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Abstract: FR-PO586

PRTN3 Polymorphism in Antineutrophil Cytoplasmic Antibody (ANCA) Vasculitis

Session Information

Category: Glomerular Diseases

  • 1302 Glomerular Diseases: Immunology and Inflammation

Authors

  • Chen, Dhruti P., University of North Carolina System, Chapel Hill, North Carolina, United States
  • Hu, Yichun, University of North Carolina System, Chapel Hill, North Carolina, United States
  • Hogan, Susan L., University of North Carolina System, Chapel Hill, North Carolina, United States
  • Falk, Ronald, University of North Carolina System, Chapel Hill, North Carolina, United States
  • Ciavatta, Dominic J., University of North Carolina System, Chapel Hill, North Carolina, United States
Background

Patients with vasculitis associated with antibodies to proteinase-3 (PR3-ANCA) experience relapse frequently. We investigated whether a polymorphism (rs62132293) upstream of the PRTN3 gene is associated with increased relapse among patients with PR3-ANCA.

Methods

Patients (n=401) and healthy controls(n=130) from the Glomerular Disease Collaborative Network were genotyped for the variant (G-allele). PRTN3 mRNA was quantified by RT-qPCR from total leukocyte RNA of 298 (MPO and PR3) patients. Plasma PR3 was quantified using enzyme-linked immunoassay and means compared using Wilcoxon test. Kaplan-Meier estimates and log rank test were used for time to relapse and multivariable Cox proportional hazards models with hazards ratios for relapse.

Results

Patients and healthy controls were genotyped, respectively:179 (44%) and 62 (48%) who were non-carriers (C/C), 181 (45%) and 54 (41%) heterogygous carriers (C/G), 41 (10%) and 14 (11%) homozygous carriers (G/G). Among patients, 170 were PR3-ANCA, remainder had MPO-ANCA(n=197), dual positive(n=9) or seronegative(n=25). PR3-ANCA patients relapsed more than MPO-ANCA (HR 1.48, 95% CI 1.09, 2.02). Variant carriers with PR3-ANCA had reduced relapse free survival and increased risk of relapse compared to MPO-ANCA (HR 1.66, 95% CI 1.08, 2.54). The relapse risk for non-carriers was similar in PR3 and MPO-ANCA (Figure 1). Among patients, carriers had higher PRTN3 gene expression compared to non-carriers (C/G vs. C/C and G/G vs. C/C, p=0.012 and p=0.001, respectively). Gene expression correlated with plasma protein levels (p <0.005) and patients with the variant had higher mean plasma PR3 levels compared to non-carriers (126.3ng/mL vs. 64.01 ng/mL, p=0.082), (Figure 2).

Conclusion

Our study highlights the clinical significance of the risk allele marked by rs62132293, and suggests increased relapse in PR3-ANCA may, in part, be explained by inheritance of the risk variant. Our results underscore disease phenotype in ANCA vasculitis may be contingent on autoantigen availability.

Funding

  • NIDDK Support