Page 129 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

Genetic Aspects of Vasculitis 105

On the other hand, a CCTTT repeat polymorphism within NOS2A, involved in the
metabolism of nitric oxide as indicated before, was associated with HSP predisposition and
nephritis presence in a cohort from northwest Spain [165]. Similarly, genetic polymorphisms
of the VEGF gene have been suggested to have a potential implication in the development of
nephritis in patients with HSP [166, 167].

Other loci involved in HSP susceptibility or nephritis development include CTLA4 and
PON1 (which inhibits T cell function and regulates the formation of oxidized lipoproteins,
respectively, as indicated before in this chapter) [147, 168].

Variable Vessel Vasculitis

Behçet Disease

Although the pathogenesis of Behçet disease (BD) is still poorly understood, major
contributors of BD genetics have been identified mainly due to the publication of three
GWASs conducted in Turkish, Japanese, Korean and Italian populations [169-171], as well as
a follow-up study of one of them [172].

HLA Association
As observed in most autoimmune diseases, the HLA region harbors the highest

susceptibility loci for BD, specifically the HLA class I region. In this sense, HLA-B51 (in
particular HLA-B51*01 and HLA-51*08) represents the most robust genetic association with
BD. This association has been confirmed in populations of different ancestry groups since it
was first described in the early eighties [169-171, 173, 174]. Subsequently, the HLA-A26
allele was also reported to have an independent contribution to disease predisposition [175].

However, a recently published analysis of imputed GWAS data from a Turkish cohort
[172] evidenced that the HLA-B51 association with BD is explained by a SNP located
between the HLA-B and MICA loci (rs116799036). The authors also identified three
additional independent signals within the extended HLA region located at the psoriasis
susceptibility 1 candidate 1 (PSORS1C1) gene, HLA-F antisense RNA 1 (HLA-F-AS1), and
HLA-Cw*1602.

Non-HLA Association
The three GWASs performed in BD [169-171] have also represented an important step

forwards to the understanding of the genetic contribution of the non-HLA loci to the disease.
One of the most significant associations with BD described to date is IL10. This gene was

previously suggested as a genetic factor for BD in candidate gene studies [176, 177], and
confirmed by the GWAS data on the Turkish [169] and Japanese [170] populations. However,
the recent GWAS on Koreans [171] failed to reproduce this finding. As indicated previously
in this chapter, this genetic association is shared with GCA and AAV, but also with other
autoimmune diseases such as ulcerative colitis, type 1 diabetes or SLE [174].

Another genomic region associated with BD at GWAS level is IL23R/IL12RB2 [169,
170, 178]. As stated before, the latter gene encodes a subunit of the IL-12 receptor whose
expression is regulated by IFN-?.

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