Identification of new risk loci shared across systemic vasculitides points towards potential target genes for drug repurposing
Lourdes Ortiz‐Fernández, Elio G. Carmona, Martin Kerick, Paul Lyons, F. David Carmona, Raquel López Mejías, Chiea Chuen Khor, Peter C. Grayson, Enrico Tombetti, Lindi Jiang, Haner Di̇reskeneli̇, Güher Saruhan‐Direskeneli, José Luís Callejas-Rubio, Augusto Vaglio, Carlo Salvarani, José Hernández‐Rodríguez, María C. Cid, Ann W Morgan, Peter A. Merkel, David Burgner, Kenneth G. C. Smith, Miguel Á. González‐Gay, Amr H. Sawalha, Javier Martı́n, Ana Márquez
Abstract
<h3>Objectives</h3> 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. <h3>Methods</h3> 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. <h3>Results</h3> 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 <i>CTLA4</i> and <i>CPLX1</i>, 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 <i>CTLA4</i>, <i>RNF145</i>, <i>IL12B</i>, <i>IL5</i>, <i>IRF1</i>, <i>IFNGR1</i>, <i>PTK2B</i>, <i>TRIM35</i>, <i>EGR2</i> and <i>ETS2</i>, 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. <h3>Conclusions</h3> 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.