Identification of IBD Susceptibility Genes

描述（由申请人提供）： 炎症性肠病（IBD）、克罗恩病（CD）和溃疡性结肠炎是具有多因素病因学的慢性疾病，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遗传因素在IBD发病机制中特别重要的假设，迄今为止发表的7个全基因组扫描结果已经确定了一些IBD易感基因座。尽管这些基因座中的大多数基因座内的疾病变体尚未被鉴定，但第一个CD相关基因Nod 2已在IBD 1易感性基因座内被鉴定。IBD的遗传模式很复杂，并且与相当大的遗传异质性相关。因此，需要鉴定和表征引起和/或调节IBD的所有基因，以充分了解IBD发病机制，并将对改进的分子诊断和治疗策略的发展产生实质性影响。此外，更好地了解导致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框架。位于多伦多的西奈山医院IBD中心先前已经进行了IBD易感基因位点的全基因组搜索。该分析的结果揭示了染色体19 p13和6p上的基因座与IBD连锁。在全基因组搜索中产生的数据支持重要IBD易感基因位于这些染色体区域的假设。因此，这些数据为在拟议的IBDGRC背景下作为遗传研究中心的申请提供了依据。 因此，本提案的具体目的是：1）细化染色体19 p13和6p上的IBD易感区域; 2）鉴定染色体19 p13和6p上的易感基因; 3）通过在IBDGRC背景下提供临床数据和生物样本，参与大规模鉴定IBD重要易感基因的工作。该提案的广泛目标是在剖析IBD发病机制的遗传机制方面取得重大进展。做到这一点将导致有能力确定“处于危险之中”的个人，并采取有针对性的预防战略进行干预。也有可能随后开发出更好的诊断测试和更安全有效的治疗方法。

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.