Equipment Supplement due 5/20/2016 P0516422

设备补充应于 2016 年 5 月 20 日 P0516422

• 批准号: 9274465
• 负责人: JOSE CARLOS FLOREZ
• 金额: $ 2.49万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-25 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9274465
• 关键词: Affect; Antidiabetic Drugs; Biguanides; Biological Markers; California; Cells; Clinical; Clinical Research; Code; DNA; Data; Diabetes Mellitus; Disease; Drug Kinetics; Drug Prescriptions; Environment; Equipment; Ethnic group; Europe; European; GLUT2 gene; Genes; Genetic; Genotype; Glucose Transporter; Glycosylated Hemoglobin; Glycosylated hemoglobin A; Goals; Health; Heart Diseases; International; Label; Liver diseases; Measurement; Meta-Analysis; Metabolic syndrome; Metformin; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Obesity; Ovarian; Participant; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenomics; Pharmacotherapy; Phenotype; Publishing; Research; Research Proposals; Sample Size; Sampling; Tail; Targeted Resequencing; Time; Variant; Work; base; clinical phenotype; cohort; computer studies; endophenotype; ethnic difference; fasting glucose; functional genomics; gene discovery; genetic variant; genome wide association study; genome-wide; glucose tolerance; glycemic control; insight; insulin sensitivity; inter-individual variation; non-alcoholic fatty liver; personalized medicine; precision medicine; predictive modeling; programs; rare variant; research study; response

 DESCRIPTION (provided by applicant) Metformin, a biguanide, is used as first-line therapy to treat type 2 diabetes (T2D), yet over 35% of patients on metformin monotherapy fail to achieve acceptable glycemic control. In addition, studies indicate that there are profound inter-ethnic differences in the pharmacokinetics and pharmacodynamics of metformin, and that genetic factors contribute to metformin response. To date, there has been only a single published genomewide association study (GWAS) of metformin response in Europeans, and no GWAS in other ethnic The major goal of our study is to identify the genetic loci and pathways that confer nonresponse to metformin in a large multi-ethnic cohort of T2D patients on metformin. Our second goal is to identify rare causal variants that underlie variation in response to metformin through detailed cellular and clinical studies. To this end, we have assembled rich and diverse clinical cohorts including two groups. large multi-ethnic cohorts of patients with T2D on metformin who have provided DNA samples and clinical information (N = 15,000) made available largely through partnerships with the Kaiser Permanente Northern California (KPNC) Research Program on Genes, Environment and Health (RPGEH) and MetGen, an international consortium, which includes multiple cohorts from Europe and the U.S. of patients on metformin (N ~ 10,000). Our overall aims are to: Aim 1. Identify genetic variants that impact response to metformin in 28,000 participants from multiple ethnic groups in the U.S. and Europe; and Aim 2. Identify the causal variants of genes discovered in Aim 1, using a multi-tier approach. In particular, we will first use genomewide approaches with meta analyses to discover variants that underlie variation in response to metformin. Next targeted resequencing will be used to associate rare variants in genes that are identified in our GWAS with metformin response. Functional genomic studies in cells will be performed to identify functional variants, which will then be associated with metformin response in our clinical cohorts. Finally, in Aim 3, we will conduct endophenotypic clinical studies to determine clinical measurements of insulin sensitivity and glucose tolerance to understand the mechanisms through which the variants modulate metformin response. Collectively, this research proposal provides a robust multi-tier approach beginning with the largest cohort of patients with T2D on metformin to identify rare and common genetic variants that underlie variation in response to metformin and importantly, to understand their mechanisms. Data generated in this project will contribute enormously to predictive models that ultimately will be used for data-driven prescribing and precision medicine for anti- diabetic drug therapy.

 描述（由适用的）二甲甲胺（Biguanide）用作治疗2型糖尿病（T2D）的一线治疗，但超过35％的二甲双胍单药治疗患者无法获得可接受的血糖控制。此外，研究表明，二甲双胍的药代动力学和药效学存在很大的种族间差异，遗传因素有助于二甲双胍反应。迄今为止，欧洲人中只有一项已发表的二甲双胍反应的全基因组关联研究（GWAS），而在其他种族中没有GWAS的主要目的是确定遗传局部和途径，该遗传局部和途径在大型T2D患者的大型多民族群体中对二甲双胍无反应。我们的第二个目标是确定通过详细的细胞和临床研究响应二甲双胍响应差异的罕见因果变异。为此，我们组装了富裕和潜水员的临床人群，其中包括两组。 large multi-ethnic cohorts of patients with T2D on metformin who have provided DNA samples and clinical information (N = 15,000) made available largely through partnerships with the Kaiser Permanente Northern California (KPNC) Research Program on Genes, Environment and Health (RPGEH) and MetGen, an international consortium, which includes multiple cohorts from Europe and the U.S. of patients on metformin (N ~ 10,000).我们的总体目的是：目标1。确定影响美国和欧洲多个族裔参与者的二甲双胍反应的遗传变异。和目标2。使用多层方法确定在AIM 1中发现的基因的因果变异。特别是，我们将首先使用元分析的全基因组方法来发现响应二甲双胍的变异的变体。接下来的靶向重新方程将用于将在我们的GWAS中鉴定出的基因中的稀有变体与二甲双胍反应相关联。将在细胞中进行功能性基因组研究以识别功能变异，然后在我们的临床队列中与二甲双胍反应有关。最后，在AIM 3中，我们将进行内生典型临床研究，以确定胰岛素敏感性和葡萄糖耐受性的临床测量，以了解变体调节二甲双胍反应的机制。总的来说，该研究建议提供了一种强大的多层方法，从二甲双胍上最大的T2D患者队列开始，以鉴定稀有和常见的遗传变异，这些变异是响应于二甲双胍的差异，并且重要的是了解其机制。该项目中产生的数据将对预测模型产生巨大贡献，这些模型最终将用于抗糖尿病药物治疗的数据驱动处方和精确医学。