Background
Pharmacodynamics of warfarin are influenced by genetic polymorphisms of its metabolic enzymes.
Objectives
To determine CYP2C9 and VKORC1 genotypes in a population in southern Thailand, and their association with warfarin maintenance doses.
Methods
We genotyped CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910), VKORC1 (rs9923231 and rs9934438) from the blood DNA of 210 healthy controls, and determined the association of 2 polymorphic markers (CYP2C9*3 and rs9923231) in 154 patients with aortic valve protheses, with warfarin maintenance dose and coagulopathy.
Results
CYP2C9*3 was detected in 17/210 controls; all were heterozygous variants (-*1*3). No CYP2C9*2 polymorphisms were detected. The 2 VKORC1 polymorphisms were in complete linkage disequilibrium. The genotype distribution of VKORC1 (rs9923231) was 118:72:20 for AA:AG:GG. The warfarin maintenance dose in patients with CYP2C9*1*3 (20.7 mg/week) was significantly less than in patients with CYP2C9*1*1 (31.7 mg/week; P < 0.01). In VKORC1 patients, the warfarin maintenance dose increased significantly with minor variants (AA:AG:GG; 23.8:35.3:47.3 mg/week). The incidence of prolonged prothrombin time (INR > 5) was significantly higher in the VKORC1-AA group (45/76) than the AG (22/64) or GG (3/16) groups. The median time to achieve a stable INR was highest for patients with a GG genotype (342 days) compared with 20 days for those with AA, and 160 days for those with AG. Other factors associated with warfarin maintenance dose were body surface area, age (>45 years), and concomitant drug use.
Conclusion
Polymorphisms of CYP2C9*3 and VKORC1 are present in southern Thais. We recommend pharmacogenetic studies of these markers as a component of warfarin therapy.
