A genome-wide search identifies potential new susceptibility loci for Crohn's disease

Ma, Yuanhong; Ohmen, Jeffrey D.; Li, Zhiming; Bentley, L. Gordon; McElree, Colleen; Pressman, Sheila; Targan, Stephan; Fischel‐Ghodsian, Nathan; Rotter, Jerome I.; Yang, Hui Ying

doi:10.1002/ibd.3780050406

Cited by 69 publications

(43 citation statements)

References 28 publications

(12 reference statements)

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“…In summary, although previous studies in CD 25 and MS 26 found suggestive linkage at chromosome 17q21, in which the STAT3 gene is located, association with this gene has only been corroborated for the IBD. Despite the already mentioned data in the MS mouse model and in MS patients pointing to an involvement of the STAT3 pathway in MS etiology (see Introduction), our results with more than 1500 patients seem to rule out the association with the STAT3 gene.…”

Section: à5mentioning

confidence: 61%

STAT3 locus in inflammatory bowel disease and multiple sclerosis susceptibility

Cénit¹,

Alcina

Márquez³

et al. 2010

Genes Immun

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STAT3 (signal transducer and activator of transcription 3) signaling is a critical component of Th17-dependent autoimmune processes. Genome-wide association studies (GWAS) have revealed the role of the STAT3 gene in inflammatory bowel disease (IBD) susceptibility, although confirmation in clinical subphenotypes is warranted. Mice with targeted deletion of Stat3 in T cells are resistant to experimental autoimmune encephalomyelitis, which is a multiple sclerosis (MS) model. Moreover, increased phosphorylated STAT3 was reported in T cells of patients evolving from clinically isolated syndrome to defined MS and in relapsing patients. These evidences led us to analyze the role of STAT3 in Crohn's disease (CD), ulcerative colitis (UC) and MS risk. Polymorphisms in the STAT3 region (rs3809758/rs744166/rs1026916/rs12948909) were genotyped and the inferred haplotypes were subsequently analyzed in 860 IBD and 1540 MS Spanish patients and 1720 ethnically matched controls. The haplotype conformed by the risk alleles of each polymorphism was significantly associated with both clinical phenotypes of IBD (CD: P ¼ 0.005, odds ratio 1.25, 95% confidence interval 1.06-1.46; and UC: P ¼ 0.002, odds ratio 1.19, 95% confidence interval 1.02-1.38). No evidence of association was detected for MS. The originally described association of IBD with STAT3 polymorphisms is corroborated for the two clinical phenotypes, CD and UC, in an independent population. A major role of this gene in MS seems unlikely.

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Section: à5mentioning

confidence: 61%

STAT3 locus in inflammatory bowel disease and multiple sclerosis susceptibility

Cénit¹,

Alcina

Márquez³

et al. 2010

Genes Immun

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“…The epidemiological data on IBD suggests a strong genetic contribution to disease pathogenesis and genetic studies indicate that CD and UC have disease-specific as well as shared susceptibility genes (1-3). Genome-wide linkage mapping studies in IBD have identified and confirmed several genomic intervals conferring risk to either CD, UC or both (4)(5)(6)(7)(8)(9)(10)(11). Association mapping, as well as candidate gene association studies, within linkage regions have led to confirmed associations between Crohn's disease and coding variants in the NOD2 gene on chromosome 16q12 and multiple associated alleles forming a risk haplotype known as IBD5 on chromosome 5q31 (8,10,(12)(13)(14).…”

Section: Introductionmentioning

confidence: 97%

Gene-centric association mapping of chromosome 3p implicates MST1 in IBD pathogenesis

Goyette

Lefèbvre

et al. 2008

Mucosal Immunology

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Association mapping and candidate gene studies within IBD linkage regions, as well as genomewide association studies in CD have led to the discovery of multiple risk genes, but these only Corresponding author: John D. Rioux, Montreal Heart Institute, 5000 Belanger Street, Montreal, Quebec, Canada, H1T 1C8, rioux@inflammgen.org. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript explain a fraction of the genetic susceptibility observed in IBD. We have thus been pursuing a region on chromosome 3p21-22 showing linkage to CD and UC using a gene-centric association mapping approach. We identified twelve functional candidate genes by searching for literature cocitations with relevant keywords and for gene expression patterns consistent with immune/ intestinal function. We then performed an association study composed of a screening phase, where tagging SNPs were evaluated in 1020 IBD patients, and an independent replication phase in 745 IBD patients. These analyses identified and replicated significant association to IBD for four SNPs within a 1.2 Mb LD region. We then identified a non-synonymous coding variant (rs3197999, R689C) in the macrophage stimulating 1 (MST1) gene (p-value 3.62×10−6) that accounts for the association signal, and shows association to both CD and UC. MST1 encodes MSP, a protein regulating the innate immune responses to bacterial ligands. R689C is predicted to interfere with MSP binding to its receptor, suggesting a role for this gene in the pathogenesis of IBD.

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“…All diagnoses of CD, UC or indeterminate colitis were confirmed by physician reviewers from each center from primary chart reviews of endoscopy, radiology and pathology data as meeting standard diagnostic criteria. [39][40][41] Forty-three percent of pedigrees included were previously studied in one of six microsatellite linkage reports from North America, 12,[14][15][16][17]20 and results of a majority of these pedigrees were included in a single genome-wide microsatellite mega-analysis we described previously. 31 Study subjects were self-identified as white race.…”

Section: Methodsmentioning

confidence: 99%

“…9 To date, 12 published genome-wide screens and follow-up studies have identified loci with genome-wide linkage evidence and confirmation in single or combined studies (IBD1-9) on chromosomes 16q21 (CD), 12p13-q24, 6p21-23, 14q11-12 (CD), 5q31 (CD), 19p13-q13, 1p36, 16p12 and 3p26-14, respectively. [10][11][12][13][14][15][16][17][18][19][20][21][22] An additional six loci have been detected with suggestive evidence of linkage in one study and replication evidence in one or more additional studies on chromosomes 2q23-35 (UC), 3q25-28, 4q22-31, 7p13-q21, 11p15-12 and Xp22-21. 22 Notably, defined risk alleles/haplotypes have been identified for the IBD1 (NOD2), IBD3 (human leukocyte antigen) and IBD5 (5q cytokine cluster) loci.…”

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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A genome-wide search identifies potential new susceptibility loci for Crohn's disease

Cited by 69 publications

References 28 publications

STAT3 locus in inflammatory bowel disease and multiple sclerosis susceptibility

STAT3 locus in inflammatory bowel disease and multiple sclerosis susceptibility

Gene-centric association mapping of chromosome 3p implicates MST1 in IBD pathogenesis

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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