Aspirin Pharmacogenomics: Role of PEAR1 in Personalized Anti-Platelet Therapy

阿司匹林药物基因组学：PEAR1 在个性化抗血小板治疗中的作用

• 批准号: 8539634
• 负责人: JOSHUA PATRICK LEWIS
• 金额: $ 16.12万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-05 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8539634
• 关键词: Accounting; Agonist; Alleles; Amish; Antiplatelet Drugs; Aspirin; Blood Platelets; Candidate Disease Gene; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Clinic; Clinical; Clinical Research; Clinical Trials; Confounding Factors (Epidemiology); Coronary artery; Coronary heart disease; Coupled; DNA; Development Plans; Dose; Equilibrium; Event; Funding; Future; Genes; Genetic; Genotype; Goals; Health; Heritability; Individual; Intervention; Knowledge; Life Style; Maryland; Measures; Medicine; Mentors; Minor; Myocardial Infarction; Outcome; Participant; Patients; Pharmaceutical Preparations; Pharmacogenomics; Pharmacotherapy; Physicians; Platelet aggregation; Primary Prevention; Randomized; Receptor Aggregation; Recruitment Activity; Regimen; Research; Research Personnel; Residual state; Resistance; Risk; Role; Secondary Prevention; Single Nucleotide Polymorphism; Structure; Translating; Translational Research; United States; Universities; Variant; acute coronary syndrome; base; biobank; career development; clinical application; clopidogrel; design; experience; follow-up; genome wide association study; human CYP2C19 protein; improved; mortality; patient oriented; patient oriented research; percutaneous coronary intervention; prevent; programs; prospective; randomized trial; research study; response; standard of care; trait

DESCRIPTION (provided by applicant): The purpose of this K23 application is to promote my career development in patient-oriented translational research and to facilitate successful transition into an independent investigator in the field of cardiovascular disease pharmacogenomics. Coronary heart disease (CHD) is the leading of mortality in the United States accounting for approximately 1 in 5 deaths. Aspirin as part of a dual antiplatelet therapy (DAPT) regimen significantly improves cardiovascular outcomes in patients with acute coronary syndrome and/or undergoing percutaneous coronary intervention (PCI). However, there is great interindividual variation in platelet response to aspirin, and patients with higher on-treatment platelet reactivity have increased risk of experiencing an ischemic event. This interindividual variation in response is the likely reason why the optimal dose of aspirin when used alone or in combination with other antiplatelet agents is highly controversial. While heritability estimates suggest that genetic factors are an important determinant of aspirin response, candidate gene approaches have failed to identify variants that are reproducibly associated with aspirin response. Recently, using a genome-wide association approach, we identified a common single nucleotide polymorphism (rs12041331) in the platelet endothelial aggregation receptor 1 (PEAR1) gene that contributes substantially to variability in platelet reactivity during DAPT. Furthermore, DAPT-treated PCI patients carrying the risk allele had a 2 to 4-fold decrease in survival at 1 year of follow-up, and aspirin-treated stable coronary artery patients had a 2-fold increase in the rate of myocardial infarction. These associations were not observed in the absence of aspirin administration. We hypothesize that PEAR1 genotype influences aspirin response and is a determinant of optimal aspirin dose. This project aims to: 1) assess the effect of aspirin dosing (81, 162, or 324 mg) on agonist-stimulated ex-vivo platelet aggregation by PEAR1 rs12041331 genotype in healthy Amish individuals (20 per genotype group), and 2) evaluate the interaction between PEAR1 rs12041331 genotype and aspirin dose (81 vs. 324 mg) on 1-year survival in approximately 1,400 PCI patients recruited as part of the PGRN-funded Pharmacogenomics of Anti-Platelet Intervention 2 (PAPI-2) Study. These studies will contribute to our knowledge regarding the genetic underpinnings and mechanisms underlying aspirin resistance as well as optimal aspirin dosing. Given the impact of aspirin therapy on primary and secondary prevention of adverse cardiovascular events, this study has important health implications since 20 - 60% of individuals carry at least 1 copy of the PEAR1 rs12041331 minor allele. Understanding drug response variability in patients taking anti- thrombotics is critical for optimizing cardiovascular pharmacotherapy and ultimately patient outcomes.

描述（由申请人提供）：本 K23 申请的目的是促进我在以患者为导向的转化研究方面的职业发展，并促进我成功转型为心血管疾病药物基因组学领域的独立研究者。冠心病 (CHD) 是美国死亡率最高的疾病，约占死亡人数的五分之一。阿司匹林作为双重抗血小板治疗 (DAPT) 方案的一部分，可显着改善急性冠脉综合征和/或接受经皮冠状动脉介入治疗 (PCI) 患者的心血管结局。然而，血小板对阿司匹林的反应存在很大的个体差异，治疗中血小板反应性较高的患者发生缺血事件的风险增加。这种个体间的反应差异可能是阿司匹林单独使用或与其他抗血小板药物联合使用时的最佳剂量备受争议的原因。虽然遗传力估计表明遗传因素是阿司匹林反应的重要决定因素，但候选基因方法未能识别与阿司匹林反应可重复相关的变异。最近，利用全基因组关联方法，我们在血小板内皮聚集受体 1 (PEAR1) 基因中发现了一个常见的单核苷酸多态性 (rs12041331)，该基因对 DAPT 期间血小板反应性的变异有很大影响。此外，携带风险等位基因的接受DAPT治疗的PCI患者在1年的随访中生存率下降了2至4倍，而接受阿司匹林治疗的稳定性冠状动脉患者的心肌梗塞发生率增加了2倍。在不服用阿司匹林的情况下没有观察到这些关联。我们假设 PEAR1 基因型影响阿司匹林反应，并且是最佳阿司匹林剂量的决定因素。该项目旨在：1) 评估阿司匹林剂量（81、162 或 324 毫克）对健康阿米什人（每个基因型组 20 人）中 PEAR1 rs12041331 基因型激动剂刺激的离体血小板聚集的影响，2) 评估PEAR1 rs12041331 基因型与阿司匹林剂量之间的相互作用（81 vs. 324） mg）对大约 1,400 名 PCI 患者的 1 年生存率进行了研究，这些患者是 PGRN 资助的抗血小板干预药物基因组学 2 (PAPI-2) 研究的一部分。这些研究将有助于我们了解阿司匹林抵抗的遗传基础和机制以及最佳阿司匹林剂量。鉴于阿司匹林治疗对不良心血管事件一级和二级预防的影响，这项研究具有重要的健康意义，因为 20-60% 的个体携带至少 1 个 PEAR1 rs12041331 次要等位基因拷贝。了解服用抗血栓药物的患者的药物反应变异性对于优化心血管药物治疗和最终患者的治疗结果至关重要。