Pharmacogenetics of Diabetes Prevention

描述(申请人提供)：噻唑烷二酮(TZD)是一种相对较新的胰岛素增敏剂，用于治疗2型糖尿病(T2 DM)，也已被证明可降低或甚至预防高危人群患T2 DM的风险。然而，30%-40%的受试者对TZD治疗没有反应。TZDS是过氧化物酶体增殖物激活受体-G2(PPARG2)的激动剂。我们推测PPARG2编码基因的变异可能介导了对TZDS的反应。我们还假设，参与TZD新陈代谢或TZD刺激途径的蛋白质编码基因的变异也可能有助于对药物的反应。我们提出了以下一系列研究来解决这些假设。首先，我们建议对有妊娠期糖尿病(GDM)的拉丁裔患者进行为期三个月的开放标签吡格列酮(PIO)试验，以增加现有数据的样本量。女性将接受为期三个月的PIO(每天45毫克)治疗，并在基线和三个月时评估身体成分、胰岛素敏感性和b细胞功能。对PIO缺乏反应将由胰岛素敏感性的非显著改善来确定。这项试验将提供更多的数据来测试遗传变异和TZD反应之间的关联，以及TZD诱导的代谢表型变化。其次，我们建议对PPARG中与曲格列酮反应相关的遗传变异进行分型，并筛选候选基因；参与PIO代谢的三个细胞色素P-450基因(CYP2C8、CYP2C9和CYP3A4)；PPARG的关键辅助因子维甲酸X受体-a(RXRA)；以及PPARG刺激途径的关键调节因子--过氧化体增殖物激活受体-g共激活MA(PPARG1A)。第三，我们提出了特定的遗传分析来测试基因分型的变异，第二个目的是与对PIO和PLO诱导的表型变化的反应相关。我们提出了控制潜在人口分层和多重比较的方法。我们还提出了探索性分析，以检验多种遗传变异(基因内和基因间)对PIO反应的影响。我们的长期目标是了解TZD反应的遗传结构，并开发预测谁会或不会对TZD反应的方法。这将帮助临床医生避免在特定的T2 DM患者中进行成功率较低的干预。

DESCRIPTION (provided by applicant): Thiazolidinediones (TZD) are a relatively new class of insulin-sensitizing agents used to treat type 2 diabetes mellitus (T2DM) and have also been shown to reduce risk for, or even prevent, T2DM in at-risk individuals. However, 30-40% of subjects do not respond to TZD therapy. TZDs are agonists for peroxisome proliferator-activated receptor-g2 (PPARG2). We hypothesize that variation in the gene encoding for PPARG2 may mediate response to TZDs. We also hypothesize that variants in genes encoding for proteins involved in the metabolism of TZDs or in the TZD-stimulated pathway may also contribute to response to drug. We propose the following series of studies to address these hypotheses. First, we propose a three- month open-label pioglitazone (PIO) trial in Latinas with previous gestational diabetes (GDM) to increase the sample size of our existing data. Women will be placed on PIO (45 mg/d) for three months and body composition, insulin sensitivity, and b cell function will be assessed at baseline and 3-months. Lack of response to PIO will be determined by a non-significant improvement in insulin sensitivity. This trial will provide additional data to test association between genetic variants and TZD response, and TZD-induced changes in metabolic phenotypes. Second, we propose to genotype genetic variants in PPARG shown to be associated with response to troglitazone and to screen candidate genes; three cytochrome P-450 genes (CYP2C8, CYP2C9, and CYP3A4), which are involved in PIO metabolism; retinoid X receptor-a (RXRA) a critical co-factor for PPARG; and peroxisome proliferator-activated receptor-g coactivatoMa (PPARGC1A) a critical regulator of the PPARG-stimulated pathway. Third, we propose specific genetic analyses to test variants genotyped in the second aim for association with response to PIO and PlO-induced changes in phenotypes. We propose methods to control for potential population stratification and multiple comparisons. We also propose exploratory analyses to examine the effect of multiple genetic variants (within genes and between genes) on response to PIO. Our long-term goal is to understand the genetic architecture of TZD response and to develop approaches to predict who will or will not respond to TZDs. This will help clinicians to avoid interventions that have a low probability of success in a given patient with T2DM.