Received on August 11, 2006
Accepted on April 12, 2007

Molecular Diagnostics and Genetics

Estimation of Warfarin Maintenance Dose Based on VKORC1 (-1639 G>A) and CYP2C9 Genotypes

¹ Pathology and Laboratory Medicine, and Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, KY
² Tm Bioscience, Toronto, ON, Canada
³ Pathology and Laboratory Medicine, and Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, KY, and PGXL Laboratories, Louisville KY
⁴ PGXL Laboratories, Louisville KY
⁵ Pathology and Laboratory Medicine, University of Louisville School of Medicine, Louisville, KY, and PGXL Laboratories, Louisville KY

^* To whom correspondence should be addressed. E-mail: zhuyu{at}musc.edu.

Background: CYP2C9 polymorphisms are associated with decreased S-warfarin clearance and lower maintenance dosage. Decreased expression of VKORC1 resulting from the -1639G>A substitution has also been implicated in lower warfarin dose requirements. We investigated the additional contribution of this polymorphism to the variance in warfarin dose.

Methods: Sixty-five patients with stable anticoagulation were genotyped for CYP2C9 and VKORC1 with Tag-It^TM allele-specific primer extension technology. Plasma S-warfarin concentrations and warfarin maintenance dose were compared among patients on the basis of the VKORC1 -1639G>A genotype.

Results: Eighty percent of CYP2C9*1/*1 patients stabilized on <4.0 mg/day warfarin had at least 1 VKORC1 -1639A allele. Mean warfarin doses (SD) were 6.7 (3.3), 4.3 (2.2), and 2.7 (1.2) mg/day for patients with the VKORC1 -1639GG, GA, and AA genotypes, respectively. Steady-state plasma concentrations of S-warfarin were lowest in patients with the VKORC1 -1639AA genotype and demonstrated a positive association with the VKORC1 -1639G allele copy number (trend P = 0.012). A model including VKORC1 and CYP2C9 genotypes, age, sex, and body weight accounted for 61% of the variance in warfarin daily maintenance dose.

Conclusions: The VKORC1 -1639A allele accounts for low dosage requirements of most patients without a CYP2C9> variant. Higher plasma S-warfarin concentrations corresponding to increased warfarin maintenance dosages support a hypothesis for increased expression of the VKORC1 -1639G allele. VKORC1 and CYP2C9 genotypes, age, sex, and body weight account for the majority of variance in warfarin dose among our study population.