Page 122 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

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

normal T-cell expressed and secreted (RANTES), encoding a potent chemotactic factor for
immune cells; the IL2/IL21 region of cytokines important in the correct function of the
immune system; IL12 receptor beta 2 (IL12RB2), a key player in the inflammatory response;
tumor necrosis factor (TNF), encoding a proinflammatory cytokine involved in the regulation
of immune cells; and IFNG, encoding a key cytokine involved in innate and adaptive
immunity against intracellular pathogens and tumor control [38-46].

The possible role of a number of important molecules for the endothelial function in
GCA predisposition and severity has been also explored. Although most of the studies were
low-powered and without replication, evidence of association was observed for intercellular
adhesion molecule 1 (ICAM1), encoding a cell surface glycoprotein involved in the
interactions between immune and endothelial cells during inflammation; vascular endothelial
growth factor (VEGF), encoding an important vasculogenic mediator; cytokine-inducible and
endothelial nitric oxide synthases (NOS2A and NOS3), involved in the regulation of the
oxidative stress; and matrix metalloproteinase 9 (MMP9), encoding an enzyme with
proteolitic activity on the extracellular matrix [40, 47-53].

Finally, genes of the innate immunity may also have a role in GCA pathogenesis.
Significant associations have been reported for toll-like receptor 4 (TLR4), implicated in
signal transduction events induced by lipopolysaccharide from Gram-negative bacteria; Fc
gamma receptor 2A and 3A (FCGR2A and FCGR3A), encoding cell-surface proteins of the
immunoglobulin superfamily; and myeloperoxidase (MPO), an important gene in the
neutrophil function [54-56]. However, all these associations require confirmation in larger
and independent cohorts.

Takayasu Arteritis

A few candidate gene studies exploring the possible role of genetic polymorphisms in
Takayasu arteritis (TAK) were performed before the publication of two recent large scan
analyses, a GWAS in a Japanese cohort [57] and an immunochip, custom-designed high-
density genotyping platform for fine-mapping of immune-related genes, in Turkish and North
Americans [58].

HLA Association
Different genetic studies showed that HLA-B alleles are involved in the disease

susceptibility. Specifically, HLA-B*5201 was associated with TAK in multiple cohorts of
diverse ethnicities including different populations from Asia and Mexico [59-64], which was
confirmed in the GWAS of Japanese [57]. However, this association was not observed in
North American and Arab populations [65, 66]. In the former [65], a positive correlation of
HLA-DR4/MB3 and a strongly negative association of HLA-DR1 with TAK were reported,
whereas in Arab patients [66] the association with this region was narrowed down to HLA-
A2, HLA-A9, HLA-Bw35 and HLA-DR7 alleles.

Studies on polymorphisms of the gene encoding the human complement factor 4 (C4),
located at the class III region of the HLA, showed a significantly high frequency of C4A2 and
C4BQ0 allotypes in strong association with HLA-Bw52 [67]. Furthermore, the analysis of
MICA, situated between the class I and class III regions, revealed an association between the
MICA-1.2 allele and TAK, even in the absence of HLA-B52 [68].

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