Drug Discov Ther. 2015;9(6):404-410. (DOI: 10.5582/ddt.2015.01066)

High prevalence of VKORC1*3 (G9041A) genetic polymorphism in north Indians: A study on patients with cardiac disorders on acenocoumarol

Sehgal T, Hira JK, Ahluwalia J, Das R, Vijayvergiya R, Rana SS, Varma N


Coumarin derivatives such as warfarin and acenocoumarol are used in various disorders such as deep venous thrombosis, pulmonary embolism, atrial fibrillation and artificial heart valves. They have improved prognosis of patients with thromboembolic disease. An individual's response to coumarins depends on several factors. The non-genetic factors include age, gender, body mass index, diet and interacting drugs. Among the genetic factors, the cytochrome P450 system and vitamin K epoxide reductase complex subunit 1 play a key role in drug metabolism. This was a prospective hospital based study in which allele and genotypic frequencies of CYP2C9 gene polymorphisms; 430C>T and 1075A>C and VKORC1 gene polymorphisms; 1639G>A, 9041G>A and 6009C>T in 106 alleles of north Indian patients with valve replacement on acenocoumarol were determined and their effect on acenocoumarol dosing was studied. To the best of our knowledge, this is first report of VKORC1 9041G>A and 6009C>T gene polymorphisms and their effect on acenocoumarol dosing from north India. In 53 patients with valve replacement on acenocoumarol with stable INR, the allele frequency of CYP2C9*2 and CYP2C9*3 gene polymorphisms was 0.05 and 0.17 respectively and that of VKORC1 *2,*3 and *4 gene polymorphisms was 0.15, 0.72 and 0.11 respectively. The presence of CYP2C9*3 or VKORC1*2 gene polymorphism were associated with decrease in acenocoumarol dose requirements (p values 0.03 and 0.02 respectively). This study confirmed the association of lower mean weekly dosages of acenocoumarol in patients with CYP2C9*3 and VKORC1*2 gene polymorphisms. An unusually high frequency of 9041A polymorphism in VKORC1 was found in study population.

KEYWORDS: CYP2C9, VKORC1, acenocoumarol, dosage, INR, PCR-RFLP

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