Warfarin sensitivity genotyping: a review of the literature and summary of patient experience

Abstract

The antithrombotic benefits of warfarin are countered by a narrow therapeutic index that contributes to excessive bleeding or cerebrovascular clotting and stroke in some patients. This article reviews the current literature describing warfarin sensitivity genotyping and compares the results of that review to the findings of our study in 189 patients at Mayo Clinic conducted between June 2001 and April 2003. For the review of the literature, we identified relevant peer-reviewed articles by searching the Web of Knowledge using key word warfarin-related adverse event. For the 189 Mayo Clinic patients initiating warfarin therapy to achieve a target international normalized ratio (INR) in the range of 2.0 to 3.5, we analyzed the CYP2C9 (cytochrome P450 2C9) and VKORC1 (vitamin K epoxide reductase complex, subunit 1) genetic loci to study the relationship among the initial warfarin dose, steady-state dose, time to achieve steady-state dose, variations in INR, and allelic variance. Results were compared with those previously reported in the literature for 637 patients. The relationships between allelic variants and warfarin sensitivity found in our study of Mayo Clinic patients are fundamentally the same as in those reported by others. The Mayo Clinic population is predominantly white and shows considerable allelic variability in CYP2C9 and VKORC1. Certain of these alleles are associated with increased sensitivity to warfarin. Polymorphisms in CYP2C9 and VKORC1 have a considerable effect on warfarin dose in white people. A correlation between steady-state warfarin dose and allelic variants of CYP2C9 and VKORC1 has been demonstrated by many previous reports and is reconfirmed in this report. The allelic variants found to most affect warfarin sensitivity are CYP2C9*1*1-VKORC1BB (less warfarin sensitivity than typical); CYP2C9*1*1-VKORC1AA (considerable variance in INR throughout initiation); CYP2C9*1*2-VKORC1AB (more sensitivity to warfarin than typical); CYP2C9*1*3-VKORC1AB (much more sensitivity to warfarin than typical); CYP2C9*1*2-VKORC1AB (much more sensitivity to warfarin than typical); CYP2C9*1*3-VKORC1AA (much more sensitivity to warfarin than typical); and CYP2C9*2*2-VKORC1AB (much more sensitivity to warfarin than typical). Although we were unable to show an association between allelic variants and initial warfarin dose or dose escalation, an association was seen between allelic variant and steady-state warfarin dose. White people show considerable variance in CYP2C9 allele types, whereas people of Asian or African descent infrequently carry CYP2C9 allelic variants. The VKORC1AA allele associated with high warfarin sensitivity predominates in those of Asian descent, whereas white people and those of African descent show diversity, carrying either the VKORC1BB, an allele associated with low warfarin sensitivity, or VKORC1AB or VKORC1AA, alleles associated with moderate and high warfarin sensitivity, respectively.

FIGURE 1.

The coagulation cascade requires vitamin K in the reduced form (vitamin K [H₂]) as a cofactor for γ-glutamyl-carboxylase to convert inactive factors II, VII, IX, and X to the active forms that are required for coagulation. Vitamin K (H₂) is oxidized during this process to vitamin K epoxide. To conserve vitamin K (H₂), the enzyme vitamin K epoxide reductase (VKOR) converts vitamin K epoxide back into vitamin K (H₂). Warfarin inhibits VKOR, decreasing vitamin K (H₂) availability, diminishing activatable factors II, VII, IX, and X and thus inhibiting coagulation. CO₂ = carbon dioxide; O₂ = oxygen.

FIGURE 2.

The coagulation cascade is inhibited by warfarin (see Figure 1). Warfarin, an enantiomeric mixture of equal concentrations of R- and S-forms, is 93%±8% absorbed from the gastrointestinal (GI) tract. Hepatic enzymes metabolize warfarin. Cytochrome P450 isomer 2C9 (CYP2C9) selectively converts S-warfarin into inactive hydroxylated metabolites. Cytochrome P450 isomers 1A2, 3A4, and 2C19 (CYP1A2, CYP3A4, and CYP2C19) selectively metabolize R-warfarin into inactive hydroxylated metabolites. The pace of metabolism for S-warfarin is approximately 3 times (3×) faster than for R-warfarin. The potency of S-warfarin at inhibiting vitamin K epoxide reductase (VKOR) is approximately 5 times that of R-warfarin. CO₂ = carbon dioxide; O₂ = oxygen; OH = hydroxide.

FIGURE 3.

Mean warfarin dose (mg/kg/wk) by week of therapy in all patients, differentiated by allelic type. Graph insert identifies allelic types and the number of patients with each allelic type. K = VKORC1 (vitamin K epoxide reductase complex, subunit 1).

FIGURE 4.

Mean observed international normalized ratio (INR) by week of therapy in all patients, differentiated by allelic type. Graph insert identifies allelic types and the number of patients with each allelic type. VK = VKORC1 (vitamin K epoxide reductase complex, subunit 1).

FIGURE 5.

Maximum observed international normalized ratio (INR) by week of therapy in all patients, differentiated by allelic type. Graph insert identifies allelic types and the number of patients with each allelic type. VK = VKORC1 (vitamin K epoxide reductase complex, subunit 1).

FIGURE 6.

Mean ± SEM warfarin dose (mg/kg/wk) in the second week of therapy in all patients, differentiated by allelic type. Key: 1 = 2C9*1*1VKORC1BB (n=50); 2 = 2C9*1*2VKORC1BB (n=12); 3 = 2C9*1*3VKORC1BB (n=7); 4 = 2C9*2*3VKORC1BB (n=4); 5 = 2C9*1*1VKORC1AB (n=52); 6 = 2C9*1*1VKORC1AA (n=21); 7 = 2C9*1*2VKORC1AB (n=18); 8 = 2C9*1*3VKORC1AB (n=7); 9 = 2C9*2*3VKORC1AB (n=5); 10 = 2C9*2*2VKORC1AB (n=6); 11 = 2C9*2*3VKORC1AA (n=5)

FIGURE 7.

Mean ± SEM warfarin dose (mg/kg/wk) in the tenth week of therapy in all patients, differentiated by allelic type. Key: 1 = 2C9*1*1VKORC1BB (n=50); 2 = 2C9*1*2VKORC1BB (n=18); 3 = 2C9*1*3VKORC1BB (n=7); 4 = 2C9*2*3VKORC1BB (n=4); 5 = 2C9*1*1VKORC1AB (n=52); 6 = 2C9*1*1VKORC1AA (n=21); 7 = 2C9*1*2VKORC1AB (n=18); 8 = 2C9*1*3VKORC1AB (n=7); 9 = 2C9*2*3VKORC1AB (n=5); 10 = 2C9*2*2VKORC1AB (n=6); 11 = 2C9*2*3VKORC1AA (n=5)