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.

胰高血糖素样肽 1 受体 (GLP1R) 激动剂是一类重要的抗糖尿病药物，具有 有吸引力的临床特征——包括改善血糖控制、减轻体重和降低重大疾病风险 不良心血管事件。虽然个体患者的严重程度存在很大差异 对这些药物的反应，没有经过验证的方法来识别最有可能具有最大 反应并获得最大的临床益处。该申请提出了一项全基因组关联研究 旧秩序阿米什人群识别预测个体药效的遗传变异 对 GLP1R 激动剂的反应。根据首席研究员研究的初步数据， 拟议的项目将测量与 GLP1R 激动剂有益作用相关的药效学终点。 将从旧秩序阿米什人中招募超重/肥胖的健康志愿者 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 经常进行静脉内葡萄糖耐量试验（FSIGT）。第一次 FSIGT 将在基线进行 给药前。第二次 FSIGT 将在治疗六周后进行 索马鲁肽（0.25 mg/wk 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。鉴定与 GLP1R 激动剂增强葡萄糖的作用相关的遗传变异 在两次 FSIGT 中（给药前和给药后）刺激第一相胰岛素分泌。 • 具体目标#2。鉴定与 GLP1R 激动剂加速作用相关的遗传变异 两次 FSIGT（给药前和给药后）评估的葡萄糖消失率。 基因分型将使用全面覆盖 DNA 序列的高密度阵列进行 变体。该项目将利用从全基因组序列数据生成的全球插补小组 通过 NHLBI 赞助的 Trans-Omics 获得约 100,000 名受试者，其中包括 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中进行的基因研究 对一般人群和相关患者群体中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 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 识别遗传生物标志物以预测个体患者对 GLP1R 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 基于有益反应的预测因素的患者。这种类型的精准医学方法基于 预测性药物基因组生物标志物，将是糖尿病药物治疗方式的变革性进步 规定。