Identification of IBD Susceptibility Genes

描述(由申请人提供)： 炎症性肠病(IBD)、克罗恩病(CD)和溃疡性结肠炎是一种具有多因素病因的慢性疾病，涉及许多遗传和环境因素之间的相互作用。一些流行病学证据支持这样的假设，即遗传因素在IBD的发病机制中特别重要，到目前为止发表的七次全基因组扫描的结果已经确定了一些IBD易感基因。虽然到目前为止，大多数这些基因座上的疾病变异还没有被确定，但第一个与CD相关的基因NOD2已经在IBD1易感基因座中被发现。IBD的遗传模式是复杂的，并与相当大的遗传异质性有关。因此，识别和鉴定所有导致和/或调节IBD的基因对于全面了解IBD的发病机制是必要的，并将对改进的分子诊断和治疗策略的发展产生实质性的影响。此外，更好地理解导致IBD发病的复杂遗传机制也可能为阐明导致疾病发病的环境因素提供一个框架。位于多伦多的西奈山医院IBD中心此前曾对IBD易感基因进行了全基因组搜索。分析结果显示，染色体19p13和6p上的基因座与IBD有关。在全基因组搜索中产生的数据支持这样的假设，即重要的IBD易感基因位于这些染色体区域。因此，这些数据为在拟议的IBDGRC的背景下作为遗传研究中心的这一申请提供了理由。 因此，这项建议的具体目的是：1)提炼染色体19p13和6p上的IBD易感区域；2)确定染色体19p13和6p上的易感基因；3)在IBDGRC的背景下，通过贡献临床数据和生物样本，参与识别重要的IBD易感基因的大规模努力。这项建议的总体目标是在剖析导致IBD发病的遗传机制方面取得重大进展。做到这一点将导致有能力识别“处于危险中”的个人，并采取有针对性的预防策略进行干预。也有可能随后开发改进的诊断测试和更安全、更有效的治疗方法。

DESCRIPTION (provided by applicant): The inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis, are chronic conditions with a multifactorial etiology involving interplay between a number of genetic and environmental factors. Several lines of epidemiological evidence support the hypothesis that genetic factors are particularly important in the pathogenesis of IBD and the results of seven genome-wide scans published to date have identified a number of IBD susceptibility loci. Although the disease variants within most of these loci have not been identified as of yet, the first CD-associated gene, Nod2, has been identified within the IBD1 susceptibility locus. The inheritance patterns of IBD are complex and are associated with considerable genetic heterogeneity. Thus, identification and characterization of all the genes which cause and/or modulate IBD is required to fully appreciate IBD pathogenesis and will impact substantively on the development of improved molecular diagnostic and therapeutic strategies. Additionally, better understanding of the complex genetic mechanisms leading to the onset of IBD may also provide a framework for elucidating the environmental factors which contribute to disease onset. The Mount Sinai Hospital IBD Center in Toronto has previously performed a genome-wide search for IBD susceptibility loci. The results of this analysis have revealed loci on chromosomes 19p13 and 6p to be linked to IBD. The data generated in this genome-wide search support the hypothesis that important IBD susceptibility genes lie in these chromosomal regions. These data, therefore, provide the rationale for this application as a Genetic Research Center in the context of the proposed IBDGRC. Therefore, the specific aims of this proposal are to: 1) refine the IBD susceptibility regions on chromosome 19p13 and 6p; 2) identify the susceptibility genes on chromosomes 19p13 and 6p; and 3) participate in large scale efforts to identify important susceptibility genes for IBD by contributing clinical data and biological samples in the context of the IBDGRC. The broad objective of this proposal is to make significant progress in dissecting the genetic mechanisms contributing to IBD pathogenesis. Accomplishing this will lead to the ability to identify "at risk" individuals and to intervene with targeted preventative strategies. The potential also exists for the subsequent development of improved diagnostic tests and safer and more efficacious therapies.