Original clinical investigation

Warfarin dose and INR related to genotypes of CYP2C9 and VKORC1 in patients with myocardial infarction

Kari Bente Foss Haug^{* 1} , Mohammad N Sharikabad^{* 1} , Marianne K Kringen¹ , Sigrid Narum¹ , Stine T Sjaatil¹ , Per Wiik Johansen¹ , Peter Kierulf¹ , Ingebjørg Seljeflot² , Harald Arnesen² and Odd Brørs¹

¹R&D, Department of Clinical Chemistry, Ulleval University Hospital, Kirkeveien 166, O407 Oslo, Norway

²Center for Clinical Research, Ulleval University Hospital, Kirkeveien 166, 0407 Oslo, Norway

author email corresponding author email* Contributed equally

Thrombosis Journal 2008, 6:7doi:10.1186/1477-9560-6-7

Published:	17 June 2008

Abstract

Background

Warfarin treatment has a narrow therapeutic range, requiring meticulous monitoring and dosage titration. Individual dosage requirement has recently partly been explained by genetic variation of the warfarin metabolizing enzyme CYP2C9 and the Vitamin K-activating enzyme VKORC1. In the WARIS-II study, comparing three different antithrombotic regimens after myocardial infarction, warfarin treatment reduced thrombotic events, but was associated with more frequent bleeding than use of acetylsalisylic acid (ASA) alone.

Aims

The primary aim of the present study was to investigate the relation between genotypes of CYP2C9 and VKORC1 and warfarin maintenance dose in myocardial infarction. The secondary aim was to relate the genotypes to international normalized ratio (INR).

Methods

Genotyping was performed in 212 myocardial infarction patients from the WARIS-II study by robotic isolation of DNA from EDTA whole blood (MagNa Pure LC) before PCR amplification (LightCycler) and melting point analysis.

Results

The 420 C>T substitution of CYP2C9*2, the 1075 A>C substitution of CYP2C9*3 and the 1173 C>T substitution of VKORC1 had minor allele frequencies of, 11.3%, 5.7% and 36.6% respectively. Warfarin weekly dose varied between 17 mg and 74 mg among the patients. INR did not vary between genotypes. Warfarin dosage requirement was significantly associated with CYP2C9 and VKORC1 genotypes, treatment group and age. The VKORC1 genotype contributed 24.5% to the interindividual variation in warfarin dosage, whereas the combined CYP2C9 genotypes were only responsible for 7.2% of the dose variation.

Conclusion

CYP2C9 and VKORC1 genotype frequencies in myocardial infarction patients appear similar to other patient groups and have similar impact on warfarin maintenance dose.