Pharmacogenetics of the Response to a GLP1R Agonist

GLP1R 激动剂反应的药物遗传学

• 批准号: 10529328
• 负责人: AMBER L BEITELSHEES
• 金额: $ 67.2万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10529328
• 关键词: Acceleration; Aftercare; Agonist; American; Amish; Amputation; Antidiabetic Drugs; Biological Markers; Blindness; Body Weight decreased; Bolus Infusion; Cardiovascular system; Circulation; Clinical; Clinical Trials; County; DNA Sequence; Data; Diabetes Mellitus; Diabetic Angiopathies; Diet; Dose; Drug Prescriptions; End stage renal failure; Environmental Risk Factor; European; Evaluation; Event; Exercise; Frequencies; GLP-I receptor; General Population; Genetic; Genetic Anticipation; Genetic Markers; Genetic study; Genotype; Glucose; Glycosylated hemoglobin A; Head; Individual; Literature; Measurement; Measures; Mediating; Mediation; National Heart, Lung, and Blood Institute; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Overweight; Participant; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenetics; Pharmacogenomics; Phase; Physicians; Physiological; Plasma; Population; Principal Investigator; Property; Publishing; Reporting; Research; Research Subjects; Risk; Sampling; Trans-Omics for Precision Medicine; Type 2 diabetic; Variant; biomarker identification; clinical predictors; clopidogrel; cost; density; design; diabetic patient; experience; genetic variant; genome wide association study; glucose metabolism; glycemic control; healthy volunteer; improved; individual patient; individual response; insulin secretion; intravenous administration; intravenous glucose tolerance test; liraglutide; logarithm; non-diabetic; optimal treatments; patient population; patient response; pharmacologic; precision medicine; predictive marker; primary endpoint; programs; recruit; response; side effect; subcutaneous; volunteer; whole genome

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.

胰高血糖素辣椒1受体（GLP1R）激动剂是一类重要类，抗糖尿病药物 有吸引力的临床特征 - 包括改善血糖控制，体重减轻和主要风险增加 不良心血管事件。虽然个别患者的大小有很大的变化 对这些药物的反应，没有经过验证的方法来识别最有可能拥有最大的患者 反应并获得最临床的好处。该申请提出了一项全基因组的关联研究 旧秩序的阿米什人种群以识别预测个体药效学的遗传变异 对GLP1R激动剂的反应。基于主要研究者研究的初步数据 拟议的项目将测量与GLP1R激动剂的有益作用相关的药效动力学终点。 超重/肥胖，否则健康的志愿者将从旧秩序的阿米什人中招募 宾夕法尼亚州兰开斯特县。为了评估药效反应，研究参与者将经历两个 经常采样静脉注射葡萄糖耐受性测试（FSIGT）。第一个FSIGT将在基线时进行 在服用药物之前。第二次FSIGT将在接受六周的治疗后进行 semaglutide（0.25 mg/wk x 4 wks; 0.5 mg/sk x 2 wks）。提案有两个具体的目标： •特定目标＃1。确定与GLP1R激动剂的作用相关的遗传变异，以增强葡萄糖 - 在两个FSIGT（药物给药之前和之后）刺激了第一相胰岛素分泌。 •特定的目标＃2。确定与GLP1R激动剂相关的遗传变异，以加速 葡萄糖消失的速率如两个FSIGT（药物给药之前和之后）所评估的。 基因分型将使用具有全面覆盖DNA序列的高密度阵列进行 变体。该项目将利用从整个基因组序列数据产生的全球插补面板上 〜100K受试者，包括通过NHLBI赞助的Trans-Omics获得的1,025名Amish个体 精密医学（顶部）计划。以前以旧顺序阿米什人种群进行的遗传研究 已经高度预测了普通人群和相关患者人群的观察结果。基于 在这些先例上，我们预计这项研究中的遗传变异很可能可以预测临床 GLP1R激动剂治疗的2型糖尿病患者的反应。拟议的研究是迈向长期的一步 鉴定遗传生物标志物以预测患者对GLP1R激动剂的反应的术语目标。 预测生物标志物的可用性将使医生能够为每个人准备最佳疗法 患者基于有益反应的预测指标。这种类型的精确医学方法，基于 预测性药物基因组生物标志物将是糖尿病药物的变革性进步 规定。