title: Genetic polymorphism, linkage disequilibrium, haplotype structure and novel allele analysis of CYP2C19 and CYP2D6 in Han Chinese.
abstract: The cytochrome P450 2C19 and 2D6 enzymes are predominantly found in the human liver, and have important functions in the metabolism of many different classes of commonly used drugs. Their genetic polymorphisms give rise to both important interethnic variability in metabolism and the risk of treatment failure or dose-dependent drug toxicity. To investigate genetic polymorphisms in CYP2C19 and CYP2D6 genes in Han Chinese, we sequenced regions of the 5' flanking region, exon, intron and 3' UTR from these two genes using 100 unrelated healthy Chinese Hans. We detected 48 genetic variants in CYP2C19. A total of 15 of them are novel, including two polymorphisms in putative transcriptional factor-binding sites. The CYP2C19*1, *2, *3, *4, *17, *23, *24 and *25 alleles have frequencies of 67.5, 25.5, 2, 0.5, 3, 0.5, 0.5 and 0.5%, respectively. Based on computational predictions, three novel alleles (CYP2C19*23, *24 and *25) are deleterious mutations of the CYP2C19 protein. In CYP2D6, we identified 84 different polymorphisms, including 18 novel single-nucleotide polymorphisms. One novel polymorphism is located in a potential cis-regulatory element of the gene. The allele frequencies of CYP2D6*1, *2, *4, *5, *6, *10, *14, *21, *36, *41, *43, *52 and *71 are 18.5, 14, 1, 7, 0.5, 49, 1.5, 0.5, 1, 4, 0.5, 1 and 1.5%, respectively. The occurrence of CYP2D6 duplication is 0.5%. The novel CYP2D6*71 is anticipated as a putative poor metabolizer allele. We also performed linkage disequilibrium analysis and observed strong linkage disequilibrium spanning of the CYP2C19 and CYP2D6 regions. In addition, network analysis showed that 15 haplotypes of CYP2C19 and 22 of CYP2D6 are classified into five and three groups, respectively. Comparisons of allele frequency distributions revealed significant interethnic and intraethnic differences in these two genes. In conclusion, this study revealed that CYP2C19 and CYP2D6 have a complicated allele composition and distinct frequency distribution in Han Chinese.
authors.affiliation: Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Zhou
authors.forename: X M
authors.initials: XM
authors.lastname: Yu
authors.forename: H B
authors.initials: HB
authors.lastname: Lin
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: Q Z
authors.initials: QZ
authors.lastname: Yun
authors.forename: S N
authors.initials: SN
authors.lastname: Hu
authors.forename: D-M
authors.initials: DM
authors.lastname: Wang
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D044466:Asian People / Q000235:genetics*; D001665:Binding Sites / Q000235:genetics; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005006:Ethnicity / Q000235:genetics; D005787:Gene Frequency; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D010802:Phylogeny; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6