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.

项目概要 尽管在过去十年中发表了心血管药物基因组学方面的大量工作，但 在理解加勒比西班牙裔的基因组多样性是否能够解释这一问题上仍然存在根本性的差距 预防性双重抗血小板治疗 (DAPT) 的临床结果存在较高的个体间差异 氯吡格雷。加勒比西班牙裔人受心脏代谢疾病的影响尤为严重，但 对现有基于基因组的算法的好处的期望有限。我们将重点开发氯吡格雷 该人群迫切需要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对药物遗传学上可行的处方药进行了首次 GWAS。 我们的建议还将采用一种新颖的方法来明确评估外加剂成分，并且也具有高度的可行性。 对于开发临床决策支持（CDS）工具具有实用性。我们将实施治疗算法 指导加勒比西班牙裔的 DAPT，并将创建一个基因组 DNA 存储库并进行完整注释 来自患有心血管疾病的加勒比西班牙裔的临床和基因组数据集。由坚强塑造 初步数据，我们将检验以下假设： 在加勒比地区，存在对氯吡格雷反应有独特影响的未知遗传变异 西班牙裔人的发展程度如此之高，以至于开发出一种包含个人种族特定基因型和 体外药效 (PD) 测试将有助于为优化医疗提供更精确的建议 该人群抗血小板治疗的结果。 该研究将在 5 年多的时间里对 1,000 名接受氯吡格雷治疗的心血管患者进行 血栓栓塞事件的二级预防。预计这项研究将推动采用 造福西班牙裔患者的精准医学 (PM) 范例。拉丁美洲人更丰富的遗传变异是 可能会极大地导致药物治疗反应的变异性，这是一个容易被忽视的因素 通过对同质人群的传统研究。这种可寻址的监督令人非常关注，因为它会 往往会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 很大程度上被排除在项目管理计划之外，这极大地增加了翻译方面的差距 药物基因组学的新发现使这一医疗服务不足的人群受益，从而加剧了 医疗保健服务中存在的不平等。因此，拟议的研究将扩展我们目前的 了解氯吡格雷的药物基因组学。增进未充分研究领域的知识 少数群体中药物遗传学的研究将产生适用于更广泛的个体化 DAPT 的结果 人口不可避免地通过混合基因组走向增加异质性。