Pharmacogenetics of Warfarin in Puerto Rican Patients using a Physiogenomics Appr

描述（由申请人提供）：华法林是治疗和预防血栓栓塞并发症的常用处方药。尽管在过去的几年中已经发表了许多关于世界各地不同人群的报告，但在了解CYP2C9和VKORC1基因的变异是否可以解释波多黎各患者对华法林反应的个体间差异方面，存在根本性的差距。这项研究是开发dna驱动的个性化指南，用于波多黎各血栓栓塞并发症患者华法林剂量优化的第一步。在强大的初步数据的指导下，该应用程序将追求两个特定目标：1)利用PG阵列对来自接受华法林治疗的波多黎各患者群体的350个样本进行生理基因组学（PG）驱动的混合分析，以研究波多黎各人的华法林药物遗传学；2)确定组合CYP2C9和VKORC1基因型是否与波多黎各患者接受华法林治疗期间的临床表型相关。在第一个目标下，同意参与这项研究的350名接受华法林治疗的波多黎各患者的DNA样本将使用基于illumina的新型pg阵列对来自相关心脏代谢和神经内分泌途径的222个候选基因进行大规模基因分型，以检查波多黎各人的种群结构，并创建用于药物遗传学研究的个体混合、等位基因频率、连锁不平衡（LD）和单倍型的参考数据库。值得注意的是，波多黎各人的情况还有待确定。在第二个目标下，将从这些患者的医疗记录中回顾性收集人口学和临床相关的非遗传数据，以便根据生存分析技术和Cox比例风险模型，对其先前获得的CYP2C9和VKORC1基因型与华法林稳定剂量的相应时间进行相关性分析。实现这一具体目标还将为利用这些患者作为学习样本，在波多黎各开发一种dna指导的华法林给药算法奠定基础。长期目标是从波多黎各人的遗传背景中获得有价值的信息，以便进一步验证药物遗传学驱动的华法林给药算法。拟议的研究意义重大，因为它有望推进和扩大对这些临床相关变异如何影响混合人群、服务不足人群对华法林的反应的理解。这是一个重要的和研究不足的药物遗传学领域，在少数民族人群中，将有潜在的适用于个体化华法林治疗。

DESCRIPTION (provided by applicant): Warfarin is a frequently prescribed drug for both the treatment and prevention of thromboembolic complications. Although many reports have been published over the past years in different populations worldwide, there is a fundamental gap in understanding whether variations in CYP2C9 and VKORC1 genes account for the inter-individual variability in response to warfarin that is observed in Puerto Rican patients. This study is a first step toward the development of DNA-driven personalized guidelines for warfarin dose optimization in Puerto Rican patients with thromboembolic complications. Guided by strong preliminary data, this application will pursuit two specific aims: 1) Develop a physiogenomic (PG)-driven admixture analysis of 350 samples from a population of warfarin-treated Puerto Rican patients using the PG array in order to study the pharmacogenetics of warfarin in Puerto Ricans and 2) Determine whether combinatorial CYP2C9 and VKORC1 genotypes are associated with clinical phenotypes during warfarin therapy in Puerto Rican patients. Under the first aim, 350 DNA specimens from warfarin-treated Puerto Rican patients who consent to participate in this study will be genotyped at large-scale using a novel Illumina-based PG-array of 222 candidate genes from relevant cardio-metabolic and neuro-endocrine pathways in order to examine the population structure of Puerto Ricans and create a reference database of individual admixture, allele frequencies, linkage disequilibrium (LD) and haplotypes for pharmacogenetics studies. Noteworthy, this information remains to be determined in Puerto Ricans. Under the second aim, demographic and clinically relevant non-genetic data will be retrospectively collected from medical records of these patients in order to perform an association analysis between their previously obtained CYP2C9 and VKORC1 genotypes and the corresponding time to achieve stable warfarin dosing following survival analysis techniques and Cox proportional hazards model. Accomplishment of this specific aim will also give the basis for developing a DNA-guided warfarin dosing algorithm in Puerto Rican by using these patients as a learning sample. The long-term goal is to generate valuable information from the genetic background of Puerto Ricans in order to further validate the pharmacogenetic-driven warfarin dosing algorithm for this admixed population. The proposed research is significant because it is expected to advance and expand understanding of how these clinically relevant variants affect the way people from an admixed, under-served population respond to warfarin. This is an important and under-investigated area of pharmacogenetics in minority populations that will have potential applicability to personalize warfarin therapy.