Genetics of vasculitis

We aim to give an overview of the recent progress in the knowledge of the genetic component of vasculitides.

Using a state-of-the-art imputation method to analyse the major histocompatibility complex (MHC) region, Ombrello and colleagues narrowed down the association between human leukocyte antigen (HLA)-B51 and Behçet's disease to a model of five amino acids of the HLA-B molecule involved in the binding of the antigen, the interactions with receptors on CD8 T cells and natural killer cells, and the signal peptide of HLA-B, suggesting a crucial role of the cellular cytotoxicity on this disease. Other recent genetic studies have identified several loci with strong effects on vasculitis predisposition, most of them representing important players in the immune and inflammatory response. These associations include ERAP1, CCR1-CCR3, STAT4, KLRC4, GIMAP4, and TNFAIP3 in Behçet's disease; BLK and CD40 in Kawasaki disease; SERPINA1 and SEMA6A in antineutrophil cytoplasmic antibody associated vasculitides; IL12B and FCGR2A/ FCGR2A in Takayasu arteritis; and CECR1 in a newly defined vascular inflammatory syndrome associated with adenosine deaminase (ADA2) deficiency. Although other vasculitides, such as giant cell arteritis (GCA) or immunoglobulin A vasculitis, have not benefitted by the great advantage of the large-scale genetic analyses yet, some interesting associations have been recently suggested, such as the classical functional PTPN22 allele rs2476601 (R620W) with GCA.

The analysis of high-throughput genotyping and exome-sequencing data has produced a considerable advance in the identification of consistent genetic risk factors in vasculitides during the last 3 years. Further collaborative efforts, which will increase the sample size, and the use of custom arrays like the immunochip, will definitively help to better understand the genetic basis of vasculitides and to identify the common and specific molecular pathways underlying their pathophysiology.