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Molecular Pharmacology

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Research ArticleArticle

Novel CYP2C9 Promoter Variants and Assessment of Their Impact on Gene Expression

Melissa A. Kramer, Allan E. Rettie, Mark J. Rieder, Erwin T. Cabacungan and Ronald N. Hines
Molecular Pharmacology June 2008, 73 (6) 1751-1760; DOI: https://doi.org/10.1124/mol.107.044149
Melissa A. Kramer
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Allan E. Rettie
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Mark J. Rieder
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Erwin T. Cabacungan
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Ronald N. Hines
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Abstract

There are a considerable number of reports identifying and characterizing genetic variants within the CYP2C9 coding region. Much less is known about polymorphic promoter sequences that also might contribute to interindividual differences in CYP2C9 expression. To address this problem, approximately 10,000 base pairs of CYP2C9 upstream information were resequenced using 24 DNA samples from the Coriell Polymorphism Discovery Resource. Thirty-one single-nucleotide polymorphisms (SNPs) were identified; nine SNPs were novel, whereas 22 were reported previously. Using both sequencing and multiplex single-base extension, individual SNP frequencies were determined in 193 DNA samples obtained from unrelated, self-reported Hispanic Americans of Mexican descent, and they were compared with similar data obtained from a non-Latino white cohort. Significant interethnic differences were observed in several SNP frequencies, some of which seemed unique to the Hispanic population. Analysis using PHASE 2.1 inferred nine common (>1%) variant haplotypes, two of which included the g.3608C>T (R144C) CYP2C9*2 and two the g.42614A>C (I359L) CYP2C9*3 SNPs. Haplotype variants were introduced into a CYP2C9/luciferase reporter plasmid using site-directed mutagenesis, and the impact of the variants on promoter activity assessed by transient expression in HepG2 cells. Both constitutive and pregnane X receptor-mediated inducible activities were measured. Haplotypes 1B, 3A, and 3B each exhibited a 65% decrease in constitutive promoter activity relative to the reference haplotype. Haplotypes 1D and 3B exhibited a 50% decrease and a 40% increase in induced promoter activity, respectively. These data suggest that genetic variation within CYP2C9 regulatory sequences is likely to contribute to differences in CYP2C9 phenotype both within and among different populations.

Footnotes

  • This work was supported in part by National Institutes of Health grant GM068797 and funds from the Children Research Institute, Children's Hospital and Health Systems.

  • ABBREVIATIONS: P450, cytochrome P450; SNP, single-nucleotide polymorphism; bp, base pair(s); 24PDR, 24 sample set from the Coriell Polymorphism Discovery Resource; DMSO, dimethyl sulfoxide; NF1/CTF, nuclear factor 1/CCAAT transcription factor site; HNF, hepatic nuclear factor; DCoH, dimerization cofactor; PCR, polymerase chain reaction; kbp, kilobase pair(s); SBE, single-base extension; PXR, pregnane X receptor; CAR, constitutive androstane receptor; ANOVA, analysis of variance.

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

  • ↵1 Current affiliation: Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota.

    • Received December 7, 2007.
    • Accepted February 28, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 73 (6)
Molecular Pharmacology
Vol. 73, Issue 6
1 Jun 2008
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Research ArticleArticle

Novel CYP2C9 Promoter Variants and Assessment of Their Impact on Gene Expression

Melissa A. Kramer, Allan E. Rettie, Mark J. Rieder, Erwin T. Cabacungan and Ronald N. Hines
Molecular Pharmacology June 1, 2008, 73 (6) 1751-1760; DOI: https://doi.org/10.1124/mol.107.044149

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Research ArticleArticle

Novel CYP2C9 Promoter Variants and Assessment of Their Impact on Gene Expression

Melissa A. Kramer, Allan E. Rettie, Mark J. Rieder, Erwin T. Cabacungan and Ronald N. Hines
Molecular Pharmacology June 1, 2008, 73 (6) 1751-1760; DOI: https://doi.org/10.1124/mol.107.044149
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