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(T2D)的一线药物，但超过35%的患者在接受二甲双胍单药治疗时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在种族间存在着深刻的差异，遗传因素对二甲双胍的反应有贡献。到目前为止，在欧洲人中只有一项已发表的关于二甲双胍反应的全基因组关联研究，在其他种族中还没有。我们研究的主要目标是确定在大量服用二甲双胍的多种族T2D患者中，导致二甲双胍无反应的遗传位点和途径。我们的第二个目标是通过详细的细胞和临床研究，找出导致二甲双胍反应变异的罕见的因果变异。为此，我们组建了包括两组在内的丰富多样的临床队列。主要通过与北加州凯撒永久基因、环境和健康研究计划(RPGEH)和MetGen(一个包括来自欧洲和美国的多个二甲双胍患者队列)的合作伙伴关系提供DNA样本和临床信息(N=15,000)的大型多民族二甲双胍患者队列。我们的总体目标是：目标1.确定影响来自美国和欧洲多个民族的28,000名参与者对二甲双胍反应的基因变异；以及目标2.使用多层次方法识别在目标1中发现的基因的因果变异。特别是，我们将首先使用全基因组方法和荟萃分析来发现对二甲双胍反应的变异背后的变异。下一步，将使用定向重测序来将我们的GWAs中识别的基因中的罕见变异与二甲双胍反应相关联。我们将在细胞中进行功能基因组研究，以确定功能变异，然后将其与临床队列中的二甲双胍反应联系起来。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，以了解变异体调节二甲双胍反应的机制。总而言之，这项研究提案提供了一种强大的多层次方法，从服用二甲双胍的最大T2D患者队列开始，以识别导致对二甲双胍反应的变异的罕见和常见的遗传变异，并重要的是，了解它们的机制。该项目产生的数据将对预测模型做出巨大贡献，这些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准药物。

 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.