Influence of CYP4F2, ApoE, and CYP2A6 gene polymorphisms on the variability of Warfarin dosage requirements and susceptibility to cardiovascular disease in Jordan (original) (raw)
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Combined effect of CYP2C9 and VKORC1 polymorphisms on warfarin maintenance dose in Omani patients
Excepting host genetic factors, other influences on the pharmacokinetic and pharmacodynamic behavior of warfarin are subject to variations during the treatment despite attempts to stabilize the INR. In 214 Omani patients on warfarin therapy, we evaluated the extent of influence of known genetic predictors of warfarin dose variability, namely CYP2C9, CYP4F2 and VKORC1 gene polymorphisms in a genetically heterogeneous patient population. When patients were stratified according to their daily warfarin maintenance dose (to maintain INR between 2 and 3) into "low dose" (sensitive), "medium dose" (intermediate) and "high dose" (resistance) groups, overall, seven patients with three or four mutant alleles fell in the sensitive group and consequently 25% (7 out of 28) of at risk patients for over anticoagulation can be recognized by prospective pharmacogenetic testing in this patient population. Pre-prescription genotyping of these loci prior to therapy initiation will therefore benefit a small fraction of this population.
Warfarin pharmacogenetics: development of a dosing algorithm for Omani patients
Journal of Human Genetics, 2012
The objective of our present study was to develop a warfarin dosing algorithm for the Omani patients, as performances of warfarin dosing algorithms vary across populations with impact on the daily maintenance dose. We studied the functional polymorphisms of CYP2C9, CYP4F2 and VKORC1 genes to evaluate their impact on the warfarin maintenance dose in an admixed Omani patient cohort with Caucasian, African and Asian ancestries. We observed a 64-fold inter-patient variability for warfarin to achieve stable international normalized ratio in these patients. Univariate analysis revealed that age, gender, weight, atrial fibrillation, deep vein thrombosis/pulmonary embolism and variant genotypes of CYP2C9 and VKORC1 loci were significantly associated with warfarin dose in the studied patient population. However, multiple regression model showed that only the atrial fibrillation, and homozygous CYP2C9 variant genotypes (*2/*3 and *3/*3) and VKORC1 GA and AA genotypes remained significant. A multivariate model, which included demographic, clinical and pharmacogenetic variables together explained 63% of the overall inter-patient variability in warfarin dose requirement in this microgeographically defined, ethnically admixed Omani patient cohort on warfarin. This locally developed model performed much better than the International Warfarin Pharmacogenetics Consortium (IWPC) model as the latter could only explain 34% of the inter-patient variability in Omani patients. VKORC1 3673G4A polymorphism emerged as the single most important predictor of warfarin dose variability, even in this admixed population (partial R 2 ¼ 0.45).
Irish Journal of Medical Science, 2014
Background Warfarin is the mainstay of anticoagulation therapy worldwide. CYP2C9 and VKORC1 are two major genetic factors associated with inter-individual and interethnic variability in the warfarin dose. Aim This study aims to assess the impact of VKORC1-1639G[A polymorphism and the most common CYP2C9 variant alleles (*2 and *3) on warfarin response in Egyptian patients. Methods Genetic analysis of VKORC1-1639G[A and CYP2C9*2, CYP2C9*3 was performed using real-time PCR system. Patients maintained on a constant dose targeting an international normalized ratio range of 2-3.5 for at least three consecutive times were considered as good candidates. A stepwise linear regression analysis was used to determine the independent effects of genetic and nongenetic factors on daily warfarin dose requirements. Results Patients carrying VKORC1 and CYP2C9 variant genotypes needed a 44.8 % lower mean daily warfarin dose as compared to wild types. Patients with G allele for VKORC1-1639G[A had a significantly higher number of thromboembolic complications per month during therapy. On the first 30 days of therapy, presence of a variant allele either in VKORC1 or in CYP2C9 was associated with increased time required to achieve stable dosing. Multiple regression analysis showed that, VKORC1-1639G[A, age, CYP2C9*3, and smoking status explained 43.4 % of the overall variability in the warfarin dose. Conclusion VKORC1-1639G[A and CYP2C9 polymorphisms contribute to the difference in warfarin dose requirements and quality of anticoagulation amongst Egyptian patients. Study results support using personalized warfarin treatment in Egyptian patients.
