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

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的工作，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在加勒比西班牙裔患者中观察到的高个体间剂量差异方面仍然存在根本差距。加勒比海裔西班牙人除了是医学上服务不足的人群，在临床研究中经常被边缘化之外，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（例如，CYP2C9*2/*5 + VKORC1-1639 a / a），这似乎挑战了当前的药物遗传学驱动的处方模型。我们的项目采用了一种新颖的方法来明确评估这种混合物成分，并且由于将其整合到定制的药物遗传算法中，将通过基于web的门户网站在“现实世界”的临床环境中实施，因此具有很高的实用性。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，这些变异可能有助于进一步解释加勒比西班牙裔人的剂量差异。根据SC2试点项目的强有力的初步数据，我们将：推导并进一步评估一个混合物调整、药物遗传学指导的处方模型的有效性和临床效用，该模型用于个性化预测加勒比西班牙裔患者华法林的有效剂量，该模型还包括遗传（常见和新变异）、非遗传临床和人口统计学因素。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年的研究。两个合作的招聘网站将通过一个基于网络的门户网站向临床医生提供精确的基因分型结果和处方建议，从而进一步联系起来。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当前的药物基因组学模型用于相关血栓栓塞疾病的临床管理，对其他人群更加准确和可预测。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。在少数民族人群中，药物遗传学这一重要且尚待研究的领域的知识进步，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向增加异质性的方向发展。最终目标是收集强有力的数据，以支持与r01相当的应用程序。

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.