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

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.

项目总结/摘要 药物基因组学处方指南，目前提供了150多个药物基因对，正在改善 药物疗效和减少数百万美国人的药物不良反应。然而，目前大部分 指南对白种人比少数民族患者人群更相关。人们早就知道， 关于遗传多态性的频率存在种族差异，但最近的研究表明， 这表明，在这些遗传因素造成的影响方面也存在显著的种族差异， 多态性这为药物基因组学和精密度方面的显著种族差异奠定了基础 药物基因组学研究主要在患者中进行， 主要或完全是高加索人的人群。为了减少这种差距，国家研究所 少数民族健康和健康差异（NIMHD）基金会发起的健康差异研究， 一个重点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。在少数健康人群中进行的基因突变研究，例如 本授权申请，不仅适用于新发现的多态性的翻译，而且适用于 确保关于药物基因组学检测的临床指南与少数群体患者相关。我们 先前的工作揭示了一种常见的功能性遗传多态性，CYP 3A 4 *22，与 在非裔美国人中辛伐他汀浓度显著更高（增加近3倍），但在 白种人重要的是，辛伐他汀是最常用的处方药之一， 全身暴露于辛伐他汀增加了辛伐他汀诱导的肌病的可能性。数百名 每年约有1000万非洲裔美国人被处方辛伐他汀， 携带至少一个拷贝的CYP 3A 4 *22多态性，因此可能在显著 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 处方的较低剂量、替代他汀类药物或替代降脂策略。基础科学，翻译 本基金中提出的临床研究提供了可能将其转化为 临床实践具体而言，肝组织（CYP 3A 4的主要位点）的体外分子遗传学研究 代谢），以更好地表征降低的程度和机制。 非裔美国人中与CYP 3A 4 *22相关的CYP 3A 4代谢，以及可能阐明任何 与非裔美国人相关的CYP 3A 4的其他多态性。拟定的临床研究将 比较非裔美国人CYP 3A 4 *22携带者和非携带者的每日辛伐他汀全身暴露量， 提供了对增加的辛伐他汀肌肉暴露的更好的量化和对增加的辛伐他汀肌肉暴露的更好的估计。 导致辛伐他汀肌病风险增加。重要的是，这项工作可以扩展到未来的研究， 其他依赖于CYP 3A 4代谢的药物。这一点有很大的希望，因为CYP 3A 4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推进药物基因组学具有重大潜力 非裔美国人的个性化医疗保健-一个重要的少数民族健康和健康差距的病人 美国的人口。