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

基本信息

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
项目类别：
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

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

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项目摘要

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.