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Clinical Chemistry 53: 1199-1205, 2007. First published May 17, 2007; 10.1373/clinchem.2006.078139
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(Clinical Chemistry. 2007;53:1199-1205.)
© 2007 American Association for Clinical Chemistry, Inc.

Molecular Diagnostics and Genetics

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

Yusheng Zhu1,a,3, Michael Shennan2, Kristen K. Reynolds1,3, Nancy A. Johnson3, Matthew R. Herrnberger3, Roland Valdes, Jr1,3 and Mark W. Linder1,3,a

1 Department of Pathology and Laboratory Medicine, University of Louisville School of Medicine, Louisville, KY.
2 Luminex Molecular Diagnostics (formerly Tm Bioscience), Toronto, ON, Canada.
3 PGXL Laboratories, Louisville KY.

aAddress correspondence to these authors at: Department of Pathology and Laboratory Medicine, University of Louisville School of Medicine, Louisville, KY 40202. Fax 502-852-1177; e-mail mwlind01{at}louisville.edu or Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425. Fax 843-792-0424; 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-ItTM 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.




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