Diabetes and recombination in the 8.1 MHC haplotype

8.1 MHC 单倍型中的糖尿病和重组

• 批准号: 7295799
• 负责人: DANIEL E. GERAGHTY
• 金额: $ 21万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7295799
• 关键词: Address; Age; Arts; Biological; Chromosomes; Chromosomes, Human, Pair 2; Clinical; Communities; Data; Development; Diabetes Mellitus; Disease susceptibility; Genetic Recombination; Genetic screening method; Genomics; Goals; Haplotypes; Human; Individual; Insulin-Dependent Diabetes Mellitus; Lead; Libraries; Methods; Onset of illness; Patients; Phase; Population; Recombinants; Research; Resources; Risk; Technology; Testing; Variant; Work; case control; diabetes risk; genetic variant; interest

DESCRIPTION (provided by applicant): The central goal of this project will be to test the hypothesis that sequence variants near the heterogeneous boundaries of the highly conserved A1-B8-DR3 ancestral MHC haplotype are causative of type 1 diabetes (T1D). By identifying the boundaries in a set of chromosomes, and then comparing extensive, complete, and phased high quality sequence data from targeted boundaries between conserved and recombinant regions identified in patients and controls, we propose that variations that modulate the course of diabetes can be identified. Derivative from this work we propose to develop typing methods which can be used to screen individuals before the age of disease onset, in order to identify high risk individuals and maximize the potential for preventative therapy. This project will also represent an important application of state of the art genomics technology that will provide access to clone resources and sequence data that can be widely disseminated to an extensive scientific community with longstanding interest in the biological problem that the RFA addresses. Towards these ends, we propose to achieve the following specific aims: 1) To precisely define the boundaries of the A1-B8-DR3 haplotype in T1D case and control chromosomes, 2) To construct fosmid libraries from A1- B8-DR3 individuals equally divided over T1D cases and controls, 3) To sequence regions defined in specific aim 1 from the libraries developed in specific aim 2, with the aim of identifying sequence variants that could be relevant to disease susceptibility, 4) To validate results obtained in specific aim 3 on a larger group of cases and controls, thereby establishing a simple genetic test(s) with powerful predictive capability to identify T1D patients before onset. Should genetic variants that distinguish A1-B8-DR3 chromosomes found in T1D patients from normal controls be found, this research has the potential to lead to the development of a test(s) useful in a clinical setting for the determination of T1D risk in susceptible human populations. Further potential to provide new direction in the treatment of T1D may emerge through an understanding of the functional consequences of that variation, and its relationship to other T1D risk haplotypes.

描述（由申请人提供）：该项目的中心目标是检验以下假设：高度保守的 A1-B8-DR3 祖先 MHC 单倍型异质边界附近的序列变异是 1 型糖尿病 (T1D) 的病因。通过识别一组染色体中的边界，然后比较来自患者和对照中确定的保守区域和重组区域之间的目标边界的广泛、完整和分阶段的高质量序列数据，我们建议可以识别调节糖尿病病程的变异。根据这项工作，我们建议开发可用于在疾病发病年龄之前筛查个体的分型方法，以便识别高风险个体并最大限度地发挥预防性治疗的潜力。该项目还将代表最先进的基因组学技术的重要应用，该技术将提供对克隆资源和序列数据的访问，这些资源和序列数据可以广泛传播给对 RFA 解决的生物学问题长期感兴趣的广大科学界。为此，我们建议实现以下具体目标：1）精确定义T1D病例和对照染色体中A1-B8-DR3单倍型的边界，2）从均分的A1-B8-DR3个体构建fosmid文库在 T1D 病例和对照中，3) 对特定目标 2 中开发的文库中特定目标 1 中定义的区域进行测序，目的是识别可能与疾病易感性相关的序列变异， 4) 在更大的病例组和对照组中验证特定目标 3 中获得的结果，从而建立具有强大预测能力的简单基因测试，以在发病前识别 T1D 患者。如果发现区分 T1D 患者和正常对照的 A1-B8-DR3 染色体的遗传变异，这项研究有可能开发出一种可用于临床环境的测试，用于确定易感人群的 T1D 风险。人口。通过了解该变异的功能后果及其与其他 T1D 风险单倍型的关系，可能会出现为 T1D 治疗提供新方向的进一步潜力。