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作者

Zhaoxu Geng Yuanting Zheng Qian Li Desi Pan Xianping Lu Fei Chen Ying Zhang Keying Li Kaixin Zhou Leming Shi You Wang

作者单位

^{2 5 State Key Laboratory of Genetic Engineering, School of Life Sciences, Human Phenome Institute and Shanghai Cancer Center, Fudan University, Shanghai, China 4 3 Shenzhen Chipscreen Biosciences Co. Ltd, Shenzhen, Guangdong, China 7g School of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China 9i Center for Translational Research, Shenzhen Bay Laboratory, Shenzhen, Guangdong, China 6f School of Clinical and Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China 8h Guangzhou Laboratory, Guangzhou International Bio Island, Guangzhou, China 1a Institute of Biophysics, Chinese Academy of Sciences, Beijing, China College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China China-Japan Friendship Hospital, Beijing, China}

刊名

Pharmacogenomics

ISSN

1462-2416

关键词

Chiglitazar therapeutic response pharmacogenetics PPAR rs1800234 dose

摘要

Background 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. Methods 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. Results...更多

Background 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. Methods 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. Results 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. Conclusion 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.收起

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期刊