Page 130 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

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

This pathway is crucial in the Th1 and Th17 cell differentiation and it is involved in the
inflammatory response. On the other hand, IL-23 is another important immunoregulatory
cytokine that also promote Th17 function associated with the active intraocular inflammation
in BD patients. Shortly before the publication of the two first BD GWASs [169, 170], an
association between IL23R and BD was reported in the Han Chinese population [178].
Similarly to IL10, the association was confirmed using the GWAS methodology in Turkish
and Japanese [169, 170], but not in Koreans [171].

In 2013, the GWAS on Koreans [171], which had a lower statistical power than those on
Turkish [169] and Japanese [170] cohorts, identified the GTPase IMAP family member
(GIMAP) cluster, whose members play an important role in T cell function as well as T cell
development and selection, as a novel genetic factor for BD. The peak signal outside the HLA
region was observed in GIMAP4.

Functional studies performed by the authors evidenced that the minor allele of the
associated polymorphism led to lower protein activity than the major allele, and that BD
patients showed a lower GIMAP4 expression in CD4 T cells.

A large number of additional genetic associations with BD have been suggested through
candidate gene studies, although most of them do not rely on consistent results. For example,
associated variants have been identified in 1) genes encoding cytokines/chemokines, such as
transforming growth factor beta 1 (TGFB1), TNF, IFNG, IL1A, IL1B, IL2, IL4, IL6, IL8,
IL17, IL18, and MCP1 amongst others [177, 179-194]; 2) genes involved in the endothelial
function, including VEGF, ICAM1, MMP9, NOS3, and glutathione S-transferase (GST) [195-
202]; 3) important immunomodulatory genes, like NFKB, IRF1, CTLA4, STAT4, and CD40
[203-209]; and 4) genes encoding receptors of the innate immunity, as TLR2, TLR4, TLR9,
TNF receptor superfamily 1A (TNFRSF1A), FCGR2A, FCGR3A and FCGR3B [210-215].
Nevertheless, studies on well-powered cohorts are required to definitively confirm or discard
these associations.

Conclusion

Despite the recent advances in the identification of the risk factors underlying
vasculitides predisposition, the genetic component of these conditions remains poorly
understood.

In most studies, the limited statistical power and the lack of replication in independent
cohorts have made difficult the identification of consistent genetic association signals.
However, a large number of the known susceptibility loci are shared amongst different
vasculitides (Figure 1), which clearly suggest that they may represent true association signals.
Moreover, this also supports the hypothesis of common molecular pathways influencing the
development of autoimmune diseases in general and vasculitides in particular.

In any case, cohorts large enough to perform adequately powered studies are needed to
identify novel risk factors and to confirm previously reported genetic associations.

The use of high throughput genotyping platform on vasculitides such as GCA, TA, and
HSP, in which only candidate gene studies have been conducted so far, would also provide an
opportunity to unravel their genetic component.

Complimentary Contributor Copy