Pharmacogenomics of Thiazolidinedione Response

说明(申请人提供)：噻唑烷二酮(TZD)是一组胰岛素增敏药物，用于治疗和可能预防2型糖尿病。然而，在接受TZDS治疗的患者中，约有三分之一的患者表现出很少或没有临床反应。仅凭简单的临床参数是无法预测疗效的。因此，深入了解控制反应的遗传机制将进一步促进合理的处方实践，并可能为新药的开发提供信息。这项拟议的研究的目的是通过给糖尿病前期患者服用TZD，定义控制临床反应的途径，并定位相关基因中的关键变异，来揭示反应的预测因素。作为我们正在进行的PPAR-伽马药物基因组学项目的延伸，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名患者在服用TZD罗格列酮3个月后的反应。这项将在治疗前和治疗后同样进行的表征集中在胰岛素敏感性、在脂肪和肌肉组织样本中观察到的临床反应的机制先兆，以及通过微阵列分析获得的这些组织的基因表达谱。(2)一旦我们确定了调控与TZD反应相关的途径，我们将确定这些途径中100个候选基因的序列变异和单倍型结构。(3)最后，我们将通过对本人群和其他接受TZD(糖尿病预防计划和Tripod/PI POD)治疗的人群的SNPs/单倍型的关联分析，确定哪些序列变异会影响TZD的反应。拟议中的研究将对广泛开出的糖尿病药物的作用机制和反应决定因素以及对胰岛素抵抗的一般情况提供重要的见解。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利的健康因素，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.