Identifying genes regulating platelet reactivity

描述（由申请人提供）：冠状动脉、脑动脉和外周动脉的血小板血栓是全球发病率和死亡率最常见的原因。这些疾病的有害临床结果有一个公认的遗传成分，但只有少数血小板基因变异与这些疾病有关。该应用程序的目的是确定负责血小板反应性的基因和遗传变异。我们的初步数据表明，血小板反应性具有遗传性和可重复性。我们发现人血小板聚集对亚极大肾上腺素刺激的反应是由双峰分布表示的，具有显著不同和不重叠的反应。我们选择了一些不相关的欧裔美国人和非裔美国人，他们的血小板表现出极端的血小板反应性。全基因组关联研究是鉴定这种复杂生理系统的限速蛋白（基因）的有力方法。在目标1中，我们将使用Illumina HumanHap550头芯片对具有高反应性和低反应性血小板的受试者的整个基因组中的bbbb55万个标签snp进行基因分型。在进行质量控制后，对基因型和单倍型数据进行分析。假发现率将用于选择一组假阳性率小于0.5的snp。为了增强我们的候选基因列表，以包括新基因和基因组扫描平台中未充分代表的基因，在Aim 2中，我们将使用来自具有极端血小板反应性的欧美和非裔美国人子集的血小板mRNA进行微阵列表达分析。在Aim 3中，在Aim 1中鉴定的位点和来自Aim 2的基因将被定位，以获得具有致病遗传变异的强LD的snp。在Aim 4中，我们将使用Aim 3中确定的snp目标数量（~300-350）对约翰霍普金斯大学GeneSTAR队列的所有受试者进行复制研究。这些研究的成功完成将通过发现负责血小板功能的新基因，对血小板生理学和关键信号通路产生新的见解。在这些基因中发现的变异有望成为改变血栓形成、出血和潜在的抗血小板药物作用的因素。我们使用数量特征极值的新方法可能对其他研究具有经济价值。

DESCRIPTION (provided by applicant): Platelet thrombi in coronary, cerebral and peripheral arteries are the most common cause of global morbidity and mortality. There is a well-established genetic component to the deleterious clinical outcomes of these disorders, but only a small number of platelet gene variations have been associated with these disorders. The goals of this application are to identify the genes and genetic variations responsible for platelet reactivity. Our preliminary data demonstrates that platelet reactivity is both heritable and reproducible. We find that the human platelet aggregation response to submaximal epinephrine stimulation is represented by a bimodal distribution with dramatically different and non-overlapping responses. We have selected groups of unrelated European American and African American subjects whose platelets demonstrate the extremes of platelet responsiveness. Genome wide association studies are powerful approaches for identifying rate- limiting proteins (genes) for this complex physiologic system. In Aim 1 we will genotype >550,000 tagSNPs throughout the genome of our subjects with hyper- and hyporeactive platelets using the Illumina HumanHap550 BeadChip. After performing quality control, analyses will be carried out on genotype and haplotype data. The False Discovery Rate will be used to select a group of SNPs with a false positive rate less than 0.5. To enhance our list of candidates to include novel genes and genes not well-represented in the genome scan platform, in Aim 2 we will perform microarray expression analyses with mRNA from platelets from a subset of European-Americans and African-Americans with extremes of platelet reactivity. In Aim 3 the loci identified in Aim 1 and the genes from Aim 2 will be mapped to obtain SNPs in stronger LD with the causative genetic variant. In Aim 4 we will use the targeted number of SNPs identified in Aim 3 (~300-350) to perform a replication study on all subjects in the Johns Hopkins University GeneSTAR cohort. The successful completion of these studies will result in new insights into platelet physiology and crucial signaling pathways via the discovery of novel genes responsible for platelet function. The variants identified in these genes are expected to be factors modifying thrombosis, hemorrhage and potentially the effects of anti-platelet agents. Our novel approach of using the extremes of a quantitative trait may prove economically valuable for other studies.