Genomic Convergence in Primary Open Angle Glaucoma

原发性开角型青光眼的基因组趋同

• 批准号: 6983393
• 负责人: Robert RAND ALLINGHAM
• 金额: $ 69.2万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6983393
• 关键词: clinical research; family genetics; gene expression profiling; glaucoma; human genetic material tag; human subject; linkage mapping; microarray technology; pathologic process; patient oriented research; single nucleotide polymorphism; trabeculotomy

DESCRIPTION (provided by applicant): The underlying hypothesis of this proposal is that identifiable genetic influences play a critical role in the pathophysiology of primary open angle glaucoma (POAG). Furthermore, we believe that the best approach toward identification of the underlying genes is a coordinated attack on this complex disorder utilizing multiple genetic and genomic avenues of investigation, a process that has come to be known as genomic convergence. The major objective of this proposal is to identify the gene that contributes to the development of an early adult onset form of POAG on chromosome 15 (mean family age at diagnosis =45.3 years). We have identified a new genetic locus for POAG on chromosome 15q11-13 through the use of statistical genetic methods suited to the investigation of complex inherited disorders and utilizing a large strictly ascertained database of multiplex POAG families. Using, a novel approach for phenotypic subsetting (ordered subset analysis [OSA]) we have shown that the phenotypic subset of families with an early adult onset form of POAG in the 4th and 5th decades of life (approximately 20% of families within the complete dataset) accounts for the majority of the chromosome 15 linkage information. Our preliminary data suggest that this new locus is a common Mendelian form of POAG. The critical element of this proposal is to apply genomic convergence, or the application of multiple scientific lines of genomic investigation, to determine the genetic contribution of disease. The primary goals of this proposal are threefold: 1) to reduce the minimal candidate interval (MCI) by expanding the size of our early-onset POAG multiplex family dataset and by establishing an association data set of early onset POAG families in conjunction with state of the art molecular and genetic analysis of these data. 2) to create a focused and enriched pool of candidate genes through the use of microarray techniques on human POAG tissue specimens while incorporating the use of existing SAGE/EST libraries; and 3) to analyze candidate genes by sequencing coding regions and conducting association analysis using SNP's. In this manner, we will integrate our family resources, statistical, and molecular expertise to identify the primary genes in POAG. This proposal offers a powerful approach to determine the genetic identity of a major cause of POAG. Determining the molecular underpinnings of POAG will provide enormous benefits in the search for new diagnostic and treatment approaches to this disease.

描述（由申请人提供）：该建议的基本假设是可识别的遗传影响在原发性开角型青光眼（POAG）的病理生理学中起关键作用。此外，我们认为，识别潜在基因的最佳方法是利用多种遗传和基因组研究途径对这种复杂疾病进行协调攻击，这一过程被称为基因组融合。该建议的主要目的是确定15号染色体上导致早发性POAG形成的基因（诊断时的平均家庭年龄=45.3岁）。我们已经确定了一个新的遗传位点POAG染色体15 q11 -13，通过使用统计遗传学方法适合复杂的遗传性疾病的调查，并利用一个大的严格确定的数据库的多重POAG家庭。使用一种新的表型子集划分方法（有序子集分析[OSA]），我们已经表明，在第4和第5个十年的生活中，具有早期成人发病形式的POAG的家族的表型子集（在完整数据集中约20%的家族）占15号染色体连锁信息的大部分。我们的初步数据表明，这个新的基因座是一个常见的孟德尔形式的POAG。这一建议的关键要素是应用基因组趋同，或应用基因组研究的多个科学路线，以确定疾病的遗传贡献。该提议的主要目标有三个：1）通过扩大我们的早发性POAG多重家族数据集的大小，并通过建立早发性POAG家族的关联数据集，结合这些数据的最新分子和遗传分析，来减少最小候选间隔（MCI）。2)通过对人POAG组织样本使用微阵列技术，同时结合使用现有的SAGE/EST文库，创建集中和富集的候选基因库;和3）通过对编码区测序和使用SNP进行关联分析来分析候选基因。以这种方式，我们将整合我们的家庭资源，统计学和分子专业知识，以确定原发性开角型青光眼的主要基因。这一建议提供了一个强有力的方法来确定遗传身份的一个主要原因POAG。 确定POAG的分子基础将为寻找这种疾病的新诊断和治疗方法提供巨大的好处。