Molecular Determinants of Statin Efficacy and Adverse Effects in Cellular Models

项目1：概要 近一半的40-75岁的美国人有资格接受他汀类药物治疗，以预防心血管疾病。 根据新的AHA/ACC胆固醇管理指南，然而，高比例 的他汀类药物治疗患者仍有CVD的风险， 治疗，特别是肌病和新发糖尿病。目前，关于这方面的信息有限。 这些不同的结果和非常少的遗传或其他生物标志物的预测基础。因此， 需要为他汀类药物治疗制定精确的医学标准。使用转录组学分析， 体外辛伐他汀或假暴露的淋巴母细胞系（LCL）从他汀类药物临床试验的参与者，我们 先前鉴定了许多涉及调节他汀类药物脂质代谢作用的新基因 治疗这些基因的生物学和临床作用的支持证据是通过体外实验获得的。 敲低和过表达研究以及通过鉴定与两种候选物相关SNP 基因表达（eQTL）和体内他汀类降脂反应。目前的总体目标 项目是利用这种通用方法来识别新的生物标志物和/或他汀类药物的决定因素 临床结局，即CVD预防的有效性，以及他汀类药物诱导的肌病和2型糖尿病的风险 糖尿病在目标1中，我们将利用Kaiser Permanente北方加州（KPNC）的POST临床核心， 从接受他汀类药物治疗的患者中获得LCL，这些患者有：1）重大不良冠状动脉事件（MACE）; 2）他汀类药物诱导的 肌病;或3）新发2型糖尿病;以及每个结果的匹配对照。LCL将在 暴露于辛伐他汀与假手术，转录组学和代谢组学测量将用于确定 用于他汀类药物功效和副作用的新型细胞生物标志物。在目标2中，与项目3合作， 信息学核心，与这些生物标志物相关的DNA变异将被识别和测试， 与MACE和他汀类药物不良反应的相关性，使用来自非常大的KPNC队列的基因型数据， 全基因组基因型数据是可用的。最后，在目标3中，与他汀类药物反应相关的新基因 在本项目或整个中心内确定的，将使用假设驱动进行功能验证 在适当的细胞模型中采用敲低和过表达的研究。总的来说，我们预计， 这些目标的完成将导致新的生物标志物（转录物，代谢物， 和/或SNP）预测他汀类药物治疗结果，其可以在开发未来的治疗方法中增加价值。 指南此外，通过扩展我们对变异的潜在分子决定因素的知识， 他汀类药物反应，本项目和整个POST中心采用的“系统”方法可能导致 开发新的治疗方法以增加他汀类药物的益处和/或降低其风险。

PROJECT 1: SUMMARY Nearly half of Americans between 40-75 yr are eligible for statin treatment for prevention of cardiovascular disease (CVD) according to new AHA/ACC guidelines for cholesterol management. However, a high proportion of statin-treated patients remain at risk for CVD, and there is significant potential for adverse effects of treatment, most notably myopathy and new onset diabetes. Currently, there is limited information regarding the basis for these varying outcomes and very few genetic or other biomarkers for their prediction. Thus, there is need for the development of precision medicine standards for statin therapy. Using transcriptomic analysis of in vitro simvastatin or sham exposed lymphoblastoid cell lines (LCLs) from participants in a statin clinical trial, we previously identified a number of novel genes implicated in modulating the lipid metabolic effects of statin treatment. Supporting evidence for the biologic and clinical roles of these genes was obtained by in vitro knock-down and overexpression studies as well as by identification of SNPs associated with both candidate gene expression (eQTLs) and in vivo statin lipid-lowering response. The overall objective of the present project is to utilize this general approach to identify novel biomarkers and/or determinants of statin clinical outcomes, namely efficacy for CVD prevention, and risk of statin-induced myopathy and type 2 diabetes. In Aim 1 we will utilize the POST Clinical Core at Kaiser Permanente Northern California (KPNC) to obtain LCLs from statin treated patients with: 1) a major adverse coronary event (MACE); 2) statin-induced myopathy; or 3) new onset type 2 diabetes; as well as matched controls for each outcome. The LCLs will be exposed to simvastatin vs. sham and transcriptomic and metabolomic measurements will be used to identify novel cellular biomarkers for statin efficacy and adverse effects. In Aim 2, in collaboration with Project 3 and the Informatics Core, DNA variants associated with these biomarkers will be identified and tested for association with MACE and statin adverse effects using genotype data from a very large KPNC cohort in which genome-wide genotype data are available. Finally, in Aim 3, novel genes associated with statin response identified within this Project or throughout the Center will be functionally validated using hypothesis-driven studies employing knock-down and overexpression in appropriate cell models. Overall, we anticipate that the completion of these aims will lead to identification and validation of new biomarkers (transcripts, metabolites, and/or SNPs) predictive of statin treatment outcomes that can add value in developing future therapeutic guidelines. Moreover, by expanding our knowledge of the underlying molecular determinants of variation in statin response, the "systems" approach employed in this project and throughout the POST Center could lead to development of new therapeutic approaches for augmenting statin's benefits and/or reducing its risks.