73. Genetic explanation for increased risk of relapse in patients with PR3-ANCA
Creators: name: Dhruti Chen1
name: Aiello1, Claudia
name: Demoris McCoy1
name: Stamey1, Taylor
name: Henderson1, Candace
name: Jiajin Yang1
name: Hogan1, Susan
name: Yichun Hu1
name: Poulton1, Caroline
name: Blazek1, Lauren
name: Vimal Derebail1
name: Wu1, Eveline
name: Jennette1, Charles
name: Falk1, Ronald
name: Ciavatta1, Dominic
Publisher: name: Zenodo
Year: 2022
Subjects: Vasculitis
ANCA
Abstracts
Giant Cell Arthritis
MPA
GPA
EGPA
Takayasu
IgA vasculitis

description: <strong>Background:</strong> The role of autoantigen levels in ANCA Vasculitis and clinical consequences are not yet fully understood. Genome-wide association studies found associations between single nucleotide polymorphisupstream of the <em>PRTN3</em> gene, encoding proteinase 3 (PR3), and GPA/PR3-ANCA serotype<sup>1-3</sup> <sup>4, 5</sup> . The risk variant rs62132293 (G-allele) was identified as an expression quantitative trait locus for <em>PR3</em> expression in healthy controls.<sup>5</sup> We sought to elucidate the clinical impact of rs62132293 in patients with ANCA Vasculitis. We postulated that the variant is associated with increased target autoantigen transcription and a more severe disease phenotype. <strong>Methods:</strong> ANCA vasculitis patients (n=401) were followed longitudinally. Patients and healthy controls were genotyped for rs62132293 (C- or G-allele). Gene expression was quantified by RT-qPCR from total leukocyte RNA of 298 patients. Kaplan-Meier estimates and log rank test were used to assess differences in time to relapse, and proportional hazards models were used to model the effect of genotype and ANCA serotype on relapse-free survival. <strong>Results:</strong> We genotyped C/C in 179 (44%) and 62 (48%), C/G in 181 (45%) and 54 (41%), and G/G in 41 (10%) and 14 (11%) of patients and healthy controls, respectively. For all genotypes <em>PRTN3</em> gene expression was elevated in patients compared to healthy controls. In the patient cohort (MPO-ANCA and PR3-ANCA, n=298), variant carriers had significantly elevated <em>PRTN3</em> gene expression compared to non-carriers (effect size 0.24). <em>MPO</em> gene expression did not differ by genotype. Risk of relapse was higher in PR3-ANCA compared to MPO-ANCA (HR 1.48, 95% CI 1.09,2.02). The frequency of relapse among PR3-ANCA patients was similar between heterozygotes (C/G, 70.4%) and homozygotes (G/G, 72.2%), suggesting variant carriage (one or two copies) was associated with relapse. We combined carriers (C/G; G/G) to analyze for serotype specific relapse risk. PR3-ANCA variant carriers had reduced relapse free survival and 1.66-fold increased risk of relapse compared to MPO-ANCA (HR 1.66, 95% CI 1.08, 2.54) while there was no difference among non-carriers (HR 1.23, 95% CI 0.77, 1.98). <strong>Conclusion</strong>: <strong>Our study is the first to correlate the risk allele, marked by rs62132293, with increased autoantigen gene expression in patients and show an impact on clinical phenotype. We found higher <em>PRTN3</em> gene expression among variant carrying patients. We postulate increased transcription of <em>PRTN3</em> results in higher protein expression and availability of PR3 autoantigen. In the presence of corresponding ANCAs there is more severe disease. In a longitudinal cohort of 401 ANCA patients, we found a 1.66-fold increased risk of relapse among PR3-ANCA patients carrying the variant compared to the MPO-ANCA patients. Together this highlights the impact of rs62132293 on PR3 autoantigen levels and disease relapse. While this variant may not fully explain severity of PR3-ANCA, it highlights the genetic contribution to autoantigen expression and clinical disease.</strong> <strong>Disclosures:</strong> J.C.J has the following disclosures: Grant support from Medimmune (2017-2019). E.Y.W. receives consulting and Advisory Board fees from Pharming Healthcare, Inc. and receives research funding from AstraZeneca and Bristol-Myers Squibb. All other authors have no financial conflicts of interest to disclose. <strong>Figure 1:</strong>