Page 121 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

Genetic Aspects of Vasculitis 97

HLA Association
The most consistent genetic associations with GCA are located within the HLA class II

region. Carriage of HLA-DRB1*04 alleles (specifically DRB1*0401 and DRB1*0404) has
been identified as the main contributor of the GCA genetic component [14-26]. An increased
predisposition for the development of visual manifestations as well as resistance to
corticosteroid treatment in GCA patients is related to the presence of HLA-DRB1*04 allele
[24, 27, 28], which gives an idea of the crucial role that this allele may have in GCA
pathophysiology. On the other hand, associations between GCA and alleles of the HLA class
I region, including HLA-B*15, HLA-A*31, HLA-B*8, HLA-Cw3 and HLA-Cw6, have been
reported [14, 29-31], although not as consistent as those of the class II region. The MHC class
I polypeptide-related sequence A (MICA) gene, encoding a stress-inducible transmembrane
molecule, was recently suggested as a GCA susceptibility locus [31].

Non-HLA Association
The protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene encodes a tyrosine

phosphatase known as LYP that it is expressed mainly in lymphoid tissues and is involved in
several signaling pathways associated with the immune response, including the T-cell
receptor (TCR) pathway in which LYP plays a central role in its negative control, but also the
humoral activity of B-cells. A functional PTPN22 variant (rs2476601/R620W) has been
associated with several autoimmune diseases, representing the clearest example of a common
genetic risk factor in autoimmunity [32]. Very recently, our group described the PTPN22
R620W as the most significant genetic association with GCA thus far [33]. This association
was initially identified in a large discovery cohort from Spain and subsequently replicated in
three European replication cohorts from the United Kingdom (UK), Germany and Norway. It
has been demonstrated that the R620W change interferes with the ability of LYP to bind its
partner c-src tyrosine kinase (CSK) [34] which prevents the formation of the complex
between both proteins and the suppression of the T-cell activation.

The NLR family pyrin domain containing 1 (NLRP1) gene, another autoimmune disease-
associated loci, has been also confirmed as a GCA susceptibility gene in a recent study on a
large case-control cohort composed of Spanish and Italian populations [35]. This gene
encodes a cytoplasmic protein involved in the assembly of the inflammasome that activates
caspases 1 and 5 which results in the activation of proinflammatory cytokines. As expected,
considering its inflammatory nature, different cytokines have been implicated in GCA
pathogenesis. Amongst them, the interleukin 10 (IL10) gene represents the most consistent
association [36, 37]. This gene encodes an anti-inflammatory Th2 cytokine with pleiotropic
effects in the immune system, including the negative control of Th1 cytokines such as
interferon gamma (IFN-?), the regulation of the B cell function, and the repression of nuclear
factor kappa-light-chain-enhancer of activated B cells (NF-?B) activity. Two independent
studies in Italian [37] and Spanish [36] populations indicated that variation of the IL10
promoter region may be involved in the pathogenic mechanisms leading to GCA.

Other genes encoding cytokine or cytokine receptors that have been suggested as possible
genetic risk factors for GCA including, IL4, which encoded protein acts reciprocally with
IFN-? inducing the Th2 immune response; IL6, with pleiotropic effects that may exert both
proinflammatory and antiinflammatory functions; IL18, encoding a proinflammatory cytokine
with cytotoxic T cell functions; monocyte chemotactic protein-1 (MCP1), encoding a
chemoattractant protein for mononuclear cells to the sites of inflammation; regulated and

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