Inflammatory Bowel Disease 23

For a general description and a discussion of genetic heterogeneity of inflammatory bowel disease (IBD), including Crohn disease (CD) and ulcerative colitis (UC), see IBD1 (266600).

Mapping

In a case-control study of 304 Australian patients with Crohn disease and 231 healthy controls, Fowler et al. (2005) found significant association between stricturing disease and the higher-producing alleles of a promoter SNP (-1082G) of the IL10 gene (124092) on chromosome 1q31-q32 and a SNP (-857C) in the TNF-alpha gene (TNF; 191160) on chromosome 6p21.3 (see IBD3, 604519). The association was strongest when these alleles were combined and persisted after multivariate analysis. Fowler et al. (2005) concluded that these 2 SNPs may help to predict disease behavior in Crohn disease patients.

Franke et al. (2008) investigated 50 previously reported susceptibility loci for IBD in a German sample of 1,850 CD patients, 1,103 UC patients, and 1,817 controls, and confirmed an association with SNP rs17419032 at 1q32.1 for both CD (p = 0.0039) and UC (p = 0.0017).

In a metaanalysis of data from 3 studies of Crohn disease involving a total of 3,230 cases and 4,829 controls (Rioux et al., 2007, the Wellcome Trust Case-Control Consortium, 2007, and Libioulle et al., 2007) with replication in 3,664 independent cases, Barrett et al. (2008) strongly confirmed 11 previously reported loci, including an association at SNP rs11584383 at 1q32 (combined p = 1.43 x 10(-11); case-control odds ratio, 1.18).

Franke et al. (2008) conducted a genomewide association study involving 440,794 SNPs genotyped in 1,167 UC patients and 777 healthy controls, followed by testing for replication of the 20 most significantly associated SNPs in 3 independent European case-control panels comprising a total of 1,855 UC patients and 3,091 controls. Among the 4 consistently replicated markers, rs3024505, immediately flanking the IL10 gene on chromosome 1q32.1, showed the most significant association in the combined verification samples (p = 1.35 x 10(-12); odds ratio, 1.46). Association between rs3024505 and Crohn disease was weak (p = 0.013; odds ratio, 1.17), suggesting that defective IL10 function is central to the pathogenesis of the UC subtype of IBD.

Anderson et al. (2009) analyzed 45 SNPs tagging 29 CD-associated loci in 2,527 UC cases and 4,070 controls and found the strongest association at chromosome 1q32 with 2 SNPs in tight linkage disequilibrium, rs2297909 and rs11584383 (p = 4.13 x 10(-8) and 5.71 x 10(-7), respectively).

In the combined analysis of a genomewide association study involving 6 panels with a total of 3,139 UC cases and 5,974 controls, Franke et al. (2010) confirmed association at chromosome 1q32.1.

McGovern et al. (2010) combined new data from 2 genomewide association studies of ulcerative colitis involving 266,047 SNPs and performed a metaanalysis with previously published data (Silverberg et al., 2009), thus bringing together a discovery set of 2,693 European UC patients and 6,791 controls; the top results from the metaanalysis were then independently replicated with 2,009 additional European UC cases and 1,580 controls. McGovern et al. (2010) confirmed association with UC at rs3024505 (combined p = 1.4 x 10(-8)).