Systematic Functional Study of Cytochrome P450 2D6 Promoter Polymorphisms in the Chinese Han Population |
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| Authors: | Xueli Gong Yichen Liu Xiaoqing Zhang Zhiyun Wei Ran Huo Lu Shen Lin He Shengying Qin |
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| Institution: | 1. Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders(Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China.; 2. Shanghai Genome Pilot Institutes for Genomics and Human Health, Shanghai, China.; 3. Shanghai Pulmonary Hospital, Shanghai, China.; 4. Institutes of Biomedical Sciences, Fudan University, Shanghai, China.; Universidad Europea de Madrid, Spain, |
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| Abstract: | The promoter polymorphisms of drug-metabolizing genes can lead to interindividual differences in gene expression, which may result in adverse drug effects and therapeutic failure. Based on the database of CYP2D6 gene polymorphisms in the Chinese Han population established by our group, we functionally characterized the single nucleotide polymorphisms (SNPs) of the promoter region and corresponding haplotypes in this population. Using site-directed mutagenesis, all the five SNPs identified and ten haplotypes with a frequency equal to or greater than 0.01 in the population were constructed on a luciferase reporter system. Dual luciferase reporter systems were used to analyze regulatory activity. The activity produced by Haplo3(−2183G>A, −1775A>G, −1589G>C, −1431C>T, −1000G>A, −678A>G), Haplo8(−2065G>A, −2058T>G, −1775A>G, −1589G>C, −1235G>A, −678A>G) and MU3(−498C>A) was 0.7−, 0.7−, 1.2− times respectively compared with the wild type in human hepatoma cell lines(p<0.05). These findings might be useful for optimizing pharmacotherapy and the design of personalized medicine. |
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