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。

• 批准号: 8881301
• 负责人: Jorge Duconge
• 金额: $ 27.28万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 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/8881301
• 关键词: Accounting; Admixture; Adopted; Adoption; Affect; African; Algorithms; Amerindian; Anticoagulant therapy; Anticoagulants; Anticoagulation; Area; CYP2C9 gene; Cardiovascular Diseases; Cardiovascular system; Caribbean region; Caring; 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; Healthcare; 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; Principal Investigator; Publishing; Puerto Rican; Recruitment Activity; Regression Analysis; Research; Risk; Services; Shapes; Site; Specimen; System; Target Populations; Testing; Therapeutic; Thromboembolism; Time; Uncertainty; Validation; Variant; Warfarin; Warfarin Sodium; Work; base; clinically relevant; combinatorial; dosage; early experience; expectation; genetic risk factor; genetic variant; improved; medically underserved population; non-genetic; novel; novel strategies; programs; randomized trial; response; simulation; sound; treatment as usual

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口中发表了大量工作，但仍有基本差距在理解与华法林相关药物基因因群中是否以及如何在华法林相关的药物基因组中造成高度个体间剂量可变性的占较高的剂量变异性。除了在临床研究中经常表现出的医学水平不足之外，加勒比西班牙裔也是基因组上异质的人群，其高水平的混合量产生了丰富的组合基因型曲目（例如CYP2C9*2/*5 + VKORC11-1639 A/A/A/A/A/A/A/A/A/A/A/A/A/A/A/A/A/PROCKERS均出现了当前的挑战。我们的项目采用了一种新颖的方法来确定评估该混合物组件，并且由于将其纳入定制的药物遗传学算法中而非常实用，该算法将通过基于Web的门户网站在“现实世界”临床环境中实现。此外，该项目还旨在执行DNA测序，以确定那些在候选药物基因因群（即CYP2C9和VKORC1）上的未知变异，这些变体可能进一步解释加勒比海西班牙裔剂量变异性。由SC2试点项目的强大初步数据塑造，我们将：进一步评估并评估由混合调整后的，药物遗传学引导的开处方模型的有效性和临床实用性，用于个性化的加勒比海西班牙裔华法蛋白剂量的个性化预测，该模型还包括遗传（常见和新颖的Variants）和非临床和临床范围和非官方临床和临床范围。该研究将在850例接受华法林的血栓栓塞疾病患者中进行4年。通过基于Web的门户网站，将通过精确提供基因分型结果和开处方建议，进一步连接两个合作的招聘网站。我们对遗传混合物的新颖评估将量化欧洲，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加勒比海西班牙裔这种药物的响应变异性中目前缺少的遗传力。如果在我们的目标人群中取得成功，那么相同的方法最终可以使当前的药物基因组学模型更加准确，对其他人群的临床管理更加准确和预测。拟议的研究将提高和扩展我们对这些临床相关变体如何影响掺假人群中对华法林的反应的理解。促进少数族裔药物遗传学领域的知识和不足研究的知识将产生结果，这些结果适用于在更广泛的人群中个性化口服抗凝治疗，因为它不可避免地通过混合基因组移动，以增加异质性。最终目标是收集强大的数据以支持R01等效应用。