Analysis of the IBD5 locus and potential gene-gene interactions in Crohn's disease

Abstract

Background and aims: Genetic variation in the chromosome 5q31 cytokine cluster (IBD5 risk haplotype) has been associated with Crohn's disease (CD) in a Canadian population. We studied the IBD5 risk haplotype in both British and Japanese cohorts. Disease associations have also been reported for CARD15/NOD2 and TNF variants. Complex interactions between susceptibility loci have been shown in animal models, and we tested for potential gene-gene interactions between the three CD associated loci. Methods: Family based association analyses were performed in 457 British families (252 ulcerative colitis, 282 CD trios) genotyped for the IBD5 haplotype, common CARD15, and TNF−857 variants. To test for possible epistatic interactions between variants, transmission disequilibrium test analyses were further stratified by genotype at other loci, and novel log linear analyses were performed using the haplotype relative risk model. Case control association analyses were performed in 178 Japanese CD patients and 156 healthy controls genotyped for the IBD5 haplotype. Results: The IBD5 haplotype was associated with CD (p=0.007), but not with UC, in the British Caucasian population. The CARD15 variants and IBD5 haplotype showed additive main effects, and in particular no evidence for epistatic interactions was found. Variants from the IBD5 haplotype were extremely rare in the Japanese. Conclusions: The IBD5 risk haplotype is associated with British CD. Genetic variants predisposing to CD show heterogeneity and population specific differences.

Inflammatory bowel disease: Genetic and epidemiologic considerations

“…This association has been subsequently replicated in a number of studies [61][62][63][64] , for both CD and UC [62,65] . Candidate polymorphisms found on this haplotype within the organic cation transporter OCTN1 (SLC22A4) and OCTN2 (SLC22A5) genes have been reported [66,67] .…”

Current status of genetics research in inflammatory bowel disease

“…Fine mapping of this locus refined the region to a 250 kb risk haplotype (surrounding the OCTNs), but precise identification of the underlying causal genetic variants was impossible due to strong LD across the region. 52 At least three independent groups subsequently confirmed association of the IBD5-risk haplotype with CD [53][54][55][56] and also with UC. 53, 55 Peltekova et al resequenced the five known genes in the IBD5 region and identified 10 new SNPs, including two novel SNPs in SLC22A4 and SLC22A5 that were predicted to have functional effects (a missense substitution in SLC22A4 (L503F) and a G-C transversion in the SLC22A5 promoter) and that were associated with susceptibility to CD.…”

Genome-wide SNP-based linkage analysis of tuberculosis in Thais

“…21 It is interesting to note that the IBD5 haplotype is distributed differently in Asian and European populations, and that the IBD5 risk haplotype in Europeans is very rare in Asians. 22 Although candidate genes including IL4 23 and CD14 24,25 have been studied in this particular region, roles of these genes in tuberculosis remain inconclusive. Small sample size and ethnicity of the study populations may partially explain these equivocal association results.…”