Pharmacogenetics of the Response to a GLP1R Agonist

胰高血糖素样肽1受体(GLP1R)激动剂是一类重要的抗糖尿病药物，具有广泛的应用前景。 有吸引力的临床资料-包括改善血糖控制、体重减轻和降低主要 不良心血管事件。虽然个体患者的数量有很大的差异 对于这些药物的反应，目前还没有有效的方法来识别最有可能患有最大 并获得最大的临床益处。这项申请提出了一项全基因组关联研究 旧式阿米什人群体识别预测个体药效的遗传变异 对GLP1R激动剂的反应。根据首席调查员研究的初步数据， 拟议的项目将测量与GLP1R激动剂的有益效果相关的药效终点。 超重/肥胖，其他方面健康的志愿者将从#年的旧秩序阿米什人口中招募 宾夕法尼亚州兰开斯特县为了评估药效学反应，研究参与者将经历两次 频繁采样静脉葡萄糖耐量试验(FSIGT)。第一次FSIGT将在基线进行 在给药之前。第二次FSIGT将在接受六周治疗后进行 赛马路德(0.25 mg/wk×4周；0.5 mg/k×2周)。该提案提出了两个具体目标： ·具体目标#1.确定与GLP1R激动剂提高血糖效果相关的遗传变异- 刺激两组FSIGT第一时相胰岛素分泌(给药前和给药后)。 ·具体目标#2.确定与GLP1R激动剂加速GLP1R作用相关的遗传变异 在两次FSIGT中评估的葡萄糖消失率(给药前后)。 基因分型将使用全面覆盖DNA序列的高密度阵列进行 变种。该项目将利用一个由全基因组序列数据生成的全球归因组 约10万名受试者，包括通过NHLBI赞助的Trans-Omics获得的1,025名阿米什人 精准医学(TOPMed)计划。先前在旧秩序阿米什人群体中进行的遗传研究 在普通人群和相关患者群体中的观察结果具有很高的预测性。基座 根据这些先例，我们预计这项研究中的基因变异很可能预测临床 GLP1R激动剂治疗2型糖尿病患者的疗效。这项拟议的研究是朝着长远的- 术语目标：识别遗传生物标记物以预测个体患者对GLP1R激动剂的反应。 预测性生物标记物的可用性将使医生能够为每个人开出最佳的治疗方案 患者基于有益反应的预测因素。这种精准医学的方法，基于 预测性药物基因组生物标记物，将是糖尿病药物的变革性进步 开了处方。

Glucagon-like peptide 1 receptor (GLP1R) agonists are an important class of antidiabetic drugs with an attractive clinical profile – including improved glycemic control, weight loss, and decreased risk of major adverse cardiovascular events. While there is substantial variation in the magnitude of individual patients’ responses to these drugs, there are no validated approaches to identify patients most likely to have the largest responses and derive the most clinical benefit. This application proposes a genome-wide association study in the Old Order Amish population to identify genetic variants that predict individuals’ pharmacodynamic responses to GLP1R agonists. Based on preliminary data from the Principal Investigators’ research, the proposed project will measure pharmacodynamic endpoints related to beneficial effects of GLP1R agonists. Overweight/obese otherwise healthy volunteers will be recruited from the Old Order Amish population in Lancaster County, PA. In order to assess pharmacodynamic responses, research participants will undergo two frequently sampled intravenous glucose tolerance tests (FSIGT). The first FSIGT will be conducted at baseline prior to administration of drug. The second FSIGT will be conducted after six weeks of treatment with semaglutide (0.25 mg/wk X 4 wks; 0.5 mg/sk X 2 wks). The proposal proposes two specific aims: • Specific Aim #1. To identify genetic variants associated with effects of a GLP1R agonist to enhance glucose- stimulated first phase insulin secretion in the two FSIGTs (before and after administration of drug). • Specific Aim #2. To identify genetic variants associated with the effect of a GLP1R agonist to accelerate the rate of glucose disappearance as assessed in the two FSIGTs (before and after administration of drug). Genotyping will be conducted using a high-density array with comprehensive coverage of DNA sequence variants. The project will leverage a global imputation panel generated from whole genome sequence data on ~ 100K subjects including 1,025 Amish individuals obtained through the NHLBI-sponsored Trans-Omics for Precision Medicine (TOPMed) program. Previous genetic studies conducted in the Old Order Amish population have been highly predictive of observations in the general population and relevant patient populations. Based on these precedents, we anticipate that genetic variants in this study are very likely to be predictive of clinical responses of GLP1R agonist-treated type 2 diabetic patients. The proposed study is a step toward the long- term objective of identifying genetic biomarkers to predict an individual patient’s response to GLP1R agonists. Availability of predictive biomarkers would enable physicians to prescribe optimal therapies for each individual patient based on predictors of beneficial response. This type of Precision Medicine approach, based on predictive pharmacogenomic biomarkers, would be a transformational advance in the way diabetes drugs are prescribed.