Ashton, James, Boukas, Konstantinos, Stafford, Imogen, Sian, Cheng, Guo, Haggarty, Rachel, Coelho, Tracy, Batra, Akshay, Afzal, Nadeem A., Williams, Anthony, Polak, Marta, Beattie, R. Mark and Ennis, Sarah (2022) Deleterious genetic variation across the NOD-signaling pathway is associated with reduced NFKB-signaling transcription and upregulation of alternative inflammatory transcripts in paediatric inflammatory bowel disease. Inflammatory Bowel Diseases. (doi:10.1093/ibd/izab318).
Abstract
Background: inflammatory bowel disease (IBD) may arise with inadequate immune response to intestinal bacteria. NOD2 is an established gene in Crohn’s disease pathogenesis, with deleterious variation associated with reduced NFKB-signaling. We hypothesised that deleterious variation across the NOD2-signaling pathway impacts on transcription.
Methods: treatment-naïve paediatric IBD patients had ileal biopsies for targeted-autoimmune RNA-sequencing and blood for whole-exome-sequencing collected at diagnostic endoscopy. Utilising GenePy, a per individual, per gene score, genes within the NOD-signaling pathway were assigned a quantitative score representing total variant burden. Where multiple genes formed complexes, GenePy scores were summed to create a ‘complex’ score. Normalised transcript expression of 95-genes within this pathway were retrieved. Regression analysis was performed to determine the impact of genomic variation on gene transcription.
Results: thirty-nine patients were included. Limited clustering of patients based on NOD-signaling transcripts was related to underlying genomic variation. Patients harbouring deleterious variation in NOD2 had reduced NOD2 (β=-0.702, p=4.3x10-5) and increased NFKBIA (β=0.486, p=0.001), reflecting reduced NFKB-signal activation. Deleterious variation in the NOD2-RIPK2 complex was associated with increased NLRP3 (β=0.8, p=3.1475x10-8) and TXN (β=-0.417, p=8.4x10-5) transcription, components of the NLRP3-inflammasome. Deleterious variation in the TAK1-TAB complex resulted in reduced MAPK14 transcription (β=-0.677, p=1.7x10-5), a key signal transduction protein in the NOD2-signaling cascade and increased IFNA1 (β=0.479, p=0.001), indicating reduced transcription of NFKB activators and alternative interferon transcription in these patients.
Conclusions: data integration identified perturbation of NOD2-signaling transcription correlated with genomic variation. A hypoimmune NFKB-signaling transcription response was observed. Alternative inflammatory pathways were activated and may represent therapeutic targets in specific patients.
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