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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：
8532032
负责人：
Rasika Ann Mathias
金额：
$ 64.28万
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 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8532032
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 Genotype Heart Heritability 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 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（由申请人提供）：活化血小板在破裂或侵蚀的动脉粥样硬化斑块上聚集，引发动脉系统血栓形成，导致缺血综合征。血小板在体内聚集的倾向可以通过体外测定来表征，并用于鉴定具有高聚集性血小板的个体，然后用于心肌梗死、中风和外周动脉闭塞的风险。这些血小板功能测定具有中度至高度遗传性，支持遗传变异是动脉血栓形成倾向个体差异的基础这一假设。在过去的七年中，在一项正在进行的NHLBI资助的名为GeneSTAR（阿司匹林反应性遗传研究）的研究中，全基因组关联研究（GWAS）揭示了多个常见的遗传位点，这些基因位点在非洲裔美国人和欧洲裔美国人CHD高风险家庭中通过了严格的GWAS阈值。发现常见的变异体可确定天然血小板聚集的变异性以及低剂量阿司匹林（阿萨）干预后的残留血小板聚集。然而，通过这种常见变异方法鉴定的基因座占GeneSTAR家族中这些表型总遗传力的不到35%。在这项研究中，我们的目标是以综合方法扩展我们基于家族的GWAS设计，以：1）鉴定与天然和残留阿萨后血小板聚集相关的基因中的罕见变异，检验血小板聚集表型中“缺失遗传性”的重要部分的假设。（即，不能由共同GWAS信号解释的）是由于这些罕见变体;和2）跟踪GWAS鉴定的基因座以确定由GWAS关联信号标记的潜在“因果”变体。在基于家族的外显子组测序方法中，我们将对选自具有血小板聚集聚集的非洲裔美国人和欧洲裔美国人GeneSTAR家族的200个高聚集性个体进行测序。这些数据将在NHLBI资助的外显子组测序项目中针对外显子组变异的公共目录进行利用，以识别富含与血小板过度聚集相关的罕见变异的基因。将根据来自其他GeneSTAR家族的1,300名非洲裔美国人和欧洲裔美国人受试者的靶向深度重测序方法，对经验证的外显子组测序鉴定的基因沿着GWAS鉴定的基因座进行随访。这种综合GWAS和外显子组方法的结果将导致更好地理解遗传变异（常见和罕见）在确定ASA后血小板聚集天然和残留中的作用，包括可能的种族差异，并应使高危个体CHD预防性治疗的基因型定制成为可能。