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Objective The TYK2 gene encodes a tyrosin kinase which is involved in multiple immune functions. A functional variant of this gene has been identified to play a protective role in multiple autoimmune diseases. The goal of this study was to evaluate the involvement of this variant of TYK2 in vasculitides [giant cell arteritis (GCA), ANCA-associated vasculitis (AAV) and IgA vasculitis (IgAV)] and viral infections [hepatitis C virus (HCV) and human immunodeficiency virus type I (HIV-1)]. Methods The study sample was composed of 13,745 European individuals. The genotyping was performed by Immunochip and TaqMan 5'allele discrimination assays and the allele frequencies were compared using PLINK. Results Although the results obtained did not reach the genome-wide level of significance, p-values at nominal significance were observed, suggesting that the TYK2 variant provides protection against two vasculitides: GCA (p=5.94E-3; OR (95%CI) = 0.56 (0.37-0.85) and AAV (p=6.79E-3; OR (95%CI) = 0.65 (0.47-0.89). However, this variant was not found to be associated with IgAV. No evidence was gained that the TYK2 variant confers susceptibility to HCV and HIV-1 infection. Conclusion This is the first study to propose the association between the TYK2 and both GCA and AAV. Our findings also suggest that TYK2 does not play a relevant role in IgAV or in susceptibility to HCV and HVI-1. This work was supported by the following grants: P12-BIO-1395 from Consejería de Innovación, Ciencia y Tecnología, Junta de Andalucía (Spain) and the Cooperative Research Thematic Network (RETICS) programme, RD16/0012/0013 (RIER), from Instituto de Salud Carlos III (ISCIII, Health Ministry, Madrid, Spain), FDC is recipient of a grant from the Ramon y Cajal programme (RYC-2014-16458) from the Spanish Ministry of Economy, Industry and Competitiveness. This work was supported by grants SAF2016-80125-R (Ministerio de Economía, Industria y Competitividad, Spain) to A. Caruz. RL-M is supported by the Miguel Servet I programme of the Spanish Ministry of Economy and Competitiveness through the grant CP16/00033.

Objective The TYK2 gene encodes a tyrosin kinase which is involved in multiple immune functions. A functional variant of this gene has been identified to play a protective role in multiple autoimmune diseases. The goal of this study was to evaluate the involvement of this variant of TYK2 in vasculitides [giant cell arteritis (GCA), ANCA-associated vasculitis (AAV) and IgA vasculitis (IgAV)] and viral infections [hepatitis C virus (HCV) and human immunodeficiency virus type I (HIV-1)]. Methods The study sample was composed of 13,745 European individuals. The genotyping was performed by Immunochip and TaqMan 5’allele discrimination assays and the allele frequencies were compared using PLINK. Results Although the results obtained did not reach the genome-wide level of significance, p-values at nominal significance were observed, suggesting that the TYK2 variant provides protection against two vasculitides: GCA (p=5.94E-3; OR (95%CI) = 0.56 (0.37–0.85) and AAV (p=6.79E-3; OR (95%CI) = 0.65 (0.47–0.89). However, this variant was not found to be associated with IgAV. No evidence was gained that the TYK2 variant confers susceptibility to HCV and HIV-1 infection. Conclusion This is the first study to propose the association between the TYK2 and both GCA and AAV. Our findings also suggest that TYK2 does not play a relevant role in IgAV or in susceptibility to HCV and HVI-1.

PTPN22 encodes a lymphoid-specific tyrosine phosphatase (LYP) that is a master regulator of the immune response. This gene is a major susceptibility factor for a wide range of autoimmune conditions, including rheumatoid arthritis (RA) for which it represents the strongest non-HLA contributor to disease risk. A missense PTPN22 allele (R620W) affecting the protein-protein interaction of LYP with other relevant players was described as the functional variant of the association. This review will focus on the role of PTPN22 in the pathogenic mechanisms underlying RA predisposition and discuss the possibility of developing LYP-based treatment strategies with a potential application in clinical practice. Areas covered: This review covers the literature showing how PTPN22 is implicated in signalling pathways involved in the autoimmune and autoinflammatory processes underlying RA. Insights obtained from studies aimed at developing novel selective LYP suppressors for treating RA are summarized. Expert opinion: Targeting key risk factors during the early steps of the disease may represent a good strategy to accomplish complete disease remission. As cumulating evidences suggest that PTPN22 R620W is a gain-of-function variant, a growing interest in developing LYP inhibitors has arisen. The potential efficacy and possible application of such compounds are discussed., FDC was recipient of a grant from the 'Ramon y Cajal' programme of the Spanish Ministry of Economy and Competitiveness (RYC-2014-16458). JM was founded by Instituto de Salud Carlos III (ISCIII), Spain, through the RETICS Program RD16/0012/0004 (RIER), and the EU/EFPIA Innovative Medicines Initiative Joint Undertaking PRECISESADS (ref: 115565).

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