title: CYP2C9 promoter variable number tandem repeat polymorphism regulates mRNA expression in human livers.
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 r(2) 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.
authors.affiliation: Program in Pharmacogenomics, Department of Pharmacology, School of Medicine, The Ohio State University, 333 West 10th Ave., Columbus, OH 43210, USA. wang.808@osu.edu
authors.forename: Danxin
authors.initials: D
authors.lastname: Wang
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Sun
authors.forename: Yan
authors.initials: Y
authors.lastname: Gong
authors.forename: Brian E
authors.initials: BE
authors.lastname: Gawronski
authors.forename: Taimour Y
authors.initials: TY
authors.lastname: Langaee
authors.forename: Mohamed Hossam A
authors.initials: MH
authors.lastname: Shahin
authors.forename: Sherief I
authors.initials: SI
authors.lastname: Khalifa
authors.forename: Julie A
authors.initials: JA
authors.lastname: Johnson
mesh_terms: D000925:Anticoagulants / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9; D015870:Gene Expression; D005787:Gene Frequency; D017930:Genes, Reporter; D056945:Hep G2 Cells; D006801:Humans; D019934:International Normalized Ratio; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D018598:Minisatellite Repeats / Q000235:genetics*; D008969:Molecular Sequence Data; D015999:Multivariate Analysis; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014162:Transfection; D014859:Warfarin / Q000493:pharmacokinetics
chemical_list: D000925:Anticoagulants; D012333:RNA, Messenger; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases