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: 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
• 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

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）：在破裂或侵蚀的动脉粥样硬化斑块上激活血小板的聚集会引发动脉系统的血栓形成，从而导致缺血性综合征。血小板在体内聚集的倾向可以以体外测定为特征，并用于鉴定具有高度诱发血小板的个体，然后在心肌梗塞，中风和外周动脉闭塞中。这些血小板功能测定在高度可遗传的情况下支持以下假设：遗传变异是动脉血栓形成趋势的个体变异性的基础。在过去的七年中，在正在进行的NHLBI资助的研究中，名为Genestar（阿司匹林反应性的遗传研究），一项全基因组关联研究（GWAS）揭示了多个常见的遗传基因座，这些基因座通过非裔美国人和欧洲美国人家庭中严格的GWAS阈值。发现常见变体确定低剂量阿司匹林（ASA）干预后天然血小板聚集的变异性以及残留的血小板聚集。但是，通过这种通用变体方法确定的基因座占基因型在基因斯塔家族中这些表型的总遗传力的35％。在这项研究中，我们旨在以一种综合方法扩展我们的基于家庭的GWAS设计：1）确定基因中的稀有变体，这些变体与天然和残留的ASA血小板聚集有关，检验了以下假设：“缺失的遗传力”的大部分是“缺失的遗传力”中的血小板聚集表型（即常见的GWAS信号未解释）是这些罕见的差异。 2）在GWAS识别的基因座上进行跟进，以确定GWAS关联信号标记的基本“因果”变体。在一种基于家庭的外显子组测序方法中，我们将对200个从非洲裔美国和欧美基因斯塔群体中选出的5个高凝集的个体，并通过血小板聚集聚集。该数据将用于NHLBI资助的外显子组测序项目中外显子差异的公共目录，以识别富含与血小板超聚集相关的稀有变体的基因。经过验证的外显子测序识别基因以及GWAS识别的基因座将依靠来自其他Genestar家族的1,300名非裔美国人和欧美受试者的目标深度重新取代方法的跟进。这种综合GWAS和外来方法的结果将使人们更好地理解遗传变异（常见和罕见）在确定血小板聚集本机和残留后ASA（包括可能的种族差异）中的作用，并应实现高风险个体中毒品志的基因型型量身定制。