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ANCA-associated vasculitis is linked to carriage of the Z allele of α1 antitrypsin and its polymers
  1. H Morris1,
  2. M D Morgan1,
  3. A M Wood2,
  4. S W Smith1,
  5. U I Ekeowa3,
  6. K Herrmann4,
  7. J U Holle4,
  8. L Guillevin5,
  9. D A Lomas3,
  10. J Perez6,
  11. C D Pusey7,
  12. A D Salama8,
  13. R Stockley2,
  14. S Wieczorek9,
  15. A J McKnight10,
  16. A P Maxwell10,
  17. E Miranda11,
  18. J Williams1,
  19. C O Savage1,
  20. L Harper1
  1. 1School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
  2. 2School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
  3. 3Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Cambridge, UK
  4. 4Department of Rheumatology, Vasculitis Center UKSH and Klinikum Bad Bramstedt, University of Lübeck, Lübeck, Germany
  5. 5Internal Medicine Department, Hopital Cochin, Paris Descartes University, Paris, France
  6. 6Departamento de Biología Celular, Genética y Fisiología, Universidad de Málaga, Málaga, España
  7. 7Renal Section, Department of Medicine, Imperial College London, Hammersmith Hospital, London, UK
  8. 8UCL Centre for Nephrology, Royal Free Hospital, London, UK
  9. 9Department of Human Genetics, Ruhr University, Bochum, Germany
  10. 10Nephrology Research, Centre for Public Health, Queen's University, Belfast, UK
  11. 11Dipartimento di Biologia e Biotecnologie ‘Charles Darwin’, Università di Roma ‘La Sapienza’, Roma, Italy
  1. Correspondence toProfessor Lorraine Harper, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK; l.harper{at}


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 χ2 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.

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  • Funding UIE is an MRC clinical training fellow. AMW is funded by the West Midlands Chest Fund, Cancer Research UK and UHB charities. The study was funded by a research grant from Talecris Biotherapeutics. JP was supported by the Spanish government (grant MCINN SAF2010–19087). DAL is supported by The Medical Research Council (UK), Alpha-1 Foundation, Papworth NHS Trust.

  • Ethics approval This study was conducted with the approval of the South Birmingham Research Ethics Committee.

  • Competing interest Professor Caroline Savage is now employed by GlaxoSmithKline, Stevenage, UK.

  • Provenance and peer review Not commissioned; externally peer reviewed.