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: 7224529
• 负责人: DANIEL E. GERAGHTY
• 金额: $ 21.63万
• 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 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7224529
• 关键词: clinical research; computer assisted sequence analysis; genetic library; genetic mapping; genetic recombination; histocompatibility antigens; histocompatibility typing; insulin dependent diabetes mellitus; molecular biology information system; nucleic acid amplification techniques; polymerase chain reaction; protein sequence; protein structure

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)：该项目的中心目标将是测试高度保守的A1-B8-DR3祖先MHC单倍型的异质性边界附近的序列变异是1型糖尿病(T1D)的原因这一假设。通过确定一组染色体中的边界，然后比较广泛、完整和阶段性的高质量序列数据，从患者和对照中确定的保守区域和重组区之间的目标边界，我们认为可以识别调节糖尿病病程的变异。从这项工作衍生出来的，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，以识别高危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，它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长期对RFA解决的生物学问题感兴趣的广泛科学界。为此，我们建议实现以下特定目标：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)构建A1-B8-DR3单倍型在T1D病例和对照中平均分布的融合文库；3)从在特定目标2中开发的文库中构建特定目标1中定义的序列区域，目的是识别可能与疾病易感性相关的序列变体；4)在更大的病例和对照群体中验证特定目标3中所获得的结果，从而建立一种简单的遗传测试(S)，该方法具有在发病前识别T1D患者的强大预测能力。如果在T1D患者中发现区分A1-B8-DR3染色体与正常对照的遗传变异，这项研究有可能导致开发一种在临床环境中用于确定易感人群中T1D风险的测试(S)。通过了解T1D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。