Estimation of warfarin maintenance dose based on VKORC1 (-1639 G>A) and CYP2C9 genotypes.

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Zhu Y, Shennan M, Reynolds KK, Johnson NA, Herrnberger MR, Valdes R Jr, Linder MW

Estimation of warfarin maintenance dose based on VKORC1 (-1639 G>A) and CYP2C9 genotypes.

Clin Chem. 2007 Jul;53(7):1199-205. Epub 2007 May 17.

PubMed ID

17510308 [ View in PubMed

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Abstract

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 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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Warfarin	Vitamin K epoxide reductase complex subunit 1	Protein	Humans	Yes	Inhibitor	Details