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: 9258474
• 负责人: Lewis C Becker
• 金额: $ 76.43万
• 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 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9258474
• 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; 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; Generations; Genes; Genetic; Genetic study; Genomics; Goals; Heritability; Individual; Intercistronic Region; Introns; Ischemia; 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; Risk; Role; Signal Transduction; Stroke; Structure; Thrombosis; Transcript; Translating; Variant; acute coronary syndrome; artery occlusion; base; caucasian American; design; differential expression; early onset; family structure; gene discovery; genome wide association study; genome-wide; insight; new therapeutic target; novel strategies; premature; proband; public health relevance; response; transcriptome; transcriptome sequencing

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形成性心血管疾病的发展中起主要作用。血小板过度聚集是心肌梗死、急性冠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者（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。这些家庭是高度丰富的血小板过度聚集和急性心血管事件的事件。尽管血小板聚集具有高度遗传性，但所有 所识别的GWAS信号一起仅解释其个体间方差的一小部分。此外，大多数已鉴定的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集反应相关。在 在本申请中，我们提出通过确定哪些基因在患有血小板过度聚集的受试者中表达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，我们将鉴定血小板转录组数量或质量的变化（例如，剪接变体）与特定血小板过度聚集表型相关的mRNA转录物。我们的目标是：（1）使用独特的基于家族的设计来发现与对照受试者相比在患有血小板过度聚集的白色和非洲裔美国人受试者中差异表达的基因，（2）利用我们先前的GWAS来鉴定与转录物表达相关的eQTL，以帮助优先考虑转录物/基因用于进一步研究， 和（3）使用定量质谱法来确定在过度聚集的血小板中基因表达的变化是否准确地反映在表达的蛋白质的相应变化中。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，以及负责欧洲人和非裔美国人血小板中特异性转录本表达的遗传位点的完整eQTL图谱。考虑到两组的LD模式不同，将两个种族包括在内将使我们能够复制mRNA发现并扩大生物学见解。这些结果将为介导最重要的基因组与血小板超聚集的功能途径提供新的见解，这些基因组与血小板超聚集在以前的GWAS研究中被确定。我们希望我们的研究将确定以前未知的蛋白质和生物学途径负责血小板过度聚集，这可能会成为新的治疗靶点，并最终成为更有效和特异性的方法，用于抑制大量血栓形成风险人群的血小板功能。 血管闭塞用抗血小板治疗。