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Pharmacogenetic discovery in the GRADE comparative effectiveness type 2 diabetes clinical trial

GRADE 2 型糖尿病有效性比较临床试验中的药物遗传学发现

基本信息

批准号：
10211219
负责人：
JOSE CARLOS FLOREZ
金额：
$ 70.49万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10211219
关键词：
Address Adverse effects Affect Agonist Beta Cell Candidate Disease Gene Cell physiology Clinical Clinical Trials Clinical Trials Cooperative Group Clinical Trials Design Complex Complications of Diabetes Mellitus Consent DNA Data Decision Making Diabetes Mellitus Disease Functional disorder GLP-I receptor Genes Genetic Genetic Determinism Genetic Markers Genetic Variation Genomic Segment Glucose Glycosylated Hemoglobin Glycosylated hemoglobin A Human Incidence Individual Knowledge Medical Metabolic Metformin Molecular Target Non-Insulin-Dependent Diabetes Mellitus OGTT Participant Pathogenicity Patients Periodicity Pharmaceutical Preparations Pharmacogenetics Pharmacogenomics Pharmacology Pharmacotherapy Phenotype Physiological Physiology Randomized Resources Risk Sampling Sulfonylurea Compounds Testing Therapeutic Agents Treatment Efficacy Validation Variant basal insulin blood glucose regulation clinical decision-making cohort comparative effectiveness comparative effectiveness trial cost diabetes mellitus therapy drug intolerance effectiveness evaluation genetic analysis genetic variant genome wide association study genome-wide genomic locus genomic variation glucose monitor individual patient individualized medicine inhibitor/antagonist insulin sensitivity new therapeutic target personalized medicine precision medicine predicting response response side effect tool trait treatment response trial comparing whole genome

项目摘要

Type 2 diabetes has a heterogeneous pathophysiology, and is treated with various glucose-lowering medications from classes that differ in their mechanisms of action. Variability in treatment efficacy may be due to genetic variation, but data are needed to guide specific pharmacotherapy addressing the pathogenic mechanisms affecting an individual patient. The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study is evaluating the effectiveness of each of the four most commonly employed glucose-lowering medications (sulfonylurea, GLP-1 receptor agonist, DPP-4 inhibitor, basal insulin) added to a background of metformin. Among 5,047 randomized participants, 4,730 have consented to genetic analyses. We propose to use a genome-wide association approach to test 1) whether specific genomic regions or polygenic scores associate with the glycemic response to each of the four drugs, or to a specific mode of action; 2) whether specific genomic regions or polygenic scores associate with key intermediate traits of glucose homeostasis (e.g. insulin sensitivity, β- cell function), or the occurrence of side effects and diabetes complications; 3) in a subset of 1,600 participants with available DNA who have undergone continuous glucose monitoring, whether specific genomic regions or polygenic scores associate with the mismatch between glycated hemoglobin and average glycemia, or with glycemic variability while on each drug; and 4) whether variants known to be associated with type 2 diabetes or related traits, polygenic scores constructed from such variants, or physiology-driven partitioned genetic scores, are associated with response to each of the four agents employed in GRADE. This proposal represents a full pharmacogenetic exploration in the GRADE clinical trial designed to advance precision medicine in type 2 diabetes.

2型糖尿病具有异质性的病理生理学，并且用各种药物治疗。降糖药物的作用机制各不相同。治疗效果的变异性可能是由于遗传变异，但需要数据来指导具体的药物治疗，解决影响个别患者。糖尿病患者降低血糖的方法：比较有效性（GRADE）研究正在评估四种最有效的方法中每一种的有效性。常用降糖药物（磺酰脲类、GLP-1受体激动剂、DPP-4抑制剂、基础胰岛素）添加至二甲双胍背景。之间 5,047名随机参与者中，有4,730人同意进行遗传分析。我们提出使用全基因组关联方法来测试1）特定基因组区域是否或多基因得分与对四种药物中的每一种的血糖反应相关，或特定的作用模式; 2）特定的基因组区域或多基因评分与葡萄糖稳态的关键中间性状（例如胰岛素敏感性、β-葡萄糖代谢）相关。细胞功能），或副作用和糖尿病并发症的发生; 3）在一个由1，600名具有可用DNA的参与者组成的子集，他们接受了连续的葡萄糖监测，无论是特定的基因组区域或多基因得分与糖化血红蛋白和平均血糖之间的不匹配，或与血糖变异性，而对每种药物;和4）是否变异已知与类型 2糖尿病或相关性状，从这些变体构建的多基因评分，或生理学驱动的分区遗传评分，与对每种四名特工被雇佣该提案代表了一个完整的药物遗传学 GRADE临床试验的探索旨在推进2型糖尿病患者的精准医疗糖尿病