The Genetics of Anti-Neutrophil Cytoplasmic Antibody Associated Vasculitis (AAV)

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.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2019

Author dc:creator

• Wong, Limy

Advisors dc:contributor.advisor

• Smith, Kenneth G. C.
• Lyons, Paul A.

• Genetics
• AAV
• GWAS

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/f5689ac0-c14b-437a-8d72-084853a0913d/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

en

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.51022

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/303938