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

• 批准号: 9899310
• 负责人: Sakima Ahmad Smith
• 金额: $ 38.03万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 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/9899310
• 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; Drug Prescriptions; 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; Recommendation; Regulation; Reporting; Research; Research Support; Risk; Sampling; Simvastatin; Site; Testing; Time; Tissues; Translating; Translations; United States; United States National Institutes of Health; Work; adverse drug reaction; 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; patient response; personalized health care; personalized medicine; population health; precision medicine; racial difference; racial disparity; response; sex; 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; Drug Prescriptions; 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; Recommendation; Regulation; Reporting; Research; Research Support; Risk; Sampling; Simvastatin; Site; Testing; Time; Tissues; Translating; Translations; United States; United States National Institutes of Health; Work; adverse drug reaction; 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; patient response; personalized health care; personalized medicine; population health; precision medicine; racial difference; racial disparity; response; sex

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.

项目摘要/摘要 目前为150多对药物对提供的药物基因组学处方指导正在改善 药物疗效并减少数百万美国人的不良药物反应。但是，大部分电流 与少数族裔患者人群相比，指导与高加索人更相关。长期以来已经理解 存在有关遗传多态性频率的种族差异，但最近的研究是 证明在那些遗传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度的重大种族差异奠定了基础 医学和此类差异继续增长，因为药物基因组学研究主要是在患者中进行的 主要是高加索人的种群。为了减少国家研究所 少数民族健康与健康差异（NIMHD）基金研究人员提出了有关健康差异的研究， 一个重点是药物基因组学研究，以确定健康中的药物反应和最佳剂量 差异人群。在少数民族健康人群中的候选基因研究，例如拟议的研究 该赠款应用不仅指向新发现的多态性的翻译，还指示 确保有关药物基因组学测试的临床指导与少数族裔患者有关。我们的 以前的工作发现了一种常见的功能性遗传多态性CYP3A4*22 非洲裔美国人的辛伐他汀的浓度明显更高，但没有 高加索人。重要的是，辛伐他汀是最常见的药物之一，更大 全身暴露于辛伐他汀增加了辛伐他汀引起的肌病的可能性。数百个 每年大约1000万非裔美国人开处方的非裔美国人是 至少一份CYP3A4*22多态性的载体，因此很可能处于明显状态 辛伐他汀引起的肌病的风险增加。这种增加的风险可能很容易通过 规定了较低剂量，替代他汀类药物类型或替代脂质降低策略。基础科学，翻译 和本赠款中提出的临床调查提供了将其转化为所需的证据 临床实践。具体而言，肝组织的体外分子遗传学研究（CYP3A4的主要位点 将进行代谢），以更好地表征下降的程度和机制 与CYP3A4*22相关的CYP3A4代谢在非洲裔美国人以及可能阐明任何 与非洲裔美国人有关的CYP3A4中的其他多态性。拟议的临床研究将 比较非裔美国人CYP3A4*22载体和非携带者的每日辛伐他汀全身暴露， 提供更好地量化肌肉的辛伐他汀暴露的增加，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 其他取决于CYP3A4代谢的药物。这具有实质性的希望，因为CYP3A4是 负责美国最常用药物的一半以上的代谢。 总而言之，研究中提出的研究具有推进药物基因组学的巨大潜力 和非洲裔美国人的个性化医疗保健 - 重要的少数民族健康和健康差异患者 在美国的人口。