CYP4F2 Research Articles

Impact of six genetic polymorphisms on Warfarin maintenance dose variation in Chinese Han population

To evaluate the effect of VKORC1, CYP2C9, GGCX, PROC, EPHX1 and CYP4F2 gene polymorphisms on Warfarin maintenance dose variation in Chinese Han Population. Four hundred eighty-eight patients with prosthetic heart valves, atrial fibrillation or pulmonary thromboembolism and achieved stable Warfarin dose were enrolled. TaqMan probe or direct sequencing were used to genotype Y9VKORC1, CYP2C9, GGCX, EPHX1 and CYP4F2 gene polymorphisms. Demographic characteristics, stable therapeutic dose of Warfarin and concomitant medications were collected for all patients. The effect of VKORC1, CYP2C9, GGCX, PROC, EPHX1 and CYP4F2 gene polymorphisms, demographic characteristics and concomitant medications on Warfarin daily maintenance dose were analyzed with statistical method. VKORC1 and CYP2C9 gene polymorphisms could explain more than 50% Warfarin maintenance dose variation in recruited patients, while CYP4F2 gene polymorphisms could only explain 1%. GGCX, PROC and EPHX1 gene polymorphisms had no impact no Warfarin maintenance dose. VKORC1 and CYP2C9 gene polymorphisms have a greater impact on Warfarin maintenance dose compared with demographic characteristics and concomitant medications. VKORC1 and CYP2C9 gene polymorphisms have a significant impact on Warfarin maintenance dose in Chinese Han population.

CYP4F2 genetic polymorphisms are associated with coronary heart disease in a Chinese population.

BackgroundTo explore the relationship between CYP4F2 gene polymorphism and coronary heart disease (CHD) in a Chinese Han population.MethodsWe selected 440 CHD patients and 440 control subjects to perform a case - control study. Four SNPs (rs2108622, rs3093100, rs3093105 and rs3093135) in CYP4F2 gene were genotyped using polymerase chain reaction - restriction fragment length polymorphism (PCR - RFLP) methods. The genotype and haplotype distributions were compared between the case and the control group.ResultsWe found both rs2108622 and rs3093105 in CYP4F2 gene were associated with the risk for CHD (P <0.01). Haplotype analysis indicated that GGGT haplotype consisted by rs2108622-rs3093100-rs3093105-rs3093135 was associated with CHD risk (OR = 4.367, 95% CI: 2.241 ~ 8.510; P < 0.001), but GGTA haplotype was associated with decreased risk for CHD (OR = 0.450, 95% CI: 0.111 ~ 0.777; P <0.001).ConclusionCYP4F2 gene polymorphisms were associated with the risk of CHD in Chinese population.

Effect of VKORC1, CYP2C9 and CYP4F2 genetic variants in early outcomes during acenocoumarol treatment.

To analyze VKORC1, CYP2C9 and CYP4F2 polymorphisms in relation to the main outcomes in the first stages of acenocoumarol therapy. Nine hundred and forty one patients who had started therapy and in whom time to stable dosage, time to over-anticoagulation and adverse events occurred during 3 first months were retrospectively analyzed. VKORC1 AA patients needed fewer days to reach stable dosage (p = 0.017). International normalized ratio [INR] at 72 h, and VKORC1 and CYP2C9 genotypes conditioned INR values >2.5 (p < 0.001, p = 0.002 and p < 0.001, respectively), whereas CYP4F2 T carriers had a low risk of the same outcome (p = 0.009). In regards to combined genotypes, CYP4F2 had a significant effect on over-anticoagulation at the beginning of therapy except for the VKORC1 AA and CYP2C9*3 combination. In addition to VKORC1 and CYP2C9, CYP4F2 gene has a slight but significant role in reaching INR >2.5 during the first weeks of acenocoumarol therapy.

Interactions Between the Dietary Polyunsaturated Fatty Acid Ratio and Genetic Factors Determine Susceptibility to Pediatric Crohn's Disease

Increased dietary ratios of ω6/ω3 polyunsaturated fatty acids have been implicated in the pathogenesis of Crohn's disease (CD), but epidemiologic data are limited. We investigated whether variants of genes that control polyunsaturated fatty acid metabolism (CYP4F3, FADS1, and FADS2), along with the dietary ratio of ω6/ω3, confers susceptibility to CD. Based on data from 182 children newly diagnosed with CD and 250 controls, we found that children who consumed a higher dietary ratio of ω6/ω3 were susceptible for CD if they were also carriers of specific variants of CYP4F3 and FADS2 genes. Our findings implicate diet-gene interactions in the pathogenesis of CD.

