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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

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
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
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.
1536-4844
Ashton, James
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Boukas, Konstantinos
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Stafford, Imogen, Sian
50987dc1-3772-408f-9093-9124f3d6b2cd
Cheng, Guo
fdfb3e03-f185-49b1-9c53-05b93bb6c8d0
Haggarty, Rachel
d79fd59d-2cdc-465a-93e4-b0aeb78583c6
Coelho, Tracy
a78b627c-ea78-41e1-9553-0390921e3c93
Batra, Akshay
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Afzal, Nadeem A.
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Williams, Anthony
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Polak, Marta
e0ac5e1a-7074-4776-ba23-490bd4da612d
Beattie, R. Mark
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Ennis, Sarah
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Ashton, James
03369017-99b5-40ae-9a43-14c98516f37d
Boukas, Konstantinos
d6d89940-c494-4ce4-a3e8-ad1372dcee00
Stafford, Imogen, Sian
50987dc1-3772-408f-9093-9124f3d6b2cd
Cheng, Guo
fdfb3e03-f185-49b1-9c53-05b93bb6c8d0
Haggarty, Rachel
d79fd59d-2cdc-465a-93e4-b0aeb78583c6
Coelho, Tracy
a78b627c-ea78-41e1-9553-0390921e3c93
Batra, Akshay
822f891e-87ca-41d9-b68d-27c395e88809
Afzal, Nadeem A.
62505946-2503-42ba-9b02-85513bb3ec87
Williams, Anthony
973ff46f-46f1-4d7c-b27d-0f53221e4c44
Polak, Marta
e0ac5e1a-7074-4776-ba23-490bd4da612d
Beattie, R. Mark
9a66af0b-f81c-485c-b01d-519403f0038a
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9

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).

Record type: Article

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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Deleterious genetic variation within the NOD_Untracked - Accepted Manuscript
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Accepted/In Press date: 13 November 2021
e-pub ahead of print date: 3 January 2022

Identifiers

Local EPrints ID: 453106
URI: http://eprints.soton.ac.uk/id/eprint/453106
ISSN: 1536-4844
PURE UUID: 12a6f929-e496-45ff-810b-ad7f410c0ebc
ORCID for Sarah Ennis: ORCID iD orcid.org/0000-0003-2648-0869

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Date deposited: 08 Jan 2022 21:22
Last modified: 12 Apr 2022 01:35

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Contributors

Author: James Ashton
Author: Konstantinos Boukas
Author: Imogen, Sian Stafford
Author: Guo Cheng
Author: Rachel Haggarty
Author: Tracy Coelho
Author: Akshay Batra
Author: Nadeem A. Afzal
Author: Marta Polak
Author: R. Mark Beattie
Author: Sarah Ennis ORCID iD

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