Whole mRNA expression of blood PBMCs identified RHOA, CDH1, and enrichment of pathways leading to neutrophil recruitment and inflammatory response in granulomatosis with polyangiitis.

Granulomatosis with polyangiitis (GPA) is a rare, complex autoimmune vasculitis. Investigating the differential mRNA expression signature in PBMCs may identify critical gene(s) implicated in GPA. This study recruited 21 GPA patients and 23 healthy controls of North Indian origin. Whole mRNA was isolated from PBMCs, and whole mRNA sequencing was performed on the discovery cohort to identify differentially expressed genes (DEGs). Pathway enrichment and protein-protein interaction analyses were performed. Hub genes were identified, and prioritized DEGs were validated using qRT-PCR in the replication cohort. DEGs were compared with expression studies on GPA available on the Gene Expression Omnibus (GEO) database. We obtained 5757 downregulated and 46 upregulated genes (adj-p < 0.05; log2FC ≥ 2/≤-2), which predicted 25 hub genes that were found to be enriched in IL-17-CXCR-TNF mediated proinflammatory pathways. Two critical hub genes RHOA (log2FC = 0.65,95%CI = 0.18 to 1.12; p = 0.02) and CDH1 (log2FC = -0.85, 95%CI = -1.47 to -0.23; p = 0.04) were significantly replicated in the replication cohort. Another proinflammatory hub gene LCN2 (log2FC = 2.15; p = 6.5E-04), was found as a shared upregulated gene in CD4+, CD8+, and CD4+CD8+ double-positive T-cells in GPA patients. The present study reported the significant differential expression of the RHOA and CDH1 in GPA. IL-17 downstream proinflammatory pathways were identified as critical for the GPA.