The impact of genetic polymorphisms and patient characteristics on warfarin dose requirements: a cross-sectional study in Iran.
BACKGROUND
Warfarin is the most commonly prescribed oral anticoagulant drug for prophylaxis and treatment of venous and arterial thromboembolic disorders. Its anticoagulant effect is widely variable between patients because of pharmacodynamic, pharmacokinetic, and pharmacogenetic factors.


OBJECTIVE
This study was conducted to identify the associations between demographic characteristics, warfarin maintenance dose, and genetic polymorphisms of cytochrome P450 (CYP) 2C19, CYP2C9, and vitamin K epoxide reductase complex subunit 1 (VKORC1).


METHODS
This study was conducted from April 2005 to April 2008 at 3 warfarin clinics affiliated with Shiraz University of Medical Sciences. Blood samples were collected from patients with stable warfarin maintenance dose and a stable target international normalized ratio of 2 to 3. Patients who had a condition (including use of an interacting medication) affecting the metabolism of warfarin were excluded. CYP2C9, CYP2C19, and VKORC1 genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism. The associations between demographic characteristics (eg, age, sex, body surface area, weight, height), genetic factors, and maintenance warfarin dose were examined by multiple linear regression. The probability of F as a criterion for removal of a variable from the multiple linear regression was set at 0.1.


RESULTS
One hundred patients were enrolled in the study; complete data were available for 55, who were included in the regression analysis. Among this smaller group, the mean (SD) age was 53 (11) years (range, 25-80 years) and mean weight was 72 (15) kg (range, 42-125 kg); the mean warfarin dose was 27.2 (13.4) mg/week. The allelic frequencies of CYP2C9*2 and CYP2C9*3 were 27% and 9%, respectively. The allelic frequencies of CYP2C19*2 and CYP2C19*3 were 11% and 1%, respectively. Fifteen percent of our patients carried a VKORC1 genotype GG, whereas the AA and GA genotypes were seen in 18% and 58% of patients, respectively. Multiple linear regression analysis found that sex (P = 0.045), height (P = 0.024), age (P = 0.081), and VKORC1 (P = 0.004) and CYP2C9 (P = 0.011) polymorphism had significant influence on the maintenance dose of warfarin. They were associated with 41.3% of the variability in warfarin maintenance dose requirement. VKORC1 polymorphism (partial R(2) = 20.3%) and height (partial R(2) = 20.3%) had the greatest effects on warfarin maintenance dose requirement.


CONCLUSIONS
Among the demographic and genetic factors evaluated in these Iranian patients, sex, height, age, CYP2C9, and VKORC1 had significant effects on warfarin maintenance dose requirements.
Namazi
Soha
S
Department of Pharmacotherapy, Shiraz University of Medical Sciences, Shiraz, Iran.
Azarpira
Negar
N
Hendijani
Fatemeh
F
Khorshid
Maryam Banan
MB
Vessal
Ghazal
G
Mehdipour
Ahmad Reza
AR
D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001827:Body Height; D001835:Body Weight; D003430:Cross-Sectional Studies; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007492:Iran; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012044:Regression Analysis; D012737:Sex Factors; D012959:Socioeconomic Factors; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000493:pharmacokinetics*
D000925:Anticoagulants; D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases