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: 8627740
• 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/8627740
• 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; Caucasoid Race; 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; Genomics; Genotype; Goals; Grant; Guidelines; 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; public health relevance; 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（由申请方提供）：尽管过去几年在世界各地不同人群中发表了大量研究，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加勒比西班牙裔患者中观察到的高个体间剂量变异性方面仍存在根本性差距。除了是一个医学服务不足的人群，通常在临床研究中很少出现，加勒比西班牙裔也是一个基因组异质性的人群，其高水平的混合产生了丰富的组合基因型库（例如，CYP 2C 9 *2/*5 + VKORC 1 -1639 A/A），似乎挑战了当前药物遗传学驱动的处方模型。我们的项目采用了一种新的方法来明确评估这种混合物组分，并且对于将其纳入定制的药物遗传学算法也非常实用，该算法将通过基于网络的门户网站在“真实世界”的临床环境中实施。此外，该项目还旨在进行DNA测序，以识别候选药物基因上的未知变体（即，CYP 2C 9和VKORC 1），可能有助于进一步解释加勒比西班牙裔美国人的剂量变异性。根据来自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的药物遗传学指导处方模型的有效性和临床效用，用于加勒比西班牙裔美国人华法林有效剂量的个性化预测，其中还包括遗传（常见和新型变体）和非遗传临床和人口统计学因素。该研究将在850例接受华法林治疗的血栓栓塞性疾病患者中进行4年。两个合作招募中心将通过基于网络的门户网站向临床医生提供基因分型结果和处方建议，进一步连接。我们对遗传混合物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物成分是否可以解释目前在加勒比海西班牙裔人中对这种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目前用于相关血栓栓塞疾病临床管理的药物基因组学模型对其他人群更准确和更具预测性。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。在少数人群中推进重要且研究不足的药物遗传学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，因为它不可避免地通过混合基因组增加异质性。最终目标是收集支持R 01等效应用程序的强大数据。