Utilizing the Phenomics of IBD to Enhance Gene Discovery

利用 IBD 的表型组学来增强基因发现

• 批准号: 8549193
• 负责人: Dermot Patrick McGovern
• 金额: $ 40.37万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8549193
• 关键词: Affect; Age of Onset; American; Appendectomy; Autophagocytosis; Biology; Caucasians; Caucasoid Race; Cell Line; Cellular Morphology; Chronic; Clinic; Clinical; Colectomy; Communities; Crohn' s disease; DNA; DNA Repository; Data; Data Set; Databases; Development; Disease; Disease Management; Disease susceptibility; Endoscopy; Environment; Environmental Risk Factor; Ethnic Origin; Ethnic group; Etiology; Gene Frequency; Genes; Genetic; Genetic Markers; Genetic Processes; Genetic Variation; Genome; Genomics; Genotype; Granulomatous; Grouping; Haplotypes; Health Care Costs; Human Herpesvirus 4; Immune; Individual; Inflammatory Bowel Diseases; Interleukin-10; International; Koreans; Life; Link; Maps; Methods; Morbidity - disease rate; Natural History; Operative Surgical Procedures; Paneth Cells; Pathway interactions; Patients; Phenotype; Population; Predisposition; Prevention; Proteins; Puerto Rican; Quantitative Trait Loci; Recruitment Activity; Relative (related person); Research; Research Infrastructure; Role; Sampling; Serum; Severities; Smoking; Specimen; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Staging; Stratification; Structure; Subgroup; Susceptibility Gene; TNFSF15 gene; Technology; Testing; Time; Transformed Cell Line; Translational Research; Ulcerative Colitis; Variant; Vitamin D; base; clinical phenotype; cohort; exome; gene discovery; gene environment interaction; gene interaction; genome wide association study; insight; microbial; microbiome; new therapeutic target; novel; novel strategies; phenomics; programs; repository

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.

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见解，这两种疾病 炎症性肠病 (IBD) 的最常见形式。已鉴定出超过 160 个 IBD 易感位点，但仍需要取得相当大的进展，以便： 确定其他易感位点；识别已知位点的“因果”变异；了解相关遗传变异的功能影响；并了解这些基因与环境的相互作用。该提议的假设基于 IBD 是异质条件的认识。我们相信，定义更多同质群体（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 （目标1）。我们将继续执行并向 IBDGC 和 IIBDGC 项目贡献大规模基因分型数据集（目标 1）。先前招募的大型队列，加上目标 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足够大小的亚组，我们相信这将有助于定义新颖且独特的遗传性 IBD 相关变异（目标2）。我们还建议通过已知环境因素对案例进行分层来创建同质子组（目标 2 和 3）。在目标 3 中，我们将研究已知 IBD 位点在影响微生物组和元蛋白酶以及功能性粘膜群落方面的作用。我们还将使用这些社区来定义同质的个体群体，以便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识别将确定治疗和预防 IBD 的潜在新治疗靶点，并推进治疗这些慢性、衰弱性疾病的个体化方法。