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：
10378153
负责人：
JOSE CARLOS FLOREZ
金额：
$ 65.23万
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/10378153
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 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病理生理学，并用各种治疗降低葡萄糖的药物与其作用机理不同的类别。治疗效率的差异可能是由于遗传差异引起的，但需要数据才能指导特定的药物治疗，以解决影响一种病原机制个体患者。糖尿病中的血糖减少方法：一种比较有效性（等级）研究正在评估四个最多的有效性通常使用的降糖药物（磺酰脲，GLP-1受体激动剂，DPP-4抑制剂，碱性胰岛素）添加到二甲双胍的背景中。之中 5,047名随机参与者，有4,730名同意遗传分析。我们建议使用全基因组关联方法测试1）特定的基因组区域是否或多基因分数与对四种药物中每种药物的血糖反应相关，或特定的行动方式； 2）特定的基因组区域还是多基因评分与葡萄糖稳态的关键中间性状相关（例如胰岛素敏感性，β- 细胞功能），或出现副作用和糖尿病并发症； 3）有1,600名参与者的子集，可用的DNA继续进行葡萄糖监测，无论是特定的基因组区域还是多基因分数糖化血红蛋白和平均血糖之间的不匹配，或血糖每种药物时的可变性； 4）是否已知已知与类型相关的变体 2种糖尿病或相关特征，从此类变体构建的多基因分数或生理驱动的分区遗传评分与对每一个的反应有关这四个代理商在成绩上工作。该建议代表了完整的药物遗传学旨在推进2型精确医学的年级临床试验中的探索糖尿病。