Genetic analysis in Finnish families with inflammatory bowel disease supports linkage to chromosome 3p21

Paavola, Paulina; Heliö, Tiina; Kiuru, Maija; Halme, Leena; Turunen, Ulla; Terwilliger, Joseph D.; Karvonen, Anna Liisa; Julkunen, Risto; Niemelä, Seppo; Nurmi, Heimo; Färkkilä, Martti; Kontula, Kimmo

doi:10.1038/sj.ejhg.5200626

Cited by 41 publications

(31 citation statements)

References 29 publications

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“…This region was first identified in a genome-wide linkage scan of British families (4) and then replicated with the findings from multiple genome-wide linkage scans (8,11,20). Subsequent association mapping studies using microsatellite markers provided additional evidence of association and some localization information (20,21).…”

Section: Introductionmentioning

confidence: 86%

“…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: 96%

“…The genomic region included in this analysis was selected based on an evaluation of the maximal overlap between previously reported linkage signals for IBD on chromosome 3p (4,8,11,20). Using this approach, a 30 Mb region containing over 400 annotated loci was targeted (position 32185205 to 64772789).…”

Section: Candidate Gene Selectionmentioning

confidence: 99%

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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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Section: Introductionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 96%

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

Goyette

Lefèbvre

et al. 2008

Mucosal Immunology

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“…This procedure and the clinical features of familial IBD in Finland have been described in detail previously. 22,23 We accepted 92 IBD families (designated as basic cohort), containing a total of 138 affected sib-pairs (ASPs), into a genome-wide linkage study (Table 1). In five of the mixed (MX) families, in which sibships with both UC and CD were present, one of the siblings had indeterminate colitis.…”

Section: Methodsmentioning

confidence: 99%

Genome-wide search in Finnish families with inflammatory bowel disease provides evidence for novel susceptibility loci

et al. 2003

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Epidemiological and genetic linkage studies have indicated a strong genetic basis for development of inflammatory bowel disease (IBD) which was recently supported by discovery of the Crohn's disease (CD) susceptibility gene termed NOD2/CARD15. We carried out a genome-wide linkage study in Finnish IBD families, providing a particular advantage to map susceptibility genes for ulcerative colitis (UC) within a genetic isolate. Initially, 92 IBD families with 138 affected sib-pairs (ASPs), were genotyped for 429 markers spaced at approximately 10 cM intervals. Next, the loci on chromosomes 2p13-11, 11p12-q13, and 12p13-12 were high-density mapped in the extended family cohort of 130 families with 173 ASPs. In this study, the most significant lod scores were observed for the UC families on chromosome 2p11 (D2S2333), in the vicinity of the REG gene cluster which is strikingly overexpressed in the IBD mucosa. The maximum two-point lod score was 3.34 (dominant model), and the corresponding NPL score 2.61. For UC, the second highest two-point NPL score of 2.00 was observed at proximal 12p13, where also some evidence for linkage disequilibrium emerged (P=0.07 and P=0.007 for the basic and extended IBD cohorts, respectively). The highest two-point NPL score for the CD families was 2.34 at D12S78 (12q23) with significant evidence for linkage disequilibrium (P=0.004), and for the mixed (MX) families 2.07 at D4S406 near the linkage peak reported previously. This study confirmed several of the IBD loci that have previously been reported and gives evidence for new IBD loci on chromosomes 2p11, 11p12-q13, 12p13-12, 12q23, and 19q13. European Journal of Human Genetics (2002) 11, 112 -120. doi:10.1038/sj.ejhg.5200936 Keywords: inflammatory bowel disease; genome-wide scan; genetic linkage Ulcerative colitis (UC) and Crohn's disease (CD) are chronic idiopathic, inflammatory disorders of the gastrointestinal tract, and are thought to arise from the interplay of genetic and environmental factors. Many features suggest a significant familial component to pathogenesis of these chronic inflammatory disorders. There is an increased risk among the first-degree relatives of IBD patients, with 5 -10% of the patients having an affected first degree-relative, and there is a higher concordance rate for monozygotic than dizygotic twins for the same disorder. 1 The concordance rate is two to three times higher in CD than in UC, suggesting that CD would be determined to a higher extent by genetic factors than UC. The assumption is, however, that CD and UC would also share at least some of the susceptibility genes, since many of the genetic loci are clearly contributed by both disorders and there are families segre-

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“…29 There were no associations with disease susceptibility or other clinical features of IBD, and none of these studies included PSC patients. [30][31][32][33][34] PSC patients have been included in two studies appearing in abstract form only. 35,36 No association with CCR5-D32 was found in the first analysis, but a significant positive association was reported in the second abstract.…”

Section: Introductionmentioning

confidence: 99%

CCR5-Δ32 mutation is strongly associated with primary sclerosing cholangitis

et al. 2004

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Genetic analysis in Finnish families with inflammatory bowel disease supports linkage to chromosome 3p21

Cited by 41 publications

References 29 publications

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

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

Genome-wide search in Finnish families with inflammatory bowel disease provides evidence for novel susceptibility loci

CCR5-Δ32 mutation is strongly associated with primary sclerosing cholangitis

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