Leveraging Genetic Findings for Precision Medicine in Vasculitis

Abstract

Vasculitides are a heterogeneous group of low frequent disorders, mainly characterized by the inflammation of blood vessels that narrows or occlude the lumen and limits the blood flow, leading eventually to significant tissue and organ damage. These disorders are classified depending on the size of the affected blood vessels in large, medium, and small vessel vasculitis. Currently, it is known that these syndromes show a complex etiology in which both environmental and genetic factors play a major role in their development. So far, these conditions are not curable and the therapeutic approaches are mainly symptomatic. Moreover, a percentage of the patients do not adequately respond to standard treatments. Over the last years, numerous genetic studies have been carried out to identify susceptibility loci and biological pathways involved in vasculitis pathogenesis as well as potential genetic predictors of treatment response. The ultimate goal of these studies is to identify new therapeutic targets and to improve the use of existing drugs to achieve more effective treatments. This review will focus on the main advances made in the field of genetics and pharmacogenetics of vasculitis and their potential application for ameliorating long-term outcomes in patient management and in the development of precision medicine.

Unraveling the Immunopathogenesis and Genetic Variants in Vasculitis Toward Development of Personalized Medicine

“…Antigen specificity is determined by specific pockets in the antigen-binding groove of the HLA molecule, and therefore the amino acid sequence of these pockets is crucial to understanding the risk for certain autoimmune diseases ( 35 ). While the MHC constitutes the strongest association in vasculitis, there are several loci outside the MHC, including SERPINA1, PRTN3, SEMA6A, PTPN22, CTLA4, FCGR3B , and ARPC1B that have also been established as genetic risk factors for these diseases, coding for immunological molecules that increase susceptibility to autoimmunity ( 36 ) ( Table 1 ).…”

“…Currently, there is not much literature on the genetic factors that contribute to CSVV pathogenesis. However, some have suggested that the gene ARPC1B may play a role in predisposition to this disease ( 36 , 37 ). The ARPC1B gene encodes ARPC1B, which is an isoform of ARPC1 (actin-related protein complex-1) and one of the regulatory subunits of the Arp2/3 complex involved in actin polymerization and cellular motility ( 35 ).…”

“…Based on findings derived from genetic studies, it has been elucidated that ANCA-mediated neutrophil activation and B cells are crucial to AAV pathogenesis, and therefore potential treatments can include B cell-depleting drugs ( 36 , 77 ). In terms of the induction of AAV remission, rituximab represents a very promising contender ( 65 ).…”

Associations and Outcomes Between Chronic Traumatic Encephalopathy and Vasculitis in Adults Patients

“…A study at Boston University showed that athletes who had TMEM106B gene in their brain were highly reactive to inflammation. The genetic risk factors of vasculitis depend on the type of condition; for example, in Takayasu arteritis, HLA (human leukocyte antigen) region occurs as the leading risk factor [16].…”

Current State of Precision Medicine in Primary Systemic Vasculitides

“…Both PLG and P4HA2 play a role in the regulation of angiogenesis and vascular remodeling. The plasminogen system is known to regulate several pathways possibly related to the GCA pathogenesis, such as lymphocyte recruitment and production of TNF-α and IL-6 cytokines (96,97). The P4HA2 gene is a hypoxia-responsive gene with a role in collagen biosynthesis and composition of ECM.…”