Page 293 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

Systemic Vasculitis and the Kidney 267

Genetic Associations

The ability to sequence DNA from humans is becoming more and more facile, and
investigators have taken full advantage of this to understand the genetic underpinnings of
AAV, uncovering disease associations with both MHC and non-MHC genes [50]. A genome-
wide association study (GWAS) of patients and healthy controls from the UK and Northern
Europe revealed an association of PR3-ANCA positive AAV with HLA-DP, SERPINA1
(encoding ?-1 antitrypsin), and PRTN3 (encoding PR3), whereas MPO-ANCA positive
disease was associated with HLA-DQ. Among non-MHC genes, an association were
demonstrated with CTLA4, which encodes a T-cell surface molecule (CTLA-4) that down-
regulates T-cell activation [51]. Two CTLA4 single nucleotide polymorphisms (SNP), +49 G
[51-53] and CT60 [51, 53, 54], have been implicated in several studies. All of the studies
identifying disease association with the CTLA4 SNP were performed in European cohorts
comprising only Caucasian patients. No such association with CTLA4 was found in Japanese
patients with AAV [55]. The SNP rs3087243 of the CTLA4 gene (54), which encodes an
inhibitory regulator of T-cell activation, and rs2476601 of the PTPN22 gene (54, 56), which
encodes a regulator of cytoplasmic tyrosine kinase and T-cell function, are both associated
with AAV in Caucasian European cohorts [54, 55]. Mutations in these genes have been
implicated in other autoimmune diseases, suggesting a predisposition to general immune
dysregulation. [54, 56].

Racial and geographic variability may reflect differences in genetic predisposition. AAV
has been rarely described in Africa [7], and it is notably rare in African Americans. An
association of the HLA-DRB1*15 alleles with PR3-ANCA positive disease has been found,
conferring a 73.3-fold higher risk in African American patients than in community-based
controls [57]. These alleles were also associated with PR3-ANCA positive disease in
Caucasians, but with an odds ratio of only 2.2. The DRB1*1501 allelic variant, which is of
Caucasian descent, was found in 50% of African American patients, whereas the
DRB1*1503, of African descent, was under-represented in this group. Only the DRB1*1501
allele was found in Caucasian patients. A significant association was found with DRB1*16 in
African American patients with MPO-ANCA positive disease. No allele has been so
significantly associated with MPO-positive disease in Caucasians. In Chinese patients, the
allelic variants DRB1*1101 and DRB1*1202 were observed significantly more often in
patients with MPO-ANCA and PR3-ANCA-associated disease, respectively, than in healthy
controls [58]. The finding in PR3-ANCA positive disease is difficult to interpret given the
overall high prevalence of this allele in the Han population. This may reflect a particular
AAV-associated haplotype. In a Japanese cohort, HLA-DRB1*0901 was significantly
associated with MPO-ANCA positive disease. [55] Collectively, these findings lend credence
to the concept that MPO- and PR3-AAV are genetically distinct diseases with phenotypic
overlap.

Clinical Presentation

The most commonly recognized presentation of AAV is pulmonary-renal syndrome, with
alveolar hemorrhage and kidney injury that typically manifests as a rapidly progressive

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