Goyette P, Lefebvre C, Ng A, Brant S R, Cho J H, Duerr R H, Silverberg M S, Taylor K D, Latiano A, Aumais G, Deslandres C, Jobin G, Annese V, Daly M J, Xavier R J, Rioux J D
Department of Medicine, Université de Montréal and Montreal Heart Institute, Research Center, Montreal, Québec, Canada.
Mucosal Immunol. 2008 Mar;1(2):131-8. doi: 10.1038/mi.2007.15. Epub 2008 Jan 16.
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 x 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.
在炎症性肠病（IBD）连锁区域内进行的关联图谱分析和候选基因研究，以及克罗恩病（CD）的全基因组关联研究，已发现多个风险基因，但这些基因仅解释了IBD中观察到的部分遗传易感性。因此，我们一直采用以基因为中心的关联图谱分析方法，研究与CD和溃疡性结肠炎（UC）连锁的3号染色体p21 - 22区域。通过搜索与相关关键词共被引的文献以及与免疫/肠道功能一致的基因表达模式，我们鉴定出12个功能候选基因。然后，我们进行了一项关联研究，该研究包括一个筛选阶段（在1020例IBD患者中评估标签单核苷酸多态性（SNP））和一个在745例IBD患者中的独立验证阶段。这些分析在一个1.2 Mb的连锁不平衡区域内鉴定并验证了4个SNP与IBD的显著关联。然后，我们在巨噬细胞刺激蛋白1（MST1）基因中鉴定出一个非同义编码变异（rs3197999，R689C）（P值为3.62×10⁻⁶），该变异解释了关联信号，并显示与CD和UC均相关。MST1编码巨噬细胞刺激蛋白（MSP），一种调节对细菌配体的固有免疫反应的蛋白质。预测R689C会干扰MSP与其受体的结合，提示该基因在IBD发病机制中的作用。
