Extending and evaluating a warfarin dosing algorithm that includes CYP4F2 and pooled rare variants of CYP2C9

Abstract

Objective Warfarin dosing remains challenging because of its narrow therapeutic window and large variability in dose response. We sought to analyze new factors involved in its dosing and to evaluate eight dosing algorithms, including two developed by the International Warfarin Pharmacogenetics Consortium (IWPC). Methods we enrolled 108 patients on chronic warfarin therapy and obtained complete clinical and pharmacy records; we genotyped single nucleotide polymorphisms relevant to the VKORC1, CYP2C9, and CYP4F2 genes using integrated fluidic circuits made by Fluidigm. Results When applying the IWPC pharmacogenetic algorithm to our cohort of patients, the percentage of patients within 1 mg/d of the therapeutic warfarin dose increases from 54% to 63% using clinical factors only, or from 38% using a fixed-dose approach. CYP4F2 adds 4% to the fraction of the variability in dose (R2) explained by the IWPC pharmacogenetic algorithm (P < 0.05). Importantly, we show that pooling rare variants substantially increases the R2 for CYP2C9 (rare variants: P =0.0065, R2 = 6%; common variants: P= 0.0034, R2 = 7%; rare and common variants: P =0.00018; R2 = 12%), indicating that relatively rare variants not genotyped in genome-wide association studies may be important. In addition, the IWPC pharmacogenetic algorithm and the Gage (2008) algorithm perform best (IWPC: R2 = 50%; Gage: R2 = 49%), and all pharmacogenetic algorithms outperform the IWPC clinical equation (R2 = 22%). VKORC1 and CYP2C9 genotypes did not affect long-term variability in dose. Finally, the Fluidigm platform, a novel warfarin genotyping method, showed 99.65% concordance between different operators and instruments. Conclusion CYP4F2 and pooled rare variants of CYP2C9 significantly improve the ability to estimate warfarin dose.

Warfarin pharmacogenetics: development of a dosing algorithm for Omani patients

“…19 The IWPC has collected data in various population groups including Asians, Blacks and Whites across four continents with a pooled population of 6256 chronic warfarin users, and developed a dosing algorithm utilizing demographic, clinical and genetic variables viz CYP2C9 and VKORC1 genotypes. 3,4 Use of this pharmacogenetic algorithm for estimation of the appropriate initial dose of warfarin is reported to result in dose recommendations that are close to the actual steady-state warfarin dose on continuous therapy for each of the major ethnic groups and for each of the 21 participating sites. 2 We therefore tested the IWPC dosing algorithm by imputing the actual warfarin dose used by our study cohort in their pharmacogenetic equation (Figure 3) and found that the IWPC algorithm did not perform reasonably well for our admixed Omani population, as it explained only 34% of the variance in Omani patients (adjusted R 2 ¼ 0.336) as opposed to 63% obtained with the locally designed algorithm (the adjusted R 2 ¼ 0.625).…”

“…[1][2][3][4] Most of these algorithms, in a multivariate regression analysis incorporate age, gender, body weight/surface area, co-medications, co-morbidities and functionally relevant genetic polymorphisms of CYP2C9, CYP4F2 and VKORC1 loci as covariates to estimate their contribution to individual warfarin dose.…”

Absence of Novel CYP4F2 and VKORC1 Coding Region DNA Variants in Patients Requiring High Warfarin Doses

“…The lack of consistent associations in their results are interesting, given that rs2189784 and rs2108622 are highly correlated through linkage disequilibrium (D' = 0.98). By contrast, Sagrieya et al 14 reported that addition of rs2108622 genotype to the International Warfarin Pharmacogenetics Consortium algorithm increased the R 2 for dosing variability by 4%.…”

“…11,12 Recently, metabolism of vitamin K by CYP4F2 was shown to measurably impact warfarin stable dose requirements. 13,14 The DNA variant rs2108622 (Val433Met) results in decreased capacity for metabolism of vitamin K, resulting in an increased stable dose requirement of up to 24% among patients encoding the variant. 7 To test the hypothesis that some patients who required high doses of warfarin had novel variants of CYP4F2, we sequenced the coding region of CYP4F2 in 16 patients whose actual dose requirement showed the highest divergence from the therapeutic warfarin dose predicted by our best regression model.…”

Autoimmune and Inflammatory Diseases Biomarkers

“…Although whole genome sequences are not used in regular practice today 26 , there are already many examples of personalized medicine in current practice. Chemotherapy medications such as trastuzumab and imatinib target specific cancers 27,28 , a targeted pharmacogenetic dosing algorithm is used for warfarin (International Warfarin Pharmacogenetics Consortium) 29,30 and the incidence of adverse events is reduced by checking for susceptible genotypes for drugs like abacavir, carbamazepine and clozapine 31,32,33 .…”