A Genomic Approach to Warfarin Dose Prescription in Admixed Caribbean Hispanics.

加勒比西班牙裔混合人群华法林剂量处方的基因组方法。

基本信息

批准号：
9107895
负责人：
Jorge Duconge
金额：
$ 24.55万
依托单位：
UNIVERSITY OF PUERTO RICO MED SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9107895
关键词：
Accounting Admixture Adopted Adoption Affect African Algorithms Amerindian Anticoagulant therapy Anticoagulants Anticoagulation Area CYP2C9 gene Cardiovascular Diseases Cardiovascular system Caribbean Hispanic Caucasians Clinical Clinical Management Clinical Research Collaborations Computer Simulation DNA DNA Sequence DNA Sequence Analysis Data Demographic Factors Development Disease Dose Environment European Foundations Genes Genetic Genetic Polymorphism Genome Genomic approach Genomics Genotype Goals Grant Guidelines Health Hemorrhage Heritability Heterogeneity High Prevalence Hispanics Hospitalization Housing Human Resources Individual Institution Knowledge Life Linear Regressions Medicine Metabolic Diseases Minority Minority Groups Modeling Online Systems Oral Outpatients Patients Performance Pharmaceutical Preparations Pharmacogenetics Pharmacogenomics Phase Phenotype Pilot Projects Population Population Heterogeneity Publishing Puerto Rican Recruitment Activity Regression Analysis Research Risk Services Shapes Site Specimen System Target Populations Testing Therapeutic Thromboembolism Time Uncertainty Validation Variant Waran Warfarin Work base clinically relevant combinatorial dosage early experience expectation genetic risk factor genetic variant genotyped patients health care disparity improved medically underserved population non-genetic novel novel strategies randomized trial response simulation sound standard of care treatment as usual

项目摘要

DESCRIPTION (provided by applicant): Despite the substantial number of work published over the past years in different populations around the world, a fundamental gap remains in understanding whether and how genomic admixture and polymorphisms in warfarin-related pharmacogenes account for the high inter-individual dose variability observed in Caribbean Hispanic patients. In addition to being a medically underserved population, often marginally represented in clinical studies, Caribbean Hispanics are also a genomically heterogeneous population whose high level of admixture has produced a rich repertoire of combinatorial genotypes (e.g., CYP2C9*2/*5 + VKORC1-1639 A/A) that appear to challenge current pharmacogenetic-driven prescribing models. Our project takes a novel approach to definitively assess this admixture component and is also highly practical for its incorporation into a customized pharmacogenetic algorithm that will be implemented in "real-world" clinical settings through a web- based portal. Moreover, the project is also aimed at performing DNA-sequencing to identify those unknown variants on candidate pharmacogenes (i.e., CYP2C9 and VKORC1) that may contribute further to explain dose variability in Caribbean Hispanics. Shaped by strong preliminary data from a SC2 pilot project, we will: Derive and further assess validity and clinical utility of an admixture-adjusted, pharmacogenetic-guided prescribing model for personalized prediction of effective warfarin dosing in Caribbean Hispanics, which also encompasses genetic (common and novel variants) and non-genetic clinical and demographic factors. The study will be conducted over 4 years in 850 patients with thromboembolic disorders receiving warfarin. Two collaborating recruiting sites will be further connected through precise delivery of genotyping results and prescribing advice to clinicians via a web-based portal. Our novel assessment of genetic admixture will quantify the contribution of European, African and Amerindian ancestry, and we will test whether this admixture component can explain the heritability that is currently missing in the response variability to this drug among Caribbean Hispanics. If successful in our target population, the same approach can ultimately render current pharmacogenomic models for clinical management of related thromboembolic conditions more accurate and predictive for other populations. The proposed research will advance and expand our understanding of how these clinically relevant variants affect the response to warfarin in an admixed population. Advancing knowledge in the important and under- investigated area of pharmacogenetics in minority populations will generate results that apply to personalize oral anticoagulation therapy in the wider population as it moves, inevitably, toward increasing heterogeneity through admixed genomes. The ultimate goal is to gather strong data in support of a R01-equivalent application.

描述（由申请人提供）：尽管过去几年在世界各地不同人群中发表了大量工作，但在理解华法林相关药物基因的基因组混合和多态性是否以及如何解释高个体间差异方面仍然存在根本差距。在加勒比西班牙裔患者中观察到的剂量变异性。除了是医疗服务不足的人群（在临床研究中经常被边缘化）之外，加勒比西班牙裔也是一个基因组异质人群，其高水平的混合产生了丰富的组合基因型（例如 CYP2C9*2/*5 + VKORC1-1639） A/A）似乎挑战了当前药物遗传学驱动的处方模型。我们的项目采用一种新颖的方法来明确评估这种混合物成分，并且将其纳入定制的药物遗传学算法中也非常实用，该算法将通过基于网络的门户在“现实世界”的临床环境中实施。此外，该项目还旨在进行 DNA 测序，以确定候选药物基因（即 CYP2C9 和 VKORC1）的未知变异，这可能有助于进一步解释加勒比西班牙裔的剂量变异性。根据 SC2 试点项目的强有力的初步数据，我们将：推导并进一步评估混合调整、药物遗传学指导的处方模型的有效性和临床实用性，用于个性化预测加勒比西班牙裔的有效华法林剂量，其中还包括遗传（常见）和新变异）以及非遗传临床和人口因素。该研究将在 850 名接受华法林治疗的血栓栓塞性疾病患者中进行，为期 4 年。两个合作招募网站将通过基于网络的门户网站精确提供基因分型结果并为临床医生提供处方建议，从而进一步连接起来。我们对遗传混合的新评估将量化欧洲、非洲和美洲印第安人血统的贡献，我们将测试这种混合成分是否可以解释目前在加勒比西班牙裔中对该药物的反应变异性中缺失的遗传性。如果在我们的目标人群中取得成功，同样的方法最终可以使当前用于相关血栓栓塞病症临床管理的药物基因组模型对其他人群更加准确和具有预测性。拟议的研究将推进和扩大我们对这些临床相关变异如何影响混合人群对华法林反应的理解。在少数群体中推进药物遗传学这一重要且尚未得到充分研究的领域的知识，将产生适用于更广泛人群的个性化口服抗凝治疗的结果，因为它不可避免地会通过混合基因组增加异质性。最终目标是收集强大的数据来支持 R01 等效应用程序。