Elucidating the pharmacogenetics of the response to GLP-1 receptor agonists for type 2 diabetes

阐明 GLP-1 受体激动剂治疗 2 型糖尿病反应的药物遗传学

• 批准号: 10524795
• 负责人: Josephine H Li
• 金额: $ 19.05万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10524795
• 关键词: Acute; Advisory Committees; Affect; Aftercare; Agonist; Algorithms; All of Us Research Program; Area; Biochemical; Bioinformatics; Body Weight decreased; Candidate Disease Gene; Cardiovascular system; Clinical Pharmacology; Clinical Trials; Collection; Complex Genetic Trait; Complications of Diabetes Mellitus; DNA; Data; Diabetes Mellitus; Diagnosis; Disease; Drug usage; Effectiveness; Electronic Health Record; Endocrine; Endocrinologist; Exposure to; Feedback; Foundations; Functional disorder; Future; GLP-I receptor; General Hospitals; Genes; Genetic; Genetic Translation; Genetic Variation; Genomics; Genotype; Glucose; Glycosylated hemoglobin A; Goals; Guidelines; Heterogeneity; Human; Hypoglycemia; Individual; Industry; Insulin; International; Investigation; Jordan; Knowledge; Leadership; Life; Link; Massachusetts; Measures; Medical; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Meta-Analysis; Metabolic; Metformin; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Oral; Outcome; Pathway interactions; Patient Rights; Patients; Periodicity; Persons; Pharmaceutical Preparations; Pharmacogenetics; Pharmacology; Phenotype; Physiological; Population; Predisposition; Protocols documentation; Provider; Public Health; Research; Research Personnel; Resources; Risk; Role; Safety; Scientific Advances and Accomplishments; Sulfonylurea Compounds; TCF7L2 gene; Techniques; Testing; Therapeutic; Therapeutic Agents; Training; Training Programs; Variant; Veterans; Weight-Loss Drugs; Work; base; biobank; career; clinical practice; clinical translation; clinical trial implementation; cohort; comparative effectiveness; cost; drug efficacy; drug mechanism; expectation; experience; gastrointestinal; genetic analysis; genetic association; genetic predictors; genetic variant; genome wide association study; genome-wide; genomic locus; glycemic control; improved; individual patient; individualized medicine; insight; insulin secretion; mortality; novel; novel drug class; patient response; personalized approach; practice setting; precision medicine; predicting response; programs; response; risk variant; side effect; skill acquisition; skills; tool

PROJECT ABSTRACT Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) represent a new drug class that have recently arisen to the forefront of the treatment algorithm for type 2 diabetes (T2D) due to their glycemic, metabolic, and cardiovascular benefits. However, their use has been hampered by gastrointestinal side effects. This proposal aims to understand the genetic predictors of GLP-1 RA response in order to target treatment to those most likely to benefit and avoid unnecessary exposure to those who are likely to experience intolerance. In Aim 1, the candidate will harness the phenotypic and genotypic data available in several biobank-linked electronic health records (EHR) to perform pharmacogenetic analyses. Outcomes of GLP-1 RA response will be curated using best practices and a genome-wide approach will test associations between genetic variation and phenotypes of GLP-1 RA response, with subsequent replication of genetic findings to be conducted in additional human cohorts. Aim 2 will focus on the creation of a drug perturbation trial with oral semaglutide in healthy individuals for the purposes of characterizing the acute biochemical response, as measured by changes in glucose and insulin levels in response to a mixed meal tolerance test. Subsequently, this protocol will be implemented in Aim 3 to assess how the acute response to oral semaglutide differs by genetic variation to generate insight into underlying drug mechanism and T2D pathophysiology. The candidate will complete the proposed work under the primary mentorship of Dr. Jose Florez, Chief of the Endocrine Division and Diabetes Unit at Massachusetts General Hospital (MGH) and an internationally recognized leader in clinical translation of genetic discoveries in T2D. Dr. Jordan Smoller will serve as a co-mentor due to his expertise on the application of EHR-based biobanking for genomic research and active leadership roles in the Mass General Brigham Biobank and the All of Us Research Program. Dr. Li will undertake coursework on bioinformatics and phenotype curation, expand on her experiences in studying complex trait genetics, develop knowledge in clinical pharmacology, refine her expertise in physiologic investigation, gain practical skills in clinical trial implementation, and receive periodic feedback from a research advisory committee with complementary areas of expertise. This application reflects a carefully planned training program directed at equipping the applicant with the tools necessary to conduct future pharmacogenetic studies in T2D and advancing the scientific career of the applicant toward independence. If successful, this proposal will generate evidence for precision medicine in T2D and serve as the foundation for a future pharmacogenetics trial of genotype-guided therapeutic selection for GLP-1 RAs.

项目摘要 胰高血糖素样肽 1 受体激动剂 (GLP-1 RA) 是最近出现的一类新药物 2 型糖尿病 (T2D) 因其血糖、代谢和血糖水平而处于治疗算法的最前沿 对心血管的好处。然而，它们的使用受到胃肠道副作用的阻碍。这个提议 旨在了解 GLP-1 RA 反应的遗传预测因子，以便针对最有可能的患者进行治疗 使那些可能遭受不宽容的人受益并避免不必要的接触。在目标 1 中， 候选人将利用几个与生物库相关的电子健康中可用的表型和基因型数据 记录（EHR）以进行药物遗传学分析。 GLP-1 RA 响应的结果将使用 最佳实践和全基因组方法将测试遗传变异和表型之间的关联 GLP-1 RA 反应，随后将在其他人类队列中复制遗传发现。 目标 2 将侧重于在健康个体中开展口服索马鲁肽的药物扰动试验，以期 通过葡萄糖和胰岛素的变化来表征急性生化反应的目的 混合膳食耐受性测试的水平。随后，该协议将在目标 3 中实现 评估口服索马鲁肽的急性反应如何因遗传变异而不同，以深入了解潜在的情况 药物机制和 T2D 病理生理学。候选人将完成主要的拟议工作 马萨诸塞州总医院内分泌科和糖尿病科主任 Jose Florez 博士的指导 Hospital (MGH) 是 T2D 基因发现临床转化领域国际公认的领导者。博士。 乔丹·斯莫勒 (Jordan Smoller) 将担任联合导师，因为他在基于电子病历的生物样本库应用方面拥有专业知识。 基因组研究以及在麻省总医院布里格姆生物库和我们所有人研究中的积极领导作用 程序。李博士将承担生物信息学和表型管理的课程，扩展她的经验 研究复杂性状遗传学，发展临床药理学知识，完善她的专业知识 生理学调查，获得临床试验实施的实践技能，并定期接收反馈 具有互补专业领域的研究咨询委员会。该应用程序体现了仔细 计划的培训计划旨在为申请人提供未来开展工作所需的工具 T2D 药物遗传学研究并推动申请人的科学事业走向独立。如果 成功后，该提案将为 T2D 精准医疗提供证据，并作为 未来基因型指导 GLP-1 RA 治疗选择的药物遗传学试验。