遗传变异决定了PPARγ的功能和抗糖尿病药物的活体反应
Raymond E Soccio1, Eric R Chen1, Satyajit R Rajapurkar1
1Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Cell
|July 4, 2015
概括
在PPARγ结合部位的遗传变异影响疾病风险和药物反应. 这些单核酸多态 (SNP) 影响基因表达和代谢特征,为个性化医学铺平了道路.
科学领域:
- 基因组学就是基因组学.
- 分子生物学分子生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- 与疾病风险相关的单核酸多态 (SNP) 经常在非编码DNA中发现.
- 氧酶增殖器激活受体玛 (PPARγ) 是抗糖尿病药物向的核受体,在脂肪组织功能中起作用.
研究的目的:
- 研究SNP在PPARγ结合位点中的作用及其对基因调节和药物反应的功能影响.
- 探索PPARγ占用率的遗传变异与对代谢疾病和药物疗效的个体易感性之间的联系.
主要方法:
- 在小鼠脂肪组织中的PPARγ结合位点对SNP丰富的分析.
- 评估SNP对PPARγ结合动机和附近基因表达的影响.
- 对小鼠特异性转录反应对 thiazolidinedione (TZD) 药物的评估.
- 检查影响PPARγ结合的人类脂肪组织SNP及其与代谢特征的关联.
主要成果:
- 在小鼠菌株选择性PPARγ结合位点上,SNP显著丰富.
- 许多SNP改变了PPARγ或其合作因子的结合动机,导致了菌株选择性基因调节.
- 基因决定的PPARγ结合解释了菌株特定的TZD药物效应.
- 在人类中,PPARγ位点中的动机改变SNP会导致差异结合,解释表达定量特征位置 (eQTL),并与代谢综合征参数相关.
结论:
- PPARγ基因组占用量的自然遗传变异是个体疾病风险和药物反应的关键决定因素.
- 了解PPARγ结合变异为在代谢疾病中提供个性化药物的分子基础.
- 影响PPARγ结合的SNP提供了对代谢特征和代谢失调的遗传结构的见解.
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