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Genetic Polymorphisms and Haplotypes of Major Drug Metabolizing Enzymes in East Asians and Their Comparison with Other Ethnic Populations

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Remarkable ethnic differences in drug response are well known, and many of these can be attributed to differences in genetic backgrounds. Accumulating evidence has shown that genetic polymorphisms can cause the alteration or even loss of activity in drug metabolizing enzymes, transporters and receptors. Thus, genetic polymorphisms may be important in understanding these ethnic differences in drug response. Furthermore, haplotypes, linked combinations of genetic polymorphisms on a chromosome, have the advantage of providing more useful information on phenotype- genotype links than individual polymorphisms. In the past 6 years, mostly as a Japanese national project, we resequenced the exons and enhancer/promoter regions of more than 30 drug metabolizing enzymes, transporters and receptors using genomic DNA from 100 to 500 Japanese subjects, analyzed linkage-disequilibrium (LD), and estimated haplotype structures. Regarding CYP2C9 and 2C19, we found linkages between CYP2C19*2 or *3 and CYP2C9*1, and between CYP2C9*3 and CYP2C19*1 haplotypes. Haplotype structures of CYP2D6 are complicated by gene duplication or recombination. In contrast, the haplotype structure of CYP3A4 was simple, but close linkages were observed with other CYP3As. As for UGT1As, the 8 first exons encoding active isoforms and common exons 2-5 were divided into 5 blocks by LD analysis, and intra- and inter-block haplotypes were estimated. Several linkages of haplotypes with functional importance were revealed, such as UGT1A7*3 - UGT1A6*2 - UGT1A1*28 or *6. In this review, we summarize polymorphisms and haplotype structures of these clinically important drug metabolizing enzymes in East Asians, mainly from our Japanese data, and compare them with those of other ethnicities.

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Keywords: CYP2C19 Alleles; CYP2C9 Polymorphisms; CYP2D6 Haplotypes; CYP3A4; UGT1A Gene

Document Type: Research Article

Affiliations: Project Team for Pharmacogenetics and Division of Biochemistry and Immunochemistry, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya, Tokyo 158-8501,Japan.

Publication date: March 1, 2007

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  • Current Pharmacogenomics provides comprehensive overviews of all current research on pharmacogenomics and pharmacogenetics. All areas of the field from pre-clinical to clinical research are covered, including related areas such as genomics, proteomics, target discovery, bioinformatics and novel diagnostics. This international journal is peer-reviewed and publishes both mini- and full review articles.

    The journal has become essential reading for all researchers and clinicians with interests in pharmacogenomics and pharmacogenetics.
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