Gene-centric association mapping of chromosome 3p implicates MST1 in IBD pathogenesis
Gene-centric association mapping of chromosome 3p implicates MST1 in IBD pathogenesis
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DOI：
10.1038/mi.2007.15
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发表时间：
2008-03-01
影响因子：
8
通讯作者：
Rioux, J. D.
中科院分区：
文献类型：
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作者：
Goyette, P.;Lefebvre, C.;Rioux, J. D.
炎症性肠病（IBD）连锁区域内的关联作图和候选基因研究，以及克罗恩病（CD）的全基因组关联研究已经发现了多个风险基因，但这些仅解释了IBD中观察到的遗传易感性的一小部分。因此，我们一直在追求一个区域上的染色体3 p21 -22显示连锁CD和溃疡性结肠炎（UC）使用基因为中心的关联映射方法。我们通过搜索相关关键词的文献引文和与免疫/肠道功能一致的基因表达模式，确定了12个功能候选基因。然后，我们进行了一项关联研究，包括筛选阶段，在1,020名IBD患者中评估了标记单核苷酸多态性（SNP），以及745名IBD患者的独立复制阶段。这些分析确定并复制了1.2 Mb连锁不平衡区域内4个SNP与IBD的显著关联。然后，我们在巨噬细胞刺激1（MST 1）基因（P值3.62 × 10（-6））中鉴定了一个非同义编码变体（rs3197999，R689 C），该变体解释了相关信号，并显示与CD和UC相关。MST 1编码巨噬细胞刺激蛋白（MSP），一种调节对细菌配体的先天免疫应答的蛋白质。预计R689 C干扰MSP与其受体的结合，表明该基因在IBD发病机制中的作用。
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.