Page 123 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

Genetic Aspects of Vasculitis 99

A subsequent study [69] in which five microsatellites, C1-2-A, MIB, C1-4-1, C1-2-5 and
C1-3-1, around the HLA-B and MICA genes were analyzed in Japanese TAK patients,
suggested two different disease-susceptibility loci for TAK, one that mapped near the C1-2-A
locus, and another closely linked to the HLA-B gene. Very recently, the MICA and the HLA-
DQB1/HLA-DRB1 regions were also described as TAK risk factors in the iChip study on
Turkish and American cohorts [58].

Non-HLA Association
The most consistent associations with TAK outside the HLA region rely on IL12B and

the FCGR2A/FCGR3A loci. IL12B showed a high association peak in both the GWAS and
iChip studies, whereas FCGR2A/FCGR3A was identified as a susceptibility region for TAK
in the iChip [57, 58]. In addition, an altered production of several cytokines, including IL-6,
IL-2 and IL-12, were detected in TAK patients. Increased levels of IL-6 and IL-12 and a
lower number of CD3+ T cells producing IL-2 in the active phase of the disease were
described [70-72]. Interestingly, polymorphisms of the genes encoding these cytokines have
been correlated with altered protein levels [73-79].

Two genes encoding members of the IL-1 cytokine family, IL1B encoding IL-1ß, and IL-
1 receptor antagonist (IL1RN) encoding IL1-Ra, were involved in TAK predisposition [80].
IL-1 may mediate the inflammatory response occurring in the vascular wall by activating
monocytes and expression of adhesion molecules on endothelial cells, inducing secretion of
other inflammatory mediators. IL1-Ra inhibits the activities of IL-1? and IL-1ß, and
modulates a variety of IL-1 related immune and inflammatory responses.

Functional and genetic studies [81-83] have reported an implication of both genes in
cardiovascular disease, a common feature in TAK patients. In addition, different
polymorphisms of IL1B and IL1RN were associated with TAK in the Mexican population
[80], which suggests a crucial role of IL-1 in the vasculitis lesions of TAK.

Genes encoding cardiovascular-related molecules may also play a role in TAK
development [84, 85]. For instance, paraoxonase 1 (PON1), a high density lipoprotein (HDL)-
associated enzyme involved in prevention of lipid peroxidation, was diminished in activity in
TAK patients suggesting a possible role of these lipoproteins in TAK vascular dysfunction
[84]. A recent study in the Mexican population [85] suggested that variation within PON1
may be involved in TAK susceptibility by influencing development and progression of
arterial damage.

Medium Vessel Vasculitis

Kawasaki Disease

A large number of genetic studies have been conducted in order to unravel the genetic
component of Kawasaki disease (KD) [86] focused mainly on candidate genes implicated in
the immune response. In addition, since the most serious complication of KD is the
development of coronary artery lesions (CAL), the role of cardiovascular-related loci has
been extensively studied. However, sample sizes have often been insufficient and only a few
associations have been replicated in subsequent studies [86].

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