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

Autor:	Ortiz-Fernández L; Institute of Parasitology and Biomedicine 'López- Neyra', CSIC, Granada, Spain anamaort@ipb.csic.es lourdes@ipb.csic.es., Carmona EG; Institute of Parasitology and Biomedicine 'López- Neyra', CSIC, Granada, Spain.; Unidad de Enfermedades Autoinmunes Sistémicas, Hospital Clínico San Cecilio, Instituto de Investigación Biosanitaria de Granada ibs.GRANADA, Granada, Spain., Kerick M; Institute of Parasitology and Biomedicine 'López- Neyra', CSIC, Granada, Spain., Lyons P; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK.; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK., Carmona FD; Departamento de Genética e Instituto de Biotecnología, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain.; Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain., López Mejías R; Research Group on Genetic Epidemiology and Atherosclerosis in Systemic Diseases and in Metabolic Bone Diseases of the Musculoskeletal System, IDIVAL, Santander, Spain., Khor CC; Duke-NUS Medical School, Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore Eye Research Institute, Singapore National Eye Centre, Singapore., Grayson PC; Systemic Autoimmunity Branch, NIAMS, National Institutes of Health, Bethesda, Maryland, USA., Tombetti E; Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Hospital, Milan, Italy.; Department of Biomedical and Clinical Sciences L. Sacco, Milan University, Milan, Italy., Jiang L; Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai, China.; Evidence-Based Medicine Center, Fudan University, Shanghai, China., Direskeneli H; Department of Internal Medicine, Division of Rheumatology, Marmara University, Faculty of Medicine, Istanbul, Turkey., Saruhan-Direskeneli G; Department of Physiology, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey., Callejas-Rubio JL; Systemic Autoimmune Diseases Unit, San Cecilio University Hospital, Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain., Vaglio A; Department of Biomedical Experimental and Clinical Sciences 'Mario Serio', University of Florence, Florence, Italy.; Nephrology and Dialysis Unit, Meyer Children's Hospital, Florence, Italy., Salvarani C; Rheumatology Unit, Azienda USL-IRCCS di Reggio Emilia and Azienda Ospedaliero - Universitaria di Modena, Università di Modena and Reggio Emilia, Reggio Emilia, Italy., Hernández-Rodríguez J; Department of Autoimmune Diseases, Hospital Clinic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain., Cid MC; Department of Autoimmune Diseases, Hospital Clinic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain., Morgan AW; School of Medicine and Leeds Institute for Data Analytics, University of Leeds, Leeds, UK.; NIHR Leeds Biomedical Research Centre and NIHR Leeds Medtech and In vitro Diagnostics Co-Operative, Leeds Teaching Hospitals NHS Trust, Leeds, UK., Merkel PA; Division of Rheumatology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Division of Epidemiology, Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Burgner D; Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.; Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.; Department of General Medicine, Royal Children's Hospital, Parkville, Victoria, Australia.; Department of Paediatrics, Monash University, Clayton, Victoria, Australia., Smith KG; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK.; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK., Gonzalez-Gay MA; Research Group on Genetic Epidemiology and Atherosclerosis in Systemic Diseases and in Metabolic Bone Diseases of the Musculoskeletal System, IDIVAL, University of Cantabria, Santander, Spain., Sawalha AH; Division of Rheumatology, Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.; Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.; Lupus Center of Excellence, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.; Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Martin J; Institute of Parasitology and Biomedicine 'López- Neyra', CSIC, Granada, Spain., Marquez A; Institute of Parasitology and Biomedicine 'López- Neyra', CSIC, Granada, Spain anamaort@ipb.csic.es lourdes@ipb.csic.es.
Jazyk:	angličtina
Zdroj:	Annals of the rheumatic diseases [Ann Rheum Dis] 2023 Jun; Vol. 82 (6), pp. 837-847. Date of Electronic Publication: 2023 Feb 16.
DOI:	10.1136/ard-2022-223697
Abstrakt:	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. Competing Interests: Competing interests: None declared. (© 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.)
Databáze:	MEDLINE
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