Page 128 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

104 F. David Carmona, Ana Márquez, Javier Martín et al.

The current knowledge of the genetic component of IgAV/HSP is based exclusively on
candidate gene studies including genes mainly involved in the immune and inflammatory
responses, but also in endothelial function, mechanisms of complement system activation,
coagulation and fibrinolysis, and antioxidation, without GWAS studies [142].

HLA Association
There are a limited number of studies on the HLA region in IgAV/HSP, all of which have

been performed in Spanish, Italian and Turkish populations [144]. In relation to the HLA
class II region, an association of the HLA-DRB1*01, HLA-DRB1*07, and HLA-DRB1*11
alleles with IgAV/HSP was first reported in Italy [145] and subsequently confirmed in
independent cohorts from North-western Spain [146] and Turkish [147]. The HLA alleles
DRB1*01 and DRB1*11 increase the risk for the disease onset, whereas DRB1*07 confer a
protective effect to the disease.

Other HLA class II alleles have been associated with specific IgAV/HSP clinical
characteristics in Turkish cohorts [147] including HLA-DRB1*14, significantly reduced in
IgAV/HSP patients with joint involvement, and HLA-DRB1*13, increased in IgAV/HSP
patients with nephrotic proteinuria. An association between HLA class I alleles and HSP have
been also reported, although they remain controversial.

HLA-B35 was first described as a susceptibility factor for nephritis development in HSP
patients from Spain [148], whereas this allele was subsequently associated with increased risk
of the overall disease in a Turkish cohort [149]. The study on HSP patients from Turkey [149]
also suggested that the presence of the antigens HLA-A2, HLA-A11, and the absence of
HLA-A1, HLA-B49, and HLA-B50, influenced HSP predisposition.

In addition, HLA-A3 and HLA-B44 were associated with joint involvement, and HLA-
A1, HLA-B56, and HLA-B58 were associated with disease severity.

Regarding class III, there is evidence of association between the C4 locus (involved in
the clearance of immune complexes) and HSP [150, 151].

Non-HLA Association
In relation to genes involved in inflammatory pathways, polymorphisms of IL1RN, IL8

and IL1B have been shown to influence renal involvement in HSP patients of European origin
[152-155]. On the other hand, a promoter polymorphism of the TGFB1 gene and a non-
synonymous variant of the Mediterranean fever gene (MEFV) have been also associated with
susceptibility and severity of HSP in Chinese children [156, 157]. Regarding MEFV, this
gene encodes a protein known as pyrin that is an important modulator of innate immunity.
The name of the gene is based on the fact that variations within this locus are related to the
phenotype of the Mediterranean fever (a hereditary periodic fever syndrome). Interestingly, a
connection between MEFV mutations and HSP has been suggested [157, 159].

Molecules involved in the endothelial function could be also important players in HSP.
Several studies [160-164] have explored the role of an INDEL polymorphism in the
angiotensin I converting enzyme (ACE) gene, which is involved in the control of the blood
pressure, with contradictory results. Some of them [160-162] suggested that the presence of
the deletion may increase the predisposition to HSP, while others did not find evidence of
association with the disease [163, 164].

Another member of the rennin–angiotensin system, the angiotensinogen (AGT) gene has
been also suggested to be involved in HPS pathophysiology [162].

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