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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

基本信息

批准号：
9128660
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
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-05 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9128660
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 Cytochrome P450 DNA Development Plans Dose Equilibrium Event Funding Future Genes Genetic Genotype Goals Health Heritability Individual Intervention Knowledge Life Style Maryland Measures Mentors Minor Myocardial Infarction Outcome Participant Patient-Focused Outcomes 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 improved inter-individual variation mortality patient oriented patient oriented research percutaneous coronary intervention personalized medicine prevent programs prospective randomized trial research study response risk variant standard of care trait

项目摘要

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.

描述(申请人提供)：本次K23申请的目的是促进我在面向患者的翻译研究方面的职业发展，并促进我成功过渡到心血管疾病药物基因组学领域的独立研究人员。在美国，冠心病(CHD)是死亡率的第一位，约占死亡人数的五分之一。阿司匹林作为双重抗血小板疗法(DAPT)的一部分，显著改善了急性冠脉综合征患者和/或接受经皮冠状动脉介入治疗(PCI)的患者的心血管预后。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经历缺血事件的风险增加。这种个体间反应的差异可能是为什么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极具争议的原因。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重复相关的变异。最近，利用全基因组关联方法，我们发现了血小板内皮细胞聚集受体1(PEAR1)基因中常见的单核苷酸多态(Rs12041331)，该多态对DAPT过程中血小板反应性的可变性有很大影响。此外，携带危险等位基因的接受DAPT治疗的经皮冠状动脉介入治疗患者在1年的随访中存活率降低了2-4倍，而接受阿司匹林治疗的稳定冠状动脉患者的心肌梗死发生率增加了2倍。在没有服用阿司匹林的情况下，没有观察到这些关联。我们假设PEAR1基因型会影响阿司匹林的反应，是最佳阿司匹林剂量的决定因素。本项目旨在：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)PEAR1 rs12041331基因激动剂刺激的体外血小板聚集的影响，以及2)评估PEAR1 rs12041331基因和阿司匹林剂量(81毫克对324毫克)对作为PGRN资助的抗血小板干预药物组学2(PAPI-2)研究一部分招募的大约1,400名经皮冠状动脉介入治疗患者一年存活率的影响。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心血管不良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%的人至少携带一份PEAR1 rs12041331次要等位基因。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结果至关重要。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Tobacco Smoke Exposure Reduces Paraoxonase Activity in a Murine Model

DOI：
10.59566/ijbs.2017.13020
发表时间：
2017-03
期刊：
International Journal of Biomedical Science : IJBS
影响因子：
0
作者：
R. Reed;Saif M. Borgan;M. Eberlein;Monica Goldklang;Joshua Lewis;Michael Miller;M. Navab;B. Kim
通讯作者：
R. Reed;Saif M. Borgan;M. Eberlein;Monica Goldklang;Joshua Lewis;Michael Miller;M. Navab;B. Kim

Influence of the paraoxonase-1 Q192R genetic variant on clopidogrel responsiveness and recurrent cardiovascular events: a systematic review and meta-analysis.

二氧释酶-1 Q192R遗传变异对氯吡格雷反应性和复发性心血管事件的影响：系统评价和荟萃分析。