Genetic variants in ANCA-associated vasculitis: a meta-analysis

Rahmattulla, Chinar; Mooyaart, Antien L.; Hooven, Daphne van; Schoones, Jan W.; Bruijn, Jan A.; Dekkers, Olaf M.; Bajema, Ingeborg M.

doi:10.1136/annrheumdis-2015-207601

Cited by 96 publications

(67 citation statements)

References 44 publications

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“…This was also highlighted in a recent meta-analysis that showed some of these genes, but also for example HLA and SERPINA1 as described above, to be associated with AAV. This study also confirmed that subdivision of AAV by ANCA serotype rather than clinical phenotype has stronger genetic basis (Rahmattulla et al 2016). …”

Section: Genetic Risk Factorssupporting

confidence: 73%

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The Contribution of Innate Immunity to the Pathogenesis of ANCA-associated Vasculitis

Söderberg¹

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"Nog finns det mål och mening med vår färd -men det är vägen som är mödan värd" − Karin Boye SupervisorMårten Segelmark, Linköping University, Sweden Co-supervisorsPer Eriksson, Linköping University, Sweden Jan Ernerudh, Linköping University, Sweden Tino Kurz, Linköping University, Sweden Faculty opponentPeter Heeringa, University of Groningen, The Netherlands Abstract Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) constitute a group of vasculitides characterized by neutrophil-rich necrotizing inflammation of small vessels and the presence of ANCA in the circulation. Dying neutrophils surrounding the walls of small vessels are a histological hallmark of AAV. Traditionally it has been assumed that these neutrophils die by necrosis, but neutrophil extracellular traps (NETs) have recently been visualized at the sites of vasculitic lesions. NETs were first described to be involved in capture and elimination of pathogens but dysregulated production and/or clearance of NETs are thought to contribute to vessel inflammation in AAV; directly by damaging endothelial cells and indirectly by acting as a link between the innate and adaptive immune system through the generation of pathogenic PR3-ANCA and MPO-ANCA that can activate neutrophils. ANCA can, however, be found in all individuals and are therefore suggested to belong to the repertoire of natural antibodies produced by innate-like B cells, implying that not all ANCA are pathogenic.In paper I, we found neutrophils in patients to be more prone to undergo NETosis/necrosis spontaneously compared with neutrophils in healthy controls (HC), as well as that active patients possessed elevated levels of NETs in the circulation. Our results also suggest that ANCA during remission could contribute to the clearance of NETs as we observed an inverse relation between ANCA and NETs. In paper II, we observed neutrophils in patients to be more easily activated upon ANCA stimulation as they produced more ROS than neutrophils in HC. In paper III, we showed for the first time that cells of adaptive immunity (B and T cells)

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Section: Genetic Risk Factorssupporting

confidence: 73%

“…PR3 released by activated neutrophils promotes formation of bradykinin and thereof increased vasopermeability and inflammation (Kahn et al 2009). This can be inhibited by the PR3 inhibitor α1-antitrypsin, but the genetic variations of this gene in AAV patients (Rahmattulla et al 2016) could possibly disrupt this regulation.…”

Section: Neutrophil Recruitmentmentioning

confidence: 99%

The Contribution of Innate Immunity to the Pathogenesis of ANCA-associated Vasculitis

Söderberg¹

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“…In addition, the eQTL risk allele was correlated with upregulation of FCGR2A in lymphoblastoid cells. This genetic locus has previously been associated with a genome-wide significance in Kawasaki disease [52], and modest significance in giant cell arteritis [53] and ANCA-associated vasculitis [54]. FCGR2A has an important role in humoral immunity, and it is expressed on most leukocytes and can bind immune complexes to initiate antibody-dependent cellular cytotoxicity and the release of pro-inflammatory mediators [55].…”

Section: Complement-binding Genesmentioning

confidence: 99%

The genetics of Takayasu arteritis

Renauer

Sawalha

2017

La Presse Médicale

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Summary Takayasu arteritis (TAK) is a rare systemic vasculitis that is characterized by granulomatous inflammation of the aorta and its major branches. The cellular and biochemical processes involved in the pathogenesis of TAK are beginning to be elucidated, and implicate both cell and antibody-mediated autoimmune mechanisms. In addition, the underlying etiology to TAK may be explained, at least in part, by a complex genetic contribution. The most well-recognized genetic susceptibility locus for the disease is the classical HLA allele, HLA-B*52, which has been confirmed in several ethnicities. The genetic susceptibility with HLA-B*52, as well as additional classical alleles and loci, implicate both HLA class I and class II involvement in TAK. Furthermore, genetic associations with genes encoding immune response regulators, pro-inflammatory cytokines and mediators of humoral immunity may directly relate to disease mechanisms. Non-HLA susceptibility loci that have been recently established for TAK with a genome-wide level of significance include FCGR2A/FCGR3A, IL12B, IL6, RPS9/LILRB3, and a locus on chromosome 21 near PSMG1. In this review, we present the complex genetic predisposition to TAK and discuss how recent findings identified potential targets in the pathogenesis and treatment of the disease.

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“…The authors found that in 76% of the genetic variants, a subdivision based on ANCA serotype resulted in higher odds ratios than a subdivision based on clinical diagnosis. The results indicated that a subdivision of AAV based on ANCA serotype has a stronger genetic basis than a subdivision based on clinical diagnosis [30]. It is important to note that GWAS identify specific DNA locations, not complete genes.…”

Section: The Complement System In Human Aavmentioning

confidence: 99%

“…The study also investigated whether diagnostic and serological subtypes within AAV have distinct genetic backgrounds [30]. The authors identified 33 genetic variants associated with AAV.…”

Section: The Complement System In Human Aavmentioning

confidence: 99%

Therapeutic Complement Targeting in ANCA-Associated Vasculitides and Thrombotic Microangiopathy

et al. 2016

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Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are a group of systemic autoimmune disorders characterized by necrotizing inflammation of medium-to-small vessels, a relative paucity of immune deposits, and an association with detectable circulating ANCAs. AAVs include granulomatosis with polyangiitis (renamed from Wegener's granulomatosis), microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). Until recently, AAVs have not been viewed as complement-mediated disorders. However, recent findings predominantly from animal studies demonstrated a crucial role of the complement system in the pathogenesis of AAVs. Complement activation or defects in its regulation have been described in an increasing number of acquired or genetically driven forms of thrombotic microangiopathy. Coinciding with this expanding spectrum of complement-mediated diseases, the question arises as to which AAV patients might benefit from a complement-targeted therapy. Therapies directed against the complement system point to the necessity of a genetic workup of genes of complement components and regulators in patients with AAV. Genetic testing together with pluripotent stem cells and bioinformatics tools may broaden our approach to the treatment of patients with aggressive forms of AAV.

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Genetic variants in ANCA-associated vasculitis: a meta-analysis

Cited by 96 publications

References 44 publications

The Contribution of Innate Immunity to the Pathogenesis of ANCA-associated Vasculitis

The Contribution of Innate Immunity to the Pathogenesis of ANCA-associated Vasculitis

The genetics of Takayasu arteritis

Therapeutic Complement Targeting in ANCA-Associated Vasculitides and Thrombotic Microangiopathy

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