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

点击翻译按钮获取中文摘要

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.