Risk of relapse of ANCA-associated vasculitis among patients homozygous for the proteinase 3 gene Val119Ile polymorphism

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-Ile(119) or PRTN3-Val(119). Results Whole blood samples for DNA calling were available in 188 patients. 75 patients with PR3-AAV had the allelic variant: 62 heterozygous PRTN3-Val(119)Ile and 13 homozygous for PRTN3-Ile(119). 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-Val(119)Ile and 7 homozygous for PRTN3-Ile(119). 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-Val(119) and 13 homozygous for PRTN3-Ile(119). The frequency of severe flares at 18 months in homozygous PRTN3-Ile(119) was significantly higher when compared with homozygous PRTN3-Val(119)(46.2% vs 19.6%, p=0.048). Multivariate analysis identified homozygous PR3-Ile(119) 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-Val(119)Ile 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.