Characterization of a Novel CYP2C9 Mutation (1009C>A) Detected in a Warfarin-Sensitive Patient

Warfarin is the most frequently prescribed anticoagulant for the long-term treatment in the clinic. Recent studies have shown that polymorphic alleles within the CYP2C9, VKORC1, and CYP4F2 genes are related to the warfarin dosage requirement. In this study, a novel non-synonymous mutation (1009C>A) in CYP2C9 was detected in a warfarin-hypersensitive patient, while the other two candidate genes were both found to be homozygous for the wild-type alleles. The newly identified point mutation results in an amino acid substitution at position 337 of the CYP2C9 protein (P337T) and has been designated as the novel allele CYP2C9*58. When expressed in insect cell microsomes, the relative intrinsic clearance values of the CYP2C9.58 variant for tolbutamide and losartan were quite similar to those of the typical defective variant CYP2C9.3, whereas the clearance value of CYP2C9.58 for diclofenac was slightly higher than that of another typical defective variant CYP2C9.2. These data suggested that when compared with wild-type CYP2C9.1, the enzymatic activity of the novel allelic variant has been greatly reduced by the 1009C>A mutation. If patients carrying this allele take drugs metabolized by CYP2C9, their metabolic rate might be slower than that of wild-type allele carriers and thus much more attention should be paid to their clinical care.

Allele Frequency and Genotype Distribution of 9 SNPs in the Kazakh Population

Background: Determining the allelic variants of xenobiotic biotransformation genes is important, especially for prescribing personalised drugs. Knowledge of the allele distribution in different populations may be considered when selecting the preferred medication regimen. The frequency of CYP2C9, VKORC1, CYP4F2, GGCX, CYP2D6 and CYP1A2 genes has been studied in many populations, but the populations in Central Asia have not yet been investigated. Methods and materials: Using real-time PCR and direct sequencing-based methods, the current study assessed the frequencies of 9 polymorphisms of genes encoding enzymes involved in drug metabolism in 450 healthy individuals from different regions of Kazakhstan and 575 healthy individuals from the West-Siberian region of Russia. Results: The allele frequencies in the Kazakh population were determined for CYP2C9*2 (0.02), CYP2C9*3 (0.03), VKORC1 c. 173+1369G>C, VKORC1 c. 173+1000C>T (0.72, ÐiYP4F2 (0.31), GGCX (0.04), CYP2D6*4 (0.07), CYP2D6*3 (0.01) and CYP1A2*1F (0.35). All alleles were in Hardy–Weinberg equilibrium (p > 0.05). The allele frequencies in the Russian population were as follows: CYP2C9*2, 0.08; CYP2C9*3, 0.08; VKORC1 (c. 173+1000C>T), 0.40; VKORC1 (c. 173+1369G>C), 0.41; ÐiYP4F2 (c. 1297G>A), 0.24; GGCX (c. 1913+45G>C), 0.08; CYP2D6*3, 0.15; CYP2D6*4, 0.22; and CYP1A2*1F (c. -9-154C>A), 0.31. All alleles were in Hardy–Weinberg equilibrium (p>0.05), except GGCX (p=0.04). Conclusion: The Kazakh population allele frequency was between the Caucasian and Asian populations for nearly all of the studied gene allele variants.

Cytochrome P450 4F2 Polymorphism in Patients with Liver Cirrhosis

1297C/T polymorphism of CYP4F2 gene was studied in 108 patients with chronic liver diseases. No significant correlation with predisposition to rapid liver cirrhosis was revealed without consideration for cirrhosis etiology (OR=0.93, 95% CI=0.28-2.99, p=0.885). In patients with viral cirrhosis, a tendency to association of 1297T allele genotypes with rapid cirrhosis development was found (OR=6.0, 95% CI=0.28-382.64, p=0.222). At the same time, CYP4F2 1297T allele was associated with mild (Child-Pugh class A-B) cirrhosis (OR=2.9, p=0.044).

GW24-e0988 A novel polymorphism of the CYP4F2 gene is associated with acute coronary syndrome

ObjectivesCYP4F2 is responsible for metabolising arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE), which plays a crucial role in the regulation of cardiovascular homeostasis. The present study aims to evaluate the association...

