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.