Cross-phenotype analysis of Immunochip data identifies <i>KDM4C</i> as a relevant <i>locus</i> for the development of systemic vasculitis.

Abstract

Systemic vasculitides represent a heterogeneous group of rare complex diseases of the blood vessels with a poorly understood aetiology. To investigate the shared genetic component underlying their predisposition, we performed the first cross-phenotype meta-analysis of genetic data from different clinically distinct patterns of vasculitis. Immunochip genotyping data from 2465 patients diagnosed with giant cell arteritis, Takayasu's arteritis, antineutrophil cytoplasmic antibody-associated vasculitis or IgA vasculitis as well as 4632 unaffected controls were analysed to identify common susceptibility <i>loci</i> for vasculitis development. The possible functional consequences of the associated variants were interrogated using publicly available annotation data. The strongest association signal corresponded with an intergenic polymorphism located between <i>HLA-DQB1</i> and <i>HLA-DQA2</i> (rs6932517, P=4.16E-14, OR=0.74). This single nucleotide polymorphism is in moderate linkage disequilibrium with the disease-specific human leucocyte antigen (HLA) class II associations of each type of vasculitis and could mark them. Outside the HLA region, we identified the <i>KDM4C</i> gene as a common risk <i>locus</i> for vasculitides (highest peak rs16925200, P=6.23E-07, OR=1.75). This gene encodes a histone demethylase involved in the epigenetic control of gene expression. Through a combined analysis of Immunochip data, we have identified <i>KDM4C</i> as a new risk gene shared between systemic vasculitides, consistent with the increasing evidences of the crucial role that the epigenetic mechanisms have in the development of complex immune-mediated conditions.