Combined effect of CYP2C9 and VKORC1 polymorphisms on warfarin maintenance dose in Omani patients
2016
Excepting host genetic factors, other influences on the pharmacokinetic and pharmacodynamic behavior of warfarin are subject to variations during the treat-ment despite attempts to stabilize the INR. In 214 Omani patients on warfarin therapy, we evaluated the extent of influence of known genetic predictors of warfarin dose variability, namely CYP2C9, CYP4F2 and VKORC1 gene polymorphisms in a genetically heterogeneous patient population. When patients were stratified according to their daily warfarin mainte-nance dose (to maintain INR between 2 and 3) into “low dose ” (sensitive), “medium dose ” (intermediate) and “high dose ” (resistance) groups, overall, seven patients with three or four mutant alleles fell in the sensitive group and consequently 25 % (7 out of 28) of at risk patients for over anticoagulation can be rec-ognized by prospective pharmacogenetic testing in this patient population. Pre-prescription genotyping of these loci prior to therapy initiation will therefore bene...
The effect of genetic and nongenetic factors on warfarin dose variability in Qatari population
The Pharmacogenomics Journal, 2019
Genetic and non-genetic factors were shown to affect warfarin dosing; however, their effect may vary from one population to the other. No previous studies were conducted on the Qatari population to elucidate these factors. Research question: What is the prevalence of VKORC1, CYP2C9, and CYP4F2 genetic variants in Qataris? and what is their contribution to warfarin dose variability? Study design: An observational cross-sectional study Methods: Hundred and fifty warfarin-treated Qatari patients on a stable dose and a therapeutic INR for at least 3 consecutive clinic visits were recruited. Saliva samples were collected using Oragene DNA self-collection kit, followed by DNA purification and genotyping via TaqMan Real-Time-PCR assay. Results: The minor allele frequency (MAF) of VKORC1 (-1639G>A) was A 0.46, while the MAF's for the CYP2C9*2 and *3 and CYP4F2*3 were T (0.12), C (0.04) and T (0.43), respectively. Carriers of at least one loss of function CYP2C9 allele (*2 or *3) required significantly lower warfarin doses iv compared to non-carriers (24 mg/week vs. 34.1 mg/week, p<0.001). VKORC1 (-1639G>A) and CYP4F2*3 polymorphisms on the other hand were not associated with warfarin dose. Multivariate analysis on the derivation cohort showed that congestive heart failure (CHF) (P=0.002), and CYP2C9*2 & *3 (P<0.001) were associated with lower warfarin dose while smoking (P=0.003) was associated with higher warfarin dose. These factors explained 24.1% of warfarin dose variability in Qatari patients. CYP2C9*2 & *3 variants accounted for 11.8% of warfarin dose variability. In the validation cohort, correlation between predicted and actual warfarin doses was moderate (Spearman's rho correlation coefficient= 0.41, p=0.005). Conclusion: This study showed that CYP2C9*2 & *3 are the most significant predictors of warfarin dose along with CHF and smoking. Dose reduction should be considered in patients with CHF and those carrying at least one of the CYP2C9*2 & *3 alleles. While dose increase should be considered in smokers. v DEDICATION To my loving family vi ACKNOWLEDGMENTS The completion of this thesis would not have been possible without the kind support and assistance of so many individuals whose names may not all be enumerated. All their efforts and contributions are highly and sincerely appreciated and acknowledged. At foremost, I want to thank GOD for giving me all the strength and good health to complete this work. I would like to extend my gratitude to my family; mom, dad, Aya & Tala, who never seemed to cease their support and reassurance even with distance keeping us apart. My beloved husband, Ammar who always believed in me and stood by my side every step of the way, my son Farouk for always being my source of joy and inspiration. I would like to extend my special thanks and gratitude to my supervisor Dr. Hazem F. Elewa for never being hesitant to share his knowledge and expertise with me, for always supporting and fostering my achievements, and always promoting me to stand out.
