Page 99 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

Epidemiology of Primary Systemic Vasculitis 75

The most strongly associated SNP were detected in three novel loci close to the coatomer
protein complex beta-2 subunits (COPB2) gene (rs1873668), rs4243399, rs16849083), as
well as, in the intronic region of the endoplasmic reticulum amino peptidase 1 (ERAP1) gene
(rs14981). COPB2 coats nonclathrin-coated vesicles and is essential for Golgi budding and
vesicular trafficking, whereas ERAP1 plays a role in trimming peptides o the optimal length
for human leukocyte antigen (HLA) class I presentation cleaving cell surface receptors for
proinflammatory cytokines. Kim and coworkers on behalf of the Korean Kawasaki Disease
Genetics Consortium [92] conducted a GWAS among 186 Korean KD patients and 600
controls employing the disease definition according to the AHA [72] noting susceptibility loci
for KD at the 1p31 region and 2p13.3 chromosomal loci. A putative KD susceptibility locus
(rs5277409) mapped to chromosome 1p31 and the coronary artery lesion (CAL) locus
(rs7604693) mapped to the Pellino 1 protein (PELI1) (rs7604693) gene in the 2p13.3 region
encoding PEL1, an intermediate component in the signaling cascade initiated by Toll-like
receptors (TLR) and the IL1 receptor (IL1R) gene, that are associated with innate and
adaptive immune responses. Khor and colleagues [93] performed a GWAS in 2,173 KD
patients of European and Asian descent noting two significant loci in the Fc fragment of IgG,
low affinity 2A receptor (FCGR2A) (rs1801274) and for the rs2233152 SNP near the
melanoma inhibitory activity (MIA), Inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene.

Whereas FCGR2A, present on monocytes, macrophages, neutrophils, natural killer (NK)
cells, T- and B-cells, participates in the phagocytosis of immune complexes and modulation
of antibody production by B-cells, ITPKC acts as a negative regulator of T-cell activation
through the Ca(2+)/NFAT signaling pathway; contributing to immune hyperactivity. Lee and
coworkers [94] performed a GWAS in 622 KD patients and 1,107 controls in a Han Chinese
population residing in Taiwan employing the AHA criteria [72] noting two loci significantly
associated with KD including one at the B-lymphoid tyrosine kinase (BLK) gene and the other
at CD40. Whereas the BLK gene appears to play an important role in the expression of B-cell
signaling, activation and antibody secretion, CD40 is instead a member of the tumor necrosis
factor receptor (TNFR) superfamily, and its interaction with the CD40 ligand (CD40L) leads
to cross-talk integrating strong antigenic signals and microbial stimuli to induce IL-17-
producing CD4+ T-cells that contribute to inflammation and the development of autoimmune
disease. Onouchi and coworkers [95, 96] performed a GWAS in 428 Japanese KD patients
and 3,379 controls noting significant associations in the FAM167A-BLK region at 8p22-23
(rs2254546) in the HLA region at 6p21.3 (rs2857151), and in the CD40 region at 20q13
(rs48130030), also replicating the association of a function SNP of FCGR2A (rs1801274).
Although ubiquitously expressed, the function of FAM167A has not been well characterized.
Yan and coworkers [96] analyzed variants of six SNP in 358 Japanese KD patients and 815
controls identifying three, rs1801274, rs2857151, and rs22554546 respectively corresponding
to FCGR2A, HLA, and BLK genes, noting significant effect and stronger association on KD
than single, 2- and 3-locus combinations, moreover, a significant association to coronary
artery lesions (CAL) was noted in KD with high-risk genotypes at both rs1801274 and
rs2857151.

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