VKORC1 and CYP2C9 genotypes and phenprocoumon anticoagulation status: interaction between both genotypes affects dose requirement.
Article Details
- CitationCopy to clipboard
Schalekamp T, Brasse BP, Roijers JF, van Meegen E, van der Meer FJ, van Wijk EM, Egberts AC, de Boer A
VKORC1 and CYP2C9 genotypes and phenprocoumon anticoagulation status: interaction between both genotypes affects dose requirement.
Clin Pharmacol Ther. 2007 Feb;81(2):185-93. Epub 2006 Dec 27.
- PubMed ID
- 17192772 [ View in PubMed]
- Abstract
In a prospective follow-up study of the effects of VKORC1 and CYP2C9 genotypes on the anticoagulation status of patients, we assessed the CYP2C9 and the VKORC1 C1173T genotypes of patients during the initial 6 months of phenprocoumon treatment. We used linear regression models and Cox proportional hazard models to determine the effects of the VKORC1 and CYP2C9 genotypes on phenprocoumon dose requirements, overanticoagulation, and time to achieve stability. Allele frequencies of interest within the cohort (N=281) were 40.8% VKORC1 T-1173, 12.8% CYP2C9*2, and 6.9% CYP2C9*3. In patients with the VKORC1 CC genotype, carriers of a CYP2C9 polymorphism needed dosages that were nearly 30% lower than those for CYP2C9*1/*1 patients (P<0.001). In patients with a VKORC1 polymorphism, differences between carriers of a CYP2C9 polymorphism and CYP2C9*1/*1 were far smaller and largely not statistically significant. A larger part of the variability in dose requirement was explained by the VKORC1 genotype than by the CYP2C9 genotype (28.7% and 7.2%, respectively). Carriers of a combination of a CYP2C9 polymorphism and a VKORC1 polymorphism had a strongly increased risk of severe overanticoagulation (hazard ratio (HR) 7.20, P=0.002). Only carriers of a CYP2C9*2 allele had a decreased chance to achieve stability compared to CYP2C9*1/*1 patients (HR 0.61, P=0.004). In conclusion, the VKORC1 genotype modifies the effect of the CYP2C9 genotype on phenprocoumon dose requirements. A combination of polymorphisms of both genotypes is associated with a strongly increased risk of overanticoagulation, whereas delayed stabilization is mainly associated with the CYP2C9 genotype.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Phenprocoumon Vitamin K epoxide reductase complex subunit 1 Protein Humans YesInhibitorDetails - Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Phenprocoumon Cytochrome P450 2C9 Protein Humans UnknownSubstrateDetails - Pharmaco-genomics
Drug Interacting Gene/Enzyme Allele name Genotypes Defining change(s) Type(s) Description Details Phenprocoumon Cytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712CYP2C9*2 (T;T) / (C;T) - T Allele (rs1799853)
ADR Directly Studied The presence of this polymorphism in CYP2C9 is associated with reduction in phenprocoumon metabolism. Details Phenprocoumon Cytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712CYP2C9*3 (C;C) / (A;C) - C Allele (rs1057910)
ADR Directly Studied The presence of this polymorphism in CYP2C9 is associated with reduction in phenprocoumon metabolism. Details Phenprocoumon Vitamin K epoxide reductase complex subunit 1
Gene symbol: VKORC1
UniProt: Q9BQB6--- (A;A) / (A;G) - G > A (rs9934438)
ADR Directly Studied The presence of this polymorphism in VKORC1 is associated with reduction in phenprocoumon metabolism. Details