Rare disease susceptibility alleles in children with Crohn disease

描述（由申请人提供）： 项目概要/摘要本拟议项目的总体目标是鉴定导致儿童期克罗恩病发作的罕见遗传变异。克罗恩病是一种慢性胃肠道炎症性疾病，病因不明，无已知治愈方法。受影响的儿童患有腹泻，腹痛，生长障碍和生活质量受损。克隆病易感等位基因的发现提高了我们对克隆病发病机制的认识。然而，鉴定出的易感性等位基因并不能解释观察到的遗传性，也没有鉴定出许多基因组区域中的致病等位基因。对于拟定的研究，我们将使用1）使用仅在犹他州可用的广泛系谱记录从高风险克罗恩病中收集的现有DNA样本，2）从患有克罗恩病的非常年幼的儿童及其父母中获得的现有DNA样本，以及3）从没有自身免疫性疾病个人或家族史的健康对照中获得的现有DNA样本。我们的总体假设是儿童期克罗恩病部分是由罕见疾病易感等位基因引起的。在目标1中，我们将在高危克罗恩病患儿中进行共享基因组片段分析和外显子组测序。在目标2中，我们将进行靶向重新测序研究和病例对照研究，其中病例是非常年幼的克罗恩病儿童。在目标3中，我们将检验这一假设，即作为进化力量的结果，克罗恩病易感性等位基因搭便车在先前确定的疾病风险单倍型上，其中致病变体仍然未知。在这项提案中，我们将使用一个新的和强大的资源，犹他州人口数据库，并进一步发展创新的分析策略，以执行基因定位研究，在大kinetics。我们将利用一个表型极端儿童发病克罗恩病的特点，在已知的易感等位基因的罕见遗传变异。最后，我们将探讨形成克罗恩病易感基因座的进化力量，这可能会提供对致病基因的深入了解。这些研究将提高我们对克罗恩病病因的理解，有助于开发临床有用的分子分类方案，并改善治疗。 公共卫生相关性： 克罗恩病是一种病因不明的慢性肠道炎症性疾病，目前尚无治愈方法。受影响的儿童患有腹泻，腹痛，生长障碍和生活质量受损。该项目的总体目标是通过研究高风险克罗恩病和受克罗恩病影响的非常年幼的儿童来确定新的遗传风险因素。这些研究可能有助于我们更好地了解克罗恩病的病因，并开发临床相关工具来分类疾病或疾病不良结局高风险患者。

DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT The overall goal of this proposed project is to identify rare genetic variants contributing to childhood onset- Crohn disease. Crohn disease is a chronic inflammatory disorder of the gastrointestinal tract of unclear etiology and no known cure. Affected children suffer from diarrhea, abdominal pain, growth disturbances, and an impaired quality of life. The identified Crohn disease susceptibility alleles have improved our understanding of Crohn disease pathogenesis. However, the identified susceptibility alleles do not account for the observed heritability, nor have disease-causing alleles in many genomic regions been identified. For the proposed studies, we will use 1) existing DNA samples collected from high-risk Crohn kindreds identified using the extensive genealogical records available only in Utah, 2) existing DNA samples obtained from very young children with Crohn disease and their parents, and 3) existing DNA samples obtained from healthy controls that are free of a personal or family history of autoimmune disorders. Our overall hypothesis is that childhood- onset Crohn disease is caused in part by rare disease susceptibility alleles. In Aim 1, we will perform shared genomic segment analysis and exome sequencing in children in high-risk Crohn disease kindreds. In Aim 2, we will perform targeted re-sequencing studies and a case-control study in which the cases are very young children with Crohn disease. In Aim 3, we will test the hypothesis that, as a consequence of the evolutionary forces, Crohn disease susceptibility alleles have hitchhiked on a previously identified disease risk haplotype in which the disease-causing variant(s) remains unknown. In this proposal, we will use a novel and powerful resource, the Utah Population Database, and further develop innovative analytical strategies to perform gene- mapping studies in large kindreds. We will utilize a phenotypic extreme-childhood-onset Crohn disease-to characterize the rare genetic variation in known susceptibility alleles. Finally, we will explore the evolutionary forces shaping a Crohn disease susceptibility locus, which may provide insight into the disease-causing gene. These studies will improve our understanding of the causes of Crohn disease, help develop clinically useful molecular classification schemes, and lead to improved therapy. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE/RELEVANCE TO PUBLIC HEATLH Crohn disease is a chronic inflammatory disorder of the intestine of unclear etiology and no known cure. Affected children suffer from diarrhea, abdominal pain, growth disturbances, and an impaired quality of life. The overall goal of this project is to identify new genetic risk factors by studying high-risk Crohn disease kindreds and very young children affected by Crohn disease. These studies may help us better understand the causes of Crohn disease, and develop clinically relevant tools to classify patients at high risk of developing disease or adverse outcomes of disease.