Rare disease susceptibility alleles in children with Crohn disease

克罗恩病儿童罕见病易感等位基因

• 批准号: 8338912
• 负责人: Stephen L Guthery
• 金额: $ 35.17万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8338912
• 关键词: 12 year old; Abdominal Pain; Accounting; Adult; Affect; Age; Alleles; Autoimmune Diseases; Base Sequence; Biopsy Specimen; Case-Control Studies; Child; Childhood; Chromosome Mapping; Chronic; Classification Scheme; Code; Crohn' s disease; DNA; DNA Sequence; Data; Diarrhea; Disease; Disease Association; Disease Outcome; Disease susceptibility; Enrollment; Etiology; European; Family history of; Gastrointestinal tract structure; Gene Frequency; Genes; Genetic; Genetic Variation; Genetic screening method; Genomic Segment; Genomics; Genotype; Goals; Growth; Haplotypes; Hemorrhage; Heritability; Individual; Inflammatory; Inflammatory disease of the intestine; Lead; Linkage Disequilibrium; Meta-Analysis; Molecular; Natural Selections; Onset of illness; Parents; Pathogenesis; Patients; Phase; Phylogeny; Population; Population Database; Predisposition; Principal Component Analysis; Quality of life; Rare Diseases; Records; Resources; Sampling; Shapes; Structure; Testing; Utah; Variant; abstracting; adverse outcome; base; case control; clinically relevant; density; disorder risk; exome; fitness; genetic risk factor; genetic variant; genome wide association study; high risk; improved; innovation; insight; interest; kindred; member; next generation; novel; rectal; statistics; tool

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.

描述(由申请人提供)： 项目摘要/摘要这一拟议项目的总体目标是确定导致儿童发病的罕见基因变异--克罗恩病。克罗恩病是一种病因不明且无法治愈的慢性胃肠道炎症性疾病。受影响的儿童会出现腹泻、腹痛、生长障碍和生活质量受损等症状。已鉴定的克隆病易感基因提高了我们对克隆病发病机制的认识。然而，已鉴定的易感等位基因不能解释观察到的遗传力，许多基因组区域的致病等位基因也没有被鉴定出来。对于拟议的研究，我们将使用1)从高危克罗恩家族收集的现有DNA样本，使用仅在犹他州可获得的广泛的家谱记录进行鉴定，2)从患有克罗恩病的非常年幼的儿童及其父母那里获得现有DNA样本，以及3)从没有个人或家族自身免疫性疾病病史的健康对照组获得现有DNA样本。我们的总体假设是，儿童发病的克罗恩病部分是由罕见的疾病易感等位基因引起的。在目标1中，我们将对高危克罗恩病家系的儿童进行共享基因组片段分析和外显子组测序。在目标2中，我们将进行有针对性的重新测序研究和病例对照研究，其中病例是患有克罗恩病的非常年幼的儿童。在目标3中，我们将测试假设，作为进化力量的结果，克罗恩病的易感等位基因已经搭上了先前发现的疾病风险单倍型的便车，其中致病变异(S)仍然未知。在这项建议中，我们将使用一个新的和强大的资源，犹他州人口数据库，并进一步开发创新的分析策略，以执行基因图谱研究在大型家系。我们将利用一种表型极端的--儿童期起病的克罗恩病--来描述已知易感等位基因中罕见的遗传变异。最后，我们将探索形成克罗恩病易感基因的进化力量，这可能为我们提供对致病基因的洞察。这些研究将提高我们对克罗恩病病因的理解，有助于开发临床上有用的分子分类方案，并导致改进的治疗。