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

项目摘要/摘要 目前为150多对药物-基因对提供的药物基因组学处方指导正在改进 为数百万美国人提供药物疗效和减少药物不良反应。然而，这股电流的很大一部分 与少数族裔患者群体相比，指导更适用于高加索人。长期以来，人们一直认为 关于基因多态频率的种族差异是存在的，但最近的研究是 表明在这些基因所造成的影响方面也存在显著的种族差异 多态现象。这为药物基因组学和精确学领域的显著种族差异奠定了基础 医学，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 主要或完全是高加索人的人口。为了缩小这一差距，美国国立卫生研究院 少数民族健康和健康差距(NIMHD)资助研究人员发起的关于健康差距的研究，以及 其中一个重点是药物基因组学研究，以确定药物反应和最佳健康剂量 不平等的人口。少数健康人群中的候选基因研究，例如在 这项拨款申请不仅适用于新发现的多态现象的翻译，还适用于 确保药物基因组学检测的临床指南适用于少数族裔患者。我们的 以前的工作发现了一种常见的功能性遗传多态，CYP3A4*22，与 在非裔美国人中辛伐他汀的浓度显著增加(近3倍)，但在 高加索人。重要的是，辛伐他汀是最常用的处方药之一，而且比 全身暴露于辛伐他汀会增加辛伐他汀诱导的肌病的可能性。数以百计 每年约有1000万非裔美国人服用辛伐他汀，其中数千人 携带至少一个拷贝的CYP3A4*22多态的携带者，因此很可能处于显著的 增加辛伐他汀所致肌病的风险。这种增加的风险可能很容易通过 处方剂量较低，替代他汀类或替代降脂策略。基础科学，翻译 这项拨款中提议的临床研究提供了所需的证据，以潜在地将这一点转化为 临床实践。具体地说，肝组织的体外分子遗传学研究(CYP3A4的优势部位 新陈代谢)将被用来更好地描述这种减少的程度和机制 与非裔美国人的CYP3A4*22代谢相关，以及潜在地阐明 与非裔美国人相关的CYP3A4基因的其他多态。拟议的临床调查将 比较非裔美国人CYP3A4*22携带者和非携带者每日辛伐他汀全身暴露， 提供了更好的量化增加的辛伐他汀肌肉暴露和更好的估计 从而增加了患辛伐他汀肌病的风险。重要的是，这项工作可以扩展到未来的研究 其他依赖于细胞色素P3A4代谢的药物。这有很大的希望，因为CYP3A4是 负责美国一半以上最常用药物的代谢。 总之，这项研究中提出的研究对推进药物基因组学具有重要的潜力 非洲裔美国人的个性化健康护理--一个重要的少数群体健康和健康差距患者 美国的人口。

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.