title: Whole-exome Sequence Analysis Implicates Rare Il17REL Variants in Familial and Sporadic Inflammatory Bowel Disease.
abstract: 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, Padj = 0.028; minor allele frequency [MAF]cases = 0.0063, MAFcontrols = 0.0021); rs200958270 (OR = 2.61, Padj = 0.082; MAFcases = 0.0045, MAFcontrols = 0.0017). For UC in CC 2: rs142430606 (OR = 1.94, P = 0.0056; MAFcases = 0.0071, MAFcontrols = 0.0045); rs200958270 (OR = 2.08, P = 0.0028; MAFcases = 0.0071, MAFcontrols = 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.
authors.affiliation: *Department of Pediatrics and †Center for Research Informatics, The University of Chicago, Chicago, Illinois; ‡Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, United Kingdom; §Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; ‖Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland; ¶F. Widjaja Family Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California; **Department of Genetics and Genomic Sciences and ††Zane Cohen Centre for Digestive Diseases, Department of Medicine, Mount Sinai Hospital, The University of Toronto, Toronto, Ontario, Canada; and ‡‡Department of Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Sasaki
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Skol
authors.forename: Eric A
authors.initials: EA
authors.lastname: Hungate
authors.forename: Riyue
authors.initials: R
authors.lastname: Bao
authors.forename: Lei
authors.initials: L
authors.lastname: Huang
authors.forename: Stacy A
authors.initials: SA
authors.lastname: Kahn
authors.forename: James M
authors.initials: JM
authors.lastname: Allan
authors.forename: Steven R
authors.initials: SR
authors.lastname: Brant
authors.forename: Dermot P B
authors.initials: DP
authors.lastname: McGovern
authors.forename: Inga
authors.initials: I
authors.lastname: Peter
authors.forename: Mark S
authors.initials: MS
authors.lastname: Silverberg
authors.forename: Judy H
authors.initials: JH
authors.lastname: Cho
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Kirschner
authors.forename: Kenan
authors.initials: K
authors.lastname: Onel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D059472:Exome / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D053722:Receptors, Interleukin-17 / Q000235:genetics*; D055815:Young Adult
chemical_list: D053722:Receptors, Interleukin-17