title: CARD15 genotype-phenotype relationships in a small inflammatory bowel disease population with severe disease affection status.
abstract: Inflammatory bowel disease (IBD; MIM# 266600) is subdivided on the basis of clinical findings as either Crohn's disease (CD), ulcerative colitis (UC), or indeterminate colitis (IC). Three previously described mutations within the IBD susceptibility gene CARD15 (R702W, G908R, 1007fs) increase susceptibility to CD with a terminal ileal and/or ileocolonic location and fibrostenosing behavior. We undertook an association study using 477 unrelated IBD patients (248 CD, 172 UC, 57 IC) and 104 population controls to determine whether these previously described associations could be replicated in a small, accurately phenotyped cohort. Case-control and family-based approaches were employed to analyze CARD15 mutant allele and haplotype data. Analyses were initially performed in unstratified IBD cohorts. The R702W mutant allele was associated with CD on case-control analysis (q=0.036, P=.004), and 1007fs with CD on pedigree disequilibrium testing (P=.020). All 3 CARD15 mutations increased susceptibility to a variety of CD subphenotypic manifestations, including early-onset CD in individuals with a family history of IBD, and CD complicated by extraintestinal disease. We also present evidence to suggest that R702W may predispose to a more generalized form of CD. Additionally, we confirm that CARD15 mutations are associated with terminal ileal/ileocolonic, and to a lesser extent, fibrostenosing CD.
authors.affiliation: Price Institute for Surgical Research, Department of Surgery, University of Louisville School of Medicine, Louisville, Kentucky, USA.
authors.forename: Nigel P S
authors.initials: NP
authors.lastname: Crawford
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Colliver
authors.forename: M Robert
authors.initials: MR
authors.lastname: Eichenberger
authors.forename: Alisa A
authors.initials: AA
authors.lastname: Funke
authors.forename: Valentina
authors.initials: V
authors.lastname: Kolodko
authors.forename: Gary A
authors.initials: GA
authors.lastname: Cobbs
authors.forename: Robert E
authors.initials: RE
authors.lastname: Petras
authors.forename: Susan
authors.initials: S
authors.lastname: Galandiuk
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D003424:Crohn Disease / Q000175:diagnosis / Q000235:genetics*; D004247:DNA / Q000235:genetics*; D016099:Endoscopy, Gastrointestinal; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000175:diagnosis / Q000235:genetics; D007421:Intestine, Small; D008297:Male; D008875:Middle Aged; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D012720:Severity of Illness Index; D013997:Time Factors
chemical_list: C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D004247:DNA