Correlation between Rs2108622 Locus of CYP4F2 Gene Single Nucleotide Polymorphism and Warfarin Dosage in Iranian Cardiovascular Patients (original) (raw)
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Journal of Thrombosis and Thrombolysis, 2015
Warfarin is a widely used anticoagulant characterized by having a narrow therapeutic index and exhibiting a wide range of inter-individual and inter-ethnic variation. Single nucleotide polymorphisms in hepatic VKORC1 and CYP2C9 genes causes decreased and increased metabolism of warfarin respectively. The objective of this study was to evaluate the allele frequency of CYP2C9 polymorphic variants *2 and *3 and the association of these allelic variants with PT/INR and daily/ weekly dose of warfarin. Seventy-four patients with heart valve replacement were selected. Patients taking low warfarin dose (4.90-17.50 mg weekly) for at least last 3 months and had a stable INR in the range of 2-3 were included in this study. CYP2C9 polymorphism was analyzed by polymerase chain reaction followed by restriction fragment length polymorphism (PCR-RFLP) technique. Among 74 patients, 9 (12.1 %) showed to have *2 allele, whereas 11 (14.1 %) had *3 allele. Genotype frequencies of wild and variant alleles were, 54.1, 17.6, 21.6 and 6.8 % for *1/*1, *1/*2, *1/*3 and *2/*3 respectively. None of the patient was homozygous for *2 and *3. Statistical analysis showed that low warfarin dose (weekly) is significantly associated with *1/*2 and *1/*3 genotypes (p value C 0.001), whereas PT/INR showed no significant association with the any genotypes of CYP2C9. Our study suggest that polymorphic variants of CYP2C9 (*2 and *3) might influence warfarin dose requirements and associated with the low dose of warfarin in patients.
Clinical Therapeutics, 2012
Background: The cytochrome P450 (CYP) 4F2 isozyme has been reported to metabolize vitamin K 1 in vitro, and the V433M polymorphism in the CYP4F2 gene has been associated with reduced vitamin K 1 metabolism and the need for a higher maintenance dosage in patients receiving warfarin. Objective: The purpose of the present study was to evaluate the effects of V433M polymorphism on warfarin response during the induction phase. Methods: Warfarin-naive white patients in whom warfarin was scheduled to be initiated with a target INR of 2 to 3 were enrolled into the study. On enrollment, a single blood sample for the genotyping of CYP4F2, CYP2C9, and VKORC1 was drawn. The international normalized ratio (INR) was followed daily during induction and twice weekly until stable anticoagulation was reached. The relationships between several markers of warfarin response during induction and CYP4F2 polymorphism were determined. Results: The cohort consisted of 241 patients (115 men; mean [SD] age, 55.2 [19.4] years; weight, 79.5 [18.3] kg). Most of the patients were carriers of the CYP4F2 CC genotype (112 patients) or the CT genotype (104 patients). In carriers of the TT genotype (25 patients), INR Ͼ3 was Ͼ4-fold lower compared with that in carriers of the CC or CT genotype, suggesting that patients with the TT genotype were less sensitive to warfarin during induction. Also in TT carriers, the extent of excessive anticoagulation was Ͼ10-fold lower than in the other carriers. Both of these findings had a nominal P value of Ͻ0.05. After adjustment for false discovery rate, none of the findings remained significant at a threshold q value of Ͻ0.05. Among CC carriers, the concurrent use of a statin was associated with a 1-mg/d reduction in warfarin maintenance dosage. No similar effect was noted in the CT or TT carriers , suggesting a possible genetic influence on warfarin-statin interaction. Conclusions: These preliminary findings suggest that among white patients treated with warfarin, CYP4F2 polymorphism had a measurable effect on warfarin responsiveness during induction; however, the observed differences failed to reach the level of statistical significance. The possibility that the effect of statins on warfarin anticoagulation varies among carriers of different CYP4F2 genotypes could not be excluded and should be evaluated further in a larger patient sample. (Clin Ther.
Warfarin maintenance dose associated with genetic polymorphisms of CYP2C9
Hippokratia, 2017
BACKGROUND Cytochrome P450 2C9 (CYP2C9) gene polymorphisms alters the required warfarin dose in patients, due to pharmacogenetic events. This study aimed to identify the frequency of the allele CYP2C9 polymorphic variants *2 and *3, and the association of these allelic variants with warfarin dosage in the population of the west Azerbaijan province in Iran. METHODS One hundred and seventy patients receiving warfarin were examined to evaluate the genotype frequency of common CYP2C9 polymorphisms. Genotype analysis for CYP2C9*2 and CYP2C9*3 polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. To assess if the dosage is different between genotypes we used one-way analysis of variance (ANOVA). RESULTS Frequency of the two variants in studied subjects was 12 % for CYP2C9*2 and 25.8 % for CYP2C9*3. Comparison of the warfarin daily maintenance dose between genotype groups showed that the daily mean dose of warfarin in patients w...