PP130—Evaluation of the influence of cytocrome P450 oxidoreductase (POR) in the stable dose of acenocoumarol

Several pharmacogenetic algorithms have been developed to achieve the desired acenocoumarol therapeutic range as soon as possible to reduce the risk of hemorrhagic events or progression of the thrombotic disease. The main SNPs recognized to influence the adequate acenocoumarol dosing are located in CYP2C9, VKORC1, and recently CYP4F2 and APOE genes (Borobia et al. PLoS One 7(7):e41360). POR is required for drug metabolism by all microsomal cytochrome P450 enzymes and has been arisen their influence in warfarin dose.

Resequencing of VKORC1, CYP2C9 and CYP4F2 genes in Italian patients requiring extreme low and high warfarin doses

PurposeThe aim of the present study was to investigate the genetic variability of VKORC1, CYP2C9 and CYP4F2 genes in patients who required a very low and high warfarin dose, in order to identify novel variants that could help to explain the particular extreme dose requirements. MethodsAmong patients followed and treated with warfarin at the Center of Haemostasis and Thrombosis of the PTV, we selected twelve patients showing a high divergence from warfarin standard doses required to achieve the therapeutic effect.All VKORC1, CYP2C9 and CYP4F2 coding regions, 3’ and 5’ UTR and exon/intron boundaries were analyzed by direct sequencing. ResultsThe 1173T and -1639A allele variants in VKORC1 gene, associated with warfarin sensitivity, were present, as expected, mostly in low dose patients while 3730A allele, linked to warfarin resistance, has been found only in high dose patients. Interestingly, we found that three out of six low dose subjects presented CYP2C9*3/*3 homozygous genotype, very rare in Caucasians.Besides these common polymorphisms, we identified 5 SNPs in CYP2C9 gene and 19 SNPs in CYP4F2 gene. Among these, all polymorphisms identified in CYP2C9 gene were present only in low dose patients and three of them resulted in linkage with CYP2C9*2 and CYP2C9*3. Regarding CYP4F2 SNPs, we did not observe differences between the high and low dose patients. At the end, the whole sequencing did not reveal any novel polymorphism/mutation. ConclusionFurther studies are required to identify other genetic factors contributing to extreme warfarin requirement.

Laboratory tests during direct oral anticoagulant treatment? Yes

Warfarin is still the most used oral anticoagulant; in Italy approximately 650,000 subjects were taking warfarin in 2006 with an annual increase of 5 % [1]. The main drawback of warfarin is the high interindividual variability in the dose–response [2]. Variability depends on both environmental factors (e.g., diet and interfering comedications) and endogenous factors (e.g., age, gender, height, weight, comorbidities and genetic). VKORC1, CYP2C9 and CYP4F2 gene polymorphisms are clearly involved in determining the variation in warfarin dose. [3]. Less variability is reported for direct oral anticoagulants although trough plasma concentration varies individually on maintenance treatment [4]. As the increase in drug concentrations is closely related to bleeding events, it is suggested to monitor their effect through specific coagulation tests. The aim would be to find out the best dose for each patient. However, direct oral anticoagulants have shown a fairly predictable effect with no need for routine coagulation monitoring [5]. Moreover, Phase III clinical studies of direct anticoagulants on stroke prevention in atrial fibrillation have clearly shown the efficacy and safety of fixed dose of direct anticoagulants [6]. This is one of the main advantages of using these new drugs. According to this assumption, physicians will follow their patient only from a clinical point of view to assure adherence and compliance to treatment. It could be argued that in specific situations assessment of patient anticoagulant status may be useful [7]. Ecarin clotting time (ECT) or diluted thrombin time (dTT) or aPTT (if the previous ones are not available) is recommended for dabigatran. Prothrombin time (PT) in comparison to control PT is a sensitive and reliable test for rivaroxaban whereas no routine coagulation test seems to be suitable for apixaban. Possible indications for laboratory testing are the following (Table 1): (1) evaluation of coagulation tests when the patient reaches a steady state, (2) evaluation of possible overor underdosing the anticoagulant due to drug interactions, (3) assessment of anticoagulant effect in frail patients. As recommended by Italian Federation of Thrombosis Centers (FCSA) appropriate coagulation tests should be performed after 2–3 months from the initiation of therapy in order to have a steady-state laboratory value that may be useful if future adverse clinical events (bleeding, thrombosis) occur. Interaction of novel anticoagulants with other drugs is apparently much lower than that of warfarin. However, dabigatran, rivaroxaban and apixaban are substrates of the P-glycoprotein (P-gp) transporter, one-third of rivaroxaban is metabolized by the liver via CYP3A4/CYP3A5 and CYP2J2-dependent pathways and apixaban which has predominant non-renal clearance is eliminated via the CYP3A4, CYP1A2 and CYP2J2-dependent pathways. Therefore, the possibility exists that drug interactions may interfere with the anticoagulant effect of these agents. In frail patients prescribed with multiple drugs as for example with elderly patients with atrial fibrillation it might be wise to perform adequate coagulation tests at regular intervals comparing them with those initially obtained at steady state. In this way, the extent of drug interaction can be measured when a potential interfering drug is added on top of their usual therapy. Definite indications to laboratory testing comprise the following: (1) major or life-threatening bleeding, (2) renal or liver impairment, (3) urgent or elective surgery or invasive manoeuvres at high risk of bleeding. Under these circumstances, if the drug used is not known, coagulation V. Pengo (&) Clinical Cardiology, Department of Cardiac Thoracic and Vascular Sciences, University of Padova, Padua, Italy e-mail: vittorio.pengo@unipd.it

