Page 124 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

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

In the last years, six GWAS on KD have been published [87-92]. This approach has
represented an important step forwards to the understanding of the genetic basis of this
vasculitis.

HLA Association
The involvement of the HLA region in KD is controversial. Association between KD and

HLA class I molecules was evidenced [93-97], but the results were inconsistent. Early studies
reported an association between HLA-Bw22 now called Bw54, and KD in the Japanese
population [93, 94], whereas the HLA-Bw51 and HLA-B44 alleles were predominantly
associated with the disease in Caucasians [95-97]. On the contrary, in a recent GWAS [91], a
significant association of HLA class II region with Japanese KD patients was identified.
Specifically, the strongest association signal was observed at the intergenic region between
HLA-DQB2 and HLA-DOB (rs2857151). This association was replicated in a subsequent
Han Chinese study [98]. A suggestive association signal was also observed in the HLA class
III region (rs2516390), close to the nuclear factor of kappa light polypeptide gene enhancer in
the B-cell inhibitor-like 1 (NFKBIL1) and lymphotoxin alpha (LTA) genes.

However, no significant associations of HLA alleles were documented in other published
GWAS. Thus, a consistent allele or haplotype of HLA conferring KD susceptibility has not
yet been identified.

Non-HLA Association
Several genes have been suggested to play a role in KD susceptibility through candidate

gene studies [99-111]. Susceptibility loci include 1) cytokines and their receptors, such as
IL4, TNF, the chemokine (C-C motif) receptor 2-3-5 (CCR2-CCR3-CCR5) gene cluster which
encodes three receptors of different chemokines that play a critical role in the selective
accumulation and activation of inflammatory cells in affected tissues; 2) genes encoding
cardiovascular-related molecules, including VEGF implicated in the predisposition to this
vasculitis and CALs development in different populations, and MMP3, 9, 13 also associated
with CAL; and 3) genes involved in innate immunity, like mannose binding lectin 2 (MBL2)
involved in complement activation and associated with an increased risk of CAL, and NLRP1
involved in the inflammasome assembly.

Potential loci implicated in KD susceptibility in Japanese families include the 19q32.2
and 4q35 regions. Subsequent fine-scale studies [112] of the 19q32.2 region have led to the
identification of functional polymorphisms of the inositol 1,4,5-triphosphate 3-kinase C
(ITPKC) gene significantly associated with the susceptibility to KD, with particular risk of
developing CAL in both Japanese and Caucasian patients. This gene encodes one of the three
isozymes that phosphorylate inositol 1, 4, 5-trisphosphate (IP3) acting as an important
molecule in the regulation of T-cell activation.

Regarding the 4q35 linkage region, several immune genes have been mapped around the
peak of linkage, including the IFN regulatory factor 2 (IRF2), TLR3 and caspase 3 (CASP3)
that play central roles in apoptosis. A subsequent positional candidate gene study [113] in
Japanese and Americans of European ancestry subjects identified a functional CASP3 variant
that altered the gene expression in immune effector cells. This SNP was shown to influence
KD susceptibility. Both the ITPKC and CASP3 associations with KD were replicated in the
Taiwanase population [114, 115].

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