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Genetic polymorphism, linkage disequilibrium, haplotype structure and novel allele analysis of CYP2C19 and CYP2D6 in Han Chinese

The Pharmacogenomics Journal volume 9, pages 380–394 (2009)Cite this article

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.

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Acknowledgements

We like to express our sincere thanks to Professor Jun Yu and Dr Xumin Wang (Beijing Institute of Genomics, CAS) for their valuable contributions. This work is supported by the Knowledge Innovation Program of the Chinese Academy of Sciences.

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  1. Q Zhou and X M Yu: These authors contributed equally to this work

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  1. Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China

    Q Zhou, X M Yu, H B Lin, L Wang, Q Z Yun, S N Hu & D-M Wang

  2. Graduate University of Chinese Academy of Sciences, Beijing, China

    Q Zhou & L Wang

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SNH and DMW conceived and designed the experiments, QZ, XMY and QZY performed the experiments, QZ, XMY, HBL and LW analyzed the data. QZ and XMY drafted the paper. SNH and DMW supervised the research and revised the paper. All authors read and approved the final paper.

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Zhou, Q., Yu, X., Lin, H. et al. Genetic polymorphism, linkage disequilibrium, haplotype structure and novel allele analysis of CYP2C19 and CYP2D6 in Han Chinese. Pharmacogenomics J 9, 380–394 (2009). https://doi.org/10.1038/tpj.2009.31

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