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

摘要 这项临床试验将揭示个体间对内源性和外源性反应的新机制。 高血糖素样多肽-1(GLP-1)在西班牙裔/拉丁裔(H/L)糖尿病前期患者中的表达。结果将移动 糖尿病前期、2型糖尿病(T2 DM)及相关代谢性疾病的管理 研究不足和高危人群中的个体化方法。糖尿病前期治疗的选择很少， 而目前对T2 DM的药物管理并不能预测药物治疗的失败，也不能预测差异 在个别治疗中的反应和不良反应。精确的、基于遗传学的方法将提供更好的 对病人的治疗管理。以GLP-1为基础的疗法降低血糖，促进减肥， 减少心血管事件，改善肾功能。之前的基因研究大多是在高加索人身上完成的， 确定了基因变异和GLP-1诱导的胰岛素分泌减少之间的关联，以努力 引导个体化治疗。然而，这些关联并不提供明确的机械性关系 在基因和表型之间。转录分析将揭示其中许多机制。在这里，我们 建议1)测试调节表达的单核苷酸多态(SNPs)(EQTL)之间的关联 在一系列相关代谢组织中具有差异GLP-1反应的11个候选基因中，2)执行RNA 对治疗前后进行测序以确定血液中预测GLP-1治疗和 建立基于风险的H/L预测模型，以及3)确定候选基因调控的效果 基因和新发现的eQTL在现有的大型生物库BioVU中广泛存在。对于目标1和目标2， 将对300名患有糖尿病前期的研究对象进行反应测量，这些受试者来自墨西哥- 美国队列通过口服最小模型方法，在GLP-1治疗前后，量化GLP-1 激素疗效和GLP-1诱导的胰岛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 用于RNA测序的集合。我们的中心假设是：(1)GLP-1的基于代谢组织的eQTL- 相关基因将与内源和外源GLP-1的生理反应相关， (2)识别与GLP-1治疗引起的全血变化相关的eQTL将识别新的 (3)这些数据将导致建立基于eQTL的相关疾病预测模型。 这项研究具有创新性，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反应，检查在药物基因组学研究中严重低于代表性的人群，并利用 研究基因表达的新统计方法和应用。新获得的这一点的意义 机械性信息最终将指导糖尿病预防和治疗的精确治疗方案 未被研究的患者的治疗、体重减轻、心血管风险降低和相关代谢并发症 人口。

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.