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性血栓性心血管疾病的发展中起重要作用。血小板高聚集是心肌梗死、急性冠状动脉综合征和中风的重要中间表型。我们在两代早发冠心病先证家族（GeneSTAR）中发现并复制了血小板聚集的GWAS信号，包括334名欧洲裔美国人和232名非洲裔美国人。这些家族高度富集血小板超聚集和突发急性心血管事件。虽然血小板聚集是高度遗传的，所有的