Genetics versus environment in inflammatory bowel disease: results of a British twin study

Thompson, Nick; Driscoll, Richard; Pounder, R. E.; Wakefield, Andrew J.

doi:10.1136/bmj.312.7023.95

Cited by 288 publications

(136 citation statements)

References 4 publications

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“…8,9 The prevalence of IBD in some western countries is as high as 0.5%. 10,11 Consistent evidence for familial clustering, 12 an increased concordance of the IBD phenotype in monozygotic twins 13,14 and consistently positive results from genetic linkage studies have repeatedly confirmed the involvement of complex genetic factors in the etiology of these conditions.…”

Section: Introductionmentioning

confidence: 88%

Haplotype structure and association to Crohn's disease of CARD15 mutations in two ethnically divergent populations

et al. 2003

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Current debate focuses on the relevance of linkage disequilibrium (LD), ethnicity and underlying haplotype structure to the search for genes involved in complex disorders. The recently described association between single nucleotide polymorphisms (SNPs) of the CARD15 (NOD2) gene and Crohn's disease (CD) in populations of north-European descent provides a test case that we have subjected to detailed SNP haplotype based analyses. We examined 23 SNPs spanning 290 kb, including CARD15, in large North-European and Korean samples of patients with Crohn's disease and normal controls. In Europeans we confirmed that the three disease-associated SNPs occur independently but share a common background haplotype. This suggests a common origin and the possibility of an undiscovered more strongly predisposing mutation. Korean CD patients present a phenotype identical to the European patients and have not previously been screened for CARD15. The three disease-associated SNPs were absent and there was no evidence of association between CARD15 and CD. Consequently, the diseaseassociated mutations in the Europeans, which are rare, have arisen recently (after the Asian -European split). Our results highlight important issues relevant to mapping the genes that predispose to complex disorders. First, although ethnically divergent populations may present identical phenotypes they do not necessarily share the same set of predisposing genes. Second, although single-locus tests of association showed consistent association with markers throughout the gene, pair-wise LD between markers (r 2 and D') yielded very little information about actual disease-association. Third, a population comparative approach allowed refining of the marker set through the examination of shared polymorphisms and common LD-groups. This approach, in conjunction with the examination of the mutational steps in a haplotype network, allows unambiguous identification of the potentially causative mutations.

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Section: Introductionmentioning

confidence: 88%

Haplotype structure and association to Crohn's disease of CARD15 mutations in two ethnically divergent populations

et al. 2003

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“…5,6 Epidemiological studies have consistently shown a familial clustering of IBD [7][8][9] as well as an increased concordance among monozygotic twins. 10,11 Genetic linkage studies in IBD provide a thorough proof for a genetic background, 12 and the first disease gene (NOD2 or CARD15) has been identified for CD. [13][14][15][16][17] Genome-wide linkage analyses in large patient cohorts of different ethnic backgrounds have defined IBD susceptibility loci located on chromosomes 3, 6, 7, 12 and 16.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of AGR2 and AGR3 as candidate genes for inflammatory bowel disease

Rosenstiel²,

Huse³

et al. 2005

Genes Immun

119

114

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Linkage analyses have implicated chromosome 7p21.3 as a susceptibility region for inflammatory bowel disease (IBD). Recently, the mouse phenotype with diarrhea and goblet cell dysfunction caused by anterior gradient protein 2 dysfunction was reported (European patent WO2004056858). The genes encoding for the human homologues AGR2 and AGR3 are localized on chromosome 7p21.3. The gene structures were verified and mutation detection was performed in 47 IBD patients. A total of 30 single nucleotide polymorphisms (SNPs) were tested for association to ulcerative colitis (UC, N ¼ 317) and Crohn's disease (CD, N ¼ 631) in a German cohort and verified in a UK cohort of 384 CD and 311 UC patients. An association signal was identified in the 5 0 region of the AGR2 gene (most significant SNP hcv1702494, nominal P TDT ¼ 0.011, P case/control ¼ 0.0007, OR ¼ 1.34, combined cohort). The risk haplotype carried an odds ratio of 1.43 in the German population (P ¼ 0.002). AGR2 was downregulated in UC patients as compared to normal controls (Po0.001) and a trend toward lower expression was seen in carriers of the risk alleles. Luciferase assays of the AGR2 promoter showed regulation by the goblet cell-specific transcription factors FOXA1 and FOXA2. In summary, AGR2 represents an interesting new avenue into the etiopathophysiology of IBD and the maintenance of epithelial integrity.

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“…[4][5][6][7] l s , the sibling recurrence risk ratio, has been estimated as 24.7 for IBD, 36.5 for CD and 16.6 for UC. 8 Both CD and UC appear genetically related as the cross-disease relative risk was observed to be 3.85 with a CD proband and 1.72 with a UC proband.…”

Section: Introductionmentioning

confidence: 99%

An SNP linkage scan identifies significant Crohn's disease loci on chromosomes 13q13.3 and, in Jewish families, on 1p35.2 and 3q29

et al. 2008

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Inflammatory bowel disease (IBD) is a complex genetic disorder of two major phenotypes, Crohn's disease (CD) and ulcerative colitis (UC), with increased risk in Ashkenazi Jews. Twelve genome-wide linkage screens have identified multiple loci, but these screens have been of modest size and have used low-density microsatellite markers. We, therefore, performed a high-density single-nucleotide polymorphism (SNP) genome-wide linkage study of 993 IBD multiply affected pedigrees (25% Jewish ancestry) that contained 1709 IBD-affected relative pairs, including 919 CD-CD pairs and 312 UC-UC pairs. We identified a significant novel CD locus on chromosome 13p13.3 (peak logarithm of the odds (LOD) score ¼ 3.98) in all pedigrees, significant linkage evidence on chromosomes 1p35.1 (peak LOD score ¼ 3.5) and 3q29 (peak LOD score ¼ 3.19) in Jewish CD pedigrees, and suggestive loci for Jewish IBD on chromosome 10q22 (peak LOD score ¼ 2.57) and Jewish UC on chromosome 2q24 (peak LOD score ¼ 2.69). Nominal or greater linkage evidence was present for most previously designated IBD loci (IBD1-9), notably, IBD1 for CD families at chromosome 16q12.1 (peak LOD score ¼ 4.86) and IBD6 in non-Jewish UC families at chromosome 19p12 (peak LOD score ¼ 2.67). This study demonstrates the ability of high information content adequately powered SNP genome-wide linkage studies to identify loci not observed in multiple microsatellite-based studies in smaller cohorts.

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Genetics versus environment in inflammatory bowel disease: results of a British twin study

Cited by 288 publications

References 4 publications

Haplotype structure and association to Crohn's disease of CARD15 mutations in two ethnically divergent populations

Haplotype structure and association to Crohn's disease of CARD15 mutations in two ethnically divergent populations

Evaluation of AGR2 and AGR3 as candidate genes for inflammatory bowel disease

An SNP linkage scan identifies significant Crohn's disease loci on chromosomes 13q13.3 and, in Jewish families, on 1p35.2 and 3q29

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