title: Systematic functional study of cytochrome P450 2D6 promoter polymorphisms in the Chinese Han population.
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.
authors.affiliation: Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Xueli
authors.initials: X
authors.lastname: Gong
authors.forename: Yichen
authors.initials: Y
authors.lastname: Liu
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Zhang
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: Wei
authors.forename: Ran
authors.initials: R
authors.lastname: Huo
authors.forename: Lu
authors.initials: L
authors.lastname: Shen
authors.forename: Lin
authors.initials: L
authors.lastname: He
authors.forename: Shengying
authors.initials: S
authors.lastname: Qin
mesh_terms: D000818:Animals; D044466:Asian People / Q000208:ethnology* / Q000235:genetics*; D019295:Computational Biology; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism*; D005006:Ethnicity / Q000235:genetics*; D017930:Genes, Reporter / Q000235:genetics; D056945:Hep G2 Cells; D006801:Humans; D008156:Luciferases / Q000235:genetics; D016297:Mutagenesis, Site-Directed; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D014157:Transcription Factors; D008156:Luciferases; D019389:Cytochrome P-450 CYP2D6