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）：最近的全基因组关联研究已可靠地鉴定出与多种常见人类疾病发病率增加相关的多个常见 SNP。这些结果提供了对复杂性状疾病本质的总体新见解和对人类主要常见疾病机制的具体理解的诱人前景。获得最大的洞察力并非易事，需要开发和应用一系列计算和实验技术。该项目的目标是开发此类方法并将其应用于当前可用的关联研究和即将推出的新结果。该项目重点关注基因和基因产物水平对人类常见疾病的贡献。这些过程构成了 SNP 影响疾病风险的多层次机制的关键部分，充分了解它们的贡献对于有效研究更高层次的途径和子系统影响至关重要。我们采取两管齐下的方法。首先，将使用计算方法在已确定的常见疾病易感位点中识别一组可能的候选 SNP。对于每一个 SNP，都检查了一组可能的作用机制。具体来说，对基因表达水平的影响；信使RNA结构；加工;稳定性和拼接；以及体内蛋白质折叠、结构、稳定性和功能的研究。其次，对于已经明确发挥重要作用的机制之一，即蛋白质中的错义SNP，我们将通过实验研究由此产生的氨基酸取代对体外功能的影响。为此，我们将克隆、表达和纯化一些受影响的蛋白质和 SNP 变体，并研究它们的特性，特别是结构稳定性和与适当结合伙伴的相互作用。初步研究针对常见疾病的大规模 WTCCC 全基因组关联数据，以及克罗恩病的其他关联数据。随着更多数据的出现，计算分析将扩展到包括额外的关联研究以及重新测序数据。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进行全面的计算分析，并且在高度优先的情况下，对相关错义 SNP 对蛋白质功能的影响进行广泛的实验表征。所有数据都将以可下载的形式以及通过交互式网络界面提供。此外，我们将开发注释和讨论工具，以便最大限度地利用结果。 公共卫生相关性：新数据首次可靠地确立了个体遗传变异与多种常见人类疾病易感性之间的许多关联。这些数据为研究疾病的机制以及开发新疗法开辟了道路。我们将利用这些新数据，使用计算和实验方法来确定基因组和蛋白质水平机制。