Utilizing the Phenomics of IBD to Enhance Gene Discovery

描述（由申请人提供）：IBD遗传学的最新进展为溃疡性结肠炎（UC）和克罗恩病（UC）的病因学提供了重要的见解，这两种疾病都是由IBD引起的。 炎症性肠病（IBD）的最常见形式。已经鉴定了超过160个IBD易感基因座，但仍需要取得相当大的进展，以便：鉴定额外的易感基因座;鉴定已知基因座的“因果”变异;了解相关遗传变异的功能效应;以及了解这些基因与环境的相互作用。这一建议的假设是基于对IBD是异质性条件的认识。我们相信，定义更多的同质群体（使用几种新方法）将使我们能够发现与IBD相关的其他遗传变异。为了促进进一步的基因发现和遗传变异的功能后果，我们将继续招募IBD相关受试者进行遗传和功能研究 (aim 1）。我们将继续执行并为IBDGC和IIBDGC项目贡献大规模基因分型数据集（目标1）。之前招募的大规模队列，以及目标1的招募和基因分型承诺，将使我们能够根据临床，人口统计学和组织病理学标准定义适当大小的亚组，我们相信这将有助于定义新的和独特的遗传IBD相关变异（目标2）。我们还建议通过已知的环境因素（目标2和3）分层的情况下，创建同质子群。在目标3中，我们将研究已知IBD基因座在影响微生物组和元蛋白以及功能性粘膜群落中的作用。我们还将使用这些社区来定义同质的个体群体，以识别与这些社区相关的独特变体。拟议的研究和与这些异质性疾病亚组相关的独特变异的鉴定将确定治疗和预防IBD的潜在新治疗靶点，并推进管理这些慢性衰弱性疾病的个体化方法。

DESCRIPTION (provided by applicant): Recent advances in IBD genetics have provided significant insights into the etiology of ulcerative colitis (UC) and Crohn's disease (UC), the two commonest forms of the inflammatory bowel diseases (IBD). Over 160 IBD susceptibility loci have been identified, but considerable progress is still required in order to: identify additional susceptibility loci; identify 'causal' variants at the known loci; to understand the functional effcts of the associated genetic variation; and to understand the interaction of these genes with the environment. The hypothesis underlying this proposal is based on the recognition that the IBDs are heterogeneous conditions. We believe that defining more homogenous groups (using several novel methods) will allow us to discover additional genetic variation associated with the IBDs. In order to facilitate further gene discovery and functional consequences of genetic variation, we will continue to recruit IBD-related subjects for both genetic and functional studies (aim 1). We will continue to perform and contribute large-scale genotyping datasets to IBDGC and IIBDGC projects (aim 1). The large size cohorts previously recruited, together with the recruitment and genotyping commitment from aim 1, will allow us to define adequately sized subgroups based upon clinical, demographic and histopathological criteria, which we believe will help define novel and unique genetic IBD associated variation (aim 2). We also propose to create homogenous subgroups through stratifying cases by known environmental factors (aims 2 and 3). In aim 3, we will investigate the role of known IBD loci in influencing both the microbiome and metaproteame and therefore functional mucosal communities. We will also use these communities to define homogenous groups of individuals in order to identify unique variants associated with these communities. The proposed research and the identification of unique variation associated with sub-groups of these heterogeneous conditions will identify potential new therapeutic targets for the treatment and prevention of the IBDs, and also advance an individualized approach to managing these chronic, debilitating conditions.