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

被引：69

作者：

Goyette, P. ^{[1
,2
]}

Lefebvre, C. ^{[1
,2
]}

Ng, A. ^{[3
,4
]}

Brant, S. R. ^{[5
]}

Cho, J. H. ^{[6
]}

Duerr, R. H. ^{[7
]}

Silverberg, M. S. ^{[8
]}

Taylor, K. D. ^{[9
,10
]}

Latiano, A. ^{[11
,12
]}

Aumais, G. ^{[13
]}

Deslandres, C. ^{[14
]}

Jobin, G. ^{[13
]}

Annese, V. ^{[11
,12
]}

Daly, M. J. ^{[15
,16
]}

Xavier, R. J. ^{[3
,4
,16
]}

Rioux, J. D. ^{[1
,2
,15
]}

机构：

[1] Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada

[2] Montreal Heart Inst, Res Ctr, Montreal, PQ H1T 1C8, Canada

[3] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA USA

[4] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Computat & Integrat Biol, Boston, MA USA

[5] Johns Hopkins Univ, Dept Med, Harvey M & Lyn P Meyerhoff Inflammatory Bowel Dis, Baltimore, MD USA

[6] Yale Univ, Dept Med, Div Gastroenterol, New Haven, CT 06520 USA

[7] Univ Pittsburgh, Sch Med, Div Gastroenterol, Dept Med Hepatol & Nutr, Pittsburgh, PA USA

[8] Univ Toronto, Mt Sinai Hosp, IBD Ctr, Toronto, ON M5G 1X5, Canada

[9] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA

[10] Cedars Sinai Med Ctr, IBD Ctr, Los Angeles, CA 90048 USA

[11] CSS RCCS Hosp, Gastrointestinal Unit, San Giovanni Rotondo, Italy

[12] CSS RCCS Hosp, Endoscopy Unit, San Giovanni Rotondo, Italy

[13] Hop Maison Neuve Rosemont, Dept Gastroenterol, Montreal, PQ H1T 2M4, Canada

[14] Hop St Justine, Dept Gastroenterol, Montreal, PQ H3T 1C5, Canada

[15] Broad Inst MIT & Harvard, Cambridge, MA USA

[16] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA USA

来源：

MUCOSAL IMMUNOLOGY | 2008年 / 1卷 / 02期

关键词：

D O I：

10.1038/mi.2007.15

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Association mapping and candidate gene studies within inflammatory bowel diseases (IBD) linkage regions, as well as genome-wide association studies in Crohn's disease (CD) have led to the discovery of multiple risk genes, but these explain only 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 ulcerative colitis (UC) using a gene-centric association mapping approach. We identified 12 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 single nucleotide polymorphisms (SNPs) were evaluated in 1,020 IBD patients, and an independent replication phase in 745 IBD patients. These analyses identified and replicated significant association with IBD for four SNPs within a 1.2 Mb linkage disequilibrium region. We then identified a non-synonymous coding variant (rs3197999, R689C) in the macrophage-stimulating 1 (MST1) gene (P-value 3.62x10(-6)) that accounts for the association signal, and shows association with both CD and UC. MST1 encodes macrophage-stimulating protein (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.

引用

页码：131 / 138

页数：8

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