VKORC1 and CYP2C9 genotypes and acenocoumarol anticoagulation status: interaction between both genotypes affects overanticoagulation.

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Schalekamp T, Brasse BP, Roijers JF, Chahid Y, van Geest-Daalderop JH, de Vries-Goldschmeding H, van Wijk EM, Egberts AC, de Boer A

VKORC1 and CYP2C9 genotypes and acenocoumarol anticoagulation status: interaction between both genotypes affects overanticoagulation.

Clin Pharmacol Ther. 2006 Jul;80(1):13-22.

PubMed ID

16815313 [ View in PubMed

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Abstract

OBJECTIVE: Our objective was to assess the effects of VKORC1 and CYP2C9 genotypes on severe overanticoagulation and time to achieve stability and their contributions to dose requirement during the initial phase of acenocoumarol treatment. METHODS: A prospective follow-up study was conducted at 2 anticoagulation clinics in The Netherlands. We assessed the CYP2C9 genotype (CYP2C9*2 and CYP2C9*3 polymorphisms) and the VKORC1 C1173T genotype of the subjects and collected data on international normalized ratio, dose, comedication, and comorbidity. RESULTS: Of the 231 patients in the cohort, 150 (64.9%) had a VKORC1 C1173T polymorphism and 84 (36.4%) had a CYP2C9*2 or CYP2C9*3 allele. Only carriers of a combination of a CYP2C9 polymorphism and a VKORC1 polymorphism had an increased risk of severe overanticoagulation compared with subjects with no polymorphism or only 1 polymorphism (hazard ratio, 3.83 [95% confidence interval, 1.62-9.05]). The time to achieve stability was associated with the possession of the CYP2C9 genotype, not with the VKORC1 genotype (hazard ratio for CYP2C9*3 allele compared with CYP2C9 wild type, 0.59 [95% confidence interval, 0.40-0.87]). Patients with a VKORC1 polymorphism required significantly lower doses than VKORC1 CC wild-type patients. A larger part of the variability in dose requirement was explained by the VKORC1 genotype than by the CYP2C9 genotype (21.4% and 4.9%, respectively). CONCLUSION: Being a carrier of a combination of polymorphisms of VKORC1 and CYP2C9, rather than of one of these polymorphisms, is associated with severe overanticoagulation. The time to achieve stability is mainly associated with the CYP2C9 genotype.

DrugBank Data that Cites this Article

Drug Targets

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

Pharmaco-genomics

Drug	Interacting Gene/Enzyme	Allele name	Genotypes	Defining change(s)	Type(s)	Description	Details
Acenocoumarol	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 single nucleotide polymorphism in VKORC1 is associated with reduction in acenocoumarol metabolism and increased risk of drug-related hemorrhage.	Details