Yale University Inflammatory Bowel Disease Genetics Research Center

耶鲁大学炎症性肠病遗传学研究中心

• 批准号: 8463772
• 负责人: JUDY H. CHO
• 金额: $ 41.02万
• 依托单位: YALE UNIVERSITY
• 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/8463772
• 关键词: 19q13; Address; Adipose tissue; Affect; African American; American; Architecture; Automobile Driving; Biology; Chromosomes; Clinical; Crohn' s disease; Data; Data Set; Development; Disease; Disease Association; Disease susceptibility; Employee Strikes; Equilibrium; European; Future; Gene Family; Gene Frequency; Generations; Genes; Genetic; Genetic Polymorphism; Genetic Research; Genetic Variation; Genomics; Goals; Human; Immune; Immune response; Immunology; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Information Networks; International; Laboratories; Medical; Microbe; Mycobacterium Infections; National Institute of Diabetes and Digestive and Kidney Diseases; Natural Selections; Pathogenesis; Pathway interactions; Patients; Phase; Play; Population; Population Group; Population Heterogeneity; Population Study; Predisposition; Protocols documentation; Publishing; Quantitative Trait Loci; Reading; Research Personnel; Resources; Role; Sample Size; Sampling; Shapes; Signal Transduction; Specimen; Tissues; Ulcerative Colitis; Universities; base; computer based statistical methods; functional genomics; genetic association; improved; innovation; interest; macrophage; microbial; microorganism interaction; mycobacterial; novel; novel strategies; population based; protein protein interaction; response; single molecule; transcription factor

DESCRIPTION (provided by applicant): The inflammatory bowel diseases (IBD) are comprised of Crohn's disease and ulcerative colitis and affect approximately 1.4 million Americans. Present medical therapies are incompletely effective. Enormous progress in defining genes contributing to IBD has been made possible through large Consortial efforts which leverage large sample sizes and complementary expertise. We present new data from the Immunochip, a collaborative international effort involving the analysis of over 75,000 samples that has resulted in the identification of 163 loci associated with IBD. A major goal of the field, moving forward, is to derive a more cohesive picture of IBD pathogenesis which moves from identifying myriad genetic loci to an approach which draws out whole pathways to deepen our understanding of the biology of the disease. In Specific Aim 1, we propose to actively participate as a genetics research center (GRC) within the larger NIDDK IBD Genetics Consortium. Future progress will be enhanced by drawing in investigators with complementary expertise. In addition to present genetic, clinical and statistical expertise in the Yale GRC, we have added expertise in mucosal immunology and host-mycobacterial interactions. We will continue to provide sample material attached to relevant information useful for genetic and genomic studies. In Specific Aim 2, we propose to define the underlying genetic architecture of IBD that has been shaped by host-microbe interactions. We identify evidence for natural selection driving many of association signals, likely driven by host-microbial interactions. We have identified a new IBD association to a region on chromosome 19q13 containing the LILR-KIR gene families. This region has been profoundly shaped by balancing selection, and a complete genetic definition of this region has been hampered by phasing challenges. We propose an innovative approach to define genetic variation in this region through long-range sequence reads in diverse populations that will resolve present phasing challenges. A striking overlap of IBD loci with mycobacterial susceptibility loci is observed, and a NOD2- focused analysis of a macrophage-enriched inflammatory module identifies additional IBD-associated genes nearby in the network that modulate host responses to mycobacterial infection. In order to provide a more cohesive understanding of the functional genomic responses, we propose studies to compare the expression and functional responses of human macrophages in response to mycobacterial infection between IBD patients and controls, and across populations. Combined with integrated, tissue-based Bayesian network analyses, these studies will deepen our understanding of the underlying mechanisms of IBD. This understanding is critical for the development of novel therapies to improve our treatment of patients affected by these often debilitating disorders. PUBLIC HEALTH RELEVANCE: A large number of genetic regions have now been associated with inflammatory bowel disease. Understanding how these genes connect into altered biologic pathways and networks will require integrating genetic data with expression-based datasets. This understanding will be critical to the development of improved therapies for these disorders.

描述（由申请人提供）：炎症性肠病（IBD）由克罗恩病和溃疡性结肠炎组成，影响约140万美国人。目前的医疗疗法无效。通过利用大量样本量和互补专业知识的大型联盟努力，已经实现了促成IBD的基因的巨大进展。我们提供了来自Immunochip的新数据，这是一项合作的国际努力，涉及对75,000多个样本的分析，这导致了与IBD相关的163个基因座的识别。该领域的主要目标， 向前迈进，是为了获得IBD发病机理的更加凝聚力的图片，该发病机理从识别无数遗传基因座转变为一种方法，该方法吸引了整个途径，以加深我们对疾病生物学的理解。在特定目标1中，我们建议在较大的NIDDK IBD遗传联盟中积极参与遗传学研究中心（GRC）。通过吸引具有互补专业知识的调查员，将增强未来的进步。除了耶鲁GRC的当前遗传，临床和统计专业知识外，我们还增加了粘膜免疫学和宿主 - 细菌相互作用的专业知识。我们将继续提供与相关信息有关的样本材料，可用于遗传和基因组研究。在特定的目标2中，我们建议定义IBD的基本遗传结构，该遗传结构是由宿主 - 微生物相互作用塑造的。我们确定了自然选择的证据，驱动许多关联信号，这可能是由宿主微生物相互作用驱动的。我们已经确定了一个新的IBD关联，该区域是含有lilr-kir基因家族的19q13染色体。该地区的选择是通过平衡选择深远影响的，并且对该区域的完整遗传定义受到了分阶段挑战的阻碍。我们提出了一种创新的方法，通过在不同种群中读取该区域的遗传变异来定义该区域的遗传变异，这将解决当前的阶段挑战。观察到IBD基因座与分枝杆菌敏感性基因座的引人注目的重叠，并以NOD2为中心的巨噬细胞增强的炎症模块以NOD2为中心的分析确定了附近的其他IBD相关基因，从而调节了对宿主对分枝杆菌感染的宿主反应。为了对功能基因组反应有更加凝聚力的理解，我们提出研究以比较人类巨噬细胞对IBD患者和对照组之间以及跨种群中人分枝杆菌感染的表达和功能反应。结合基于组织的综合贝叶斯网络分析，这些研究将加深我们对IBD潜在机制的理解。这种理解对于开发新疗法的发展至关重要，以改善我们经常使人衰弱的疾病影响的患者的治疗。 公共卫生相关性：许多遗传区域与炎症性肠病有关。了解这些基因如何连接到改变的生物学途径和网络将需要将遗传数据与基于表达的数据集集成在一起。这种理解对于发展这些疾病的改善疗法至关重要。