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PMID: 18439550 Published · ppublish English Journal Article Multicenter Study Research Support, Non-U.S. Gov't

Genetic analysis of innate immunity in Crohn's disease and ulcerative colitis identifies two susceptibility loci harboring CARD9 and IL18RAP.

American journal of human genetics ·Vol. 82 ·No. 5 ·2008-05-00 ·Pages 1202-10

Zhernakova A, Festen EM, Franke L, Trynka G, van Diemen CC, Monsuur AJ, Bevova M, Nijmeijer RM, van 't Slot R, Heijmans R, Boezen HM, van Heel DA, van Bodegraven AA, Stokkers PC, Wijmenga C, Crusius JB, Weersma RK

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.

MeSH Terms
CARD Signaling Adaptor Proteins/genetics Colitis, Ulcerative/genetics,immunology Crohn Disease/genetics,immunology Female Genetic Predisposition to Disease Humans Immunity, Innate Interleukin-18 Receptor beta Subunit/genetics Linkage Disequilibrium Male
Chemicals
CARD Signaling Adaptor Proteins CARD9 protein, human IL18RAP protein, human Interleukin-18 Receptor beta Subunit
Authors & Affiliations
17 authors, click to expand affiliations / ORCID
Zhernakova Alexandra
Complex Genetics Section, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
Festen Eleanora M
Franke Lude
Trynka Gosia
van Diemen Cleo C
Monsuur Alienke J
Bevova Marianna
Nijmeijer Rian M
van 't Slot Ruben
Heijmans Roel
Boezen H Marike
van Heel David A
van Bodegraven Adriaan A
Stokkers Pieter C F
Wijmenga Cisca
Crusius J Bart A
Weersma Rinse K
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Article Info
Journal
American journal of human genetics
Abbr.
Am J Hum Genet
ISSN
1537-6605
DOI
10.1016/j.ajhg.2008.03.016
Published
2008-05-00
Epub
2008-00-24
Pages
1202-10
Language
English
Region
United States
NLM ID
0370475
PMCID
PMC2427314
Subset
IM
External Links
PubMed source DOI: 10.1016/j.ajhg.2008.03.016 PMC Full Text View journal details
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