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Research ArticleArticle

CYP2C9 Promoter Variable Number Tandem Repeat Polymorphism Regulates mRNA Expression in Human Livers

Danxin Wang, Xiaochun Sun, Yan Gong, Brian E. Gawronski, Taimour Y. Langaee, Mohamed Hossam A. Shahin, Sherief I. Khalifa and Julie A. Johnson
Drug Metabolism and Disposition May 2012, 40 (5) 884-891; DOI: https://doi.org/10.1124/dmd.111.044255
Danxin Wang
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Xiaochun Sun
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Yan Gong
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Brian E. Gawronski
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Taimour Y. Langaee
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Mohamed Hossam A. Shahin
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Sherief I. Khalifa
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Julie A. Johnson
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Abstract

CYP2C9 is involved in metabolism of nearly 25% of clinically used drugs. Coding region polymorphisms CYP2C9*2 and *3 contribute to interperson variability in drug dosage and clinical outcomes, whereas the role of a regulatory polymorphism remains uncertain. Measuring allelic RNA expression in 87 human liver samples, combined with genotyping, sequencing, and reporter gene assays, we identified a promoter variable number tandem repeat polymorphism (pVNTR) that fully accounted for allelic CYP2C9 mRNA expression differences. Present in three different variant forms [short (pVNTR-S), medium (pVNTR-M), and long (pVNTR-L)], only the pVNTR-S allele reduced the CYP2C9 mRNA level compared with the pVNTR-M (reference) allele. pVNTR-S is in linkage disequilibrium with *3, with linkage disequilibrium r2 of 0.53 to 0.75 in different populations. In patients who were taking a maintenance dose of warfarin, the mean warfarin dose was associated with the copies of pVNTR-S (p = 0.0001). However, in multivariate regression models that included the CYP2C9*3, pVNTR-S was no longer a significant predictor of the warfarin dose (p = 0.60). These results indicate that although pVNTR-S reduced CYP2C9 mRNA expression, the in vivo effects of pVNTR-S on warfarin metabolism cannot be separated from the effects of *3. Therefore, it is not necessary to consider pVNTR-S as an additional biomarker for warfarin dosing. Larger clinical studies are needed to define whether the pVNTR-S has a minimal effect in vivo, or whether the effect attributed to *3 is really a combination of effects on expression by the pVNTR-S along with effects on catalytic activity from the nonsynonymous *3 variant.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Allergy and Infectious Diseases [Grant R21-AI074399] (to D.W.); and the National Institutes of Health National Institute of General Medical Sciences [Grants U01-GM092655, U01-GM074492] (to D.W. and J.A.J., respectively).

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    http://dx.doi.org/10.1124/dmd.111.044255.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    kb
    kilobase
    pVNTR
    promoter variable number tandem repeat
    pVNTR-S
    short pVNTR
    pVNTR-M
    medium pVNTR
    pVNTR-L
    long pVNTR
    AEI
    allelic expression imbalance
    LD
    linkage disequilibrium
    H1
    haplotype 1
    H2
    haplotype 2
    HNF1α
    human hepatocyte nuclear factor 1α
    HNF4α
    human hepatocyte nuclear factor 4α
    CAR
    constitutive androstane receptor
    CEBPA
    CCAAT/enhancer binding protein α
    PXR
    pregnane X receptor
    SNP
    single-nucleotide polymorphism
    PCR
    polymerase chain reaction
    SMX
    sulfomethoxazole
    hnRNA
    heteronuclear RNA
    bp
    base pair
    GATA4
    GATA binding protein 4.

  • Received December 8, 2011.
  • Accepted January 30, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (5)
Drug Metabolism and Disposition
Vol. 40, Issue 5
1 May 2012
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Research ArticleArticle

CYP2C9 PROMOTER pVNTR POLYMORPHISM REGULATES GENE EXPRESSION

Danxin Wang, Xiaochun Sun, Yan Gong, Brian E. Gawronski, Taimour Y. Langaee, Mohamed Hossam A. Shahin, Sherief I. Khalifa and Julie A. Johnson
Drug Metabolism and Disposition May 1, 2012, 40 (5) 884-891; DOI: https://doi.org/10.1124/dmd.111.044255

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Research ArticleArticle

CYP2C9 PROMOTER pVNTR POLYMORPHISM REGULATES GENE EXPRESSION

Danxin Wang, Xiaochun Sun, Yan Gong, Brian E. Gawronski, Taimour Y. Langaee, Mohamed Hossam A. Shahin, Sherief I. Khalifa and Julie A. Johnson
Drug Metabolism and Disposition May 1, 2012, 40 (5) 884-891; DOI: https://doi.org/10.1124/dmd.111.044255
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