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MAST3: a novel IBD risk factor that modulates TLR4 signaling

Genes & Immunity volume 9, pages 602–612 (2008)Cite this article

Abstract

Inflammatory bowel disease (IBD) is a chronic disorder caused by multiple factors in a genetically susceptible host. Significant advances in the study of genetic susceptibility have highlighted the importance of the innate immune system in this disease. We previously completed a genome-wide linkage study and found a significant locus (IBD6) on chromosome 19p. We were interested in identifying the causal variant in IBD6. We performed a two-stage association mapping study. In stage 1, 1530 single-nucleotide polymorphisms (SNPs) were selected from the HapMap database and genotyped in 761 patients with IBD. Among the SNPs that passed the threshold for replication, 26 were successfully genotyped in 754 additional patients (stage 2). One intronic variant, rs273506, located in the microtubule-associated serine/threonine-protein kinase gene-3 (MAST3), was found to be associated in both stages (pooled P=1.8 × 10−4). We identified four MAST3 coding variants, including a non-synonymous SNP rs8108738, correlated to rs273506 and associated with IBD. To test whether MAST3 was expressed in cells of interest, we performed expression assays, which showed abundant expression of MAST3 in antigen-presenting cells and in lymphocytes. The knockdown of MAST3 specifically decreased Toll-like receptor-4-dependent NF-κB activity. Our findings are additional proofs of the pivotal role played by modulators of NF-κB activity in IBD pathogenesis.

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Acknowledgements

This project was funded by grants from the National Institute of Diabetes and Digestive and Kidney Diseases DK062432 to JDR and AI062773 to RJX. The Broad Institute Center for Genotyping and Analysis is supported by Grant U54 RR020278 from the National Center for Research Resources. C Labbé is the recipient of a Fond de Recherche en Santé du Québec studentship award. We thank Marcia Budarf, Marie-Pierre Lévesque and Jing Lian for their help in the review of the paper.

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Authors and Affiliations

  1. Institut de Cardiologie de Montréal, Montréal, Québec, Canada

    C Labbé, P Goyette, C Lefebvre & J D Rioux

  2. Département de médecine, Université de Montréal, Montréal, Québec, Canada

    C Labbé & J D Rioux

  3. The Broad Institute of MIT and Harvard, Cambridge, MA, USA

    C Stevens, T Green, M K Tello-Ruiz, M J Daly & J D Rioux

  4. Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Z Cao, A L Landry, M J Daly & R J Xavier

  5. Mount Sinai Hospital IBD Center, University of Toronto, Toronto, Ontario, Canada

    J Stempak, A H Steinhart & M S Silverberg

  6. Gastrointestinal & Endoscopy Units, IRCCS Hospital, San Giovanni Rotondo, Italy

    V Annese & A Latiano

  7. Meyerhoff Inflammatory Bowel Disease Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    S R Brant

  8. Division of Gastroenterology, Inflammatory Bowel Disease Genetics Program, University of Pittsburgh School of Medicine, Hepatology and Nutrition, Pittsburgh, PA, USA

    R H Duerr

  9. Medical Genetics Institute and IBD Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    K D Taylor

  10. Division of Gastroenterology, Department of Medicine, IBD Center, Yale University, New Haven, CT, USA

    J H Cho

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  1. C Labbé
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Correspondence to J D Rioux.

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The authors have declared that no competing interest exists.

Supplementary Information accompanies the paper on Genes and Immunity website (http://www.nature.com/gene)

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Labbé, C., Goyette, P., Lefebvre, C. et al. MAST3: a novel IBD risk factor that modulates TLR4 signaling. Genes Immun 9, 602–612 (2008). https://doi.org/10.1038/gene.2008.57

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