Adopting a Precision Medicine Paradigm in Puerto Rico: leveraging ancestral diversity to identify predictors of clopidogrel response in Caribbean Hispanics

项目总结 尽管过去十年在心血管药物基因组学方面发表了大量工作，但 在理解加勒比海拉美裔美国人的基因组多样性是否会导致 预防性双重抗血小板治疗(DAPT)的临床结果的个体间高度变异性 氯吡格雷。加勒比海拉美裔美国人受心脏代谢紊乱的影响不成比例，但 从现有的基于基因组的算法中获益的期望有限。我们将重点开发氯吡格雷 为这一人群提供急需的基因组驱动的处方指南。为此，我们建议 在加勒比海拉美裔美国人中进行有史以来第一次具有药效遗传作用的处方药的GWA。 我们的建议还将采用一种新的方法来确定评估混合材成分，并高度 对于临床决策支持(CDS)工具的开发是实用的。我们将实现一个治疗算法 以指导加勒比拉美裔的DAPT，并将创建基因组DNA和完整注释的存储库 加勒比拉美裔心血管疾病患者的临床和基因组数据集。由强者塑造 初步数据显示，我们将检验以下假设： 在加勒比海地区，有一些未知的遗传变异对氯吡格雷的反应有独特的贡献 拉美裔美国人到了这样一个程度，一个开发的CDS工具，它结合了个人种族特定的基因类型和 体外药效学(PD)测试将有助于实现更精确的建议，以优化医疗 抗血小板治疗在这一人群中的结果。 这项研究将在1000名接受氯吡格雷治疗的心血管患者中进行，为期5年 血栓事件的二级预防。预计这项研究将推动采用一种 为拉美裔患者造福的精准医学(PM)范例。拉丁裔的基因变异更丰富的是 可能在很大程度上造成药物治疗反应的变异性，这是一个将被忽略的组成部分 通过在同质群体中进行的传统研究。这一可解决的疏忽非常令人担忧，因为它将 这往往会加剧美国拉美裔人口已经经历的医疗差距。拉美裔美国人 在很大程度上被排除在PM计划之外，这极大地增加了翻译方面的差异 从药物基因组学的新发现中受益于这一医疗服务不足的人群，加剧了 医疗服务中存在的不平等。因此，拟议的研究将扩大我们目前的 对氯吡格雷药物基因组学的认识。在调查不足的领域推进知识 在少数民族人群中的药物遗传学研究将产生适用于更广泛的个性化DAPT的结果 随着种群的发展，不可避免地会通过混合基因组增加异质性。

PROJECT SUMMARY Despite the substantial work in cardiovascular pharmacogenomics published over the past decade, a fundamental gap remains in understanding whether the genomic diversity of Caribbean Hispanics accounts for high inter-individual variability of clinical outcomes to preventive dual antiplatelet therapy (DAPT) with clopidogrel. Caribbean Hispanics are disproportionately affected by cardio-metabolic disorders, but with a limited expectation of benefits from existing genomic-based algorithms. We will focus on clopidogrel to develop urgently-needed genomic-driven prescription guidelines for this population. To this purpose, we propose to perform the first ever GWAS of a pharmacogenetically actionable prescription drug in Caribbean Hispanics. Our proposal will also take a novel approach to definitively assess the admixture component and is also highly practical for the development of a clinical decision support (CDS) tool. We will implement a treatment algorithm to guide DAPT in Caribbean Hispanics and will create a repository of genomic DNAs and fully annotated clinical and genomic dataset from Caribbean Hispanics with cardiovascular diseases. Shaped by strong preliminary data, we will test the following hypothesis: There are unknown genetic variants that uniquely contribute to clopidogrel responsiveness in Caribbean Hispanics to such extent that a developed CDS tool that incorporates personal ethno-specific genotypes and ex vivo pharmacodynamic (PD) testing will help enable more precise recommendations for optimizing medical outcomes to antiplatelet therapy in this population. The study will be conducted over 5 years in 1,000 cardiovascular patients treated with clopidogrel for secondary prevention of thromboembolic events. It is expected that this study advances the adoption of a Precision Medicine (PM) paradigm for the benefit of Hispanic patients. The richer genetic variance in Latinos is likely to contribute substantially to variability in response to drug treatments, a component that will be missed by traditional studies in homogeneous populations. This addressable oversight is of great concern, since it will tend to exacerbate the healthcare disparity already experienced by Hispanic populations in the US. Hispanics have been largely excluded from PM initiatives, which increase dramatically the disparities in translating benefits from new findings in pharmacogenomics to this medically underserved population, exacerbating the existing inequity in healthcare services. Accordingly, the proposed research will expand our current understanding on the pharmacogenomics of clopidogrel. Advancing knowledge in the under-investigated area of pharmacogenetics in minority populations will generate results that apply to personalize DAPT in the wider population as it moves, inevitably, toward increasing heterogeneity through admixed genomes.