权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

A Family-based Exome Sequencing Approach to Identify Platelet Aggregation Genes

基于家族的外显子组测序方法来识别血小板聚集基因

基本信息

批准号：
9120488
负责人：
Rasika Ann Mathias
金额：
$ 244.22万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9120488
关键词：
Accounting African American Agonist American Arterial Fatty Streak Aspirin Atherosclerosis Biological Assay Blood Platelets Cataloging Catalogs Clinical Control Groups DNA Resequencing DNA Sequence Data Databases Dideoxy Chain Termination DNA Sequencing Dose Epidemiologist European Event Exons Family Funding Genes Genetic Genetic Variation Genetic study Genotype Heart Heritability High-Throughput Nucleotide Sequencing Human Genome Individual Intervention Lead Lung Measures Myocardial Infarction National Heart, Lung, and Blood Institute Open Reading Frames Outcome Patients Peripheral Phenotype Physiological Platelet aggregation Population Preventive Primary Prevention Rare Diseases Recruitment Activity Research Design Research Personnel Residual state Resistance Risk Risk Factors Role Rupture Sampling Secondary Prevention Siblings Signal Transduction Single Nucleotide Polymorphism Stroke Syndrome System Testing Thrombosis Validation Variant artery occlusion base cost cost effective design exome exome sequencing follow-up genetic pedigree genetic variant genome wide association study high risk in vitro Assay in vivo premature racial difference rare variant response segregation success trait

项目摘要

DESCRIPTION (provided by applicant): Aggregation of activated platelets on ruptured or eroded atherosclerotic plaques initiates thromboses of the arterial system, resulting in ischemic syndromes. The propensity of platelets to aggregate in vivo can be characterized by in vitro assays and used to identify individuals with hyper-aggregable platelets at risk then for myocardial infarction, stroke, and peripheral arterial occlusions. These platelet function assays are moderately to highly heritable supporting the hypothesis that genetic variations underlie individual variability in the tendency for arterial thrombosis. During the past seven years, in an ongoing NHLBI-funded study called GeneSTAR (Genetic Study of Aspirin Responsiveness), a genome-wide association study (GWAS) revealed multiple common genetic loci that pass stringent GWAS thresholds in African American and European Americans families at high risk for CHD. Common variants were found to determine variability in native platelet aggregation as well as residual platelet aggregation after low dose aspirin (ASA) intervention. However, collectively the loci identified through this common variant approach account for less than 35% the total heritability of these phenotypes in the GeneSTAR families. In this study we aim to extend our family-based GWAS design in an integrative approach to: 1) identify rare variants in genes that are associated with native and residual post- ASA platelet aggregation, testing the hypothesis that a significant fraction of the 'missing heritability' in platelet aggregation phenotypes (i.e. that not explained by the common GWAS signal) is due to these rare variants; and 2) follow up on the GWAS-identified loci to determine the underlying 'causal' variants tagged by the GWAS association signal. In a family-based exome sequencing approach we will sequence 200 hyper-aggregable individuals selected from African American and European American GeneSTAR families with clustering of platelet aggregation. This data will be leveraged against a public catalog of exome variation in the NHLBI-funded Exome Sequencing Project to identify genes enriched for rare variants associated with platelet hyper aggregation. Validated exome sequencing-identified genes along with the GWAS-identified loci will be followed up relying on a targeted deep resequencing approach of 1,300 African American and European American subjects from additional GeneSTAR families. The results from this integrative GWAS and exome approach will lead to a better understanding of the role of genetic variants (common and rare) in the determination of platelet aggregation native and residual post-ASA, including possible racial differences, and should enable genotypic tailoring of preventive therapy for CHD in high-risk individuals.

描述(申请人提供)：激活的血小板聚集在破裂或侵蚀的动脉粥样硬化斑块上，引发动脉系统血栓，导致缺血综合征。体内血小板聚集的倾向可以通过体外试验来表征，并用于识别具有高聚集血小板风险的个体，然后是心肌梗死、中风和外周动脉闭塞。这些血小板功能分析具有中等到高度的遗传性，支持这样一种假设，即遗传变异是动脉血栓形成倾向的个体差异的基础。在过去的七年里，在一项由NHLBI资助的名为GeneSTAR(阿司匹林响应性的遗传研究)的正在进行的研究中，全基因组关联研究(GWAS)发现，在患有冠心病的高危非裔美国人和欧洲裔美国人家庭中，有多个共同的基因座位超过了严格的GWAS阈值。低剂量阿司匹林(ASA)干预后，常见的变异体决定了天然血小板聚集的变异性和残余的血小板聚集。然而，通过这种共同的变异方法确定的基因座加在一起，在GeneSTAR家族中占这些表型总遗传力的不到35%。在这项研究中，我们的目标是以一种综合的方法扩展我们的基于家族的GWAS设计：1)确定与ASA后天然和残留的血小板聚集相关的基因中的罕见变异，测试假设，即血小板聚集表型中的很大一部分“缺失遗传性”(即，未被常见的GWAS信号解释的)是由于这些罕见变异；以及2)跟踪GWAS识别的基因座，以确定由GWAS关联信号标记的潜在的“因果”变异。在基于家族的外显子组测序方法中，我们将对从非洲裔美国人和欧洲裔美国人GeneSTAR家族中挑选出来的200个超聚集个体进行血小板聚集的测序。这些数据将被用来对照NHLBI资助的Exome测序项目中的外显子组变异的公共目录，以识别与血小板超聚集相关的稀有变异的丰富基因。对来自其他GeneSTAR家族的1300名非洲裔美国人和欧洲裔美国人受试者进行有针对性的深度重测序方法，将对经过验证的外显子组测序鉴定的基因以及GWAS鉴定的基因座进行后续追踪。这一综合GWAS和Exome方法的结果将有助于更好地理解遗传变异(常见的和罕见的)在确定本地和ASA术后残留的血小板聚集方面的作用，包括可能的种族差异，并应使高危个体的CHD预防治疗的基因剪裁成为可能。