title: ANCA-associated vasculitis is linked to carriage of the Z allele of α₁ antitrypsin and its polymers.
abstract: BACKGROUND
  Small studies have linked α1 antitrypsin (α1AT) deficiency to patients with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV).
  
  
  OBJECTIVE
  To test the validity and the mechanism of this association between α1AT and AAV.
  
  
  METHODS
  The distribution of α1AT deficiency alleles Z and S was compared between 856 White Europeans with AAV and 1505 geographic and ethnically matched healthy controls. Genotyping was performed by allelic discrimination assay.
  
  
  RESULTS
  were compared between cases and controls using χ(2) tests. The serum and renal biopsies for α1AT polymers were compared using the polymer-specific 2C1 antibody. The role of α1AT polymers in promoting inflammation was investigated by examining their ability to prime neutrophils for ANCA activation as assessed by CD62L shedding, superoxide production and myeloperoxidase degranulation. Results The Z but not the S allele was over-represented in the patients compared with controls (HR=2.25, 95% CI 1.60 to 3.19). Higher concentrations of polymers of α1AT were detected in serum from patients carrying the Z allele than in those not carrying the Z allele (median (IQR) 1.40 (0.91-3.32) mg/dl vs 0.17 (0.06-0.28) mg/dl, p<0.001); polymers of α1AT were also seen in the renal biopsy of a patient with vasculitic glomerulonephritis. Polymers of α1AT primed neutrophils with CD62L shedding and increased superoxide production following ANCA activation. Carriage of the Z allele was not associated with disease severity, survival or relapse.
  
  
  CONCLUSIONS
  The Z but not the S deficiency allele is associated with AAV. Polymers of α1AT are present in the serum and glomeruli of at least some patients with the Z allele, which may promote inflammation through priming of neutrophils.
authors.affiliation: School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: H
authors.initials: H
authors.lastname: Morris
authors.forename: M D
authors.initials: MD
authors.lastname: Morgan
authors.forename: A M
authors.initials: AM
authors.lastname: Wood
authors.forename: S W
authors.initials: SW
authors.lastname: Smith
authors.forename: U I
authors.initials: UI
authors.lastname: Ekeowa
authors.forename: K
authors.initials: K
authors.lastname: Herrmann
authors.forename: J U
authors.initials: JU
authors.lastname: Holle
authors.forename: L
authors.initials: L
authors.lastname: Guillevin
authors.forename: D A
authors.initials: DA
authors.lastname: Lomas
authors.forename: J
authors.initials: J
authors.lastname: Perez
authors.forename: C D
authors.initials: CD
authors.lastname: Pusey
authors.forename: A D
authors.initials: AD
authors.lastname: Salama
authors.forename: R
authors.initials: R
authors.lastname: Stockley
authors.forename: S
authors.initials: S
authors.lastname: Wieczorek
authors.forename: A J
authors.initials: AJ
authors.lastname: McKnight
authors.forename: A P
authors.initials: AP
authors.lastname: Maxwell
authors.forename: E
authors.initials: E
authors.lastname: Miranda
authors.forename: J
authors.initials: J
authors.lastname: Williams
authors.forename: C O
authors.initials: CO
authors.lastname: Savage
authors.forename: L
authors.initials: L
authors.lastname: Harper
mesh_terms: D000328:Adult; D000368:Aged; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000209:etiology* / Q000235:genetics; D001706:Biopsy; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D005921:Glomerulonephritis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D018375:Neutrophil Activation; D000515:alpha 1-Antitrypsin / Q000097:blood / Q000235:genetics*; D019896:alpha 1-Antitrypsin Deficiency / Q000150:complications* / Q000235:genetics
chemical_list: D000515:alpha 1-Antitrypsin