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Exome sequencing and genotyping identify a rare variant in NLRP7 gene associated with ulcerative colitis

Lookup NU author(s): Dr John Mansfield



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2016 European Crohn's and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. Background and Aims: Although genome-wide association studies [GWAS] in inflammatory bowel disease [IBD] have identified a large number of common disease susceptibility alleles for both Crohn's disease [CD] and ulcerative colitis [UC], a substantial fraction of IBD heritability remains unexplained, suggesting that rare coding genetic variants may also have a role in pathogenesis. We used high-throughput sequencing in families with multiple cases of IBD, followed by genotyping of cases and controls, to investigate whether rare protein-altering genetic variants are associated with susceptibility to IBD. Methods: Whole-exome sequencing was carried out in 10 families in whom three or more individuals were affected with IBD. A stepwise filtering approach was applied to exome variants, to identify potential causal variants. Follow-up genotyping was performed in 6025 IBD cases [2948 CD; 3077 UC] and 7238 controls. Results: Our exome variant analysis revealed coding variants in the NLRP7 gene that were present in affected individuals in two distinct families. Genotyping of the two variants, p.S361L and p.R801H, in IBD cases and controls showed that the p.S361L variant was significantly associated with an increased risk of ulcerative colitis [odds ratio 4.79, p = 0.0039] and IBD [odds ratio 3.17, p = 0.037]. A combined analysis of both variants showed suggestive association with an increased risk of IBD [odds ratio 2.77, p = 0.018]. Conclusions: The results suggest that NLRP7 signalling and inflammasome formation may be a significant component in the pathogenesis of IBD.

Publication metadata

Author(s): Onoufriadis A, Stone K, Katsiamides A, Amar A, Omar Y, de Lange KM, Taylor K, Barrett JC, Pollok R, Hayee B, Mansfield JC, Sanderson JD, Simpson MA, Mathew CG, Prescott NJ

Publication type: Article

Publication status: Published

Journal: Journal of Crohn's and Colitis

Year: 2018

Volume: 12

Issue: 3

Pages: 321-326

Print publication date: 28/02/2018

Online publication date: 04/12/2017

Acceptance date: 30/11/2017

Date deposited: 04/06/2018

ISSN (print): 1873-9946

ISSN (electronic): 1876-4479

Publisher: Oxford University Press


DOI: 10.1093/ecco-jcc/jjx157


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Funder referenceFunder name
Wellcome Trust [094491/Z/10/Z]