Geng Zhaoxu, Zheng Yuanting, Li Qian, Pan Desi, Lu Xianping, Chen Fei, Zhang Ying, Li Keying, Zhou Kaixin, Shi Leming, Wang You
Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.
Pharmacogenomics. 2024;25(14-15):605-610. doi: 10.1080/14622416.2024.2430163. Epub 2024 Nov 18.
Our objective was to explore the pharmacogenetic impact of three known functional variants in drug target genes and determine whether they can explain the inter-individual variation in therapeutic response.
In a post hoc analysis of data from randomized controlled clinical trials of chiglitazar, we genotyped 481 Chinese patients with T2DM and investigated the association of variants in PPAR genes with the therapeutic outcome separated by dose using linear regression.
rs1800234, a gain-of-function variant of PPARA, had a dose-dependent pharmacogenetic impact on the therapeutic response to chiglitazar. The C allele was significantly associated with reduced therapeutic response in the 48 mg group, while no significant association was observed in the 32 mg group. In addition, in patients without the C allele, patients treated with 48 mg chiglitazar had a better therapeutic response than those treated with 32 mg chiglitazar. To the contrary, in patients with the C allele, patients treated with 48 mg chiglitazar had a worse therapeutic response than those treated with 32 mg of chiglitazar.
The PPARA variant rs1800234 had a dose-dependent pharmacogenetic impact on the therapeutic response to chiglitazar. It could help explain the absence of a dose effect of chiglitazar and serve as a potential biomarker for the chosen dose of chiglitazar in the future. In addition, our study provided important reference for the design and clinical application of multi-target drugs.
我们的目的是探讨药物靶基因中三个已知功能变异的药物遗传学影响，并确定它们是否能够解释个体间治疗反应的差异。
在一项关于吡格列酮的随机对照临床试验数据的事后分析中，我们对481例中国2型糖尿病患者进行基因分型，并使用线性回归研究PPAR基因变异与按剂量区分的治疗结果之间的关联。
PPARA的功能获得性变异rs1800234对吡格列酮的治疗反应具有剂量依赖性的药物遗传学影响。C等位基因在48mg组中与治疗反应降低显著相关，而在32mg组中未观察到显著关联。此外，在没有C等位基因的患者中，接受48mg吡格列酮治疗的患者比接受32mg吡格列酮治疗的患者具有更好的治疗反应。相反，在有C等位基因的患者中，接受48mg吡格列酮治疗的患者比接受32mg吡格列酮治疗的患者治疗反应更差。
PPARA变异rs1800234对吡格列酮的治疗反应具有剂量依赖性的药物遗传学影响。它有助于解释吡格列酮剂量效应的缺失，并可作为未来选择吡格列酮剂量的潜在生物标志物。此外，我们的研究为多靶点药物的设计和临床应用提供了重要参考。
