Pharmacogenetics of Warfarin in Puerto Rican Patients using a Physiogenomics Appr

描述（由申请方提供）：Warcantine是一种治疗和预防血栓栓塞并发症的常用处方药。尽管过去几年在全球不同人群中发表了许多报告，但在理解CYP2C9和VKORC 1基因变异是否解释了在波多黎各患者中观察到的华法林反应的个体间变异性方面存在根本性差距。这项研究是在波多黎各血栓栓塞并发症患者中制定华法林剂量优化的DNA驱动个性化指南的第一步。在强大的初步数据的指导下，该应用程序将追求两个具体目标：1）使用PG阵列对来自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）驱动的混合物分析，以研究华法林在波多黎各人中的药物遗传学，以及2）确定波多黎各患者华法林治疗期间CYP2C9和VKORC1基因型组合是否与临床表型相关。在第一个目标下，将使用来自相关心脏代谢和神经内分泌途径的222个候选基因的新型基于Illumina的PG阵列对来自同意参与本研究的华法林治疗的波多黎各患者的350个DNA标本进行大规模基因分型，以检查波多黎各人的群体结构并创建个体混合物、等位基因频率、连锁不平衡（LD）和单倍型用于药物遗传学研究。值得注意的是，波多黎各人的这一信息仍有待确定。根据第二个目的，将从这些患者的病历中回顾性收集人口统计学和临床相关非遗传数据，以便根据生存分析技术和考克斯比例风险模型，对其先前获得的CYP 2C9和VKORC 1基因型与达到稳定华法林剂量的相应时间之间进行关联分析。这一特定目标的实现也将为通过使用这些患者作为学习样本在波多黎各开发DNA指导的华法林给药算法提供基础。长期目标是从波多黎各人的遗传背景中产生有价值的信息，以进一步验证该混合人群的药物遗传学驱动的华法林给药算法。这项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来自混合、服务不足人群的人对华法林反应的理解。这是少数人群中一个重要且研究不足的药物遗传学领域，可能适用于华法林个体化治疗。

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.