GENETIC MAPPING STUDIES IN IBD

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。特发性炎症性肠病(IBD)由克罗恩病(CD)和溃疡性结肠炎(UC)两大亚型组成，是一种复杂的多基因疾病。这项研究的假设是特定的风险等位基因(在基因组DNA中可识别的遗传变异)解释了IBD的表型表达。特定风险等位基因的因果关系的证据是通过连锁和关联研究以及最终的功能相关性来提供的。我们和其他人已经证实，16号染色体上NOD2/CARD15基因的Arg702Trp、Gly908Arg和Leu1007fsinsC与CD2-4高度相关。然而，NOD2/CARD15和其他介导宿主对细菌肽反应的基因突变导致CD的确切功能机制仍不完全清楚。最近，OCTN1/SLC22A4-OCTN2/SLC22A5(染色体5q)5、DLG5(染色体10q)6和MDR1(染色体7q)7基因的遗传变异与CD和IBD相关。然而，联合Meta-8和Mega分析的连锁研究显示，这些区域在染色体5q、10q和7q上的得分相对较低，而其他区域的得分明显较高。具有特殊意义的是染色体3q27-28上的D3S1262和D3S2455定义的5.2Mb区域。因此，我们的目标是通过精细定位关联研究确定这些特定区域和易感基因，并进行功能分析，以确定易感基因突变导致IBD的机制。这样的研究将提供对这些疾病发病机制的早期步骤的洞察，并有助于识别导致IBD易感性的功能变异。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The idiopathic inflammatory bowel diseases (IBD) are comprised of two major subtypes, Crohn's disease (CD) and ulcerative colitis (UC) and are complex, multigenic disorders. The hypothesis of this study is that specific risk alleles (genetic variants identifiable in genomic DNA) account for the phenotypic expression of IBD. Proof of causation for specific risk alleles is provided by linkage and association studies, and ultimately, functional correlations. We and others have established that Arg702Trp, Gly908Arg, and Leu1007fsinsC in the NOD2/CARD15 gene on chromosome 16 are highly associated with CD 2-4. However, the exact functional mechanisms by which these mutations in NOD2/CARD15 and other genes mediating host response to bacterial peptidoglycan lead to CD are still incompletely defined. Recently, genetic variants within the OCTN1/SLC22A4-OCTN2/SLC22A5 (chromosome 5q) 5, DLG5 (chromosome 10q) 6 and MDR1 (chromosome 7q) 7 genes have been associated with CD and IBD. However, combined meta- 8 and mega-analyses of linkage studies demonstrate relatively modest scores in these regions on chromosomes 5q, 10q and 7q, with other regions demonstrating significantly higher scores. Of special significance is a 5.2 Mb region defined by D3S1262 and D3S2455 on chromosome 3q27-28. Our aim, therefore, is to identify these specific regions and susceptibility genes through Fine-mapping association studies and perform functional analyses to define the mechanisms by which mutations in susceptibility genes lead to IBD. Such studies will provide insight into early steps in the pathogenesis of these diseases and help identify functional variants contributing to IBD susceptibility.