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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Asian People / ethnology*
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Asian People / genetics*
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Computational Biology
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Cytochrome P-450 CYP2D6 / genetics*
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Cytochrome P-450 CYP2D6 / metabolism*
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Ethnicity / genetics*
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Genes, Reporter / genetics
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Hep G2 Cells
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Humans
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Luciferases / genetics
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Mutagenesis, Site-Directed
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Polymorphism, Single Nucleotide*
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Promoter Regions, Genetic / genetics*
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Transcription Factors / metabolism
Substances
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Transcription Factors
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Luciferases
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Cytochrome P-450 CYP2D6
Grants and funding
This work was supported by the 863 Program (2012AA02A515),the 973 Program (2010CB529600), the National Key Technology R&D Program (2012BAI01B09), the National Nature Science Foundation of China (30900799, 30972823, 81273596,81121001), the Shanghai Jiao Tong University Med-X Fund (YG2010MS61), the Public Science and Technology Research Funds(201210056), the Shanghai Jiao Tong University Interdisciplinary Research fund, the Major Program of the Shanghai Committee of Science and Technology (11dz1950300 ) and the Shanghai Leading Academic Discipline Project (B205). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.