Pharmacogenetics-Based Warfarin Dosing in Patients With Cardiac Valve Replacement: The Effects of CYP2C9 and VKORC1 Gene Polymorphisms

Abstract

Many lines of evidence suggest that warfarin dosing variability is significantly associated with cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) variant alleles. Therefore, we investigated the influence of CYP2C9*2 (430C/T), *3 (1075A/C) and VKORC1 (-1639G/A) polymorphisms on warfarin dose requirements in patients who underwent cardiac valve surgery during the postoperative period.A total of 100 patients with heart valve replacement who had a prescribed target international normalized ratio (INR) range of 2-3 were enrolled in the study. Genotyping of CYP2C9 and VKORC1 was carried out using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The demographic and clinical data were collected using a precodified questionnaire and clinical examination and then were analyzed.Our findings revealed that the prevalence of CYP2C9 *2, *3 and VKORC1 -1639A alleles in patients were 10.5%, 39%, and 48%, respectively. We also found that patients with CYP2C9 *1 and VKORC1 -1639G alleles required the highest dosages of warfarin, while the carriers of CYP2C9 variant *2 and *3 alleles and VKORC1 -1639A required less warfarin. Univariate regression analysis showed that age and presence of CYP2C9 *2 allele significantly influenced the daily warfarin dose requirement. Our findings provide additional evidence to support the hypothesis that CYP2C9*2 (430C/T), *3 (1075A/C) and VKORC1 (-1639G/A) polymorphisms explain a considerable proportion of interindividual variability in warfarin dose. Therefore, testing for these variants might be helpful for adjusting patient warfarin dosage to an effective and safe level.

Pharmacogenetic-Guided Algorithm to Improve Daily Dose of Warfarin in Elder Han-Chinese Population

“…Multiple in vivo studies and clinical case reports have showed that the expression of CYP2C9 * 2 and * 3 alleles significantly reduced the metabolism and daily dose requirements of selected CYP2C9 substrates such as warfarin ( Farzamikia et al., 2017 ; Flora et al., 2017 ). In particular, CYP2C9 * 2 was virtually absent in Asians ( Johnson et al., 2011 ).…”

“…Subsequently, numerous studies displayed that gene polymorphisms could influence warfarin dose requirements ( Johnson, 2012 ). Especially, more and more evidences suggested that genetic variants of the cytochrome P450 complex subunit 2C9 ( CYP2C9 ) and vitamin K epoxide reductase complex subunit 1 ( VKORC1 ) greatly affected effective warfarin dose ( Bourgeois et al., 2016 ; Farzamikia et al., 2017 ; Liu et al., 2019 ). Observational studies also demonstrated that age, body mass index, and polymorphism of CYP2C9 and VKORC1 accounted for nearly 50% of individual variations in warfarin stable dose ( Bourgeois et al., 2016 ).…”

Genotype‐guided warfarin therapy: Still of only questionable value two decades on

“…Apart from atrial fibrillation (AF), indications studied include stroke, prophylaxis associated with the use of artificial heart valves and continuous‐flow left ventricular assist devices, deep venous thrombosis and pulmonary embolism . Patients studied came from diverse ethnic/racial backgrounds and included not only adult but also paediatric populations …”

Association between four microRNA binding site-related polymorphisms and the risk of warfarin-induced bleeding complications

“…Products of two important genes, VKORC1 (vitamin K epoxide reductase complex subunit 1) and CYP2C9 , are responsible for the majority of the pharmacodynamics and pharmacokinetics of warfarin, respectively (Farzamikia et al, 2018[ 12 ]; Wu, 2018[ 49 ]). Firstly, warfarin is metabolized by the hepatic CYP2C9 enzyme and then inhibits the coagulation cascade through the targeting of the VKORC1 enzyme to decrease the active vitamin K regeneration from vitamin K epoxide (Krajciova et al, 2014[ 21 ]; Sridharan et al, 2016[ 41 ]).…”