Abstract
BackgroundThe 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.MethodsDNA 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-Ile119or PRTN3-Val119.ResultsWhole 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-Val119and 13 homozygous for PRTN3-Ile119. The frequency of severe flares at 18 months in homozygous PRTN3-Ile119was significantly higher when compared with homozygous PRTN3-Val119(46.2% vs 19.6%, p=0.048). Multivariate analysis identified homozygous PR3-Ile119as main predictor of severe relapse (HR 4.67, 95% CI 1.16 to 18.86, p=0.030).ConclusionIn 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.
Funder
Boston University
Juvenile Diabetes Research Foundation
NIAMS
Genentech
Biogen Idec
Arthritis Foundation
National Institutes of Health
Roche Inc
Connor Group
NCRR
Vasculitis Foundation
Mayo Clinic and Foundation
Immune Tolerance Network
Johns Hopkins University
National Center for Research Resources
Mayo Foundation
National Institute of Allergy and Infectious Diseases
Subject
Immunology,Immunology and Allergy,Rheumatology