title: IL23R variation determines susceptibility but not disease phenotype in inflammatory bowel disease.
abstract: OBJECTIVE
  Identification of inflammatory bowel disease (IBD) susceptibility genes is key to understanding pathogenic mechanisms. Recently, the North American IBD Genetics Consortium provided compelling evidence for an association between ileal Crohn's disease (CD) and the IL23R gene using genome-wide association scanning. External replication is a priority, both to confirm this finding in other populations and to validate this new technique. We tested for association between IL23R and IBD in a large independent UK panel to determine the size of the effect and explore subphenotype correlation and interaction with CARD15.
  
  
  METHODS
  Eight single nucleotide polymorphism markers in IL23R tested in the North American study were genotyped in 1902 cases of Crohn's disease (CD), 975 cases of ulcerative colitis (UC), and 1345 controls using MassARRAY. Data were analyzed using chi(2) statistics, and subgroup association was sought.
  
  
  RESULTS
  A highly significant association with CD was observed, with the strongest signal at coding variant Arg381Gln (allele frequency, 2.5% in CD vs 6.2% in controls [P = 1.1 x 10(-12)]; odds ratio, 0.38; 95% confidence interval, 0.29-0.50). A weaker effect was seen in UC (allele frequency, 4.6%; odds ratio, 0.73; 95% confidence interval, 0.55-0.96). Analysis accounting for Arg381Gln suggested that other loci within IL23R also influence IBD susceptibility. Within CD, there were no subphenotype associations or evidence of interaction with CARD15.
  
  
  CONCLUSIONS
  This study shows an association between IL23R and all subphenotypes of CD with a smaller effect on UC. This extends the findings of the North American study, providing clear evidence that genome-wide association scanning can successfully identify true complex disease genes.
authors.affiliation: IBD Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge, England, UK
authors.forename: Mark
authors.initials: M
authors.lastname: Tremelling
authors.forename: Fraser
authors.initials: F
authors.lastname: Cummings
authors.forename: Sheila A
authors.initials: SA
authors.lastname: Fisher
authors.forename: John
authors.initials: J
authors.lastname: Mansfield
authors.forename: Rhian
authors.initials: R
authors.lastname: Gwilliam
authors.forename: Andrew
authors.initials: A
authors.lastname: Keniry
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Nimmo
authors.forename: Hazel
authors.initials: H
authors.lastname: Drummond
authors.forename: Clive M
authors.initials: CM
authors.lastname: Onnie
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Prescott
authors.forename: Jeremy
authors.initials: J
authors.lastname: Sanderson
authors.forename: Francesca
authors.initials: F
authors.lastname: Bredin
authors.forename: Carlo
authors.initials: C
authors.lastname: Berzuini
authors.forename: Alastair
authors.initials: A
authors.lastname: Forbes
authors.forename: Cathryn M
authors.initials: CM
authors.lastname: Lewis
authors.forename: Lon
authors.initials: L
authors.lastname: Cardon
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.forename: Derek
authors.initials: D
authors.lastname: Jewell
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Mathew
authors.forename: Miles
authors.initials: M
authors.lastname: Parkes
authors.forename: Jack
authors.initials: J
authors.lastname: Satsangi
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D015331:Cohort Studies; D003093:Colitis, Ulcerative / Q000235:genetics / Q000473:pathology; D003424:Crohn Disease / Q000235:genetics / Q000473:pathology; D004739:England; D004843:Epistasis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000473:pathology; D008297:Male; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D018123:Receptors, Interleukin / Q000235:genetics*; D012307:Risk Factors; D012606:Scotland
chemical_list: C515500:IL23R protein, human; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D018123:Receptors, Interleukin