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Whole-exome Sequence Analysis Implicates Rare Il17REL Variants in Familial and Sporadic Inflammatory Bowel Disease

Lookup NU author(s): Professor James Allan


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Background: Rare variants (<1%) likely contribute significantly to risk for common diseases such as inflammatory bowel disease (IBD) in specific patient subsets, such as those with high familiality. They are, however, extraordinarily challenging to identify.Methods: To discover candidate rare variants associated with IBD, we performed whole-exome sequencing on 6 members of a pediatric-onset IBD family with multiple affected individuals. To determine whether the variants discovered in this family are also associated with nonfamilial IBD, we investigated their influence on disease in 2 large case-control (CC) series.Results: We identified 2 rare variants, rs142430606 and rs200958270, both in the established IBD-susceptibility gene IL17REL, carried by all 4 affected family members and their obligate carrier parents. We then demonstrated that both variants are associated with sporadic ulcerative colitis (UC) in 2 independent data sets. For UC in CC 1: rs142430606 (odds ratio [OR] = 2.99, P-adj = 0.028; minor allele frequency [MAF](cases) = 0.0063, MAF(controls) = 0.0021); rs200958270 (OR = 2.61, P-adj = 0.082; MAF(cases) = 0.0045, MAF(controls) = 0.0017). For UC in CC 2: rs142430606 (OR = 1.94, P = 0.0056; MAF(cases) = 0.0071, MAF(controls) = 0.0045); rs200958270 (OR = 2.08, P = 0.0028; MAF(cases) = 0.0071, MAF(controls) = 0.0042).Conclusions: We discover in a family and replicate in 2 CC data sets 2 rare susceptibility variants for IBD, both in IL17REL. Our results illustrate that whole-exome sequencing performed on disease-enriched families to guide association testing can be an efficient strategy for the discovery of rare disease-associated variants. We speculate that rare variants identified in families and confirmed in the general population may be important modifiers of disease risk for patients with a family history, and that genetic testing of these variants may be warranted in this patient subset.

Publication metadata

Author(s): Sasaki MM, Skol AD, Hungate EA, Bao RY, Huang L, Kahn SA, Allan JM, Brant SR, McGovern DPB, Peter I, Silverberg MS, Cho JH, Kirschner BS, Onel K

Publication type: Article

Publication status: Published

Journal: Inflammatory Bowel Diseases

Year: 2016

Volume: 22

Issue: 1

Pages: 20-27

Print publication date: 01/01/2016

Acceptance date: 01/01/1900

ISSN (print): 1078-0998

ISSN (electronic): 1536-4844

Publisher: Lippincott Williams & Wilkins, Ltd.


DOI: 10.1097/MIB.0000000000000610


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Funder referenceFunder name
Barnett family of Chicago
Alscher family of Chicago
American Cancer Society-Illinois Division
Biological Science Division
Cancer Research Foundation
New York Crohn's Foundation
CA40046National Institutes of Health
CA129045National Institutes of Health
HD0433871National Institutes of Health
NIH UL1 RR024999Institute for Translational Medicine/CTSA at The University of Chicago
R01 DK092235National Institutes of Health
U01 DK62429National Institutes of Health
U01 DK62422National Institutes of Health