Session Title: Vasculitis
Session Type: Abstract Submissions (ACR)
Background/Purpose: Nasal disease occurs in the majority of patients with granulomatosis with polyangiitis (Wegener’s, GPA) and is often a presenting symptom of the disease. The objectives of this study were to use gene expression profiling techniques to gain insight into the biology of upper airway disease in GPA and explore the potential utility of genome-wide gene expression signatures as measures of nasal disease activity.
Methods: Nasal brushings of the inferior turbinate were obtained from 32 subjects with GPA (n=10 active nasal disease, n=13 prior nasal disease, n=9 never nasal disease) and 35 comparator subjects with and without inflammatory nasal disease (n=12 healthy, n=15 sarcoidosis, n=8 allergic rhinitis). RNA extracted from the brushings was processed and hybridized to Affymetrix Human Gene 1.0 ST Arrays. Gene expression changes associated with nasal disease activity were identified with a linear mixed effects model controlling for microarray batch, use of prednisone, and use of other immunosuppressant medication. Significant differences were defined at a threshold of false discovery rate (FDR) <0.1 and fold change > 1.5. Functional enrichment of biologic pathways among the gene expression profiles associated with nasal disease activity was determined using Gene Set Enrichment Analysis (GSEA) (FDRGSEA<0.25). The relationship of nasal gene expression profiles to peripheral blood mononuclear and neutrophil gene expression levels associated with GPA (Cheadle et al A&R 2010) was determined using GSEA.
Results: The expression levels of 452 genes were associated with active nasal disease, 309 with prior nasal disease, and 20 never nasal disease in subjects with GPA. GSEA revealed enrichment of several biologic pathways among genes associated with nasal disease activity. The 20 most significantly enriched pathways among subjects with active nasal disease were also significantly enriched among subjects with prior nasal disease and included pathways related to immune response (eg HSA04679 Leukocyte Transendothelial Migration) and thrombosis (eg HSA04610 Complement And Coagulation Cascade). There was no overlap between biologic pathways enriched in subjects with never nasal disease, and pathways enriched among subjects with active or prior nasal disease. Peripheral blood neutrophil and mononuclear gene expression levels associated with GPA were similarly altered in the nasal gene expression profiles of subjects with active or prior nasal disease, but were not significantly enriched in subjects with never nasal disease.
Conclusion: Nasal gene expression profiles are associated with nasal disease activity in subjects with GPA. Pathways analysis suggests that the biologic functions of genes altered in subjects with active nasal disease are similar to subjects with prior nasal disease, and distinct from subjects with never nasal disease. Upper airway gene expression profiles in subjects with active and prior nasal disease were similar to patterns of gene expression changes derived from fractionated peripheral blood in GPA, suggesting that nasal gene expression profiles in GPA may reflect systemic disease activity.
P. C. Grayson,
P. A. Monach,
P. A. Merkel,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/upper-airway-gene-expression-profiling-in-granulomatosis-with-polyangiitis/