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Almeida et al. Vessel Plus 2021;5:44 https://dx.doi.org/10.20517/2574-1209.2021.66 Page 3 of 14

Table 1. Anti-neutrophil cytoplasmic antibody-associated vasculitis risk factors
Risk factor Evidence
Genetics Significant association HLA-DP locus and GPA; DQ loci and MPO-ANCA; HLA-DP allele and GPA
SERPINA-1, α-1-antitrypsin allele deficiency, proteinase 3 gene (PR3) polymorphism and variant
increasing PTPN22 activity
Epigenetics MPO and PRTN3 promoter methylation
Exposome Seasonality Discrepant results in literature
Onset observed in autumn and winter months
Latitude and UV Increased prevalence of MPA and GPA in hot and cold countries, respectively
radiation Higher latitudes correlate with higher GPA incidence
Infections Exposure to toxic shock syndrome toxin-1
Nasal S. aureus colonization related to relapse rates
Pollution Silica 2.5-fold increased risk, even higher for patients with renal involvement, GPA or
MPA
Farming GPA associated with 12 months prior-visits and significant livestock exposure
Gardening, namely digging, mowing and planting
Other pollutants Exposure to carbon monoxide, hydrocarbon and high organic solvent
Drugs e.g., propylthiouracil, methimazole, hydralazine, minocycline or cocaine
Smoking Weak correlation

GPA: Granulomatosis with polyangiitis; MPO: myeloperoxidase; ANCA: anti-neutrophil cytoplasmic antibody; MPA: microscopic polyangiitis.

Besides MHC genes, several single-nucleotide polymorphisms (SNP) associated with the AAVs have been
found. The variant that increases the activity of PTPN22, which negatively regulates IL-10 (an
immunosuppressive cytokine), increases the likelihood of PR3-ANCA (OR = 1.63). Oppositely, SNPs
related to SERPINA1, PRTN3, and SEMA6A showed profiles protective against AAV .
[11]
Epigenetics
Gene expression regulation of MPO and PRTN3 genes were linked to DNA methylation and histone 3
lysine 27 (H3K27me3). MPO and PRTN3 promoter methylation are negatively correlated with patients with
active AAV and increase during remission of the disease . H3K27me3 trimethylation reduction was also
[13]
[14]
associated with active disease by expressing aberrant MPO and PRTN3 genes .
Exposome
[1]
The initial report of AAV was coupled with an infectious disease . More recently, AAVs have been shown
to be triggered by infectious agents, namely after exposure to toxic shock syndrome toxin-1, a toxin secreted
by Staphylococcys aureus, and relapses have also been associated with higher nasal S. aureus
colonization [15,16] .

Many other factors appear to be related with higher risk for AAVs. Seasonality shows discrepant results in
the literature, but AAVs, namely GPA, seem to have a more prevalent onset in autumn and winter months.
The prevalence of AAV subtypes also seems linked with temperature, latitude, and UV radiation [17,18] .

As mentioned above, some drugs can precipitate AAV; thus, drug indications need to be weighed when
studying the correlation between drugs and the risk for AAVs. Alopurinol seems to be the only drug that
conferred a greater risk for developing GPA .
[19]
The role of airborne particles has also been studied, with multiple approaches suggesting a higher disease
risk when being exposed to certain pollutants, namely silica, carbon monoxide, hydrocarbons, and high
organic solvents and particles associated with farming and gardening activities. As for smoking, there is a
weak correlation to higher risk for developing the disease [17,20-22] .