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Novel Hispanic American CYP2C9 Genetic Variants and Assessment of Their Impact on Gene Expression
Author(s) -
Kramer Melissa A.,
Rettie Allan E.,
Rieder Mark J.,
Hines Ronald N.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a415
Subject(s) - haplotype , single nucleotide polymorphism , genetics , biology , gene , snp , promoter , dna sequencing , allele , microbiology and biotechnology , genotype , gene expression
Genetic variants within CYP2C9 regulatory sequences were identified by re‐sequencing ~10 kbp of 5′‐flanking information using 24 DNA samples from the Coriell Polymorphism Discovery Resource. Thirty‐one single nucleotide polymorphisms (SNPs) were identified. DNA sequencing and multiplex single‐base extension were used to determine SNP frequencies in 193 DNA samples from unrelated Hispanic Americans of Mexican descent and compared to similar data obtained from a non‐Latino white cohort. Significant interethnic differences were observed in the frequency of variants, some of which appeared unique to the Hispanic population. Nine haplotypes >1% were inferred using Phase 2.1, two of which included the R144C ( CYP2C9*2 ) and two the I359L ( CYP2C9*3 ) SNPs. Haplotype variants were introduced into a CYP2C9 /luciferase reporter plasmid using site‐directed mutagenesis and the impact on constitutive and PXR‐mediated inducible promoter activity assessed by transient expression in HepG2 cells. 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 CYP2C9 regulatory polymorphisms contribute to differences in CYP2C9 phenotype both within and among different populations. (Supported by PHS GM068797)