{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/303938"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/303938","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"The Genetics of Anti-Neutrophil Cytoplasmic Antibody Associated Vasculitis (AAV)","abstract":"Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a multi-systemic autoimmune disorder with evidence of circulating pathogenic ANCA. There are two main antigenic targets: proteinase 3 (PR3) and myeloperoxidase (MPO). Previous genome-wide association studies (GWAS) have provided evidence that PR3-AAV and MPO-AAV are genetically distinct autoimmune syndromes, though only three loci specific to PR3-AAV and one to MPO-AAV have been identified to date. With the European Vasculitis Genetics Consortium, we conducted a larger GWAS, powered to discover additional risk loci in both PR3-AAV and MPO-AAV independently. A meta-analysis of two European cohorts was conducted, comprising 1,610 PR3-AAV cases, 870 MPO-AAV cases and 11,947 controls. For PTPN22 (rs6679677), a further replication cohort, previously genotyped using the Sequenom MassARRAY platform, and comprising 1,122 PR3-AAV and 347 MPO-AAV cases and 1,531 controls was included in the combined analysis. This is the largest genome-wide association study of AAV to date and we have identified a total of 12 AAV susceptibility loci. Previously genome-wide significant loci were confirmed, including HLA class II, SERPINA1, PRTN3 and PTPN22. Seven new genome-wide significant loci were identified: three associated with PR3-AAV (BCL2L11-MIR4435-2HG, EBF3-MGMT, IGHV1-69), two with MPO-AAV (BACH2, ANKRD11-SPG7) and two shared by both (CTLA-4 and DGUOK-TET3). Further analyses based on common variants suggested that a substantial component of the genetic architecture was shared between PR3-AAV and MPO-AAV, similar to that observed between ulcerative colitis and Crohn’s disease. In addition, Mendelian randomisation analysis confirmed that a higher eosinophil count increased the risk of PR3-AAV but not MPO-AAV, and this effect might, in part, be modulated by MIR4435-2HG through prolongation of eosinophil survival. MIR4435-2HG encodes a long non-coding RNA that plays a critical role in the regulation of BCL2L11 transcription (a Bcl2 family member essential for controlling apoptosis) in myeloid cells and hence their lifespan. We have also identified a missense variant in IGHV1-69 (rs11845244) that leads to a loss in neutralising function of antibodies generated against the NEAT2 domain of Staphylococcus aureus. This therefore provides a plausible host genetic factor in determining the susceptibility to infectious disease and as a potential driver of PR3-AAV. Overall, this study provides key novel insights into disease biology for AAV and potential therapeutic targets.","abstract_html":"Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a multi-systemic autoimmune disorder with evidence of circulating pathogenic ANCA. There are two main antigenic targets: proteinase 3 (PR3) and myeloperoxidase (MPO). Previous genome-wide association studies (GWAS) have provided evidence that PR3-AAV and MPO-AAV are genetically distinct autoimmune syndromes, though only three loci specific to PR3-AAV and one to MPO-AAV have been identified to date. With the European Vasculitis Genetics Consortium, we conducted a larger GWAS, powered to discover additional risk loci in both PR3-AAV and MPO-AAV independently. A meta-analysis of two European cohorts was conducted, comprising 1,610 PR3-AAV cases, 870 MPO-AAV cases and 11,947 controls. For PTPN22 (rs6679677), a further replication cohort, previously genotyped using the Sequenom MassARRAY platform, and comprising 1,122 PR3-AAV and 347 MPO-AAV cases and 1,531 controls was included in the combined analysis. This is the largest genome-wide association study of AAV to date and we have identified a total of 12 AAV susceptibility loci. Previously genome-wide significant loci were confirmed, including HLA class II, SERPINA1, PRTN3 and PTPN22. Seven new genome-wide significant loci were identified: three associated with PR3-AAV (BCL2L11-MIR4435-2HG, EBF3-MGMT, IGHV1-69), two with MPO-AAV (BACH2, ANKRD11-SPG7) and two shared by both (CTLA-4 and DGUOK-TET3). Further analyses based on common variants suggested that a substantial component of the genetic architecture was shared between PR3-AAV and MPO-AAV, similar to that observed between ulcerative colitis and Crohn’s disease. In addition, Mendelian