Diabetes and recombination in the 8.1 MHC haplotype

描述（由申请人提供）：该项目的中心目标将是测试高度保守的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）病因的假设。通过确定一组染色体的边界，然后比较广泛、完整、分阶段的高质量序列数据，这些数据来自患者和对照组中确定的保守区和重组区之间的目标边界，我们提出可以确定调节糖尿病病程的变异。在此基础上，我们建议开发可用于在发病年龄之前筛查个体的分型方法，以识别高风险个体并最大限度地发挥预防治疗的潜力。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，这些数据可以广泛传播给广泛的科学界，这些科学界对RFA解决的生物问题长期感兴趣。为此，我们建议达致以下具体目标：1)精确定义的边界A1-B8-DR3单体型在近年来情况下和控制染色体,2)构建fosmid库从A1 - B8-DR3个人同样分歧内转病例和控制,3)序列区域针对性1中定义的库开发的针对性,目标是确定序列变异与疾病易感性,针对性3中4)验证结果在更大的病例组和对照组,从而建立一种具有强大预测能力的简单基因测试，在发病前识别T1D患者。如果在T1D患者和正常对照中发现区分A1-B8-DR3染色体的遗传变异，该研究有可能导致在临床环境中确定易感人群T1D风险的有用测试的发展。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，可能会进一步为T1D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.