title: Genetic analysis of innate immunity in Crohn's disease and ulcerative colitis identifies two susceptibility loci harboring CARD9 and IL18RAP.
abstract: The two main phenotypes of inflammatory bowel disease (IBD)--Crohn's disease (CD) and ulcerative colitis (UC)--are chronic intestinal inflammatory disorders with a complex genetic background. Using a three-stage design, we performed a functional candidate-gene analysis of innate immune pathway in IBD. In phase I, we typed 354 SNPs from 85 innate immunity genes in 520 Dutch IBD patients (284 CD, 236 UC) and 808 controls. In phase II, ten autosomal SNPs showing association at p < 0.006 in phase I were replicated in a second cohort of 545 IBD patients (326 CD, 219 UC) and 360 controls. In phase III, four SNPs with p < 0.01 in the combined phase I and phase II analysis were genotyped in an additional 786 IBD samples (452 CD, 334 UC) and 768 independent controls. Joint analysis of 1851 IBD patients (1062 CD, 789 UC) and 1936 controls demonstrated strong association to the IL18RAP rs917997 SNP for both CD and UC (p(IBD) 1.9 x 10(-8); OR 1.35). Association in CD is independently supported by the Crohn's disease dataset of the Wellcome Trust Case Control Consortium (imputed SNP rs917997, p = 9.19 x 10(-4)). In addition, an association of the CARD9 rs10870077 SNP to CD and UC was observed (p(IBD) = 3.25 x 10(-5); OR 1.21). Both genes are located in extended haplotype blocks on 2q11-2q12 and 9q34.3, respectively. Our results indicate two IBD loci and further support the importance of the innate immune system in the predisposition to both CD and UC.
authors.affiliation: Complex Genetics Section, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zhernakova
authors.forename: Eleanora M
authors.initials: EM
authors.lastname: Festen
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
authors.forename: Gosia
authors.initials: G
authors.lastname: Trynka
authors.forename: Cleo C
authors.initials: CC
authors.lastname: van Diemen
authors.forename: Alienke J
authors.initials: AJ
authors.lastname: Monsuur
authors.forename: Marianna
authors.initials: M
authors.lastname: Bevova
authors.forename: Rian M
authors.initials: RM
authors.lastname: Nijmeijer
authors.forename: Ruben
authors.initials: R
authors.lastname: van 't Slot
authors.forename: Roel
authors.initials: R
authors.lastname: Heijmans
authors.forename: H Marike
authors.initials: HM
authors.lastname: Boezen
authors.forename: David A
authors.initials: DA
authors.lastname: van Heel
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: van Bodegraven
authors.forename: Pieter C F
authors.initials: PC
authors.lastname: Stokkers
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.forename: J Bart A
authors.initials: JB
authors.lastname: Crusius
authors.forename: Rinse K
authors.initials: RK
authors.lastname: Weersma
mesh_terms: D053468:CARD Signaling Adaptor Proteins / Q000235:genetics*; D003093:Colitis, Ulcerative / Q000235:genetics* / Q000276:immunology; D003424:Crohn Disease / Q000235:genetics* / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007113:Immunity, Innate; D053728:Interleukin-18 Receptor beta Subunit / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male
chemical_list: D053468:CARD Signaling Adaptor Proteins; C505855:CARD9 protein, human; C115629:IL18RAP protein, human; D053728:Interleukin-18 Receptor beta Subunit