Pharmacogenetics of the Response to a GLP1R Agonist

胰高血糖素样肽1受体（GLP 1 R）激动剂是一类重要的抗糖尿病药物， 具有吸引力的临床特征-包括改善血糖控制，体重减轻和降低主要 不良心血管事件。虽然个体患者的疼痛程度有很大差异， 对这些药物的反应，没有经过验证的方法来确定最有可能发生最大反应的患者。 反应，并获得最大的临床效益。本申请提出了一种全基因组关联研究， 旧秩序阿米什人群体，以确定预测个体药效学的遗传变异 对GLP 1 R激动剂的反应。根据主要研究者的初步研究数据， 拟议项目将测量与GLP 1 R激动剂有益作用相关的药效学终点。 超重/肥胖，否则健康的志愿者将从旧秩序阿米什人人群中招募， 宾夕法尼亚州兰开斯特县。为了评估药效学反应，研究参与者将接受两次 静脉葡萄糖耐量试验（FSIGT）。首次FSIGT将在基线时进行 在给药前。第二次FSIGT将在治疗6周后进行， Semaglutide（0.25 mg/周X 4周; 0.5 mg/sk X 2周）。该提案提出了两个具体目标： ·具体目标#1。为了鉴定与GLP 1 R激动剂增强葡萄糖代谢的作用相关的遗传变异， 在两个FSIGT中刺激第一时相胰岛素分泌（给药前和给药后）。 ·具体目标#2。为了鉴定与GLP 1 R激动剂加速细胞凋亡的作用相关的遗传变异， 在两个FSIGT中评估的葡萄糖消失率（给药前和给药后）。 将使用高密度阵列进行基因分型，该阵列具有DNA序列的全面覆盖 变体。该项目将利用全基因组序列数据生成的全球插补小组， 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。以前在旧秩序阿米什人中进行的遗传研究 对一般人群和相关患者人群的观察结果具有高度预测性。基于 根据这些先例，我们预计本研究中的遗传变异很可能预测临床 GLP 1 R激动剂治疗的2型糖尿病患者的反应。这项研究是朝着长期目标迈出的一步- 鉴定遗传生物标志物以预测个体患者对GLP 1 R激动剂的反应的长期目标。 预测性生物标志物的可用性将使医生能够为每个人开出最佳治疗方案 患者基于有益反应的预测因素。这种精准医学方法，基于 预测性药物基因组学生物标志物，将是糖尿病药物治疗方式的变革性进步。 规定的。

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.