A new algorithm to predict warfarin dose from polymorphisms of CYP4F2, CYP2C9 and VKORC1 and clinical variables: Derivation in Han Chinese patients with non valvular atrial fibrillation

Abstract

Few pharmacogenomic dosing regimens of warfarin have been developed for Chinese patients with non valvular atrial fibrillation (NVAF). The objective of this study was to develop a new algorithm by polymorphisms of CYP2C9, VKORC1 and CYP4F2 to predict the daily stable dose of warfarin in Chinese patients with NVAF. A total of 325 Chinese NVAF patients on stable dose of warfarin with a target international normalised ratio of 1.5 to 3.0 were recruited and divided randomly into two cohorts. CYP2C9*3, VKORC1-1639, VKORC1 1173 and CYP4F2 were detected by ligase detection reaction method. The new algorithm was developed with multivariate linear regression in cohort 1 (260 patients) and assessed with Pearson Correlation Analysis (PCA) in cohort 2 (65 patients). From 260 enrolled patients, the model (R2 = 51.7%) was developed as: Dose = 3.47 - 0.022 (AGE) + 0.017 (WT) + 0.189 (PTE) - 0.283 (β-blocker) - 0.471 (AMIO) - 0.586 (CYP2C9 *1/*3) - 0.296 (VKORC1 CT) - 0.648 (VKORC1 TT) + 0.219 (CYP4F2 TT). PCA displayed that the algorithm was good (r = 0.658). The residual plots revealed that the predicted doses by the algorithm tend to be overestimated when lower doses were administered to patients and to be underestimated in higher doses. The algorithm developed by us might predict warfarin dose used by Chinese NVAF patients.

A Pharmacogenetics-Based Warfarin Maintenance Dosing Algorithm from Northern Chinese Patients

“…The non-genetic factors, age, BSA and target INR value, contribute most to the variability of warfarin dose, which is consistent with previous studies [28], [29], [30], [31], [32], [33], [39], [40], [41], [42], [43]. In common concurrent medications and comorbidities, we found that DM status and treatment with amiodarone and digoxin should also be included in the algorithm.…”

“…We also included some functional SNPs in related genes including F2 (coagulation factor II), F5 (coagulation factor V), F11 (coagulation factor XI), and PROCR (protein C receptor), whose proteins are involved in thrombosis. Previous studies constructed many algorithms to predict the warfarin maintenance dose in Chinese individuals [16], [28], [29], [30], [31], [32]. However, they frequently used relatively small populations (<400 subjects) except in two studies where one included 845 from Southern China [16], and the other included 641 from Central China [33].…”

Pharmacogenetics of warfarin: challenges and opportunities

“…A few recently developed algorithms also included CYP4F2 and other genetic factors. 78,79 Over 20 dosing algorithms for various ethnic groups have been developed. 12,80–82 In general, most of these algorithms showed that demographic factors (age, gender, weight and height) and the use of concomitant drugs account for approximately 25% of the variability in dosage.…”

Pharmacogenetics and Cardiovascular Disease—Implications for Personalized Medicine

“…The activity of CYP4F2 is reduced in individuals with the CYP4F2 p.Val433Met SNP (rs2108622, c.1297G.A), resulting in reduced vitamin K metabolism and greater vitamin K availability (McDonald et al, 2009). Studies in both Caucasians and Asians have shown higher warfarin dose requirements with the Met433Met genotype (Caldwell et al, 2008;Cha et al, 2010;Sagreiya et al, 2010;Gong et al, 2011;Wei et al, 2012). In a GWAS done in European and Asian populations, CYP4F2 emerges as a predictor of warfarin dose after controlling TABLE 4 Reported prevalence of CYP2C9 and VKORC1 gene polymorphisms by ancestry (Limdi et al, 2008a,b;Cavallari et al, 2010;Limdi et al, 2010;Chan et al, 2012a) Allele Prevalence* European African Asian for CYP2C9 and VKORC1, explaining an additional 1 to 3% of the overall variability in warfarin dose requirements (Takeuchi et al, 2009;Cha et al, 2010).…”