Hematology
Contributions
Type: Publication Only
Background
warfarin is the most commonly used drug for chronic prevention of thromboembolic events and stroke, it also ranks high among drugs that cause serious adverse events. The narrow therapeutic index coupled with substantial inter-individual variability in warfarin dose requirement puts patients at increased risk for hemorrhagic events, and the variability in dose requirements has been attributed to inter-individual differences in medical, personal, and genetic factor. Cytochrome P-450 2C9 is the principle enzyme that terminates the anticoagulant effect of warfarin by catalyzing the conversion of the pharmacologically more potent S-enantiomer to its inactive metabolites. Warfarin exerts its anticoagulant effect by reducing the regeneration of vitamin K from vitamin K epoxide in the vitamin K cycle, through inhibition of vitamin K epoxide reductase. This protein is encoded by the recently identified vitamin K epoxide reductase complex subunit 1 gene (VKORC1).
Aims
The current study aimed to investigate the pharmacogenetic effect of CYP2C9 and VKORC1 gene polymorphisms on the patients response to warfarin.
Methods
This study was carried out on 100 cases starting warfarin treatment. Informed consent was obtained from each subject or patient prior to participating in this work. The mean daily dose of warfarin (mg) was calculated from patient’s medical records. For each patient, <10% variability in warfarin dose and a target international normalized ratio (INR) within the therapeutic target range (2–3) and for patients having valve replacement and recurrent pulmonary embolism target was (2.5-3.5), were required for at least 3 months for one of the following indications (Deep vein thrombosis, Pulmonary embolism, cerberovascular stroke and Myocardial infarction ) prior to inclusion in the study. Molecular genetic study was performed to determine CYP2C9*2, CYP2C9 *3, and the VKORC1 1639G > A genetic polymorphisms. The genotypes were determined with the tetraprimer amplification refractory mutation system (T-ARMS) using specific outer and inner primers. Plasma warfarin determination was performed using rapid flouremetric assay.
Results
The median age of the studied cases as shown in table 1 was 49 years (range, 33–68).The males represented 56% of the cases while the females represented 44%. The body mass index of the patients ranged from 19.81 to 42.44. The plasma warfarin concentration ranged from 2.19 - 10.98 µg/ml with a median 3.52 µg/ml. The patients were stratified into three different groups based on their maintenance dose (>2.5 mg is the low dose group, ≤2.5 mg to 7 mg is the standard dose group and > 7 is the high dose group). The INR ranged from 2 to 4 wth a Mean of 2.58 ± 0.62(SD).The incidence of supratherpeutic INR was presented in 11% of the cases. Thromboembolic complications occurred to 7% of the cases. While 8% of the cases experienced major bleeding. The majority of the patients receiving high maintenance dose (>7 mg/day) had combined non VKORC1*2 and homozygous wild-type CYP2C9 (CYP2C9*1*1) alleles, representing 52.2% of the high dose group while the majority of the patients recieving low maintenance dose are carriers of the Variant (AG + AA)/ Wild (*1/*1) representing 55.6% of the low dose group .These results were statistically significant with p value <0.001. With respect to Incidence of supratherapeutic INR, a significantly increased risk occurred in patients carrying the CYP2C9 variant in the multivariate logistic regression model. Also with respect to thromboembolic complications and incidence of supratherapeutic INR, higher risk was observed in patients carrying combined VKORC1 Variant (AG + AA) and CYP2C9 Variant (*2/*3).
Summary
Data from our study suggest that together with clinical factors, VKORC1 and CYP2C9 polymorphisms are important contributors to warfarin dosing and may help predict adverse effects in Egyptian patients.
Keyword(s): Polymorphism, Warfarin
Session topic: Publication Only
Type: Publication Only
Background
warfarin is the most commonly used drug for chronic prevention of thromboembolic events and stroke, it also ranks high among drugs that cause serious adverse events. The narrow therapeutic index coupled with substantial inter-individual variability in warfarin dose requirement puts patients at increased risk for hemorrhagic events, and the variability in dose requirements has been attributed to inter-individual differences in medical, personal, and genetic factor. Cytochrome P-450 2C9 is the principle enzyme that terminates the anticoagulant effect of warfarin by catalyzing the conversion of the pharmacologically more potent S-enantiomer to its inactive metabolites. Warfarin exerts its anticoagulant effect by reducing the regeneration of vitamin K from vitamin K epoxide in the vitamin K cycle, through inhibition of vitamin K epoxide reductase. This protein is encoded by the recently identified vitamin K epoxide reductase complex subunit 1 gene (VKORC1).
Aims
The current study aimed to investigate the pharmacogenetic effect of CYP2C9 and VKORC1 gene polymorphisms on the patients response to warfarin.
Methods
This study was carried out on 100 cases starting warfarin treatment. Informed consent was obtained from each subject or patient prior to participating in this work. The mean daily dose of warfarin (mg) was calculated from patient’s medical records. For each patient, <10% variability in warfarin dose and a target international normalized ratio (INR) within the therapeutic target range (2–3) and for patients having valve replacement and recurrent pulmonary embolism target was (2.5-3.5), were required for at least 3 months for one of the following indications (Deep vein thrombosis, Pulmonary embolism, cerberovascular stroke and Myocardial infarction ) prior to inclusion in the study. Molecular genetic study was performed to determine CYP2C9*2, CYP2C9 *3, and the VKORC1 1639G > A genetic polymorphisms. The genotypes were determined with the tetraprimer amplification refractory mutation system (T-ARMS) using specific outer and inner primers. Plasma warfarin determination was performed using rapid flouremetric assay.
Results
The median age of the studied cases as shown in table 1 was 49 years (range, 33–68).The males represented 56% of the cases while the females represented 44%. The body mass index of the patients ranged from 19.81 to 42.44. The plasma warfarin concentration ranged from 2.19 - 10.98 µg/ml with a median 3.52 µg/ml. The patients were stratified into three different groups based on their maintenance dose (>2.5 mg is the low dose group, ≤2.5 mg to 7 mg is the standard dose group and > 7 is the high dose group). The INR ranged from 2 to 4 wth a Mean of 2.58 ± 0.62(SD).The incidence of supratherpeutic INR was presented in 11% of the cases. Thromboembolic complications occurred to 7% of the cases. While 8% of the cases experienced major bleeding. The majority of the patients receiving high maintenance dose (>7 mg/day) had combined non VKORC1*2 and homozygous wild-type CYP2C9 (CYP2C9*1*1) alleles, representing 52.2% of the high dose group while the majority of the patients recieving low maintenance dose are carriers of the Variant (AG + AA)/ Wild (*1/*1) representing 55.6% of the low dose group .These results were statistically significant with p value <0.001. With respect to Incidence of supratherapeutic INR, a significantly increased risk occurred in patients carrying the CYP2C9 variant in the multivariate logistic regression model. Also with respect to thromboembolic complications and incidence of supratherapeutic INR, higher risk was observed in patients carrying combined VKORC1 Variant (AG + AA) and CYP2C9 Variant (*2/*3).
Summary
Data from our study suggest that together with clinical factors, VKORC1 and CYP2C9 polymorphisms are important contributors to warfarin dosing and may help predict adverse effects in Egyptian patients.
Keyword(s): Polymorphism, Warfarin
Session topic: Publication Only