Pharmacogenetics of Warfarin in Puerto Rican Patients using a Physiogenomics Appr

描述（由申请人提供）：华法林是一种常用的处方药，用于治疗和预防血栓栓塞并发症。尽管过去几年在全球不同人群中发表了许多报告，但对于 CYP2C9 和 VKORC1 基因的变异是否解释了波多黎各患者对华法林反应的个体间差异的理解，仍存在根本性的差距。这项研究是为患有血栓栓塞并发症的波多黎各患者华法林剂量优化制定 DNA 驱动的个性化指南的第一步。在强有力的初步数据的指导下，该应用将追求两个具体目标：1) 使用 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 (PG) 驱动的混合分析，以研究波多黎各人华法林的药物遗传学；2) 确定 CYP2C9 和 VKORC1 组合基因型是否与华法林治疗期间的临床表型相关波多黎各患者的治疗。第一个目标是，来自同意参与本研究的接受华法林治疗的波多黎各患者的 350 份 DNA 样本将使用基于 Illumina 的新型 PG 阵列进行大规模基因分型，该阵列包含来自相关心脏代谢和神经内分泌途径的 222 个候选基因，以检查波多黎各人的人口结构，并创建个体混合、等位基因频率、连锁不平衡 (LD) 和用于药物遗传学研究的单倍型。值得注意的是，这一信息仍有待波多黎各人确定。第二个目标是从这些患者的病历中回顾性收集人口统计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，对之前获得的CYP2C9和VKORC1基因型与实现稳定华法林剂量的相应时间进行关联分析。这一具体目标的实现也将为在波多黎各使用这些患者作为学习样本开发 DNA 引导的华法林剂量算法奠定基础。长期目标是从波多黎各人的遗传背景中生成有价值的信息，以便进一步验证针对该混合人群的药物遗传学驱动的华法林剂量算法。拟议的研究意义重大，因为它有望促进和扩大对这些临床相关变异如何影响混合、服务不足的人群对华法林反应方式的理解。这是少数群体中药物遗传学的一个重要且尚未得到充分研究的领域，它将具有潜在的适用性来个体化华法林治疗。

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.