1. MAST3: a novel IBD risk factor that modulates TLR4 signaling.
- Author
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Labbé C, Goyette P, Lefebvre C, Stevens C, Green T, Tello-Ruiz MK, Cao Z, Landry AL, Stempak J, Annese V, Latiano A, Brant SR, Duerr RH, Taylor KD, Cho JH, Steinhart AH, Daly MJ, Silverberg MS, Xavier RJ, and Rioux JD
- Subjects
- Animals, Antigens, CD19 biosynthesis, B-Lymphocyte Subsets immunology, B-Lymphocyte Subsets metabolism, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Cells, Cultured, Gene Expression Regulation, Enzymologic immunology, Humans, Inflammatory Bowel Diseases metabolism, Introns genetics, Linkage Disequilibrium immunology, Mice, Mice, Inbred C57BL, Microtubule-Associated Proteins biosynthesis, Microtubule-Associated Proteins genetics, Protein Serine-Threonine Kinases antagonists & inhibitors, Protein Serine-Threonine Kinases biosynthesis, Protein Serine-Threonine Kinases genetics, Risk Factors, Toll-Like Receptor 4 metabolism, Genetic Predisposition to Disease, Inflammatory Bowel Diseases genetics, Inflammatory Bowel Diseases immunology, Microtubule-Associated Proteins physiology, Protein Serine-Threonine Kinases physiology, Signal Transduction genetics, Signal Transduction immunology, Toll-Like Receptor 4 physiology
- 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 x 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-kappaB activity. Our findings are additional proofs of the pivotal role played by modulators of NF-kappaB activity in IBD pathogenesis.
- Published
- 2008
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