randomisation analysis confirmed that a higher eosinophil count increased the risk of PR3-AAV but not MPO-AAV, and this effect might, in part, be modulated by MIR4435-2HG through prolongation of eosinophil survival. MIR4435-2HG encodes a long non-coding RNA that plays a critical role in the regulation of BCL2L11 transcription (a Bcl2 family member essential for controlling apoptosis) in myeloid cells and hence their lifespan. We have also identified a missense variant in IGHV1-69 (rs11845244) that leads to a loss in neutralising function of antibodies generated against the NEAT2 domain of Staphylococcus aureus. This therefore provides a plausible host genetic factor in determining the susceptibility to infectious disease and as a potential driver of PR3-AAV. Overall, this study provides key novel insights into disease biology for AAV and potential therapeutic targets.","abstract_has_math":false,"creators":["Wong, Limy"],"institution":"University of Cambridge","degree_name":"Doctor of Philosophy (PhD)","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Smith, Kenneth G. C.","Lyons, Paul A."],"committee_chairs":[],"committee_members":[],"year":2019,"date_issued":"2019-09","date_published":"2019-09","updated_at":"2026-07-22T22:24:27Z","subjects":["Genetics","AAV","GWAS"],"languages":["en"],"rights":[],"rights_urls":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/f5689ac0-c14b-437a-8d72-084853a0913d/download","https://www.rioxx.net/licenses/all-rights-reserved/"],"identifier_entries":[]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.51022","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Smith, Kenneth G. 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Previously genome-wide significant loci were confirmed, including HLA class II, SERPINA1, PRTN3 and PTPN22. Seven new genome-wide significant loci were identified: three associated with PR3-AAV (BCL2L11-MIR4435-2HG, EBF3-MGMT, IGHV1-69), two with MPO-AAV (BACH2, ANKRD11-SPG7) and two shared by both (CTLA-4 and DGUOK-TET3). Further analyses based on common variants suggested that a substantial component of the genetic architecture was shared between PR3-AAV and MPO-AAV, similar to that observed between ulcerative colitis and Crohn’s disease. In addition, Mendelian randomisation analysis confirmed that a higher eosinophil count increased the risk of PR3-AAV but not MPO-AAV, and this effect might, in part, be modulated by MIR4435-2HG through prolongation of eosinophil survival. MIR4435-2HG encodes a long non-coding RNA that plays a critical role in the regulation of BCL2L11 transcription (a Bcl2 family member essential for controlling apoptosis) in myeloid cells and hence their lifespan. 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For PTPN22 (rs6679677), a further replication cohort, previously genotyped using the Sequenom MassARRAY platform, and comprising 1,122 PR3-AAV and 347 MPO-AAV cases and 1,531 controls was included in the combined analysis. This is the largest genome-wide association study of AAV to date and we have identified a total of 12 AAV susceptibility loci. Previously genome-wide significant loci were confirmed, including HLA class II, SERPINA1, PRTN3 and PTPN22. Seven new genome-wide significant loci were identified: three associated with PR3-AAV (BCL2L11-MIR4435-2HG, EBF3-MGMT, IGHV1-69), two with MPO-AAV (BACH2, ANKRD11-SPG7) and two shared by both (CTLA-4 and DGUOK-TET3). Further analyses based on common variants suggested that a substantial component of the genetic architecture was shared between PR3-AAV and MPO-AAV, similar to that observed between ulcerative colitis and Crohn’s disease. In addition, Mendelian randomisation analysis confirmed that a higher eosinophil count increased the risk of PR3-AAV but not MPO-AAV, and this effect might, in part, be modulated by MIR4435-2HG through prolongation of eosinophil survival. MIR4435-2HG encodes a long non-coding RNA that plays a critical role in the regulation of BCL2L11 transcription (a Bcl2 family member essential for controlling apoptosis) in myeloid cells and hence their lifespan. We have also identified a missense variant in IGHV1-69 (rs11845244) that leads to a loss in neutralising function of antibodies generated against the NEAT2 domain of Staphylococcus aureus. This therefore provides a plausible host genetic factor in determining the susceptibility to infectious disease and as a potential driver of PR3-AAV. 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