Effect of CYP2C9 and VKORC1 genetic polymorphisms on mean daily maintenance dose of acenocoumarol in South Indian patients

• Published in: Thrombosis research 2013-04, Vol.131 (4), p.363-367
• Main Authors: Krishna Kumar, Dhakchinamoorthi, Madhan, Sivalingam, Balachander, Jayaramen, Sai Chandran, B.V, Thamijarassy, Bascarne, Adithan, Chandrasekaran
• Format: Article
• Language: English
• Subjects: Acenocoumarol; Acenocoumarol - administration & dosage; Acenocoumarol - pharmacokinetics; Adult; Anticoagulants - administration & dosage; Anticoagulants - pharmacokinetics; Aryl Hydrocarbon Hydroxylases - genetics; Aryl Hydrocarbon Hydroxylases - metabolism; Cytochrome P-450 CYP2C9; Female; Genotype; Heart Valve Prosthesis; Heart Valve Prosthesis Implantation - methods; Hematology, Oncology and Palliative Medicine; Humans; India; Male; Oral anticoagulants; Pharmacogenetics; Pharmacogenomics; Polymorphism, Single Nucleotide; Polymorphisms; South Indians; Vitamin K Epoxide Reductases - genetics; Vitamin K Epoxide Reductases - metabolism
• ISSN: 0049-3848; 1879-2472
• DOI: 10.1016/j.thromres.2013.02.006

Abstract Aim To determine the effect of CYP2C9 and VKORC1 genetic polymorphisms on mean daily maintenance dose of acenocoumarol in South Indian patients with heart valve replacement. Materials and methods The study was conducted in 170 patients on therapy with acenocoumarol following heart valve replacement surgery. Single nucleotide polymorphisms (SNP) namely CYP2C9*2 ( rs1799853 ), CYP2C9*3 ( rs1057910 ), and VKORC1 ( rs9923231 ) were identified by quantitative Real-Time Polymerase Chain Reaction (RT-PCR) method. Results Patients with at least one variant allele of CYP2C9 ( *1*2 or *1*3 ) required 44% and 28.2% lower daily maintenance dose of acenocoumarol (2.0 mg and 2.5 mg, respectively) than the normal CYP2C9*1*1 genotype group (3.4 mg) (p < 0.05). Patients with VKORC1 GG genotype required higher dose (3.3 mg) as compared to those with genotype VKORC1 GA (2.3 mg) and VKORC1 AA (1.0 mg) (p < 0.001). Patients with both CYP2C9*1*2/*1*3 and VKORC1 GA genotype required 38% lower dose (2.46 mg) than patients with CYP2C9*1*1 and VKORC1 GG genotype (3.52 mg) (p < 0.0001). The clinical (age, body mass index) and genetic variables (VKORC1-1639 G>A, CYP2C9*2, CYP2C9*3) contribute together to predict 30.4% of the required maintenance dose of acenocoumarol. Conclusion The genetic polymorphisms of CYP2C9 and VKORC1 results in decreased requirement of daily maintenance dose of acenocoumarol. The polymorphism VKORC1 (–1639 G>A) was found to be the major predictor of acenocoumarol dose requirement in South Indian population.