TY - JOUR
T1 - Whole-exome Sequence Analysis Implicates Rare Il17REL Variants in Familial and Sporadic Inflammatory Bowel Disease
AU - Sasaki, Mark M.
AU - Skol, Andrew D.
AU - Hungate, Eric A.
AU - Bao, Riyue
AU - Huang, Lei
AU - Kahn, Stacy A.
AU - Allan, James M.
AU - Brant, Steven R.
AU - McGovern, Dermot P.B.
AU - Peter, Inga
AU - Silverberg, Mark S.
AU - Cho, Judy H.
AU - Kirschner, Barbara S.
AU - Onel, Kenan
N1 - Funding Information:
Supported by Grants from the National Institutes of Health (HD0433871, CA129045 and CA40046 to K. Onel; U01 DK62429, U01 DK62422, R01 DK092235 to J. H. Cho); SUCCESS (I. Peter, J. H. Cho); the American Cancer Society-Illinois Division (K. Onel); the New York Crohn's Foundation (I. Peter); and the Cancer Research Foundation (K. Onel); financial support of the Barnett and Alscher families of Chicago (B. S. Kirschner). The Center for Research Informatics is funded by the Biological Science Division and The Institute for Translational Medicine/CTSA (NIH UL1 RR024999) at The University of Chicago.
Publisher Copyright:
© 2015 Crohn's & Colitis Foundation of America, Inc.
PY - 2016/1/1
Y1 - 2016/1/1
N2 - 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.
AB - 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.
KW - complex disease genetics
KW - familial inflammatory bowel disease
KW - inflammatory bowel disease risk
KW - ulcerative colitis
KW - whole-exome sequencing
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U2 - 10.1097/MIB.0000000000000610
DO - 10.1097/MIB.0000000000000610
M3 - Article
C2 - 26480299
AN - SCOPUS:84964607411
SN - 1078-0998
VL - 22
SP - 20
EP - 27
JO - Inflammatory bowel diseases
JF - Inflammatory bowel diseases
IS - 1
ER -