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VKORC1 and CYP2C9 genotypes and phenprocoumon anticoagulation status: interaction between both genotypes affects dose requirement.
Clin Pharmacol Ther. 2007 Feb; 81(2):185-93.CP

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.

Authors+Show Affiliations

Division of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University, Utrecht, The Netherlands. t.schalekamp@pharm.uu.nlNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

17192772

Citation

Schalekamp, T, et al. "VKORC1 and CYP2C9 Genotypes and Phenprocoumon Anticoagulation Status: Interaction Between Both Genotypes Affects Dose Requirement." Clinical Pharmacology and Therapeutics, vol. 81, no. 2, 2007, pp. 185-93.
Schalekamp T, Brassé BP, Roijers JF, et al. VKORC1 and CYP2C9 genotypes and phenprocoumon anticoagulation status: interaction between both genotypes affects dose requirement. Clin Pharmacol Ther. 2007;81(2):185-93.
Schalekamp, T., Brassé, B. P., Roijers, J. F., van Meegen, E., van der Meer, F. J., van Wijk, E. M., Egberts, A. C., & de Boer, A. (2007). VKORC1 and CYP2C9 genotypes and phenprocoumon anticoagulation status: interaction between both genotypes affects dose requirement. Clinical Pharmacology and Therapeutics, 81(2), 185-93.
Schalekamp T, et al. VKORC1 and CYP2C9 Genotypes and Phenprocoumon Anticoagulation Status: Interaction Between Both Genotypes Affects Dose Requirement. Clin Pharmacol Ther. 2007;81(2):185-93. PubMed PMID: 17192772.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - VKORC1 and CYP2C9 genotypes and phenprocoumon anticoagulation status: interaction between both genotypes affects dose requirement. AU - Schalekamp,T, AU - Brassé,B P, AU - Roijers,J F M, AU - van Meegen,E, AU - van der Meer,F J M, AU - van Wijk,E M, AU - Egberts,A C G, AU - de Boer,A, Y1 - 2006/12/27/ PY - 2006/12/29/pubmed PY - 2007/4/24/medline PY - 2006/12/29/entrez SP - 185 EP - 93 JF - Clinical pharmacology and therapeutics JO - Clin. Pharmacol. Ther. VL - 81 IS - 2 N2 - 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. SN - 0009-9236 UR - https://www.unboundmedicine.com/medline/citation/17192772/VKORC1_and_CYP2C9_genotypes_and_phenprocoumon_anticoagulation_status:_interaction_between_both_genotypes_affects_dose_requirement_ L2 - https://doi.org/10.1038/sj.clpt.6100036 DB - PRIME DP - Unbound Medicine ER -