Identification of new risk loci shared across systemic vasculitides points towards potential target genes for drug repurposing

Abstract

Objectives: The number of susceptibility loci currently associated with vasculitis is lower than in other immune-mediated diseases due in part to small cohort sizes, a consequence of the low prevalence of vasculitides. This study aimed to identify new genetic risk loci for the main systemic vasculitides through a comprehensive analysis of their genetic overlap.

Methods: Genome-wide data from 8467 patients with any of the main forms of vasculitis and 29 795 healthy controls were meta-analysed using ASSET. Pleiotropic variants were functionally annotated and linked to their target genes. Prioritised genes were queried in DrugBank to identify potentially repositionable drugs for the treatment of vasculitis.

Results: Sixteen variants were independently associated with two or more vasculitides, 15 of them representing new shared risk loci. Two of these pleiotropic signals, located close to CTLA4 and CPLX1, emerged as novel genetic risk loci in vasculitis. Most of these polymorphisms appeared to affect vasculitis by regulating gene expression. In this regard, for some of these common signals, potential causal genes were prioritised based on functional annotation, including CTLA4, RNF145, IL12B, IL5, IRF1, IFNGR1, PTK2B, TRIM35, EGR2 and ETS2, each of which has key roles in inflammation. In addition, drug repositioning analysis showed that several drugs, including abatacept and ustekinumab, could be potentially repurposed in the management of the analysed vasculitides.

Conclusions: We identified new shared risk loci with functional impact in vasculitis and pinpointed potential causal genes, some of which could represent promising targets for the treatment of vasculitis.

Keywords: Autoimmunity; Polymorphism, Genetic; Systemic vasculitis.

Figure 1

Manhattan plot showing the results of the cross-phenotype meta-analysis. The −log10 of the p values are plotted against their physical chromosomal position. The red line represents the genome-wide level of significance (p<5×10⁻⁸). Loci reaching the significant threshold are annotated in the plot. Loci representing new shared risk loci in vasculitis are highlighted in bold.

Figure 2

Novel risk loci shared across vasculitides. Effect of the independent genetic variants reaching genome-wide significant level in the subset-based meta-analysis is shown. Circles represent the analysed phenotypes of vasculitis. AAV, ANCA-associated vasculitis; BD, Behçet’s disease; EGPA, eosinophilic granulomatosis with polyangiitis; GCA, giant cell arteritis; KD, Kawasaki disease; IgAV, IgA vasculitis; TAK, Takayasu’s arteritis.

Figure 3

Functional annotation of the identified pleiotropic variants. Colours indicate both lead and proxy polymorphisms overlapping with the different regulatory elements analysed. CI (yellow), chromatin interactions; E (orange), enhancers; P (blue), promoters; eQTL (green), expression quantitative trait loci.

Figure 4

Results of the histone mark enrichment analysis of the set of pleiotropic variants. First column shows the analysed cell-types. The remaining columns denote the analysed histone modifications, including histone marks associated with enhancers (red colour), promoters (orange colour) and accessible genes (green). Results of the enrichment analysis are represented in a scale-based colour gradient depending on the p value. Blue indicates enrichment and white indicates no statistical significance.