Pharmacogenomics of Anti-platelet Response

抗血小板反应的药物基因组学

• 批准号: 8306789
• 负责人: Rehan Qayyum
• 金额: $ 13.97万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8306789
• 关键词: ADP Receptors; Acute myocardial infarction; Address; Affect; African American; Agonist; Alleles; American; Angiography; Arachidonic Acids; Arterial Fatty Streak; Aspirin; Binding Sites; Biology; Blood Platelets; Blood Vessels; Brain; Candidate Disease Gene; Cardiovascular system; Cephalic; Cerebrovascular Disorders; Chemoprophylaxis; Clinical; Clinical Trials; Clinical Trials Design; Collagen; Coronary; Coronary Arteriosclerosis; Coronary heart disease; Disease; Dose; Epinephrine; European; Event; Failure; Family; Framingham Heart Study; Future; Gene-Modified; Genes; Genetic; Genetic Polymorphism; Genotype; Goals; Guanine; Heart; Heritability; Individual; Introns; Knowledge; Magnetic Resonance Imaging; Measures; Mediating; Mentors; Myocardial Infarction; Natural History; Outcome; Pathway interactions; Persons; Pharmaceutical Preparations; Pharmacogenomics; Phenotype; Platelet Activation; Platelet aggregation; Play; Population; Prevention; Preventive; Primary Prevention; Prostaglandins I; Proteins; Public Health; Recording of previous events; Recurrence; Regimen; Regulation; Research; Research Personnel; Residual state; Risk; Risk Factors; Role; Sampling; Science; Signal Transduction; Stratification; Stroke; Structure; Target Populations; Thrombosis; Thromboxanes; Translating; Variant; Vascular Diseases; Woman; Work; bZIP Domain; base; career; career development; clopidogrel; cyclooxygenase 1; design; early onset; genome wide association study; high risk; men; mortality; novel; patient oriented research; premature; proband; programs; protein expression; public health relevance; receptor; response; virtual

DESCRIPTION (provided by applicant): This K23 application is designed to develop my career in patient-oriented research through a structured mentored program enabling a transition from my purely clinical role to one as a fully independent research investigator working in the pharmacogenomics of antithrombotic regimens. Platelets play a key role in the natural history of clinical atherothrombotic events and anti-platelet agents are highly effective in the prevention of coronary and stroke events. Aspirin (ASA) is still a mainstay of primary prevention in high risk persons. Failure of ASA to protect all individuals at risk has been attributed in part to suboptimal platelet suppression. The addition of another drug that inhibits platelets through a different pathway might benefit persons selected on the basis of a high risk phenotype. In European Americans, we have recently discovered a common A/G variant at rs12041331 locus in the intron1 of the PEAR1 gene that is associated with native and post-ASA platelet aggregation and increased PEAR1 protein levels in platelets. This finding has been replicated in an independent sample of African Americans and in the Framingham Heart Study. I have also completed a first-pass genome-wide association study (GWAS) for collagen-related platelet phenotypes pre and post-ASA, with a significant signal (p<10-11) on Chr 19, a region with genes possibly involved in platelet function. The studies I propose extend the science of these findings and will examine the role of PEAR1 variant on platelet responsiveness. My proposed studies include continued efforts to discover novel genes, using GWAS, in specific platelet activation pathways before and after low dose ASA. Discovery of novel genes may promote platelet pharmacogenomics research focusing on specific platelet pathways in at-risk primary prevention populations. Further in my proposed studies, I will create a new framework for translating findings into risk-stratification for primary prevention. Specifically, the proposed project aims to determine the extent to which a variant identified in the PEAR1 gene modifies the responsiveness of platelets to inhibition by clopidogrel alone and in combination with ASA in a high risk subset of GeneSTAR subjects (N=200) having both significant occult CAD identified by coronary CT angiography, and small vessel cerebrovascular disease identified by cranial MRI. This study has important public health implications given the notable potential impact of effective anti-platelet therapy on coronary disease and stroke outcomes in high risk persons. Identifying a high-risk population on the basis of phenotype and genotype may demonstrate persons in whom chemoprophylaxis can be tailored. PUBLIC HEALTH RELEVANCE: This application is aimed at promoting career development of the applicant by proposing a didactic program, analysis of a genome-wide scan of platelet function before and after aspirin, and a clinical trial examining the role of genetic polymorphism on the effect of clopidogrel (with or without aspirin) on platelet response in persons at very high-risk for myocardial infarction or stroke. The proposed study has the potential of helping clinicians in choosing appropriate anti-platelet treatment based on the knowledge of genetic background.

描述（由申请人提供）：此 K23 申请旨在通过结构化指导计划发展我在以患者为导向的研究方面的职业生涯，使我能够从纯粹的临床角色转变为一名完全独立的研究调查员，从事抗血栓治疗方案的药物基因组学工作。血小板在临床动脉粥样硬化血栓事件的自然病程中发挥着关键作用，抗血小板药物在预防冠状动脉和中风事件方面非常有效。阿司匹林（ASA）仍然是高危人群一级预防的支柱。 ASA 未能保护所有处于危险中的个体，部分原因是血小板抑制效果不佳。添加另一种通过不同途径抑制血小板的药物可能会使根据高风险表型选择的人受益。在欧洲裔美国人中，我们最近在 PEAR1 基因内含子 1 的 rs12041331 位点发现了一个常见的 A/G 变异，该变异与天然和 ASA 后血小板聚集以及血小板中 PEAR1 蛋白水平增加有关。这一发现已在非裔美国人的独立样本和弗雷明汉心脏研究中得到重复。我还完成了 ASA 前后胶原相关血小板表型的首次全基因组关联研究 (GWAS)，在 Chr 19 上有显着信号 (p<10-11)，该区域的基因可能参与血小板功能。我提议的研究扩展了这些发现的科学性，并将研究 PEAR1 变异对血小板反应性的作用。我提出的研究包括继续努力使用 GWAS 在低剂量 ASA 前后的特定血小板激活途径中发现新基因。新基因的发现可能会促进血小板药物基因组学研究，重点关注高危一级预防人群中特定的血小板途径。在我提议的研究中，我将创建一个新的框架，将研究结果转化为一级预防的风险分层。具体来说，拟议的项目旨在确定 PEAR1 基因中发现的变体在多大程度上改变血小板对单独使用氯吡格雷和与 ASA 联合使用氯吡格雷抑制的反应程度，在 GeneSTAR 受试者的高风险子集中 (N = 200) 具有显着的显着性和显着性。通过冠状动脉CT血管造影发现隐匿性CAD，通过头颅MRI发现小血管脑血管疾病。鉴于有效的抗血小板治疗对高危人群的冠心病和中风结局具有显着的潜在影响，这项研究具有重要的公共卫生意义。根据表型和基因型识别高危人群可能会表明可以针对哪些人进行化学预防。 公共健康相关性：本申请旨在通过提出教学计划、阿司匹林服用前后血小板功能的全基因组扫描分析以及检查遗传多态性对阿司匹林影响的临床试验来促进申请人的职业发展。氯吡格雷（联合或不联合阿司匹林）对心肌梗死或中风高危人群血小板反应的影响。拟议的研究有可能帮助临床医生根据遗传背景知识选择适当的抗血小板治疗。