Page 125 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

Genetic Aspects of Vasculitis 101

In 2009, the first GWAS performed on KD Caucasian patients [87] led to the
identification of eight putative novel susceptibility loci. Five of these genes, calcium/
calmodulin-dependent protein kinase II delta (CAMK2D), CUB and Sushi multiple domains 1
(CSMD1), ligand of numb-protein X1 (LNX1), N-acetylated alpha-linked acidic dipeptidase-
like 2 (NAALADL2), and t-complex 1 (TCP1), formed a functionally close network of 35
genes defined in the Ingenuity database (Ingenuity Systems, Redwood City, CA,
www.ingenuity.com). This gene network suggests possible mechanisms by which one or
more infectious triggers may lead to dysregulated inflammation and apoptosis, and
cardiovascular pathology.

In 2011, another GWAS [89] was conducted in a Korean population, and two novel
susceptibility signals were identified: a SNP close to the Dab reelin signal transducer
homolog 1 (DAB1) gene associated with KD predisposition, and an intronic variant of pellino
E3 ubiquitin protein ligase 1 (PELI1) gene which is involved in the TLR pathway associated
with CAL development. The first GWAS in the Han Chinese population [92] identified
several putative genetic variants associated with KD susceptibility, although none of them
reached GWAS statistical significance due to a limited sample size.

The highest peaks included three SNP close to coatomer protein complex beta-2 subunit
(COPB2) gene, one located within the intronic region of endoplasmic reticulum amino
peptidase 1 (ERAP1), and six clustered in an area containing immunoglobulin heavy chain
variable region (IGHV) genes.

A well-powered GWAS [88] in KD patients from different populations of European
ancestry (Australia, UK, Netherlands and US) identified two loci that exceeded the threshold
for GWAS significance. One of them was ITPKC, confirming this gene as a risk factor for
KD, and a functional polymorphism (H131R, rs1801274) of FCGR2A. Finally, both
Taiwanese [90] and Japanese [91] groups independently reported GWAS results in 2012 [90,
91]. In both studies, significant associations were observed in the B-lymphoid tyrosine kinase
(BLK) region. The most strongly associated polymorphism in the Taiwanese study [90] was
in high linkage disequilibrium (LD) with a genetic variant associated with systemic levels of
BLK and increased risk of systemic lupus erythematosus (SLE). SNP around cluster domain
40 (CD40, a member of the TNFR superfamily that potentially contributes to inflammation
and autoimmune disease processes through the selection of autoreactive T cells in the thymus
and the activation of B- and T- cells) were also associated with KD at GWAS level in both
studies. Interestingly, increased cell surface expression of CD40L, the ligand of CD40, and
elevated serum levels of soluble CD40L have been detected in KD. On the other hand, the
Japanese study also replicated the association of the previously identified FCGR2A functional
SNP.

Small Vessel ANCA-Associated Vasculitis

Early genetic studies in antineutrophil cytoplasmic antibody (ANCA)-associated
vasculitis (AAV), which comprises granulomatosis with polyangiitis (GPA) [Wegener type],
microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA)
(Churg-Strauss type), focused on self-evident candidate genes encoding respective ANCA
target antigens, proteinase 3 (PR3) and myeloperoxidase (MPO).

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