Ortiz-Fernández, L, Carmona, EG, Kerick, M et al. (22 more authors) (2023) Identification of new risk loci shared across systemic vasculitides points towards potential target genes for drug repurposing. Annals of the Rheumatic Diseases, 82 (6). pp. 837-847. ISSN 0003-4967
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/. |
Keywords: | Autoimmunity; Polymorphism, Genetic; Systemic vasculitis |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM) > Discovery & Translational Science Dept (Leeds) |
Funding Information: | Funder Grant number NIHR National Inst Health Research BRC MRC (Medical Research Council) MR/N011775/1 EU - European Union 813545 NIHR National Inst Health Research NIHR202395 NIHR National Inst Health Research Not Known |
Depositing User: | Symplectic Publications |
Date Deposited: | 10 Mar 2023 10:32 |
Last Modified: | 16 Jun 2023 13:56 |
Status: | Published |
Publisher: | BMJ |
Identification Number: | 10.1136/ard-2022-223697 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:197201 |