Common diplotypesb | Expected population frequency, %c | PK/PD phenotype | Clinical phenotype | FDA guidelines | ||
---|---|---|---|---|---|---|
Caucasian ancestry | African ancestry | East Asian ancestry | ||||
Warfarin and CYP2C9 | Â | |||||
CYP2C9*1/*1 | 67 | 76 | 88 | EM: normal enzymatic function and normal drug elimination | Expected to have a normal response at standard dose of warfarin | The warfarin drug label includes a table of CYP2C19 and VKORC1 genotype-based therapeutic dosing guidelines, which provides the range of expected therapeutic doses based on genotype combinations (based on VKORC1 -1639G > A (rs9923231) and CYP2C9*2 and CYP2C9*3 variants) (see Additional file 1: Table S17) |
CYP2C9*1/*2, CYP2C9*1/*14 and other rare diplotypes (see Additional file 1: Table S12) | 20 | 17 | 4 | IM: reduced enzymatic function, leading to reduced drug elimination and greater drug exposure | At increased risk of bleeding at standard dose of warfarin.d. Takes longer to reach therapeutic INR; requires lower dose of warfarin | |
CYP2C9*1/*3, CYP2C*2/*2, CYP2C*2/*3, CYP2C*3/*3, and other rare diplotypes (see Additional file 1: Table S12) | 13 | 7 | 8 | PM: greatly reduced enzymatic function, leading to reduced drug elimination and greatly increased drug exposure | At increased risk of bleeding at standard dose of warfarin.d Takes longer to reach therapeutic INR; requires lower dose of warfarin | |
Warfarin and VKORC1 | ||||||
−1639G > A (rs9923231): GG | 40 | 74 | 1 | Normal mRNA expression; normal enzyme activity and efficient vitamin K cycling | Associated with a requirement for higher therapeutic warfarin dose.d Potentially at increased risk of thrombosis at standard dose | |
−1639G > A (rs9923231): GA | 47 | 24 | 20 | Reduced mRNA expression; reduced enzyme activity and vitamin K cycling | Associated with a requirement for intermediate therapeutic warfarin dosed | |
−1639G > A (rs9923231): AA | 13 | 2 | 79 | Greatly reduced mRNA expression level; significant reduction in enzyme activity and vitamin K cycling | Associated with a requirement for lower therapeutic warfarin dose.d Potentially at increased risk of bleeding events | |
Warfarin and CYP4F2 | Â | |||||
1297G > A, CYP4F2 V433M: GG | 53 | 83 | 63 | Higher CYP4F 2 activity results in reduced hepatic vitamin K levels | Associated with a requirement for lower therapeutic warfarin dose.d Potentially at increased risk of bleeding events | – |
1297G > A, CYP4F2 V433M: GA | 40 | 16 | 33 | Intermediate CYP4F2 activity results in intermediate hepatic vitamin K levels | Associated with a requirement for intermediate therapeutic warfarin dosed | – |
1297G > A, CYP4F2 V433M: AA | 7 | 1 | 4 | Reduced CYP4F2 activity results in increased hepatic vitamin K levels | Associated with a requirement for higher therapeutic warfarin dose.d Potentially at increased risk of thrombosis at standard dose | – |