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: 10615867
• 负责人: Absalon Dennis Gutierrez
• 金额: $ 69.49万
• 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/10615867
• 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; Exclusion; 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; 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; progression risk; 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.

抽象的 该临床试验将发现对内源性和外源性的个体间反应的新机制 西班牙裔/拉丁裔（H/LS）中的胰高血糖素样肽-1（GLP-1），具有糖尿病前期。结果移动 糖尿病前期，2型糖尿病（T2DM）和相关代谢疾病的管理 在一个研究且高危人群中的个性化方法。糖尿病前治疗的选择很少， T2DM的当前药物管理无法预测药物治疗失败，也没有差异 在个人治疗反应和不良反应中。基于遗传学的精确方法将为优越 患者的治疗管理。基于GLP-1的疗法减少血糖，促进体重减轻， 减少心血管事件并改善肾功能。先前在高加索人完成的遗传研究， 鉴定出遗传变异和降低GLP-1诱导的胰岛素分泌之间的关联，以努力 指导个性化治疗。但是，这些关联没有提供明确的机械关系 在基因型和表型之间。转录组分析将发现许多此类机制。在这里，我们 提议1）测试调节表达（EQTL）的单核苷酸多态性（SNP）的关联 在具有差异GLP-1反应的一系列相关代谢组织中的11个候选基因的中，2）执行RNA 在治疗前后进行测序以鉴定血液中的EQTL，以预测对GLP-1治疗的反应和 在H/LS中开发基于风险的预测模型，3）确定候选者遗传调节的影响 基因和新发现的EQTL现象在Biovu的大型现有生物库中。对于目标1和2， 将在300名研究受试者中测量反应，并从已建立的墨西哥 - 通过口服最小模型方法，GLP-1治疗前后，美国队列，量化GLP-1 激素功效和GLP-1诱导的胰腺β细胞胰岛素释放和周围胰岛素敏感性。 程序包括血浆葡萄糖，胰岛素，C肽和GLP-1的系列测量以及外周血 用于RNA测序的收集。我们的中心假设是：（1）GLP-1-的代谢组织eqtls 相关的基因将与对内源性和外源性GLP-1的生理反应有关， （2）鉴定与GLP-1治疗引起的全血的变化相关的EQTL将鉴定出新的 基因靶标，（3）这些数据将导致创建基于EQTL的相关疾病预测模型。 该研究具有创新性，因为它使用了EQTL分析和口服最小模型的新型组合来评估 GLP-1反应研究了药物基因组学研究中人口高度不足的人群，并利用 新的统计方法和研究基因表达的应用。这个新获得的意义 机械信息最终将指导预防糖尿病的精确治疗方案 治疗，体重减轻，降低心血管风险和相关代谢并发症 人口。