Risk of relapse of ANCA-associated vasculitis among patients homozygous for the proteinase 3 gene Val119Ile polymorphism
John H Stone,
Peter C Grayson,
Ulrich Specks,
E William St Clair,
Peter A Merkel,
Philip Seo,
Carol A Langford,
Paul A Monach,
Cees G M Kallenberg,
Robert F Spiera,
Fernando C Fervenza,
Zuoming Deng,
Wei Tew,
Marta Casal Moura,
Stephen R Brooks,
Marco Prunotto
Affiliations
John H Stone
Vasculitis and Glomerulonephritis Center, Rheumatology, Immunology and Allergy Division, Massachusetts General Hospital, Boston, Massachusetts, USA
Peter C Grayson
National Institutes of Health/NIAMS, Bethesda, Maryland, USA
Ulrich Specks
Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota, USA
E William St Clair
7 Rheumatology, Duke University School of Medicine, Durham, North Carolina, USA
Peter A Merkel
Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Philip Seo
Rheumatology, Johns Hopkins University, Baltimore, Maryland, USA
Carol A Langford
Rheumatic and Immunologic Diseases, Cleveland Clinic, Cleveland, Ohio, USA
Paul A Monach
Rheumatology Section, VA Boston Health Care System Jamaica Plain Campus, Boston, Massachusetts, USA
Cees G M Kallenberg
Department of Rheumatology and Clinical Immunology, Groningen University Medical Centre, University of Groningen, The Netherlands
Robert F Spiera
Hospital for Special Surgery, New York, New York, USA
Fernando C Fervenza
8 Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
Zuoming Deng
5National Human Genome Research Institute, NIH, Bethesda, Maryland
Wei Tew
3Department of ITGR Diagnostics Discovery, Genentech, South San Francisco, California, USA
Marta Casal Moura
Pulmonary and Critical Care Medicine, Mayo Foundation for Medical Education and Research, Rochester, Minnesota, USA
Stephen R Brooks
Office of Science and Technology, Biodata Mining and Discovery Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA
Marco Prunotto
School of Pharmaceutical Sciences, University of Geneva, Geneve, Switzerland
Background The frequency of proteinase 3 gene (PRTN3) polymorphisms in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is not fully characterised. We hypothesise that the presence of a PRTN3 gene polymorphism (single nucleotide polymorphism (SNP) rs351111) is relevant for clinical outcomes.Methods DNA variant calling for SNP rs351111 (chr.19:844020, c.355G>A) in PRTN3 gene assessed the allelic frequency in patients with PR3-AAV included in the Rituximab in ANCA-Associated Vasculitis trial. This was followed by RNA-seq variant calling to characterise the mRNA expression. We compared clinical outcomes between patients homozygous for PRTN3-Ile119 or PRTN3-Val119.Results Whole blood samples for DNA calling were available in 188 patients. 75 patients with PR3-AAV had the allelic variant: 62 heterozygous PRTN3-Val119Ile and 13 homozygous for PRTN3-Ile119. RNA-seq was available for 89 patients and mRNA corresponding to the allelic variant was found in 32 patients with PR3-AAV: 25 heterozygous PRTN3-Val119Ile and 7 homozygous for PRTN3-Ile119. The agreement between the DNA calling results and mRNA expression of the 86 patients analysed by both methods was 100%. We compared the clinical outcomes of 64 patients with PR3-AAV: 51 homozygous for PRTN3-Val119 and 13 homozygous for PRTN3-Ile119. The frequency of severe flares at 18 months in homozygous PRTN3-Ile119 was significantly higher when compared with homozygous PRTN3-Val119 (46.2% vs 19.6%, p=0.048). Multivariate analysis identified homozygous PR3-Ile119 as main predictor of severe relapse (HR 4.67, 95% CI 1.16 to 18.86, p=0.030).Conclusion In patients with PR3-AAV, homozygosity for PRTN3-Val119Ile polymorphism appears associated with higher frequency of severe relapse. Further studies are necessary to better understand the association of this observation with the risk of severe relapse.
