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

描述(申请人提供)：尽管过去几年在世界各地不同的人群中发表了大量的工作，但在理解是否以及如何解释与华法林相关的药物基因中的基因组混合和多态是在加勒比拉美裔患者中观察到的个体间剂量变异性高的原因方面，仍然存在一个根本的差距。除了是一个医疗服务不足的群体，通常在临床研究中处于边缘地位，加勒比拉美裔美国人也是一个基因异质性群体，其高水平的混合产生了丰富的组合基因型谱(例如，CYP2C9*2/*5+VKORC1-1639 A/A)，似乎挑战了当前由药物遗传驱动的处方模式。我们的项目采用了一种新的方法来最终评估这种混合物成分，而且它也非常实用，因为它将被纳入一个定制的药物遗传算法，该算法将通过一个基于网络的门户在“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，以确定候选药源(即CYP2C9和VKORC1)上的那些未知变异，这些变异可能有助于进一步解释加勒比拉美裔人的剂量变异性。在来自SC2试点项目的强大初步数据的影响下，我们将：推导并进一步评估混合物调整、药物遗传学指导的处方模型的有效性和临床实用性，该模型用于个性化预测加勒比拉美裔美国人的有效华法林剂量，该模型还包括遗传(常见和新的变种)和非遗传临床和人口统计因素。这项研究将在接受华法林治疗的850名血栓栓塞性疾病患者中进行，为期4年。两个协作招聘网站将通过精确提供基因分型结果并通过基于网络的门户网站向临床医生提供建议而进一步联系起来。我们对基因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加勒比拉美裔美国人对这种药物的反应变异性中目前缺失的遗传性。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临床治疗相关血栓栓塞症的药物基因组模型对其他人群更准确和更具预测性。这项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中对华法林的反应的理解。在少数群体中重要的和未被研究的药物遗传学领域的知识的进步将产生适用于在更广泛的人群中个性化口服抗凝治疗的结果，因为它不可避免地朝着通过混合基因组增加异质性的方向发展。最终目标是收集强大的数据来支持R01等效应用程序。

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.