Gene Transcripts and Proteomics in Families with Platelet Hyperaggregation

血小板过度聚集家族的基因转录和蛋白质组学

• 批准号: 8696113
• 负责人: Lewis C Becker
• 金额: $ 79.09万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8696113
• 关键词: Acute; Adenosine Diphosphate; African American; Agonist; American; Arterial Fatty Streak; Atherosclerosis; Biological; Biology; Blood; Blood Platelets; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Chromosome Mapping; Coagulation Process; Collagen; Coronary heart disease; Development; Epinephrine; Equipment and supply inventories; Ethnic Origin; European; Event; Family; Family Study; Family history of; Family member; Future; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic; Genomics; Goals; Individual; Intercistronic Region; Introns; Ischemia; Lead; Maps; Mass Spectrum Analysis; Mediating; Membrane; Messenger RNA; Methods; Myocardial Infarction; Participant; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenotype; Platelet aggregation; Play; Population; Process; Protein Isoforms; Proteins; Proteomics; RNA Splicing; Relative (related person); Risk; Role; Signal Transduction; Staging; Stroke; Structure; Thrombosis; Transcript; Translating; Variant; acute coronary syndrome; artery occlusion; base; caucasian American; design; early onset; family structure; gene discovery; genome wide association study; genome-wide; insight; new therapeutic target; novel strategies; premature; proband; public health relevance; response

DESCRIPTION (provided by applicant): Platelets play a major role in the development of atherothrombotic cardiovascular diseases. Platelet hyperaggregation is an important intermediate phenotype for myocardial infarction, acute coronary syndromes, and strokes. We have discovered and replicated GWAS signals for platelet aggregation in two-generational families of premature coronary disease probands (GeneSTAR), 334 European Americans and 232 African Americans. These families are highly enriched with both platelet hyper-aggregation and incident acute cardiovascular events. Although platelet aggregation is highly heritable, all of the identified GWAS signals together explain only a small fraction of its variance among individuals. In addition, most of the identified GWAS signals are located in introns and intergenic regions, so it is not clear how the variant is functionally related to the aggregation response. In this application we propose to discover new pathways regulating platelet aggregation by determining which genes are expressed in subjects with platelet hyperaggregation. By sequencing the entire platelet transcriptome we will identify changes in the amount or quality (e.g., splice variants) of mRNA transcripts that are associated with specific platelet hyperaggregation phenotypes. Our aims are to: (1) use a unique family-based design to discover the genes that are differentially expressed in white and African American subjects with platelet hyperaggregation compared to control subjects, (2) leverage our prior GWAS to identify eQTLs associated with transcript expression to help prioritize transcripts/genes for further study, and (3) use quantitative mass spectrometry to determine whether changes in gene expression in hyperaggregating platelets are accurately reflected in corresponding changes in expressed proteins. This study will produce a complete quantitative inventory of all mRNA transcripts present in platelets, as well as a complete eQTL map of genetic loci responsible for transcript expression specifically in platelets in both European and African Americans. The inclusion of both ethnicities will allow us to both replicate mRNA findings and amplify biological insights, given the different LD patterns of the two groups. The results will provide new insights into the functional pathways mediating the most important genomic associations with platelet hyperaggregation identified in previous GWAS studies. We expect that our studies will identify previously unknown proteins and biological pathways responsible for platelet hyperaggregation, which may then serve as new therapeutic targets and ultimately more effective and specific approaches for inhibition of platelet function in the large number of people at risk for thrombotic vascular occlusions being treated with anti-platelet therapy.

描述（由申请人提供）：血小板在动脉粥样硬化血栓性心血管疾病的发展中发挥着重要作用。血小板过度聚集是心肌梗塞、急性冠状动脉综合征和中风的重要中间表型。我们在两代早产冠心病先证者家族 (GeneSTAR)、334 名欧洲裔美国人和 232 名非洲裔美国人中发现并复制了血小板聚集的 GWAS 信号。这些家族富含血小板过度聚集和急性心血管事件。尽管血小板聚集具有高度遗传性，但所有 所识别的 GWAS 信号加起来只能解释个体间差异的一小部分。此外，大多数已识别的 GWAS 信号位于内含子和基因间 区域，因此尚不清楚该变体在功能上如何与聚合响应相关。在 在本申请中，我们建议通过确定血小板过度聚集受试者中表达的基因来发现调节血小板聚集的新途径。通过对整个血小板转录组进行测序，我们将识别与特定血小板过度聚集表型相关的 mRNA 转录物的数量或质量（例如剪接变体）的变化。我们的目标是：(1) 使用独特的基于家族的设计来发现血小板过度聚集的白人和非裔美国受试者与对照受试者相比差异表达的基因，(2) 利用我们之前的 GWAS 来识别与转录本相关的 eQTL表达以帮助优先考虑转录本/基因以供进一步研究， (3)使用定量质谱法确定高聚集血小板中基因表达的变化是否准确地反映在表达蛋白的相应变化中。这项研究将产生血小板中存在的所有 mRNA 转录本的完整定量清单，以及负责欧洲和非裔美国人血小板中转录本表达的完整基因位点 eQTL 图谱。考虑到两个群体不同的 LD 模式，纳入两个种族将使我们能够复制 mRNA 研究结果并放大生物学见解。这些结果将为介导先前 GWAS 研究中发现的血小板过度聚集最重要的基因组关联的功能途径提供新的见解。我们期望我们的研究将确定以前未知的导致血小板过度聚集的蛋白质和生物途径，然后它们可能作为新的治疗靶点，并最终为大量有血栓风险的人抑制血小板功能提供更有效和具体的方法。 血管闭塞正在接受抗血小板治疗。