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


CONCLUSIONS
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.
Schalekamp
Tom
T
Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands. t.schalekamp@pharm.uu.nl
Brassé
Bjorn P
BP
Roijers
Janine F M
JF
Chahid
Youssef
Y
van Geest-Daalderop
Johanna H H
JH
de Vries-Goldschmeding
Hanneke
H
van Wijk
Eduard M
EM
Egberts
Antoine C G
AC
de Boer
Anthonius
A
D000074:Acenocoumarol / Q000494:pharmacology*; D000368:Aged; D000925:Anticoagulants / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001777:Blood Coagulation / Q000187:drug effects; D002986:Clinical Trials as Topic; D065729:Cytochrome P-450 CYP2C9; D004347:Drug Interactions; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D015337:Multicenter Studies as Topic; D009426:Netherlands; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000494:pharmacology*
D000925:Anticoagulants; D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D000074:Acenocoumarol