic variants in ANCA-associated vasculitis: a meta-analysis. Ann Rheum Dis. 2016;75(9):1687-1692. doi:10.1136/annrheumdis-2015-207601
  2. Li W, Huang H, Cai M, Yuan T, Sheng Y. Antineutrophil cytoplasmic antibody-associated vasculitis update: genetic pathogenesis. Front Immunol. 2021;12:624848. doi:10.3389/fimmu.2021.624848
  3. Bonatti F, Reina M, Neri TM, Martorana D. Genetic susceptibility to ANCA-associated vasculitis: state of the art. Front Immunol. 2014;5:577. doi:10.3389/fimmu.2014.00577
  4. Alberici F, Martorana D, Bonatti F, Gioffredi A, Lyons PA, Vaglio A. Genetics of ANCA-associated vasculitides: HLA and beyond. Clin Exp Rheumatol. 2014;32(Suppl 82):S90-S97.

Reviewed by Kyle Habet, MD, on 3/21/2023.