Translational Candidate-Gene Studies of Simvastatin-Induced Myopathy in African Americans

非裔美国人辛伐他汀诱发肌病的转化候选基因研究

基本信息

批准号：
9384510
负责人：
Joseph Paul Kitzmiller
金额：
$ 37.87万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-24 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9384510
关键词：
Accounting Adverse effects Affect African American Age Alcohol or Other Drugs use Alleles American Applications Grants Area Basic Science Biological Markers Body Composition CYP3A4 gene Candidate Disease Gene Cardiovascular system Caucasians Clinical Dose Drug Kinetics Drug Labeling Ensure Enzymes Exposure to FDA approved Frequencies Funding Future Genes Genetic Genetic Polymorphism Genetic study Goals Grant Hour Hyperlipidemia In Vitro Institutes Investigation Investigator-Initiated Research Lead Lipids Liver Medicine Messenger RNA Metabolism Minority Molecular Molecular Genetics Muscle Myopathy Outcome Pathway interactions Patients Pharmaceutical Preparations Pharmacogenomics Pharmacotherapy Population RNA Splicing Race Reaction Recommendation Regulation Reporting Research Research Support Risk Sampling Simvastatin Site Testing Time Tissues Translating Translations United States United States National Institutes of Health Work base clinical investigation clinical practice cohort cost effectiveness disparity reduction drug efficacy health disparity improved individual patient interest minority health non-compliance novel patient population personalized health care personalized medicine population health precision medicine racial difference racial disparity response sex

项目摘要

Project Summary/Abstract Pharmacogenomics prescribing guidance, currently provided for more than 150 drug-gene pairs, is improving drug efficacy and reducing adverse drug reactions for millions of Americans. However, much of this current guidance is more relevant to Caucasians than minority patient populations. It has long been understood that racial differences regarding the frequencies of genetic polymorphisms exist, but more recent investigations are demonstrating that significant racial differences exist also regarding the effects resulting from those genetic polymorphisms. This has set the stage for significant racial disparities in Pharmacogenomics and Precision Medicine, and such disparities continue to grow as pharmacogenomics research is largely conducted in patient populations that are predominantly or exclusively Caucasian. To reduce this disparity the National Institute on Minority Health and Health Disparities (NIMHD) funds investigator-initiated research on health disparities, and one focus is pharmacogenomic studies to determine medication response and optimal dosing in health disparity populations. Candidate-gene studies in minority health populations, such as the proposed research in this grant application, are indicated not only for the translation of newly discovered polymorphisms but also to ensure that clinical guidance regarding pharmacogenomics testing has relevance for minority patients. Our previous work uncovered a common functional genetic polymorphism, CYP3A4*22, to be associated with significantly higher concentrations (nearly 3-fold increase) of simvastatin in African Americans but not in Caucasians. Importantly, simvastatin is one of the most commonly prescribed medications, and greater systemic exposure to simvastatin increases the likelihood of simvastatin-induced myopathy. Hundreds of thousands of the approximate 10 million African Americans prescribed simvastatin on an annual basis are carriers of at least one copy of the CYP3A4*22 polymorphism and therefore are likely at a significantly increased risk of simvastatin-induced myopathy. This increased risk could potentially be readily mitigated by a prescribed lower dose, alternate statin type or alternate lipid-lowering strategy. The basic science, translational and clinical investigations proposed in this grant provide the evidence needed to potentially translate this into clinical practice. Specifically, in vitro molecular genetics studies of liver tissue (predominant site of CYP3A4 metabolism) will be performed to better characterize the extent and mechanisms underlying the decrease of CYP3A4 metabolism associated with CYP3A4*22 in African Americans as well as to potentially elucidate any additional polymorphisms in CYP3A4 relevant to African Americans. The proposed clinical investigation will compare daily simvastatin systemic exposure in African American CYP3A4*22 carriers and non-carriers, providing better quantification of the increased simvastatin exposure of muscle and better estimation of the resulting increase in risk of simvastatin myopathy. Importantly, this work can be extended to future studies of other medications dependent on CYP3A4 metabolism. This holds substantial promise because CYP3A4 is responsible for the metabolism of more than half of the most commonly used medications in the United States. In summary, the research proposed in the study has significant potential for advancing Pharmacogenomics and Personalized Health Care in African Americans - an important minority health and health disparity patient population in the United States.

项目概要/摘要目前为 150 多个药物基因对提供的药物基因组学处方指南正在改进药物疗效并减少数百万美国人的药物不良反应。然而，当前的大部分与少数族裔患者群体相比，指导对白种人更有意义。人们很早就认识到遗传多态性频率存在种族差异，但最近的研究表明证明在这些遗传因素造成的影响方面也存在显着的种族差异多态性。这为药物基因组学和精确度方面的显着种族差异奠定了基础医学方面，随着药物基因组学研究主要在患者身上进行，这种差异继续扩大主要是或完全是白种人的人口。为了缩小这种差距，国家研究所少数族裔健康和健康差异 (NIMHD) 资助研究者发起的健康差异研究，以及重点之一是药物基因组学研究，以确定药物反应和健康的最佳剂量人口差距。少数健康人群的候选基因研究，例如拟议的研究该资助申请不仅用于新发现的多态性的翻译，还用于确保有关药物基因组学测试的临床指导与少数族裔患者相关。我们的之前的工作发现了一个常见的功能遗传多态性 CYP3A4*22，与非裔美国人中辛伐他汀的浓度显着升高（增加了近 3 倍），但在白种人。重要的是，辛伐他汀是最常用的处方药物之一，而且更有效。全身暴露于辛伐他汀会增加辛伐他汀诱发肌病的可能性。数百个每年约有 1000 万非裔美国人服用辛伐他汀，其中数千人至少一个 CYP3A4*22 多态性拷贝的携带者，因此可能处于显着的辛伐他汀诱发肌病的风险增加。这种增加的风险可能很容易通过以下方式减轻：处方较低剂量、替代他汀类药物或替代降脂策略。基础科学、转化本次拨款中提出的临床研究提供了可能将其转化为所需的证据临床实践。具体来说，肝组织（CYP3A4的主要位点）的体外分子遗传学研究代谢）将被执行，以更好地表征减少的程度和机制 CYP3A4 代谢与非裔美国人中的 CYP3A4*22 相关，并可能阐明任何 CYP3A4 中与非裔美国人相关的其他多态性。拟议的临床研究将比较非洲裔美国人 CYP3A4*22 携带者和非携带者每日辛伐他汀的全身暴露量，更好地量化肌肉中辛伐他汀暴露量的增加，并更好地估计导致辛伐他汀肌病的风险增加。重要的是，这项工作可以扩展到未来的研究其他药物依赖于 CYP3A4 代谢。这具有重大前景，因为 CYP3A4 是负责美国一半以上最常用药物的代谢。总之，该研究中提出的研究对于推进药物基因组学具有巨大潜力非裔美国人的个性化医疗保健——重要的少数族裔健康和健康差异患者美国的人口。