GENETIC MAPPING STUDIES IN INFLAMMATORY BOWEL DISEASE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 特发性炎症性肠病（IBD）由克罗恩病（CD）和溃疡性结肠炎（UC）两种主要亚型组成，并且是复杂的多基因疾病。 这项研究的假设是，特定的风险等位基因（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由连锁和关联研究提供的，最终是功能相关性。 我们和其他人已经确定16号染色体上NOD 2/CARD 15基因中的Arg 702 Trp、Gly 908 Arg和Leu 1007 fsinsC与CD 2-4高度相关。然而，NOD 2/CARD 15和其他介导宿主对细菌肽聚糖反应的基因中的这些突变导致CD的确切功能机制仍然不完全确定。 最近，OCTN 1/SLC 22 A4-OCTN 2/SLC 22 A5（染色体5 q）5、DLG 5（染色体10 q）6和MDR 1（染色体7 q）7基因内的遗传变异与CD和IBD相关。然而，结合Meta- 8和连锁研究的大型分析显示，在染色体5 q，10 q和7 q上的这些区域的得分相对较低，其他区域的得分显着较高。特别重要的是在染色体3q 27 -28上由D3 S1262和D3 S2455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来识别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。 这些研究将提供对这些疾病发病机制的早期步骤的深入了解，并有助于确定有助于IBD易感性的功能变体。

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.