Genetic Analysis of Innate Immunity in Crohn's Disease and Ulcerative Colitis Identifies Two Susceptibility Loci Harboring CARD9 and IL18RAP

Complex Genetics Section, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
The American Journal of Human Genetics (Impact Factor: 10.93). 06/2008; 82(5). DOI: 10.1016/j.ajhg.2008.03.016
Source: OAI


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.

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    • "Unlike most genetic risk factors for complex diseases, CARD9 alleles exist in both predisposing and protective forms for IBD. The predisposing variant, CARD9 S12N, is caused by a common coding SNP that was identified via genome-wide association studies (GWASs) and is associated with increased expression of CARD9 mRNA (Franke et al., 2010; Jostins et al., 2012; McGovern et al., 2010; Zhernakova et al., 2008). The protective variant, CARD9 S12ND11, is caused by a rare splice variant in which exon 11 of CARD9 is deleted. "
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