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

• 批准号: 8845599
• 负责人: Rasika Ann Mathias
• 金额: $ 65.66万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 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/8845599
• 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

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）：破裂或侵蚀的动脉粥样硬化斑块上活化的血小板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，并用于识别具有心肌梗塞、中风和外周动脉闭塞风险的血小板过度聚集的个体。这些血小板功能测定具有中度至高度遗传性，支持这样的假设：遗传变异是动脉血栓形成倾向的个体差异的基础。在过去的七年中，NHLBI 资助的一项名为 GeneSTAR（阿司匹林反应性基因研究）的持续研究中，一项全基因组关联研究 (GWAS) 揭示了非洲裔美国人和欧洲裔美国人家庭中多个通过严格 GWAS 阈值的常见基因位点。冠心病的高风险。发现常见变异可决定天然血小板聚集的变异性以及低剂量阿司匹林 (ASA) 干预后残留的血小板聚集。然而，通过这种常见变异方法鉴定的基因座总共占 GeneSTAR 家族中这些表型总遗传力的不到 35%。在这项研究中，我们的目标是通过综合方法扩展我们基于家族的 GWAS 设计，以：1）识别与天然和残余 ASA 后血小板聚集相关的基因中的罕见变异，检验以下假设：“缺失的很大一部分”血小板聚集表型中的“遗传性”（即不能用常见的 GWAS 信号解释）是由于这些罕见的变异； 2) 跟踪 GWAS 识别的基因座，以确定由 GWAS 关联信号标记的潜在“因果”变异。在基于家族的外显子组测序方法中，我们将对选自非洲裔美国人和欧洲裔美国人 GeneSTAR 家族中具有血小板聚集聚集的 200 个高度聚集个体进行测序。这些数据将用于 NHLBI 资助的外显子组测序项目中的外显子组变异公共目录，以识别富含与血小板过度聚集相关的罕见变异的基因。将依靠对来自其他 GeneSTAR 家族的 1,300 名非裔美国人和欧洲裔美国人受试者的有针对性的深度重测序方法，对经过验证的外显子组测序识别的基因以及 GWAS 识别的基因座进行跟踪。这种综合 GWAS 和外显子组方法的结果将有助于更好地了解遗传变异（常见和罕见）在确定 ASA 后血小板聚集天然和残留的作用，包括可能的种族差异，并且应该能够进行基因型定制高危人群冠心病的预防性治疗。