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 这项临床试验将揭示内源性和外源性的个体间反应的新机制 胰高血糖素样肽-1（GLP-1）在西班牙裔/拉丁裔（H/Ls）糖尿病前期患者中的作用。结果将 糖尿病前期、2型糖尿病（T2 DM）和相关代谢疾病的管理， 个体化的方法在研究不足和高危人群。糖尿病前期治疗的选择很少， 目前的T2 DM药物管理不能预测药物治疗失败， 个体治疗反应和副作用。一个精确的，基于遗传学的方法将提供上级 患者的治疗管理。基于GLP-1的治疗降低血糖，促进体重减轻， 减少心血管事件，改善肾功能。先前的遗传学研究，大多数是在高加索人中进行的， 确定了遗传变异与GLP-1诱导的胰岛素分泌减少之间的关联， 指导个体化治疗。然而，这些关联并没有提供一个明确的机械关系 基因型和表现型之间的区别转录组学分析将揭示许多这些机制。这里我们 建议1）测试调节表达的单核苷酸多态性（SNP）（eQTL）的关联 在具有差异GLP-1应答的一系列相关代谢组织中的11个候选基因中，2）进行RNA转录， 治疗前后测序，以鉴定血液中预测GLP-1治疗应答的eQTL， 建立基于风险的H/L预测模型，3）确定候选基因的遗传调控效应 基因和新发现的eQTL表型广泛的一个大型现有的生物库，BioVU。对于目标1和2， 将在300名患有前驱糖尿病的研究受试者中测量反应，这些受试者是从一个已建立的墨西哥- 通过口服最小模型方法，在GLP-1治疗前后定量GLP-1的美国队列 激素功效和GLP-1诱导胰腺β细胞胰岛素释放和外周胰岛素敏感性。 程序包括连续测量血糖、胰岛素、C肽和GLP-1以及外周血 收集RNA测序。我们的中心假设是：（1）GLP-1的代谢组织eQTL- 相关基因将与对内源性和外源性GLP-1的生理反应相关， (2)识别与GLP-1治疗诱导的全血变化相关的eQTL将识别新的 基因靶点，以及（3）这些数据将导致创建基于eQTL的相关疾病预测模型。 这项研究是创新的，因为它使用了eQTL分析和口腔最小模型的新组合来评估 GLP-1应答，检查药物基因组学研究中代表性极低的人群，并利用 研究基因表达的新型统计方法和应用。这个新获得的重要性 机械信息将最终指导糖尿病预防的精确治疗方案， 治疗、减肥、心血管风险降低和相关代谢并发症， 人口