PPARA variant rs1800234 had a dose dependent pharmacogenetics impact on the therapeutic response to chiglitazar.

Autor:	Geng Z; Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.; College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China., Zheng Y; State Key Laboratory of Genetic Engineering, School of Life Sciences, Human Phenome Institute and Shanghai Cancer Center, Fudan University, Shanghai, China., Li Q; College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China., Pan D; Shenzhen Chipscreen Biosciences Co. Ltd, Shenzhen, Guangdong, China., Lu X; Shenzhen Chipscreen Biosciences Co. Ltd, Shenzhen, Guangdong, China., Chen F; China-Japan Friendship Hospital, Beijing, China., Zhang Y; School of Clinical and Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China., Li K; School of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China., Zhou K; Guangzhou Laboratory, Guangzhou International Bio Island, Guangzhou, China., Shi L; State Key Laboratory of Genetic Engineering, School of Life Sciences, Human Phenome Institute and Shanghai Cancer Center, Fudan University, Shanghai, China., Wang Y; Center for Translational Research, Shenzhen Bay Laboratory, Shenzhen, Guangdong, China.
Jazyk:	angličtina
Zdroj:	Pharmacogenomics [Pharmacogenomics] 2024 Nov 18, pp. 1-6. Date of Electronic Publication: 2024 Nov 18.
DOI:	10.1080/14622416.2024.2430163
Abstrakt:	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.
Databáze:	MEDLINE
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