Page 127 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

Genetic Aspects of Vasculitis 103

The patients positive for anti-PR3 showed a stronger association with PRTN3 rs62132295
than those positive for anti-MPO, when they were compared against the control cohort.
Additionally, the allele frequencies of this SNP also differed considerably between both
subsets of patients. Similar results were observed for the serpin A1 (SERPINA1) gene [117],
which encodes a serine protease inhibitor known as ?1-antitrypsin whose targets include PR3
that protects tissues against enzymes from inflammatory cells like neutrophils. The Z (null)
allele seems to be specifically associated with anti-PR3 presence rather than with the clinical
subtypes, since the most significant P-value was obtained when the AAV patients showing
this autoantibody were compared against controls. SERPINA1 was the only loci outside the
HLA region that reached GWAS significance. The association between this gene and ANCA
positivity has been confirmed in many candidate gene studies [126-131]. Hence, SERPINA1
could be considered the best defined non-HLA genetic risk factor for AAV described so far.
The autoimmune disease-associated PTPN22 functional variant R620W has been also
reported to confer risk to AAV [132, 133]. Specifically, it was first implicated in the
susceptibility to develop GPA [133], and this association was further confirmed in a higher
cohort in which both GPA and MPA patients were included [132]. However, a recently
published study [134] did not find evidence of association between this SNP and either MPA
or EGPA but only with GPA, and particularly with ANCA-positive subsets of patients.

Another gene that has been associated with AAV predisposition is cytotoxic T-
lymphocyte associated antigen 4 (CTLA4), which encodes a central regulatory molecule
expressed on T- cells that inhibits T-cell function and peripheral tolerance. It has been
reported that elevated levels of CTLA4 are expressed in GPA patients [135].

In concordance, many studies have described associations of different CTLA4
polymorphisms with AAV [136-141], thus supporting the idea that CTLA4 represents another
common susceptibility factor in autoimmunity.

There are other genes of the immune system that showed less consistent evidence of
association with AAV, and confirmation in independent cohorts is still required [142].
These include, IL10, CD226, an adhesion molecule expressed on the surface of natural killer
cells, platelets, monocytes and T cells; IL2 receptor alpha (IL2RA), an important regulatory
T-cell marker; leukocyte immunoglobulin-like receptor A2 (LILRA2), an immunoreceptor
expressed in immune cells; integrin, beta 2 complement component 3 receptor 3 and 4 subunit
(ITGB2), which participates in cell adhesion as well as cell-surface mediated signaling; and
FCGR2A/3B members of IgG receptor family. Except for SERPINA1, PRTN3, CTLA4 and
CD226, none of the above described genetic associations have been confirmed at the 95%
significance level in the AAV GWAS [117].

Small Vessel Immune Complex Vasculitis

IgA Vasculitis/Henoch-Schönlein Purpura

Similar to the other vasculitides, the understanding of the genetic background of IgA
vasculitis/Henoch-Schönlein purpura (IgAV/HSP) remains elusive, and further research on
well-powered cohorts is still needed to unravel the genetic basis and pathogenic mechanisms
leading to this vasculitis.

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