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

项目摘要 胰升糖素样多肽1受体激动剂(GLP-1RAs)是近年来兴起的一类新的药物。 2型糖尿病(T2D)治疗算法的前沿是由于他们的血糖、代谢和 心血管方面的好处。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-1RA反应的遗传预测因素，以便有针对性地治疗那些最有可能发生的疾病 使那些可能经历不宽容的人受益并避免不必要的接触。在目标1中， 候选人将利用几个生物库链接的电子健康中可用的表型和基因数据 记录(EHR)以执行药物遗传学分析。GLP-1 RA反应的结果将使用 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，随后将在更多的人类队列中复制基因发现。 目标2将专注于在健康个体中创建一项口服赛马路德的药物扰动试验 描述急性生化反应的目的，通过血糖和胰岛素的变化来衡量 对混合餐耐受试验的反应水平。随后，该议定书将在目标3中实施，以 评估对口服赛马路德的急性反应如何因遗传变异而不同，以洞察潜在的 药物机制和T2D病理生理学。候选人将在初选中完成拟议的工作 马萨诸塞州综合医院内分泌科和糖尿病科主任何塞·弗洛雷斯博士的指导 MGH是T2D基因发现临床翻译方面的国际公认领先者。Dr。 乔丹·斯莫勒将担任共同导师，因为他在应用基于EHR的生物库方面具有专业知识 基因组研究和在大众Brigham生物库和我们所有人研究中的积极领导作用 程序。李博士将从事生物信息学和表型管理的课程工作，扩大她的经验 研究复杂性状遗传学，发展临床药理学知识，完善她在 生理调查，获得临床试验实施的实用技能，并定期收到来自 具有互补专业领域的研究咨询委员会。这个应用程序反映了一个谨慎的 有计划的培训计划，旨在使申请者具备开展未来工作所需的工具 T2D的药物遗传学研究，并推动申请人的科学事业走向独立。如果 如果成功，这项提议将为T2D的精准医学提供证据，并为 GLP-1RAS基因导向性治疗选择的未来药物遗传学试验。

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.