Gene-centric association mapping of chromosome 3p implicates MST1 in IBD pathogenesis |
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| Institution: | 1. Department of Medicine, Université de Montréal and the Montreal Heart Institute, Research Center, Montreal, Québec, Canada;2. Gastrointestinal Unit and Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA;3. Department of Medicine, Johns Hopkins University, Harvey M and Lyn P Meyerhoff Inflammatory Bowel Disease Center, Baltimore, Maryland, USA;4. Division of Gastroenterology, Department of Medicine, Yale University, New Haven, Connecticut, USA;5. Division of Gastroenterology, Department of Medicine, Hepatology and Nutrition, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA;6. Mount Sinai Hospital IBD Centre, University of Toronto, Toronto, Ontario, Canada;7. Medical Genetics Institute and IBD Center, Cedars-Sinai Medical Center, Los Angeles, California, USA;8. Gastrointestinal & Endoscopy Units, CSS-RCCS Hospital, Viale Cappuccini, San Giovanni Rotondo, Italy;9. Department of Gastroenterology, Hôpital Maisonneuve-Rosemont, Montréal, Québec, Canada;10. Department of Gastroenterology, Hôpital Sainte-Justine, Montreal, Québec, Canada;11. The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA;12. Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA |
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| Abstract: | 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 3.62 × 10–6) 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. |
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