PT  - JOURNAL ARTICLE
AU  - Alexandros Onoufriadis
AU  - Kristina Stone
AU  - Antreas Katsiamides
AU  - Ariella Amar
AU  - Yasmin Omar
AU  - Katrina de Lange
AU  - Kirstin Taylor
AU  - Jeffrey C. Barrett
AU  - Richard Pollok
AU  - Bu’Hussain Hayee
AU  - John C. Mansfield
AU  - Jeremy D. Sanderson
AU  - Michael A. Simpson
AU  - Christopher G. Mathew
AU  - Natalie J. Prescott
TI  - Exome sequencing and genotyping identify a rare variant in <em>NLRP7</em> gene associated with ulcerative colitis
AID  - 10.1101/182113
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 182113
4099  - http://biorxiv.org/content/early/2017/08/29/182113.short
4100  - http://biorxiv.org/content/early/2017/08/29/182113.full
AB  - 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 which 3 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 6,025 IBD cases (2,948 CD; 3,077 UC) and 7,238 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.