title: Genetic evidence for interaction of the 5q31 cytokine locus and the CARD15 gene in Crohn disease.
abstract: A common haplotype spanning 250 kb in the cytokine gene cluster on chromosome 5q31 has recently been reported to be strongly associated with Crohn disease (CD) in Canadian families. We have replicated this finding by both the transmission-disequilibrium test (TDT) (P=.016) and in a case-control association study (P=.008) in a large European cohort of patients with CD, although the increase in disease risk was small (odds ratio 1.49 for homozygotes, 95% CI 1.11-2.0). No association was detected in families or individuals with ulcerative colitis (UC). Stratification of offspring with CD in the TDT sample by mutation status in the CD susceptibility gene CARD15 showed that the association with the 5q31 risk haplotype was present only in offspring with at least one of the known CARD15 disease susceptibility alleles (P=.044). The 5q31 risk haplotype frequency was 53.1% in unrelated individuals with CD who had one or two CARD15 mutations versus 43.7% in control subjects (P=.0001) but was not significantly elevated in individuals with CD who had no CARD15 mutations (45.4%, P=.41). Kaplan-Meier survival analysis of age at disease onset showed a significantly earlier onset in homozygotes for the 5q31 risk haplotype (P=.0019). These findings suggest that genetic variants at the 5q31 (IBD5) locus may hasten the onset of Crohn disease and cooperate with CARD15 in disease causation.
authors.affiliation: Division of Medical and Molecular Genetics, Guy's, King's, and Thomas's School of Medicine, King's College London, Guy's Hospital, London, United Kingdom.
authors.forename: Muddassar M
authors.initials: MM
authors.lastname: Mirza
authors.forename: Sheila A
authors.initials: SA
authors.lastname: Fisher
authors.forename: Kathy
authors.initials: K
authors.lastname: King
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Cuthbert
authors.forename: Jochen
authors.initials: J
authors.lastname: Hampe
authors.forename: Jeremy
authors.initials: J
authors.lastname: Sanderson
authors.forename: John
authors.initials: J
authors.lastname: Mansfield
authors.forename: Peter
authors.initials: P
authors.lastname: Donaldson
authors.forename: Andrew J S
authors.initials: AJ
authors.lastname: Macpherson
authors.forename: Alastair
authors.initials: A
authors.lastname: Forbes
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Cathryn M
authors.initials: CM
authors.lastname: Lewis
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Mathew
mesh_terms: D000375:Aging; D002170:Canada; D002352:Carrier Proteins / Q000235:genetics*; D002874:Chromosome Mapping; D002895:Chromosomes, Human, Pair 5; D003093:Colitis, Ulcerative / Q000235:genetics; D003424:Crohn Disease / Q000453:epidemiology / Q000235:genetics* / Q000401:mortality; D016207:Cytokines / Q000235:genetics*; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D053473:Nod2 Signaling Adaptor Protein; D016017:Odds Ratio; D010375:Pedigree; D012016:Reference Values; D012044:Regression Analysis; D012307:Risk Factors; D016019:Survival Analysis
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein