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

2型糖尿病具有不同的病理生理机制，治疗方法有多种 作用机制不同类别的降糖药物。 治疗效果的可变性可能是由于遗传变异，但需要数据来证明 指导针对影响AN的致病机制的特异性药物治疗 个别病人。糖尿病患者降血糖方法的比较 有效性(年级)研究是评估四个最重要的 常用降糖药物(磺脲类、GLP-1受体 激动剂、DPP-4抑制剂、基础胰岛素)添加到二甲双胍的背景中。其中 5047名随机参与者中，4730人同意进行基因分析。我们建议 使用全基因组关联方法来测试1)特定的基因组区域 或与对四种药物中的每一种的血糖反应相关的多基因评分，或 特定的作用方式；2)特定的基因组区域或多基因得分 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)，或副作用和糖尿病并发症的发生；3) 1600名具有可用DNA的参与者中的一组，他们已经连续 血糖监测，无论是特定的基因组区域还是多基因评分与 糖化血红蛋白与平均血糖或与血糖不匹配 在每种药物上的可变性；以及4)已知的变异是否与类型相关 2糖尿病或相关性状，由这些变异构成的多基因评分，或 生理驱动的分区遗传分数与对每个 这四名特工是按级别雇用的。这项提议代表了一种完整的药物遗传学 推进2型精准医学分级临床试验的探索 糖尿病。

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.