Pharmacogenomics of Statin Therapy

他汀类药物治疗的药物基因组学

基本信息

批准号：
8934878
负责人：
RONALD M KRAUSS
金额：
$ 283.67万
依托单位：
CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
依托单位国家：
美国
项目类别：
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/8934878
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 Medicine Clinical Pharmacology Collaborations Control Locus Coronary Coronary heart disease Custom DNA Data Data Analyses Diabetes Mellitus Disease Outcome Drug effect disorder Electronic Health Record Electronics Environmental Risk Factor Ethnic Origin 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 Training Transcript Treatment outcome United States Variant adverse outcome alternative treatment base 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 improved in vivo innovation interdisciplinary approach lymphoblast lymphoblastoid cell line metabolomics mouse model new therapeutic target novel novel marker novel strategies population based prevent programs public health relevance response statistics tool transcriptomics treatment strategy

项目摘要

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.

DESCRIPTION (provided by applicable): 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 informative tools, to identify and validate biomarkers for effectiveness of statin drugs in reducing Riskof cardiovascular disease (CVD), and for adverse effects of statins, specifically肌病和2型糖尿病。这种多学科的方法是由具有基因组学专业知识（人类，老鼠和分子），统计和信息的研究人员组成的团队，以及临床医学和药理学。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和代谢组标志物，以实现他汀类药物的临床有效性和不良影响。与未受毒素治疗的对照相比，在汀类药物暴露的淋巴细胞细胞系中分析汀类药物淋巴细胞细胞系或2型糖尿病的肌病或2型糖尿病的发作，与未经影响的他汀类药物治疗的对照相比，可以实现这一点。此外，将使用来自这些患者的基因组广泛的基因型，将鉴定出与他汀类药物诱导的转录本和代谢物变化有关的DNA变异，这些变体最严重地区分受影响的患者和对照。项目2将使用100个近交小鼠菌株的独特，特征良好的面板，以发现与他汀类药物诱导的肌病和血糖症相关的遗传变异。将研究这些作用的机制，重点是通过他汀类药物治疗自噬失调的作用。项目1和2还将分别使用相关的细胞和小鼠模型来执行功能研究，以验证所有邮政项目中确定的基因的影响，以调节他汀类药物有效性或不良影响。在项目3中，将利用源自全基因组基因型，电子健康记录和药房数据的信息，以识别和复制与他汀类药物有效性（降低脂质和CVD事件的降低）和不良影响（肌酸和2型糖尿病）的遗传关联，以评估这些遗传性（Myopathy and 2型糖尿病），以评估这些整体性能。总部位于北加州Kaiser Permanente的临床核心将为项目1和3提供临床信息和生物材料。在所有项目中。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，研究该中心的程序为药品的“系统”方法提供了一种创新模型，该模型结合了完整的研究工具，以发现和验证遗传影响的药物反应。此外，这些发现有可能引导更有效地利用他汀类药物来降低CVD风险并最大程度地减少不良反应，并确定调节这种广泛使用类药物的多重作用的途径的生物标志物。