Mechanisms of action of SNPs associated with common disease

SNP与常见疾病相关的作用机制

• 批准号: 7713409
• 负责人: OSNAT HERZBERG
• 金额: $ 15.31万
• 依托单位: UNIVERSITY OF MD BIOTECHNOLOGY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-04-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7713409
• 关键词: Affect; Affinity; Amino Acid Substitution; Binding; Circular Dichroism; Communities; Complex; Computer Analysis; Computing Methodologies; Crohn' s disease; Data; Databases; Development; Differential Scanning Calorimetry; Disease; Disease susceptibility; Gene Expression; Gene Proteins; Genes; Genetic Variation; Genome; Goals; In Vitro; Incidence; Individual; Information Systems; Investigation; Messenger RNA; Methods; Mutate; Nature; Outcome; Pathway interactions; Play; Predisposition; Process; Property; Proteins; RNA Splicing; Relative (related person); Resources; Risk; Role; Structure; Surface; Techniques; Thermodynamics; Time; Variant; base; disorder risk; genome wide association study; human disease; in vivo; insight; mutant; protein folding; protein function; public health relevance; research study; trait; web interface

DESCRIPTION (provided by applicant): Recent genome wide association studies have led to the reliable identification of multiple common SNPs associated with increased incidence of a number of common human diseases. These results offer the tantalizing prospect of major new insights into the nature of complex trait disease in general and specific understanding of the mechanisms underlying major common human diseases. Deriving maximum insight is not trivial, and requires the development and application of a range of computational and experimental techniques. The goal of this project is to develop and apply such methods to the currently available association studies and new results that will be available shortly. The project focuses on the gene and gene product level contributions to common human disease. These processes constitute a key part of the multiple level mechanisms by which SNPs influence disease risk, and a full understanding of their contributions is essential to effective investigation of higher level pathway and subsystems impact. We take a two pronged approach. First, computational methods will be used to identify a set of possible candidate SNPs in established susceptibility loci for common diseases. For each of these SNPs, a set of possible mechanisms of action is examined. Specifically, effects on gene expression level; messenger RNA structure; processing; stability and splicing; and on protein folding, structure, stability and function in vivo. Secondly, for one of the mechanisms that it is already clear plays a significant role, missense SNPs in proteins, we will experimentally investigate the impact of the resulting amino acid substitutions on in vitro function. To this end, we will clone, express and purify a number of affected proteins and the SNP variants, and investigate their properties, particularly structural stability and interaction with appropriate binding partners. Initial studies are on the large scale WTCCC genome wide association data for common diseases, and on additional association data for Crohn's disease. As more data become available, the computational analysis will be extended to include additional association studies as well as re-sequencing data. The outcome will be a comprehensive computational analysis of the mechanisms by which SNPs influence disease susceptibility at the gene and protein level, and in high priority cases, extensive experimental characterization of the impact of relevant missense SNPs on protein function. All data will be made available in downloadable form, as well as through an interactive web interface. In addition, we will develop an annotation and discussion facility, so that the results can be maximally exploited. PUBLIC HEALTH RELEVANCE: New data are for the first time reliably establishing many associations between genetic variation among individuals and susceptibility to a number of common human diseases. These data open the way for investigation of the mechanisms underlying disease and hence the development of new therapies. We will use computational and experimental methods to determine the genome and protein level mechanisms, making use of these new data.

描述（由申请人提供）：最近的基因组广泛关联研究导致对多种常见SNP的可靠鉴定，与许多常见人类疾病的发生率增加有关。这些结果提供了对复杂性状疾病本质的主要新见解的诱人前景，并对主要共同疾病的机制进行了具体理解。得出最大的洞察力并不是微不足道的，需要开发和应用一系列计算和实验技术。该项目的目的是将这些方法开发和应用于当前可用的协会研究，并将很快获得新的结果。该项目着重于基因和基因产品水平对常见人类疾病的贡献。这些过程构成了SNP会影响疾病风险的多层次机制的关键部分，并且对它们的贡献充分理解对于有效研究高级途径和子系统影响至关重要。我们采取了两种统计的方法。首先，计算方法将用于确定一组可能的常见疾病易感基因座中可能的候选SNP。对于这些SNP中的每一个，都检查了一组可能的作用机理。具体而言，对基因表达水平的影响；信使RNA结构；加工;稳定性和剪接；以及在体内蛋白质折叠，结构，稳定性和功能。其次，对于已经很明显起着重要作用的一种机制，即蛋白质中的错义SNP，我们将实验研究所得氨基酸取代对体外功能的影响。为此，我们将克隆，表达和纯化许多受影响的蛋白质和SNP变体，并研究其特性，尤其是结构性稳定性以及与适当结合伴侣的相互作用。最初的研究是关于常见疾病的大规模WTCCC基因组宽结合数据，以及克罗恩病的其他关联数据。随着越来越多的数据可用，将扩展计算分析以包括其他关联研究以及重新列出数据。结果将是对SNP在基因和蛋白质水平上影响疾病易感性的机制的全面计算分析，在高优先级的情况下，对相关错义SNP对蛋白质功能的影响进行了广泛的实验表征。所有数据将以可下载的形式以及通过交互式Web界面提供。此外，我们将开发注释和讨论设施，以便可以最大程度地利用结果。 公共卫生相关性：新数据首次可靠地建立了个体之间的遗传变异与对许多常见人类疾病的敏感性之间的许多关联。这些数据为研究疾病潜在机制的研究开辟了道路，从而开发了新疗法。我们将使用计算和实验方法来确定这些新数据的基因组和蛋白质水平机制。