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

项目摘要 尽管在过去十年中发表了大量关于心血管药物基因组学的研究， 在理解加勒比西班牙裔的基因组多样性是否占 预防性双联抗血小板治疗（DAPT）的临床结局个体间变异性较高， 氯吡格雷加勒比地区的西班牙裔人不成比例地受到心脏代谢紊乱的影响， 对现有基于基因组的算法的益处的期望有限。我们将专注于氯吡格雷的开发 为这一人群提供急需的基因组驱动处方指南。为此，我们建议 在加勒比海西班牙裔人中进行了有史以来第一次药物遗传学可操作处方药的GWAS。 我们的建议还将采取一种新的方法来明确评估外加剂成分， 实际用于临床决策支持（CDS）工具的开发。我们将实施一种治疗方法 指导加勒比海西班牙裔的DAPT，并将创建一个基因组DNA库， 临床和基因组数据集来自加勒比海西班牙裔心血管疾病。由强大的 根据初步数据，我们将检验以下假设： 在加勒比地区，有一些未知的遗传变异对氯吡格雷的反应性有独特的影响 西班牙裔到这样的程度，一个发达的CDS工具，结合个人的种族特异性基因型， 离体药效学（PD）测试将有助于实现更精确的建议，以优化医疗 抗血小板治疗的结果。 这项研究将在1,000名接受氯吡格雷治疗的心血管患者中进行5年， 血栓栓塞事件的二级预防。预计这项研究将推动采用一种 精准医学（PM）范式，为西班牙裔患者的利益。拉丁美洲人更丰富的遗传变异是 很可能对药物治疗反应的变异性有很大贡献，这是一个将被忽略的组成部分。 传统的同质人群研究。这一可解决的疏忽令人非常关切，因为它将 倾向于加剧美国西班牙裔人口已经经历的医疗保健差距。西班牙裔 在很大程度上被排除在项目管理计划之外，这大大增加了翻译中的差异。 受益于药物基因组学的新发现，这一医疗服务不足的人群，加剧了 医疗服务不公平。因此，拟议的研究将扩大我们目前的 了解氯吡格雷的药物基因组学。在调查不足的领域增进知识 药物遗传学在少数群体中的应用将产生适用于更广泛的个性化DAPT的结果 人口，因为它的移动，不可避免地走向增加异质性，通过混合基因组。

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.