Exome Sequencing and Genotyping Identify a Rare Variant in NLRP7 Gene Associated With Ulcerative Colitis.

Alexandros Onoufriadis,Natalie J Prescott,Jeremy D Sanderson,Katrina M De Lange,Kristina Stone,John C Mansfield,Christopher G Mathew,Richard Pollok,Yasmin Omar,Michael A Simpson,Jeffrey C Barrett,Antreas Katsiamides,Ariella Amar,Bu’Hussain Hayee,Kirstin Taylor

doi:10.1093/ecco-jcc/jjx157

Abstract

Background and AimsAlthough 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.MethodsWhole-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.ResultsOur 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].ConclusionsThe results suggest that NLRP7 signalling and inflammasome formation may be a significant component in the pathogenesis of IBD.

Highlights

Genome-wide association scans [GWAS] have been very successful in the identification of susceptibility genes for many common, complex disorders [https://www.ebi.ac.uk/gwas/]
Background and Aims: 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 have a role in pathogenesis
The results suggest that NLRP7 signalling and inflammasome formation may be a significant component in the pathogenesis of IBD

Summary

Introduction

Genome-wide association scans [GWAS] have been very successful in the identification of susceptibility genes for many common, complex disorders [https://www.ebi.ac.uk/gwas/]. A recent study by the International IBD Genetics Consortium used a fine-mapping approach in 67 852 individuals, in an attempt to pinpoint the true disease-causing DNA variants at 94 of the top IBD loci.[4] This identified 18 single independent causal DNA variants at 14 loci with > 95% certainty, and 27 single independent genetic variants at 26 loci with > 50% certainty Taken together, these 45 independent associations at 37 loci were enriched for 13 variants which elicit changes in the protein-coding sequences of seven genes. 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 have a role in pathogenesis. Conclusions: The results suggest that NLRP7 signalling and inflammasome formation may be a significant component in the pathogenesis of IBD

Methods

Results

Conclusion