TY - JOUR T1 - Novel <em>CYP2C9</em> Promoter Variants and Assessment of Their Impact on Gene Expression JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1751 LP - 1760 DO - 10.1124/mol.107.044149 VL - 73 IS - 6 AU - Melissa A. Kramer AU - Allan E. Rettie AU - Mark J. Rieder AU - Erwin T. Cabacungan AU - Ronald N. Hines Y1 - 2008/06/01 UR - http://molpharm.aspetjournals.org/content/73/6/1751.abstract N2 - 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 (&gt;1%) variant haplotypes, two of which included the g.3608C&gt;T (R144C) CYP2C9*2 and two the g.42614A&gt;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. The American Society for Pharmacology and Experimental Therapeutics ER -