Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease

Abstract

Linkage disequilibrium (LD) mapping provides a powerful method for fine-structure localization of rare disease genes, but has not yet been widely applied to common disease. We sought to design a systematic approach for LD mapping and apply it to the localization of a gene (IBD5) conferring susceptibility to Crohn disease. The key issues are: (i) to detect a significant LD signal (ii) to rigorously bound the critical region and (iii) to identify the causal genetic variant within this region. We previously mapped the IBD5 locus to a large region spanning 18 cM of chromosome 5q31 (P<10(-4)). Using dense genetic maps of microsatellite markers and single-nucleotide polymorphisms (SNPs) across the entire region, we found strong evidence of LD. We bound the region to a common haplotype spanning 250 kb that shows strong association with the disease (P< 2 x 10(-7)) and contains the cytokine gene cluster. This finding provides overwhelming evidence that a specific common haplotype of the cytokine region in 5q31 confers susceptibility to Crohn disease. However, genetic evidence alone is not sufficient to identify the causal mutation within this region, as strong LD across the region results in multiple SNPs having equivalent genetic evidence-each consistent with the expected properties of the IBD5 locus. These results have important implications for Crohn disease in particular and LD mapping in general.

Spontaneous development of intestinal and colonic atrophy and inflammation in the carnitine-deficient jvs (OCTN2−/−) mice

“…These studies included diverse populations and originated from Canada [6,13,14], the UK [15][16][17][18], Germany [19], New Zealand [20], Spain [21], Italy [22,23], Belgium [24], Greece [25], Sweden [26] and Japan [27,28]. One Japanese and another Hungarian study with a small number of subjects found no association between OCTN 1&2 transporter polymorphisms and CD [28,29]; thus there could be ethnic differences in IBD5 locus mutations and propensity for Crohn's disease [7].…”

“…After the initial association study of IBD5 locus with CD by Rioux et al in 2001 [13], 19 large scale independent studies involving more than 5000 patients with CD and equal numbers of controls have confirmed this association with an odds ratio varying from 1.1 to 20. Our metaanalysis of the combined data from 12 of these studies including 3420 patients and an equal number of matched controls, indicated that the odds of acquiring CD when the risk haplotype was present ranged from 1.5 to 2.0 (Table 1).…”

Local adaptation and population differentiation at the interleukin 13 and interleukin 4 loci

“…5,6 Genome-wide linkage studies have identified evidence of linkage of this region with bronchial asthma [7][8][9] and other inflammatory disease such as Crohn's disease. 10 Despite numerous genetic-association studies, [11][12][13][14][15][16][17] the involvement of the IL-13/ IL-4 locus in susceptibility to allergic disease is unclear. Since the two loci are so closely linked and similar in function, it is not clear as to which might be responsible for the observed association.…”

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

“…20 In addition, this region on chromosome 5 coincides with the IBD5 region that showed significant evidence of linkage and association with Crohn's disease, an inflammatory bowel disease closely associated with Mycobacterium paratuberculosis. 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.…”