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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.

 Authorship: Ortiz-Fernández L., Carmona E.G., Kerick M., Lyons P., Carmona F.D., Mejías R.L., Khor C.C., Grayson P.C., Tombetti E., Jiang L., Direskeneli H., Saruhan-Direskeneli G., Callejas-Rubio J.L., Vaglio A., Salvarani C., Hernández-Rodríguez J., Cid M.C., Morgan A.W., Merkel P.A., Burgner D., Smith K.G.C., Gonzalez-Gay M.A., Sawalha A.H., Martin J., Marquez A.,

 Fuente: Annals of the Rheumatic Diseases, 2023, 82, 837-847

 Publisher: BMJ Publishing Group

 Year of publication: 2023

 No. of pages: 11

 Publication type: Artículo de Revista

 DOI: 10.1136/ard-2022-223697

 ISSN: 0003-4967,1468-2060

 Spanish project: MCIN/AEI /10.13039/501100011033

 Publication Url: http://dx.doi.org/10.1136/ard-2022-223697

Authorship

ORTIZ-FERNÁNDEZ, LOURDES

CARMONA, ELIO G.

KERICK, MARTIN

LYONS, PAUL

CARMONA, FRANCISCO DAVID

LÓPEZ MEJÍAS, RAQUEL

KHOR, CHIEA CHUEN

GRAYSON, PETER C.

TOMBETTI, ENRICO

JIANG, LINDI

DIRESKENELI, HANER

SARUHAN-DIRESKENELI, GUHER

CALLEJAS-RUBIO, JOSÉ-LUIS

VAGLIO, AUGUSTO

HERNÁNDEZ-RODRÍGUEZ, JOSÉ

CINTA CID, MARÍA

MORGAN, ANN W.

MERKEL, PETER A.