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

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.
HELICAL Innovative Training Network
European Commission funded-under the Marie Sklodowska-Curie 813545
Cooperative Research Thematic Network programme RD16/0012/0013
Redes de Investigacion Cooperativa Orientadas a Resultados en Salud (RICORS) RD21/0002/0039
Instituto de Salud Carlos III PI18/00040
Juan de la Cierva Incorporacion fellowship IJC2019- 040746-I
United States Department of Health & Human Services
National Institutes of Health (NIH) - USA
NIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) R01 AR070148
National Health and Medical Research Council (NHMRC) of Australia GTN1175744
Victorian Government's Operational Infrastructure Support Program
Rare Diseases Clinical Research Network (RDCRN)
initiative of the Office of Rare Diseases Research (ORDR)
NIH National Center for Advancing Translational Sciences (NCATS)
NIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) U54 AR057319
NIH National Center for Research Resources (NCRR) U54 RR019497