Inflammatory Bowel Disease 24

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

Kugathasan et al. (2008) carried out a genomewide association analysis in a cohort of 1,011 individuals with pediatric-onset IBD and 4,250 matched controls. They identified significantly associated loci at chromosome 20q13, rs2315008T and rs4809330A; P = 6.30 x 10(-8) and 6.95 x 10(-8), respectively, with an odds ratio of 0.74 for both. These signals were replicated in an independent cohort of 173 IBD cases and 3,481 controls collected according to the same definition as the discovery cohort, as well as in the IBD cohort from the Wellcome Trust Case Control Consortium (2007), which included individuals with CD. For the Wellcome Trust CD cohort, the odds ratio for each of these SNPs was 0.842 with a 95% confidence interval of 0.753 to 0.939; combined P values for both replication sets were 8.85 x 10(-15) for rs2315008 and 1.62 x 10(-14) for rs4809330. The linkage disequilibrium (LD) peak on chromosome 20q13 includes the gene TNFRSF6B (603361). Kugathasan et al. (2008) noted that the protein product for TNFRSF6B acts as a decoy receptor (DCR3) in preventing FasL (134638)-induced cell death, and resistance to FasL-dependent apoptosis had been shown for T lymphocytes in CD. Kugathasan et al. (2008) compared the serum DCR3 concentration in individuals with IBD and controls and, within the IBD group, in those with and without the identified at-risk variants captured by the TNFRSF6B-tagging SNPs. The mean +/- standard error of the mean (SEM) serum DCR3 concentration increased from 84 +/- 37 pg/ml in healthy controls to 4,333 +/- 1,637 pg/ml in individuals with IBD carrying the major allelic variants, and 11,793 +/- 2,452 pg/ml in individuals with IBD carrying the minor allelic variants, (P less than 0.05 for IBD vs control, and within IBD for major vs minor allelic variants).

The UK IBD Genetics Consortium & the Wellcome Trust Case Control Consortium 2 (2009) performed a genomewide association scan in 2,361 ulcerative colitis (UC) cases and 5,417 controls followed by genotyping in an independent set of 2,321 UC cases and 4,818 controls, and found the strongest association (combined p = 8.5 x 10(-17)) at rs6017342, which maps within a recombination hotspot on 20q13 and is located 5 kb distal to the 3-prime UTR of the HNF4A gene (600281), within an expressed sequence tag (DB076868).