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

在波多黎各采用精准医学范式：利用祖先多样性来确定加勒比西班牙裔氯吡格雷反应的预测因素

• 批准号: 10203763
• 负责人: Jorge Duconge
• 金额: $ 36.19万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 2022-09-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10203763
• 关键词: Admixture; Adopted; Adoption; Affect; African; Algorithms; Alleles; Amerindian; Area; Biochemical; Biological Specimen Banks; Blood Platelets; CYP2C19 gene; Cardiometabolic Disease; Cardiovascular Diseases; Cardiovascular system; Caribbean Hispanic; Caucasians; Clinical; Clinical Management; Clinical Research; Clinical Services; Collaborations; Data; Development; Drug Prescriptions; Drug usage; European; Event; Future; Genetic; Genome; Genomic DNA; Genomics; Genotype; Grant; Guidelines; Haplotypes; Heritability; Heterogeneity; High Prevalence; Hispanics; Institution; Island; Knowledge; Latino; Measures; Medical; Minority; Minority Groups; Modeling; Online Systems; Outcome; Pathway interactions; Patients; Pharmacodynamics; Pharmacogenetics; Pharmacogenomics; Pharmacology; Pharmacotherapy; Phenotype; Physiological; Pilot Projects; Population; Population Control; Population Heterogeneity; Precision Medicine Initiative; Preventive; Publishing; Puerto Rican; Puerto Rico; Recommendation; Research; Research Personnel; Residual state; Resources; Secondary Prevention; Signal Transduction; Target Populations; Test Result; Testing; Time; Translating; United States; Work; base; clinical decision support; clinical development; clinically significant; clopidogrel; combinatorial; expectation; experience; genetic testing; genetic variant; genome wide association study; genomic data; health care disparity; health care service; health disparity; inter-individual variation; loss of function; medically underserved population; minority health; novel strategies; personalized medicine; population stratification; precision medicine; prediction algorithm; repository; response; structural genomics; support tools; tool

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.

项目摘要 尽管在过去十年中发表的心血管药物基因组学上做了大量工作，但 基本差距仍然在理解加勒比西班牙裔基因组多样性是否涉及 临床结果对预防双重抗血小板治疗（DAPT）的高个体间变异性 氯吡格雷。加勒比西班牙裔人受心脏代谢性疾病的影响不成比例，但 现有基于基因组的算法对收益的期望有限。我们将专注于氯吡格雷以发展 迫切需要针对该人群的基因组驱动的处方指南。为此，我们建议 在加勒比西班牙裔中，执行有史以来可操作的处方药的第一个GWA。 我们的建议还将采用一种新颖的方法来确定评估混合组件，并且也很高 开发临床决策支持（CD）工具的实用性。我们将实施治疗算法 指导DAPT在加勒比西班牙裔中，并将创建一个基因组DNA的存储库并完全注释 来自心血管疾病的加勒比西班牙裔的临床和基因组数据集。由强壮的人塑造 初步数据，我们将检验以下假设： 有一些未知的遗传变异，它们有助于加勒比海的氯吡格雷反应性 西班牙裔在于，开发的CD工具结合了个人民族特异性基因型和 离体药效学（PD）测试将有助于启用更精确的建议以优化医疗 该人群中抗血小板治疗的结果。 这项研究将在1,000名用氯吡格雷治疗的心血管患者中进行5年以上 预防血栓栓塞事件。预计这项研究会推进采用 精密医学（PM）范式为西班牙裔患者受益。拉丁美洲人的遗传差异是 可能会导致对药物治疗的响应可变性，这将是遗漏的组成部分 通过统一人群的传统研究。这种可寻址的监督非常关注，因为它将 倾向于加剧美国西班牙裔人群已经遇到的医疗保健差异。西班牙裔 在PM倡议中已被排除在很大程度上，这大大增加了翻译的差异 药物基因组学的新发现带来了这一医疗服务不足的人群，加剧了该人群 医疗服务中现有的不平等。因此，拟议的研究将扩大我们的当前 了解氯吡格雷的药物基因组学。在未评价的领域中提高知识 少数族裔的药物遗传学将产生适用于个性化DAPT的结果 人口不可避免地会通过混合基因组来增加异质性。