Pharmacogenetics of the Response to GLP-1 in Mexican-Americans with Prediabetes

患有糖尿病前期的墨西哥裔美国人对 GLP-1 反应的药物遗传学

• 批准号: 10448426
• 负责人: Absalon Dennis Gutierrez
• 金额: $ 68.87万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-09 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10448426
• 关键词: Adult; Adverse effects; Affect; Aftercare; Agonist; Algorithms; American; Beta Cell; Blood; Blood Glucose; Body Weight decreased; C-Peptide; Candidate Disease Gene; Cardiovascular Diseases; Cardiovascular system; Caucasians; Chemosensitization; Chronic; Chronic Disease; Clinical; Clinical Trials; Collection; Communities; County; DNA Databases; Data; Databases; Diabetes Mellitus; Diabetes prevention; Disease; Electronic Health Record; Event; GLP-I receptor; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Models; Genetic study; Genomics; Genotype; Glucose; Goals; Health; Hispanic; Hispanic Populations; Hormones; Individual; Insulin; Kidney; Kidney Diseases; Knowledge; Latino Population; Link; Measurement; Measures; Metabolic; Metabolic Diseases; Methods; Mexican; Mexican Americans; Modeling; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oral; Outcome; Pathway interactions; Patients; Peripheral; Persons; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Pharmacologic Substance; Pharmacotherapy; Phenotype; Physiological; Plasma; Population; Populations at Risk; Precision therapeutics; Prediabetes syndrome; Prevention; Procedures; Quantitative Trait Loci; Regimen; Regulation; Renal function; Risk; Risk Reduction; Role; Single Nucleotide Polymorphism; Standardization; Statistical Methods; Structure of beta Cell of islet; Study Subject; Testing; Therapeutic; Tissues; Translating; Treatment Failure; United States; Variant; Whole Blood; base; biobank; cardiovascular risk factor; cohort; comorbidity; drug efficacy; functional genomics; gene function; genetic variant; genomic locus; genomic variation; glucagon-like peptide 1; improved; indexing; individual response; individualized medicine; innovation; insulin secretion; insulin sensitivity; interest; meetings; novel; peripheral blood; personalized approach; personalized therapeutic; phenome; precision genetics; precision medicine; predicting response; predictive modeling; recruit; response; transcriptome sequencing; transcriptomics; treatment response

ABSTRACT This clinical trial will uncover new mechanisms of inter-individual responses to endogenous and exogenous glucagon-like peptide-1 (GLP-1) in Hispanics/Latinos (H/Ls) with prediabetes. The results move the management of prediabetes, type 2 diabetes mellitus (T2DM), and relevant metabolic diseases to a more individualized approach in an understudied and at-risk population. Few options exist for prediabetes treatment, and the current pharmaceutical management of T2DM does not predict drug treatment failures, nor differences in individual treatment responses and adverse effects. A precise, genetics-based approach will provide superior therapeutic management for patients. GLP-1-based therapies reduce blood glucose, promote weight loss, decrease cardiovascular events, and improve renal function. Prior genetic studies, most done in Caucasians, identified associations between genetic variants and decreased GLP-1-induced insulin secretion, in an effort to guide individualized treatment. However, these associations do not provide a clear mechanistic relationship between genotype and phenotype. Transcriptomic analyses will uncover many of these mechanisms. Here, we propose to 1) test the association of single nucleotide polymorphisms (SNPs) that regulate expression (eQTLs) of 11 candidate genes in a range of relevant metabolic tissues with differential GLP-1 response, 2) perform RNA sequencing before and after treatment to identify eQTLs in blood that predict response to GLP-1 therapy and develop risk-based prediction models in H/Ls, and 3) determine the effects of genetic regulation of candidate genes and newly discovered eQTLs phenome-wide in a large existing biobank, BioVU. For aims 1 and 2, responses will be measured in 300 study subjects with prediabetes recruited from an established Mexican- American cohort via the oral minimal model method, before and after GLP-1 therapy, quantifying GLP-1 hormone efficacy and GLP-1-induced pancreatic beta cell insulin release and peripheral insulin sensitivity. Procedures include serial measurements of plasma glucose, insulin, C-peptide, and GLP-1, and peripheral blood collection for RNA sequencing. Our central hypotheses are: (1) metabolic tissue-based eQTLs of GLP-1- associated genes will be associated with physiological response to endogenous and exogenous GLP-1, (2) identification of eQTLs associated with GLP-1 treatment-induced changes in whole blood will identify new gene targets, and (3) this data will lead to the creation of eQTL-based prediction models for related diseases. The study is innovative because it uses a novel combination of eQTL analysis and oral minimal model to assess GLP-1 response, examines a population highly underrepresented in pharmacogenomic studies, and utilizes novel statistical methods and applications to study gene expression. The significance of this newly acquired mechanistic information will ultimately guide precision therapeutic regimens for diabetes prevention and treatment, weight loss, cardiovascular risk reduction, and related metabolic complications in an understudied population.

摘要