Pharmacogenetics of Warfarin in Puerto Rican Patients using a Physiogenomics Appr

使用生理基因组学方法研究波多黎各患者华法林的药物遗传学

• 批准号: 8223295
• 负责人: Jorge Duconge
• 金额: $ 11.25万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-07 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8223295
• 关键词: Accounting; Address; Admixture; Affect; Age; Algorithms; Alleles; American; Anticoagulation; Area; Atrial Fibrillation; Blood Coagulation Factor; CYP2C9 gene; Candidate Disease Gene; Clinical; Clinical Management; Coagulation Process; Complex; Consent; Cox Proportional Hazards Models; Cytochrome P450; DNA; Data; Data Analyses; Databases; Deposition; Development; Disease; Dose; Drug Kinetics; Drug Prescriptions; Elderly; Endocrine; Enzymes; Faculty; Frequencies; Funding; Gene Frequency; Genes; Genetic; Genetic Polymorphism; Genetic Structures; Genetic Variation; Genetic screening method; Genomics; Genotype; Goals; Guidelines; Haplotypes; Health; Health care facility; Healthcare; Hemorrhage; Hispanics; Individual; Individuality; Investigation; Learning; Linkage Disequilibrium; Maintenance; Medical; Medical Records; Metabolic; Metabolism; Minority; Minority-Serving Institution; Mixed Function Oxygenases; Natural regeneration; Outcome; Pathway interactions; Patients; Pattern; Peer Review; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenetics; Pharmacogenomics; Pilot Projects; Play; Population; Prevalence; Prevention; Protein Isoforms; Protein Subunits; Prothrombin; Publications; Publishing; Puerto Rican; Puerto Rico; Regimen; Registries; Reporting; Research; Research Personnel; Research Project Grants; Risk; Role; Sampling; Science; Single Nucleotide Polymorphism; Specimen; Staging; Structure; Survival Analysis; Techniques; Testing; Time; TimeLine; Underserved Population; Universities; Variant; Vitamin K; Warfarin; base; career development; clinical phenotype; clinically relevant; combinatorial; design; dosage; enantiomer; enzyme activity; ethnic difference; experience; health disparity; high risk; improved; interest; knowledge base; member; non-genetic; novel; polypeptide; programs; promoter; repository; response; statistics; vitamin K epoxide reductase

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.

描述（由申请人提供）：华法林是一种经常处方的药物，可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的人群中发表了许多报告，但了解CYP2C9和VKORC1基因的变化是否构成了波多黎各人患者中观察到的华法林的个体差异。这项研究是在波多黎各人血栓栓塞并发症患者中以DNA驱动的个性化指南开发Warfarin剂量优化的第一步。在强大的初步数据的指导下，该应用将追求两个具体的目的：1）对使用PG阵列进行的350种样本的350个样品开发出生理基因组（PG）驱动的混合分析，使用PG阵列使用PG阵列，以研究Puerto Ricanial and 2 Cypors and comminial comporsciptcipcipccicpcciptc and comminator comporsic and comporsial comporsic and comporic insotic comporic and comporsic ciptcipcic andcompiqun。波多黎各患者的华法林治疗期间的临床表型。在第一个目的下，同意参加这项研究的华法林处理的波多黎各患者的350个DNA标本将在大规模上进行基因型，使用一个基于Illumina的新型PG阵列的222个候选基因的PG - 来自相关的心脏代谢和神经内分泌途径，以便为所有人提供了puerto ricix of Puerto ricix absector of Soth of Sothere the Inloto ricecrine the Inlcocal and the Inloto-neuro-Metetaboloic和Neuro-Meter-oblecorine path。用于药物遗传学研究的频率，连锁不平衡（LD）和单倍型。值得注意的是，这些信息在波多黎各人中仍有待确定。在第二个目标下，将从这些患者的病历中回顾性地收集人口统计学和临床​​相关的非遗传数据，以便在先前获得的CYP2C9和VKORC1基因型和相应的时间之间进行关联分析，以实现在生存分析技术和COX比较比例Habards模型后实现稳定的华法蛋白剂量的时间。实现这一特定目标还将为在波多黎各人的DNA引导的华法林剂量算法开发通过将这些患者用作学习样本的基础。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种群的药物遗传学驱动的华法林给药算法。拟议的研究之所以重要，是因为它有望促进和扩展对这些临床相关变体如何影响人群中人们对华法林反应的人们的方式。这是少数群体中的药物遗传学领域的重要且不足的领域，它可能适用于个性化华法林治疗。 公共卫生相关性：竞争性研究计划SC2机制的支持旨在鼓励飞行员和发展研究项目，通过为提高少数派服务机构的竞争力提供支持，这些机构正处于发展的早期阶段，并正在寻求收集初步数据。拟议的研究将填补华法林的药物遗传学的空白，从而提供有关波多黎各人中CYP2C9（代谢）和VKORC1（敏感性）多态性的新信息，以及它们在这种混乱人群中观察到的WARFARIN反应变异性中的作用。我是波多黎各大学医学科学校园的新调查员和教职员工，这是一家少数派服务机构，而这个SC2型试点项目是我首次获得外部联邦资金的尝试。这种机制将支持我作为一名有兴趣更好地理解波多黎各人观察到的药物反应变异性的遗传基础的药物遗传学家的最初职业发展，该机制通过在这项服务不足的人群中进行了一项试验性药物遗传学研究，这可能解决WARFARIN治疗的临床管理中的潜在卫生差异。