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Genetic variants in ANCA-associated vasculitis: a meta-analysis
  1. Chinar Rahmattulla1,
  2. Antien L Mooyaart1,
  3. Daphne van Hooven1,
  4. Jan W Schoones2,
  5. Jan A Bruijn1,
  6. Olaf M Dekkers3,4,5,
  7. European Vasculitis Genetics Consortium,
  8. Ingeborg M Bajema1
  1. 1Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands
  2. 2Walaeus Library, Leiden University Medical Centre, Leiden, The Netherlands
  3. 3Department of Clinical Epidemiology, Leiden University Medical Centre, Leiden, The Netherlands
  4. 4Department of Medicine, Division Endocrinology, Leiden University Medical Centre, Leiden, The Netherlands
  5. 5Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
  1. Correspondence to Chinar Rahmattulla, Department of Pathology, L1-Q (P0-107), Leiden University Medical Centre, PO Box 9600, Leiden 2300 RC, The Netherlands; C.Rahmattulla{at}lumc.nl

Abstract

Background Genetic factors may influence the pathogenic pathways leading to antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We performed a meta-analysis to determine the genetic variants most likely associated with AAV and investigated whether diagnostic and serological subtypes within AAV have distinct genetic backgrounds.

Methods Studies investigating the association between genetic variants and AAV in humans were searched in PubMed, EMBASE and Web of Science. All variants investigated in at least two studies were selected. Subsequently, all studies assessing these variants were included in this meta-analysis. Additionally, data on these variants from the largest genome-wide association studies in AAV were included to increase the validity of this meta-analysis.

Results The literature search yielded 5180 articles. 62 articles investigating 140 genetic variants were included, 33 of which were associated with AAV in a meta-analysis. These genetic variants were in or near the following genes: CD226, CTLA-4, FCGR2A, HLA-B, HLA-DP, HLA-DQ, HLA-DR, HSD17B8, IRF5, PTPN22, RING1/RXRB, RXRB, STAT4, SERPINA1 and TLR9. Moreover, we identified genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis and between proteinase 3 ANCA vasculitis and myeloperoxidase ANCA vasculitis. In 76% of the genetic variants, subdivision based on ANCA serotype resulted in higher ORs than subdivision based on clinical diagnosis.

Conclusions This meta-analysis identified 33 genetic variants associated with AAV, supporting a role for alpha-1-antitrypsin, the major histocompatibility complex system, and several distinct inflammatory processes in AAV pathogenesis. Our results indicate that subdivision of AAV based on ANCA serotype has a stronger genetic basis than subdivision based on clinical diagnosis.

  • Autoimmune Diseases
  • Systemic vasculitis
  • Gene Polymorphism
  • Granulomatosis with polyangiitis

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