Pharmacogenetics of Diabetes Prevention

描述（由申请人提供）：噻唑烷二酮（TZD）是一类相对较新的胰岛素增敏药物，用于治疗2型糖尿病（T2DM），也被证明可以降低风险，甚至预防高危人群的T2DM。然而，30-40%的受试者对TZD治疗没有反应。tzd是过氧化物酶体增殖激活受体-g2 （PPARG2）的激动剂。我们假设PPARG2基因编码的变异可能介导了对TZDs的反应。我们还假设，参与tzd代谢或tzd刺激通路的蛋白质编码基因的变异也可能有助于对药物的反应。我们提出以下一系列的研究来解决这些假设。首先，我们建议对既往妊娠糖尿病（GDM）的拉丁裔患者进行为期3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。妇女将服用PIO (45mg /d) 3个月，并在基线和3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无显著改善来确定。该试验将提供额外的数据来测试遗传变异与TZD反应之间的关系，以及TZD诱导的代谢表型变化。其次，我们建议对显示与曲格列酮反应相关的PPARG遗传变异进行基因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）；类维甲酸X受体-a （RXRA）是PPARG的关键辅助因子；和过氧化物酶体增殖物激活受体-g共激活oma （PPARGC1A）是pparg刺激途径的关键调节因子。第三，我们提出了特定的遗传分析，以测试基因分型的变异与PIO和plo诱导的表型变化的关联。我们提出了控制潜在人群分层和多重比较的方法。我们还提出探索性分析，以检查多种遗传变异（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，并开发方法来预测谁会或不会对TZD作出反应。这将有助于临床医生避免对T2DM患者进行低成功率干预。

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.