International Journal of Medical Sciences, 2021
Cardiovascular diseases are among the leading causes of death worldwide. Many of those diseases require treatment with warfarin, an anticoagulant that has a large high inter and intra-variability in the required doses. The aim of this study is to find if there are any associations between rs2108622 of CYP4F2, rs7412 and rs405509 of ApoE, and rs1801272 of CYP2A6, and CVD and warfarin dose variability. The selected genes and their polymorphisms are involved in many GWAS associated with cardiovascular disease and variability in warfarin treatment. The study sample consisted of 212 Jordanian Cardiovascular patients and 213 healthy controls. DNA was extracted and the Mass ARRAY™ system was used to genotype four selected SNPs within three genes (CYP4F2, ApoE, and CYP2A6). Only one out of the four selected SNPs (ApoE rs7412 SNP) was found to be associated with the risk of cardiovascular disease. Also, this SNP showed significant differences in warfarin initial doses. CYP2A6 rs1801272 SNP was found to be associated with warfarin sensitivity during the initiation phase of therapy and with warfarin responsiveness and INR measurement during the stabilization phase of therapy. This study improves the current understanding of the high inter and intra-variabilities in response to warfarin, including the variety of dosing requirements and the susceptibility to cardiovascular disease in the Jordanian Arab population. Further study on a larger sample and in different ethnic groups could help in improving our understanding of warfarin's pharmacogenetics and its application in personalized medicine.
Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis, 2016
Polymorphisms in cytochrome P450 (CYP) 2C9 (CYP2C9) gene result in interindividual variability in warfarin dose requirement. There is a need for characterization of genotype frequency distribution in different populations for construction of customized dosing algorithms to enhance the efficacy and reduce the toxicity of warfarin therapy. This study was carried out in Pakistani population to evaluate the contribution of common CYP2C9 polymorphisms to warfarin therapy. A total of 550 stable patients taking warfarin were enrolled after medical history, physical examination, and laboratory investigations. Single blood sample was collected after informed consent. Genomic DNA was extracted, and genotype analysis for CYP2C9*2 and CYP2C9*3 polymorphisms was done by polymerase chain reaction-restriction fragment length polymorphism assay. A number of samples were also analyzed by direct DNA sequencing for validation of the results. Data were analyzed using SPSS version 20. Genotype frequency...
Influence of CYP4F2 rs2108622 (V433M) on Warfarin Dose Requirement in Asian Patients
Warfarin exhibits wide interpatient variability in dosing requirements. Recent studies have shown a novel polymorphism (rs2108622, V433M) in the CYP4F2 gene to be associated with variability in warfarin requirements in Caucasians. The purpose of this study was to evaluate the impact of rs2108622 on warfarin dose requirements in the Asian population. The mean warfarin dose was found to be significantly lower in patients carrying homozygous wild-type allele CC when compared with patients carrying variant alleles CT and TT (CC vs CT+TT: 3.0 mg/day vs 3.75 mg/day, p = 0.033). In patients harboring VKORC1 diplotypes associated with low warfarin requirements, a linear regression model which included age, weight, CYP2C9 and CYP4F2 variants accounted for 38% of the variability in warfarin dose. Approximately 11% of the dose variation was explained by CYP4F2 rs2108622 (p = 0.004). The influence of rs2108622 in patients harboring VKORC1 diplotypes associated with high warfarin requirements was not significant. This study suggests that CYP4F2 rs2108622 may significantly affect warfarin dose requirements in carriers of VKORC1 low-dose-associated diplotypes.
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.
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...
Identification of CYP2C9 and VKORC1 polymorphisms in Iranian patients who are under warfarin therapy
International Journal of Hematology-Oncology and Stem Cell Research, 2015
Background: Although catalytic properties of different genetic polymorphisms of VKORC1 and CYP2C9 products have been identified, there is limited study available regarding warfarin dose requirement in Iranian patient population. This study investigates the impact of these polymorphisms on 115 patients, referred to Payvand Clinical and Specialty Laboratory for determining the appropriate dose of warfarin. Results of the study may be applicable to individuals who are under warfarin therapy to avoid warfarin resistance or intolerance. Subjects and Methods: PT-INR test was utilized as a screening method. Genotyping were performed for VKORC1 and CYP2C9 using PCR method. Statistical analyses including unpaired t-test or ANOVA and regression were done using SPSS. Results: VKORC1 GA was the most common genotype of VKORC1 allele among the study samples, with a rate of 57.4%. In CYP2C9 variant, 20% and 14.8% of subjects carried CYP2C9*1/*2 and CYP2C9*1/*3 genotyping, respectively. By contrast...