Pharmacogenomics of Statin Therapy

他汀类药物治疗的药物基因组学

• 批准号: 9326327
• 负责人: RONALD M KRAUSS
• 金额: $ 268.86万
• 依托单位: CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-07 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9326327
• 关键词: Adverse effects; Adverse event; Affect; Animal Model; Autophagocytosis; Biological; Biological Markers; California; Candidate Disease Gene; Cardiovascular Diseases; Cause of Death; Cell Line; Cell model; Clinical; Clinical Markers; Clinical Medicine; Clinical Pharmacology; Collaborations; Coronary; Coronary heart disease; Custom; DNA; Data; Data Analyses; Diabetes Mellitus; Disease Outcome; Drug effect disorder; Electronic Health Record; Environmental Risk Factor; Ethnic group; Event; Fostering; Gene Expression; Genes; Genetic; Genetic Variation; Genomics; Genotype; Goals; Health; Heritability; Human; Human Genetics; Hybrids; Hyperglycemia; In Vitro; Inbred Strains Mice; Informatics; Lead; Leadership; Lipids; Machine Learning; Metabolic; Modeling; Molecular; Mus; Muscle function; Myopathy; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacogenomics; Pharmacy facility; Population Heterogeneity; Predisposition; Public Health; Race; Recombinants; Records; Research; Research Personnel; Residual state; Resistance; Risk; Role; Sampling; Simvastatin; Stroke; Symptoms; System; Testing; Transcript; Treatment outcome; United States; Variant; Visualization software; adverse outcome; alternative treatment; base; biomarker identification; blood glucose regulation; candidate validation; cardiovascular disorder prevention; cardiovascular disorder risk; clinical efficacy; clinical phenotype; clinical practice; clinically relevant; cohort; data integration; data visualization; design; disability; disorder risk; exome; genetic analysis; genetic association; genetic variant; genome wide association study; genome-wide; genotyped patients; improved; in vivo; innovation; inter-individual variation; interdisciplinary approach; lymphoblast; lymphoblastoid cell line; metabolomics; mouse model; multidisciplinary; new therapeutic target; novel; novel marker; novel strategies; population based; predictive marker; prevent; programs; public health relevance; response; risk minimization; statistics; tool; training opportunity; transcriptomics; treatment strategy

 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.

 描述（由申请人提供）：“他汀类药物治疗的药物基因组学”（POST）中心的总体目标是应用基因组学、转录组学和代谢组学分析，以及细胞和动物模型研究以及创新信息工具，来识别和验证他汀类药物在降低心血管疾病（CVD）风险方面的功效以及他汀类药物的不良反应的生物标志物，特别是 肌病和 2 型糖尿病。这种多学科方法是由具有基因组学（人类、小鼠和分子）、统计学和信息学以及临床医学和药理学专业知识的研究人员团队实现的。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 的主要目的是鉴定细胞转录组学和代谢组学标记物，以了解他汀类药物的临床疗效和不良反应。这将通过对暴露于他汀类药物的淋巴细胞系进行分析来完成，这些细胞系来自患有严重不良冠状动脉事件、或在他汀类药物治疗中出现肌病或2型糖尿病的患者，并与未受影响的他汀类药物治疗对照进行比较。此外，利用来自这些患者的全基因组基因型，将鉴定与他汀类药物诱导的转录物和代谢物变化相关的DNA变异，这些变化最能强烈地区分受影响的患者和对照。项目 2 将使用由 100 只近交小鼠品系组成的独特且特征明确的小组来发现与他汀类药物诱发的肌病和血糖异常相关的遗传变异。将研究这些影响的机制，重点是他汀类药物治疗对自噬失调的作用。项目 1 和 2 还将分别使用相关的细胞和小鼠模型进行功能研究，以验证所有 POST 项目中确定的基因的作用，这些基因是调节他汀类药物疗效或不良反应的有力候选者。在项目 3 中，将利用来自庞大且多样化人群的患者队列中的全基因组基因型、电子健康记录和药学数据的信息来识别和复制与他汀类药物功效（降脂和减少 CVD 事件）和不良反应（肌病和 2 型糖尿病）的遗传关联，并评估这些反应的整体遗传性。位于北加州 Kaiser Permanente 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整合 跨所有项目。行政核心将为中心提供科学领导和管理，并促进科学互动和培训机会。总体而言，研究 该中心的计划为药物基因组学“系统”方法提供了一个创新模型，该模型结合了补充研究工具来发现和验证药物反应的遗传影响决定因素。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尽量减少不良反应，并确定调节此类广泛使用的药物的多种作用途径的生物标志物。