Genetics of ANCA-associated vasculitides: HLA and beyond

The pathogenesis of ANCA-associated vasculitis (AAV) is multifactorial and most likely involves the interaction of environmental and genetic factors. During the past few years, a number of studies have investigated genetic associations with AAV; earlier studies explored associations with single nucleotide polymorphisms (SNPs) at genes of potential pathogenetic interest ('candidate gene' studies), whereas more recent larger studies analysed associations with SNPs covering ~90% of the human genome (genome-wide association studies - GWAS). The latter studies have significantly advanced our understanding of the genetic aspects of AAV, confirming some previously reported findings and uncovering new genetic associations. In addition, these studies have also shown that different AAV subtypes such as granulomatosis with polyangiitis (Wegener's, GPA) and microscopic polyangiitis (MPA) are underpinned by distinct genetic risk factors, with GPA being associated with HLA-DP, SERPINA1 (encoding α1-antitrypsin), PRTN3 (encoding proteinase-3, PR3, the main GPA-related autoantigen) and SEMA6A (semaphorin 6A), whereas MPA has been mainly associated with HLA-DQ. Interestingly, in the European GWAS, which included both GPA and MPA patients, the HLA-DP, SERPINA1, PRTN3 and HLA-DQ SNPs were more significantly associated with ANCA-specificities (PR3 vs. myeloperoxidase, MPO) than with the clinical syndromes. In addition, the finding of GPA and PR3-positive subsets being associated with SNPs of genes encoding PR3 and α1-antitrypsin, a protease able to inactivate PR3, highlighted the central role of PR3 as an auto-antigen in AAV. This paper reviews the main genetic association studies in AAV, with particular emphasis on the two GWAS performed so far.