A genomics-based strategy to precision phenotyping and drug repositioning in cardiometabolic diseases

基于基因组学的心脏代谢疾病精准表型分析和药物重新定位策略

基本信息

批准号：
10564666
负责人：
Marijana Vujkovic
金额：
$ 37.5万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10564666
关键词：
Acceleration Affect Alanine Alanine Transaminase Alleles Biological Factors Blood Glucose Body Weight Cardiometabolic Disease Cardiovascular system Case Series Cessation of life Cirrhosis Clinical Complex Data Development Diabetes Mellitus Disease Disease model Drug Targeting Early Diagnosis Environmental Risk Factor Etiology Evaluation Exhibits FDA approved Functional disorder Gene Expression Gene Expression Profile General Population Genes Genetic Genetic Risk Genome Genomics Genotype Goals Health Healthcare Systems Hepatic IRS1 gene Individual Intervention Knowledge Link Liver Liver Fibrosis Liver diseases Malignant neoplasm of liver Mediating Mediation Mediator Medicine Mendelian randomization Methods Mission Modeling National Institute of Diabetes and Digestive and Kidney Diseases Natural History Non-Insulin-Dependent Diabetes Mellitus Obesity Obesity Epidemic Onset of illness Outcome PPARG gene Pathway interactions Patients Persons Pharmaceutical Preparations Pharmacoepidemiology Pharmacotherapy Phenotype Positioning Attribute Predisposition Primary carcinoma of the liver cells Risk Risk Factors Signal Transduction Strategic Planning Sum Symptoms Therapeutic Transferase Treatment Efficacy Veterans Veterans Health Administration Work bench to bedside biobank blood lipid burden of illness candidate identification cardiometabolism clinical data warehouse clinical risk cost effective data warehouse diabetes risk disorder prevention drug candidate drug development drug discovery drug efficacy drug repurposing effective therapy endophenotype follow-up genetic architecture genetic association genome wide association study genomic locus improved insight instrument liver transplantation multiple omics non-alcoholic fatty liver disease non-genomic nonalcoholic steatohepatitis novel personalized medicine precision medicine predictive modeling primary outcome programs risk prediction social factors statistics trait transcriptome

项目摘要

Project Summary / Abstract A total of 18.2 million people in the U.S. currently live with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). Susceptibility to cardiometabolic diseases is highly variable, and currently no FDA-approved drugs exist to treat NAFLD. Recent work suggests that cardiometabolic diseases share several genetic factors, and our long-term goal is to reveal the complex interplay between genomic and non-genomic risk factors in the development of disease to improve risk prediction and identify drug targets for repurposing to treat NAFLD. In our first aim we will apply causal single and multiple causal mediation analysis in the UK Biobank to identify intermediate or moderating endophenotypes that can serve as potential intervention targets for type 2 diabetes and NAFLD. We provide a framework for precision phenotyping and quantify how much individual-level genetic burden for disease can be reduced if one would intervene on intermediary endophenotypes. It may ultimately enable clinicians to detect early departures from patient-specific baseline risk that, while themselves are still asymptomatic, are predictive of the subsequent onset of disease symptoms. Our second aim is to identify and validate drug targets for potential repurposing in NAFLD using genomic and real-world data. We will identify candidate drug targets using two approaches: 1) instrumental variable analysis using genetic instruments of the `druggable' genome (e.g., Mendelian Randomization analysis) and 2) a computational gene expression signature-based approach based on the knowledge of drug activity and disease pathophysiology. Predictive validity of drug efficacy for candidate drug targets will be assessed using real-world data of 9.1 million Veterans in the Veterans Health Administration healthcare system, 3.6 million patients in the Penn Medicine clinical data warehouse, and 3.5 million patients in the Vanderbilt Synthetic Derivative. Long-term therapeutic efficacy will be evaluated using emulated target trials in NAFLD patients with cirrhosis, hepatic decompensation, liver transplant, and liver cancer as the primary treatment endpoint during five years of follow-up. Short-term drug efficacy will be evaluated in healthy patients using self-controlled case series analysis with change in alanine transferase as the primary outcome. It is anticipated that our genomics- informed and pharmaco-epidemiological approach to drug repurposing will accelerate drug-discovery efforts and lead to the use of existing agents to treat NAFLD with shortened drug development times.

项目摘要 /摘要目前，美国总共有1,820万人患有2型糖尿病和非酒精性脂肪肝病（NAFLD）。对心脏代谢疾病的敏感性高度可变，目前尚无FDA批准的药物存在用于治疗nafld。最近的工作表明，心脏代谢性疾病具有多种遗传因素，并且我们的长期目标是揭示基因组和非基因组风险因素之间的复杂相互作用疾病的发展以改善风险预测并确定重新利用NAFLD的药物靶标。在我们的第一个目标中，我们将在英国生物库中应用因果单一和多因果中介分析来识别可以用作2型糖尿病的潜在干预靶标的中间或调节性内表型和nafld。我们为精确表型提供了一个框架，并量化了多少个个人水平的遗传如果人们干预中间的内表型，则可以减轻疾病负担。最终可能使临床医生能够发现早期偏离了特定于患者的基线风险，尽管他们自己仍然是无症状，可以预测随后的疾病症状发作。我们的第二个目的是使用基因组和基因组和现实世界数据。我们将使用两种方法确定候选药物目标：1）仪器变量分析使用“可药”基因组的遗传仪器（例如，孟德尔随机分析）和2）基于药物活动的知识和疾病病理生理学。药物疗效对候选药物靶标的预测有效性将使用老兵卫生管理局中910万退伍军人的现实数据，360万 Penn Medicine临床数据仓库中的患者和范德比尔特合成的350万患者衍生物。长期治疗功效将使用NAFLD患者的模拟目标试验评估肝硬化，肝功能补偿，肝移植和肝癌作为主要治疗终点随访五年。短期药物疗效将在健康患者中使用自控病例评估以丙氨酸转移酶为主要结果的串联分析。预计我们的基因组学 - 知情的和药物的药物学方法重新利用将加速药物发现的努力并导致使用现有代理在药物开发时间缩短的情况下治疗NAFLD。