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: 10689328
• 负责人: Josephine H Li
• 金额: $ 19.08万
• 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/10689328
• 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 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; Patients; Periodicals; Persons; Pharmaceutical Preparations; Pharmacogenetics; Phenotype; Physiological; Population; Predisposition; Protocols documentation; Provider; Public Health; Recommendation; 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; Work; biobank; career; clinical practice; clinical translation; clinical trial implementation; cohort; comparative effectiveness; cost; drug efficacy; drug mechanism; expectation; experience; gastrointestinal; genetic analysis; 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; pharmacologic; practice setting; precision medicine; predicting response; programs; response; risk variant; side effect; skill acquisition; skills; tool; translational genetics

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）代表了最近出现的一类新药， 2型糖尿病（T2 D）治疗算法的最前沿，因为它们的血糖，代谢， 心血管益处。然而，它们的使用受到胃肠道副作用的阻碍。这项建议 旨在了解GLP-1 RA应答的遗传预测因子，以便将治疗靶向于最可能 以避免不必要地接触那些可能经历不容忍的人。在目标1中， 候选人将利用表型和基因型数据在几个生物库链接的电子健康 记录（EHR）进行药物遗传学分析。GLP-1 RA缓解的结局将使用 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应答，随后在其他人类队列中复制遗传学结果。 目标2将侧重于在健康个体中开展口服Semaglutide的药物扰动试验， 表征急性生化反应的目的，如通过葡萄糖和胰岛素的变化所测量的 混合餐耐受性试验的反应水平。随后，将在目标3中实施该议定书， 评估Semaglutide口服制剂的急性反应如何因遗传变异而不同，以深入了解潜在的 药物机制和T2 D病理生理学。候选人将完成初选下的拟议工作 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 医院（MGH）和国际公认的T2 D遗传发现临床转化的领导者。博士 Jordan Smoller将担任共同导师，因为他在基于EHR的生物库应用方面具有专业知识， 基因组研究和积极的领导作用，在马萨诸塞州一般布里格姆生物银行和我们所有的研究 程序.李博士将承担生物信息学和表型策展的课程， 在研究复杂的性状遗传学，发展临床药理学知识，完善她的专业知识， 生理调查，获得临床试验实施的实践技能，并定期收到来自 一个研究咨询委员会，具有互补的专业领域。该应用程序仔细反映了 计划的培训计划，旨在为申请人提供必要的工具，以进行未来的 T2 D药物遗传学研究，并推动申请人的科学事业走向独立。如果 如果成功，该提案将为T2 D中的精准医学提供证据，并为 GLP-1 RA基因型指导治疗选择的未来药物遗传学试验。