TY - JOUR T1 - CYP2C9 Promoter Variable Number Tandem Repeat Polymorphism (pVNTR) Regulates mRNA Expression in Human Livers JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.111.044255 SP - dmd.111.044255 AU - Danxin Wang AU - Xiaochun Sun AU - Yan Gong AU - Brian E Gawronski AU - Taimour Y Langaee AU - Mohamed Hossam A Shahin AU - Sherief I Khalifa AU - Julie A Johnson Y1 - 2012/01/01 UR - http://dmd.aspetjournals.org/content/early/2012/01/30/dmd.111.044255.abstract N2 - Cytochrome P450 2C9 (CYP2C9) is involved in metabolism of nearly 25% of clinically used drugs. Coding region polymorphisms CYP2C9*2 and *3 contribute to inter-person variability in drug dosage and clinical outcomes, while the role of 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 CYP2C9 mRNA level compared to the pVNTR-M (reference) allele. pVNTR-S is in linkage disequilibrium with *3, with LD R2 of 0.53 to 0.75 in different populations. In patients who were taking 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 minimal effect in vivo, or 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 non-synonymous *3 variant. ER -