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

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 1,600名有可用DNA的参与者的子集，这些参与者接受了连续的 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 GRADE雇用的四名特工。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

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.