Diabetes and recombination in the 8.1 MHC haplotype

描述（由申请人提供）：本项目的中心目标是检验高度保守的A1-B8-DR 3祖先MHC单倍型异质边界附近的序列变异是1型糖尿病（T1 D）的病因这一假设。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识别的保守和重组区域之间的靶向边界的广泛、完整和阶段性高质量序列数据，我们提出可以识别调节糖尿病病程的变异。从这项工作的衍生，我们建议开发分型方法，可用于筛选发病年龄之前的个人，以确定高风险的个人，并最大限度地提高预防性治疗的潜力。该项目还将代表最先进的基因组学技术的重要应用，该技术将提供克隆资源和序列数据，这些数据可以广泛传播给广泛的科学界，这些科学界对RFA所解决的生物学问题长期感兴趣。为此，我们建议实现以下具体目标：1）精确定义T1 D病例和对照染色体中A1-B8-DR 3单倍型的边界，2）从T1 D病例和对照中等分的A1- B8-DR 3个体构建fosmid文库，3）从特定目的2中开发的文库中对特定目的1中定义的区域进行测序，目的是鉴定可能与疾病易感性相关的序列变体，4）在更大的病例组和对照组上验证具体目的3中获得的结果，从而建立具有强大预测能力的简单遗传测试，以在发病前鉴定T1 D患者。如果发现T1 D患者与正常对照中发现的A1-B8-DR 3染色体的遗传变异，则该研究有可能导致开发在临床环境中用于确定易感人群中T1 D风险的测试。通过了解这种变异的功能后果及其与其他T1 D风险单倍型的关系，可能会出现进一步的潜力，为T1 D的治疗提供新的方向。

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.