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

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）是美国死亡率最高的疾病，约占死亡人数的五分之一。阿司匹林作为双联抗血小板治疗（DAPT）方案的一部分，可显著改善急性冠状动脉综合征和/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性事件的风险增加。这种个体间反应的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存在高度争议的原因。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，使用全基因组关联的方法，我们确定了一个共同的单核苷酸多态性（rs 12041331）在血小板内皮聚集受体1（PEAR 1）基因，大大有助于在DAPT血小板反应性的变化。此外，接受DAPT治疗的携带危险等位基因的PCI患者在1年随访时生存率降低2至4倍，接受阿司匹林治疗的稳定性冠状动脉患者心肌梗死发生率增加2倍。在没有阿司匹林给药的情况下，未观察到这些相关性。我们假设PEAR 1基因型影响阿司匹林的反应，是最佳阿司匹林剂量的决定因素。该项目旨在：1）评估阿司匹林剂量的影响（81、162或324 mg）对健康Amish个体中PEAR 1 rs 12041331基因型激动剂刺激的离体血小板聚集的影响（每个基因型组20个），和2）评估PEAR 1 rs 12041331基因型和阿司匹林剂量之间的相互作用（81与324 mg）对约1，400名PCI患者的1年生存率的影响，这些患者是作为PGRN资助的抗血小板干预药物基因组学2（PAPI-2）研究的一部分招募的。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。考虑到阿司匹林治疗对不良心血管事件的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PEAR 1 rs 12041331次要等位基因拷贝。了解服用抗血栓药物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结局至关重要。

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.