Pharmacogenetics of Warfarin in Puerto Rican Patients using a Physiogenomics Appr

说明(申请人提供)：华法林是治疗和预防血栓栓塞症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，但对于波多黎各患者观察到的对华法林的反应是否存在个体间差异，在理解CYP2C9和VKORC1基因变异方面存在根本差距。这项研究是开发DNA驱动的个性化指南的第一步，该指南用于波多黎各有血栓栓塞症并发症的患者的华法林剂量优化。在强大的初步数据的指导下，这项应用将追求两个具体目标：1)使用PG阵列对来自波多黎各华法林治疗患者的350个样本进行由生理基因组(PG)驱动的混合分析，以研究华法林在波多黎各人中的药物遗传学；2)确定组合的CYP2C9和VKORC1基因型别是否与波多黎各患者华法林治疗过程中的临床表型相关。在第一个目标下，350个同意参与这项研究的接受华法林治疗的波多黎各患者的DNA样本将使用基于Illumina的新的PG阵列进行大规模的基因分型，该阵列包括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群体结构，并创建用于药物遗传学研究的个人混合、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，这一信息仍有待波多黎各人确定。在第二个目标下，将从这些患者的病历中回顾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，对他们先前获得的CYP2C9和VKORC1基因与达到稳定华法林剂量的相应时间进行关联分析。这一特定目标的实现也将为在波多黎各开发DNA引导的华法林剂量算法奠定基础，将这些患者作为学习样本。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，以便进一步验证针对这一混合人群的药物遗传驱动的华法林剂量算法。这项拟议的研究具有重要意义，因为它有望促进和扩大对这些临床相关变异如何影响来自混合的、服务不足的人群的人对华法林反应的理解。这是少数群体药物遗传学的一个重要且研究不足的领域，将有可能适用于个性化华法林疗法。 公共卫生相关性：竞争性研究计划SC2机制的支持旨在通过为少数族裔服务机构中处于早期发展阶段并寻求收集初步数据的教职员工提高竞争力提供支持，以鼓励试点和发展研究项目。拟议的研究将填补华法林药物遗传学方面的空白，提供有关波多黎各人中CYP2C9(代谢)和VKORC1(敏感性)基因多态的新信息，以及它们在这一混合人群中观察到的华法林反应变异性中的作用。我是波多黎各大学医学校园的一名新研究员和教员，这是一所为少数族裔服务的机构，这个SC2类型的试点项目是我第一次尝试获得外部联邦资金。这一机制将支持我最初的职业发展，成为一名有兴趣更好地了解波多黎各人中观察到的药物反应变异性的遗传基础的药物遗传学家，方法是在这一服务不足的人群中进行一项试点药物遗传学研究，可能解决华法林疗法临床管理中潜在的健康差距。

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. PUBLIC HEALTH RELEVANCE: The Support of Competitive Research Program SC2 mechanism is intended to encourage pilot and developmental research projects by providing support for increasing competitiveness of faculty members at minority-serving institutions who are in their early stages of development and are seeking to gather preliminary data. The proposed studies will fill a gap in the pharmacogenetics of warfarin, providing new information on the prevalence of CYP2C9 (metabolism) and VKORC1 (sensitivity) polymorphisms in Puerto Ricans as well as their role in the warfarin response variability observed in this admixed population. I am a new investigator and faculty member at the University of Puerto Rico Medical Sciences Campus, a minority-serving institution, and this SC2-type pilot project is my first attempt to obtain external federal funds. This mechanism will support my initial career development as a pharmacogeneticist interested in better understanding the genetic basis of the observed drug response variability among Puerto Ricans, by conducting a pilot pharmacogenetic study in this under-served population that might address potential health disparities in the clinical management of warfarin therapy.