Validation of a Proposed Warfarin Dosing Algorithm Based on the Genetic Make-Up of Egyptian Patients
Molecular Diagnosis & Therapy, 2013
Background Warfarin is the most frequently prescribed oral anticoagulant worldwide. Due to its narrow therapeutic index and inter-patient variability in dose requirement, this drug has been considered an ideal target for personalised medicine. Several warfarin dosing algorithms have been proposed to tailor the warfarin dosage in the European, Asian and African-American populations. However, minimal interest was directed towards Middle East countries. The factors affecting warfarin dose requirement could be different in patients from different geographical and ethnic groups, limiting the value of published dosing algorithms. Objective The first objective of this study was to examine the contribution of genetic and nongenetic factors on the variability of warfarin dose requirements in the Egyptian population using an easy, cost-effective and rapid analysis of vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 (CYP) 2C9 single nucleotide polymorphism (SNP) genotyping of patients. A second objective was to develop and validate an algorithm for warfarin dose prediction that is tailored to Egyptian patients. Methods Eighty-four patients, 41 males and 43 females, with a median (25th-75th percentiles) age of 39 (31-48) Electronic supplementary material The online version of this article (
Journal of Personalized Medicine, 2020
The purpose of this study was to investigate the effects of the SH2B3, MTHFD1L, GGCX, and ITGB3 gene variants on the efficacy of warfarin treatment and its effects on the risk of cardiovascular disorders in Jordanian patients. The selected genes and their polymorphisms are involved in many Genome-Wide Association Study (GWAS) associated with cardiovascular disease and the variability of warfarin therapy. The current study conducted a genetic association and pharmacogenetics study in (212) Jordanian cardiovascular patients treated with warfarin and (213) healthy controls. DNA extraction and the Mass ARRAY™ system were used to genotype ten selected polymorphisms within four genes (SH2B3, MTHFD1L, GGCX, and ITGB3). This study confirmed a genetic association of MTHFD1L rs6922269 Single Nucleotide Polymorphism (SNP) with warfarin sensitivity during the initial and stabilization phases of treatment. Moreover, this SNP showed significant differences in the initial and maintenance doses of ...
Genetic polymorphisms of patients on stable warfarin maintenance therapy in a Ghanaian population
BMC Research Notes, 2016
Background: Warfarin is a widely prescribed anticoagulant with narrow therapeutic window for thromboembolic events. Warfarin displays large individual variability in dose requirements. The purpose of this study is to assess the contribution of patient-specific and genetic risk factors to dose requirements of patients on either high or low warfarin maintenance dose in Ghana. Blood samples were collected from 141 (62 males, 79 females) Ghanaian patients on stable warfarin dose to determine their INR. Influence of patient specific factors and gene variations within VKORC1, CYP2C9 and CYP4F2 were determined in patients on either high or low warfarin maintenance dose. Results: One hundred and forty-one patients took part in the study with 79 (56%) participants being Female. The median age of the study participants was 48 years [IQR: 34-58]. The median duration for patients to be on warfarin therapy was 24 months [IQR: 10-72]. Majority of the study participants (80.9%, n = 114) did not have any side effects to warfarin. CYP2C9*2 and CYP2C9*3 variant alleles were not detected. VKORC1 variant allele was observed at 6% and CYP4F2 variant allele was observed at 41%. Duration of patients on warfarin therapy was marginally associated with high warfarin dose (adjusted OR = 1.01 [95% CI 1.00-1.02], p = 0.033) while the odds of heterozygous individuals (G/A) for VKORC1 gene to have high warfarin dose compared to persons with homozygous (G/G) (adjusted OR = 0.06 [95% CI 0.01-0.63], p = 0.019). Age, gender, diagnosis, presence of side effects and other medications were not associated with warfarin dose (p = 0.05). Conclusion: This study provides data on VKORC1 and CYP4F2 variants among an indigenous African population. Duration of patients on warfarin therapy was marginally associated with high warfarin dose. CYP2C9*2 and *3 variants were not detected and may not be the most important genetic factor for warfarin maintenance dose among Ghanaians.