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测试以下假设：高度保守的A1-B8-DR3祖先MHC单倍型在异质边界附近的序列变体是1型糖尿病（T1D）的原因。通过识别一组染色体中的边界，然后比较在患者和对照组中鉴定出的保守和重组区域之间有针对性边界的广泛，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进程的变化。我们建议从这项工作中衍生出来，以开发拼字方法，这些方法可用于在疾病发作之前筛查个体，以识别高风险个人并最大程度地提高预防治疗的潜力。该项目还将代表最先进的基因组技术状态的重要应用，该技术将提供对克隆资源和序列数据的访问，这些数据可以广泛传播到广泛的科学界，对RFA解决的生物学问题长期兴趣。走向这些目的，我们建议实现以下特定目的：1）精确定义T1D情况和控制染色体的A1-B8-DR3单倍型的边界，2）构建来自A1-B8-DR3个体的Fosmid库，从T1D案例中均等划分，并在T1D案例中均等划分的目标，3）与序列的序列相同，3）的目标1，以序列的序列序列序列。可能与疾病易感性相关的序列变体，4）在较大的病例和对照组中验证在特定目标3中获得的结果，从而建立了具有强大预测能力的简单基因检测，可以在发病前识别T1D患者。如果发现在T1D患者中发现的A1-B8-DR3染色体与正常对照组中发现的A1-B8-DR3染色体的遗传变异，这项研究有可能导致在临床环境中开发用于确定敏感人类T1D风险的测试。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，可以出现在T1D治疗中提供新方向的进一步潜力。