Pharmacogenomics of Thiazolidinedione Response

描述（由申请人提供）：噻唑烷二酮（TZDs）是一类胰岛素增敏药物，可用于治疗和预防2型糖尿病。然而，大约1/3接受TZDs治疗的个体表现出很少或没有临床反应。反应性不能从简单的临床参数来预测。因此，深入了解控制反应的遗传机制将进一步合理的处方实践，并可能为新药的开发提供信息。本研究的目的是通过对糖尿病前期个体给予TZD，确定控制临床反应的途径，并定位相关基因中的关键变异，从而揭示反应的预测因素。作为我们正在进行的PPAR-gamma项目的药物基因组学的延伸，拟议研究的具体目标有三个方面。(1)首先，我们将广泛描述75名患者对TZD罗格列酮治疗3个月的反应。该表征将在治疗前后进行，重点关注胰岛素敏感性，在脂肪和肌肉组织样本中观察到的临床反应的机制前体，以及通过微阵列分析从这些组织中获得的基因表达谱。(2)一旦我们确定了与TZD应答相关的调控通路，我们将确定这些通路中100个候选基因的序列变异和单倍型结构。(3)最后，我们将通过对我们的人群和其他接受TZD治疗的人群（糖尿病预防计划和TRIPOD/PI POD）的snp /单倍型的关联分析，确定哪些序列变异影响TZD反应。拟议的研究将为广泛处方糖尿病药物的作用机制和反应性的决定因素以及一般的胰岛素抵抗提供重要的见解。胰岛素抵抗是代谢综合征的核心因素，代谢综合征是一系列不良健康因素的集合，影响着五分之一的美国成年人。

DESCRIPTION (provided by applicant): Thiazolidinediones (TZDs) are a group of insulin-sensitizing drugs useful in the treatment and possibly in the prevention of type 2 diabetes mellitus. However, approximately 1/3 of individuals treated with TZDs show little or no clinical response. Responsiveness cannot be predicted from simple clinical parameters. Therefore, insight into the genetic mechanisms governing responsiveness will further rational prescription practices and may inform the development of new drugs. The purpose of the proposed research is to uncover predictors of response by administering a TZD to pre-diabetic individuals, defining the pathways governing clinical response, and locating crucial variants in the implicated genes. As an extension of our ongoing Pharmacogenomics of PPAR-gamma project, the Specific Aims of the proposed research are threefold. (1) First, we will characterize extensively the response of 75 individuals to 3 months of treatment with the TZD rosiglitazone. This characterization, which will be performed identically before and after treatment, focuses on insulin sensitivity, mechanistic precursors of clinical response observed in fat and muscle tissue samples, and gene expression profiles from these tissues obtained by microarray analysis. (2) Once we have identified the pathways whose regulation is correlated with TZD response, we will define sequence variation and haplotype structure of 100 candidate genes in these pathways. (3) Lastly, we will determine which sequence variants influence TZD response through association analysis of SNPs/haplotypes in our population and other populations treated with a TZD (Diabetes Prevention Program and TRIPOD/PI POD). The proposed studies will provide important insights into the mechanisms of action and determinants of responsiveness to a widely prescribed diabetes medication, as well as into insulin resistance in general. Insulin resistance is a central element of the metabolic syndrome, a constellation of adverse health factors that affects one in five adult Americans.