Pharmacogenomics of Statin Therapy

 描述(申请人提供)：“他汀类药物治疗的药物基因组学”中心(POST)的总体目标是应用基因组学、转录学和代谢学分析，以及细胞和动物模型研究，以及创新的信息学工具，以识别和验证他汀类药物在降低心血管疾病(CVD)风险和他汀类药物不良反应(特别是肌病和2型糖尿病)方面的有效性的生物标记物。这一多学科方法是由一组在基因组学(人类、老鼠和分子)、统计学和信息学以及临床医学和药理学方面具有专业知识的研究人员团队促成的。该中心由三个项目、两个研究核心和一个行政核心组成。项目1的一个主要目标是确定他汀类药物临床疗效和不良反应的细胞转录和代谢组学标记。这将通过分析他汀类药物暴露的淋巴母细胞株来完成，这些淋巴母细胞系来自有主要不良冠状动脉事件、肌病或2型糖尿病发作的他汀类药物治疗的患者，与未受影响的他汀类药物治疗的对照组相比。此外，利用这些患者的全基因组基因类型，将识别与他汀类药物诱导的转录物和代谢物变化相关的DNA变体，这些转录物和代谢物最强烈地区分受影响的患者和对照组。项目2将使用一个由100个近交系小鼠品系组成的独特的、特征良好的小组来发现与他汀类药物诱导的肌病和血糖异常有关的遗传变异。这些效应的潜在机制将被研究，重点是他汀类药物治疗对自噬的失调的作用。项目1和项目2还将分别使用相关的细胞和小鼠模型进行功能研究，以验证在所有后续项目中被确定为调节他汀类药物疗效或不良反应的有力候选基因的效果。在项目3中，将利用从非常大和多样化的基于人群的患者队列中的全基因组基因型、电子健康记录和药房数据获得的信息来识别和复制与他汀类药物疗效(降脂和心血管事件减少)和不良反应(肌病和2型糖尿病)的遗传关联，以及评估这些反应的总体遗传性。位于北加州凯泽永久的临床核心将为项目1和项目3提供临床信息和生物材料。信息学核心的研究人员将优化数据分析和结果集成 横跨所有项目。行政核心将为中心提供科学的领导和管理，并促进科学互动和培训机会。总的来说，这项研究 该中心的计划为药物基因组学的“系统”方法提供了一种创新模式，该方法结合了补充的研究工具，以发现和验证受基因影响的药物反应决定因素。此外，这些发现有可能指导更有效地使用他汀类药物来降低心血管疾病风险和将不良反应降至最低，并识别调节这一广泛使用的药物的多种作用的途径的生物标志物。

 DESCRIPTION (provided by applicant): The overall objective of the Center "Pharmacogenomics of Statin Therapy" (POST) is to apply genomic, transcriptomic, and metabolomic analyses, together with studies in cellular and animal models, and innovative informatic tools, to identify and validate biomarkers for efficacy of statin drugs in reducing riskof cardiovascular disease (CVD), and for adverse effects of statins, specifically myopathy and type 2 diabetes. This multidisciplinary approach is enabled by a team of investigators with expertise in genomics (human, mouse, and molecular), statistics and informatics, and clinical medicine and pharmacology. The Center is comprised of three Projects, two Research Cores, and an Administrative Core. A major aim of Project 1 is the identification of cellular transcriptomic and metabolomic markers for clinical efficacy and adverse effects of statins. This will be accomplished by analyses in statin-exposed lymphoblast cell lines derived from patients with major adverse coronary events, or onset of myopathy or type 2 diabetes on statin treatment, compared with unaffected statin- treated controls. In addition, using genome wide genotypes from these patients, DNA variants will be identified that are associated with statin-induced changes in the transcripts and metabolites that most strongly discriminate affected patients and controls. Project 2 will use a unique, well-characterized panel of 100 inbred mouse strains to discover genetic variation associated with statin-induced myopathy and dysglycemia. Mechanisms underlying these effects will be investigated, with emphasis on the role of dysregulation of autophagy by statin treatment. Projects 1 and 2 will also use relevant cellular and mouse models, respectively, to perform functional studies to validate effects of genes identified in all POST projects as strong candidates for modulating statin efficacy or adverse effects. In Project 3, information derived from genome-wide genotypes, electronic health records, and pharmacy data in a very large and diverse population-based patient cohort will be leveraged to identify and replicate genetic associations with statin efficacy (lipid lowering and CVD event reduction) and adverse effects (myopathy and type 2 diabetes), as well as to assess the overall heritability of these responses. The Clinical Core, based in Kaiser Permanente of Northern California, will provide the clinical information and biologic materials for both Projects1 and 3. Investigators in the Informatics Core will optimize data analysis and integration of results across all projects. The Administrative Core will provide scientific leadership and management of the Center, and foster scientific interactions and training opportunities. Overall, the research program of this Center provides an innovative model for a "systems" approach to pharmacogenomics that incorporates complementary investigative tools to discover and validate genetically influenced determinants of drug response. Moreover, the findings have the potential for guiding more effective use of statins for reducing CVD risk and minimizing adverse effects, and identifying biomarkers of pathways that modulate the multiple actions of this widely used class of drugs.