Equipment Supplement due 5/20/2016 P0516422

 描述（申请人提供）二甲双胍是一种双胍类药物，被用作治疗2型糖尿病（T2 D）的一线疗法，但超过35%的二甲双胍单药治疗患者未能达到可接受的血糖控制。此外，研究表明，二甲双胍的药代动力学和药效学存在深刻的种族间差异，遗传因素有助于二甲双胍的反应。迄今为止，只有一项已发表的欧洲人二甲双胍应答的全基因组关联研究（GWAS），其他种族中没有GWAS。我们研究的主要目标是在接受二甲双胍治疗的大型多种族T2 D患者队列中确定导致二甲双胍无应答的遗传基因座和途径。我们的第二个目标是通过详细的细胞和临床研究，确定二甲双胍应答变异的基础罕见因果变异。为此，我们收集了丰富多样的临床队列，包括两组。提供DNA样本和临床信息的接受二甲双胍治疗的T2 D患者的大型多种族队列（N = 15，000）主要通过与Kaiser Permanente北方加州（KPNC）基因、环境和健康研究计划（RPGEH）和MetGen（一个国际财团，包括来自欧洲和美国的多个二甲双胍患者队列）的合作提供（N ~ 10 000）。我们的总体目标是：目标1。在来自美国和欧洲多个种族的28，000名参与者中确定影响二甲双胍反应的遗传变异;目标2。使用多层方法识别目标1中发现的基因的因果变体。特别是，我们将首先使用全基因组方法进行Meta分析，以发现二甲双胍应答变异的基础变异。下一步靶向重测序将用于将我们GWAS中鉴定的基因中的罕见变异与二甲双胍反应相关联。将在细胞中进行功能基因组研究以鉴定功能变体，然后将其与我们临床队列中的二甲双胍应答相关。最后，在目标3中，我们将进行内表型临床研究，以确定胰岛素敏感性和葡萄糖耐量的临床测量，以了解变体调节二甲双胍反应的机制。总的来说，这项研究提案提供了一种强大的多层方法，从最大的二甲双胍T2 D患者队列开始，以确定罕见和常见的遗传变异，这些变异是二甲双胍反应变异的基础，重要的是，了解它们的机制。该项目产生的数据将极大地有助于预测模型，最终将用于数据驱动的处方和抗糖尿病药物治疗的精确医学。

 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.