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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：
10589095
负责人：
JOSE CARLOS FLOREZ
金额：
$ 65.07万
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/10589095
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 Continuous Glucose Monitor 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 Individual Differences Knowledge Medical Metabolic Metformin Molecular Target Non-Insulin-Dependent Diabetes Mellitus OGTT Participant Pathogenicity Patients Periodicals Pharmaceutical Preparations Pharmacogenetics Pharmacogenomics 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 individual patient individualized medicine inhibitor insulin sensitivity new therapeutic target personalized medicine pharmacologic precision medicine predicting response predictive tools response side effect 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，治疗方法多种多样