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: 8354496
• 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/8354496
• 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; 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. PUBLIC HEALTH RELEVANCE: Aspirin as part of a dual antiplatelet therapy regimen is the standard of care for preventing adverse cardiovascular outcomes in patients with acute coronary syndrome and/or undergoing percutaneous coronary intervention. Given the wide variability of platelet function and clinical outcomes in response to aspirin therapy, it is importnt to identify the factors that cause dose-response variability and to optimize antiplatelet treatment based on knowledge of these factors. The proposed study will help guide physicians in choosing the most appropriate antiplatelet therapy in the context of PEAR1 genotype, a newly discovered and potentially important genetic contributor to aspirin resistance.

描述（由申请人提供）：该K23申请的目的是促进我在面向患者的转化研究中的职业发展，并促进成功过渡到心血管疾病药物基因组学领域的独立研究者。冠心病（CHD）是美国死亡率的领先，约有5人死亡。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状动脉综合征和/或接受经皮冠状动脉介入干预（PCI）患者的心血管结局。然而，血小板对阿司匹林的血小板反应有很大的差异，并且在治疗血小板反应性较高的患者中会增加患缺血性事件的风险。这种个体的反应变化是阿司匹林在单独使用或与其他抗血小板剂结合使用时的最佳剂量的可能原因。尽管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鉴定出与阿司匹林反应可重复相关的变体。最近，使用全基因组缔合方法，我们确定了血小板内皮构构受体1（PEAR1）基因中常见的单核苷酸多态性（rs12041331），该基因在DAPT期间对血小板反应性的可变性有很大贡献。此外，携带风险等位基因的DAPT治疗的PCI患者在随访1年后的生存率下降了2至4倍，阿司匹林治疗的稳定冠状动脉患者的心肌梗死率增加了2倍。在没有阿司匹林给药的情况下，未观察到这些关联。我们假设PEAR1基因型会影响阿司匹林反应，并且是最佳阿司匹林剂量的决定因素。该项目的目的是：1）评估阿司匹林剂量（81、162或324 mg）对pear1 rs12041331 rs12041331基因型在健康阿米什人个体中通过PEAR 1 rs12041331和2）评估Pear1 rs1 rs1204131基因的相互作用（每个基因型20）在健康阿米什人（20个基因型组）中对激动剂刺激的Ex-Vivo血小板聚集的影响。作为PGRN资助的抗血域干预2（PAPI-2）研究的一部分，大约1,400名PCI患者的生存率（PAPI-2）。这些研究将有助于我们关于阿司匹林耐药性以及最佳阿司匹林剂量的遗传基础和机制的知识。鉴于阿司匹林治疗对初级和继发性心血管事件的影响，这项研究具有重要的健康影响，因为20-60％的个体携带了至少1份Pear1 rs12041331次要的小等位基因。了解服用抗血栓形成的患者的药物反应变异性对于优化心血管药物疗法和最终患者预后至关重要。 公共卫生相关性：阿司匹林作为双重抗血小板治疗方案的一部分是预防急性冠状动脉综合征和/或接受经皮冠状动脉干预患者的心血管不良结局的护理标准。考虑到血小板功能和临床结果的广泛差异，响应阿司匹林疗法，进口不确定引起剂量反应变异性并优化抗血小板治疗的因素 基于对这些因素的知识。拟议的研究将帮助医生在Pear1基因型的背景下选择最合适的抗血小板治疗，这是新发现的，对阿司匹林耐药性的新发现且潜在的重要遗传贡献。