Does CALU SNP rs1043550 Contribute Variability to Therapeutic Warfarin Dosing Requirements?

Calumenin, a molecular chaperone, exerts a regulatory effect on the vitamin K-dependent γ-carboxylation redox cycle that inhibits transfer of the reduced vitamin K from VKORC1, the pharmacological target of warfarin, to the γ-carboxylase. Because of its polymorphic structure and central role in the warfarin metabolic pathway, a contributory role for calumenin to warfarin dose variability has been posited. The current study sought to validate modulation of therapeutic dosing requirements by a single nucleotide polymorphisms (SNP) occurring in the calumenin gene (CALU) reported in previous studies. The CALU SNP was further modeled to detect interaction with SNPs occurring in VKORC1, CYP2C9, and CYP4F2 genes and characterize any additional contribution to variability in therapeutic warfarin dose requirement. The study was undertaken in an established, well-characterized cohort of subjects treated with warfarin in the Anticoagulation Clinic of Marshfield Clinic in Marshfield, Wisconsin. Subjects (N=491) previously genotyped for SNPS known to contribute variability to therapeutic warfarin dose requirement were genotyped for CALU SNP rs1043550, using TaqMan assays. Contribution of CALU SNP rs1043550 was modeled relative to other genotypic and phenotypic characteristics including gender, diagnosis, age, body surface area, underlying indication for warfarin, comorbidities, and pharmacological exposures. Interaction between SNPs impacting on warfarin dose requirements and calumenin SNPs was also modeled. Small differences in warfarin dosing requirements detected among individuals encoding the mutant G allele in the calumenin SNP were not statistically or clinically significant relative to therapeutic warfarin dose requirement and did not independently contribute significantly to the warfarin dosing model. Interaction between calumenin and VKORC1 SNPs contributed only minor additional variability to that ascribed to the wild type VKORC1 genotype. The impact of the CALU SNP on warfarin dose variability was minor and did not contribute significantly to therapeutic warfarin dose requirement in our study cohort. While no contribution was noted for the SNP examined in the present study, further examination of interaction between genetic elements contributing major impact on therapeutic warfarin dose requirements and genes exhibiting a lesser contribution is warranted.

Creating a genotype-based dosing algorithm for acenocoumarol steady dose

Acenocoumarol is a commonly prescribed anticoagulant drug for the prophylaxis and treatment of venous and arterial thromboembolic disorders in several countries. In counterpart of warfarin, there is scarce information about pharmacogenetic algorithms for steady acenocoumarol dose estimation. The aim of this study was to develop an algorithm of prediction for acenocoumarol.The algorithm was created using the data from 973 retrospectively selected anticoagulated patients and was validated in a second independent cohort adding up to 2,683 patients. The best regression model to predict stable dosage in the Primary Cohort included clinical factors (age and body mass index, BSA) and genetic variants (VKORC1, CYP2C9* and CYP4F2 polymorphisms) and explained up to 50% of stable dose. In the validation study the clinical algorithm yielded an adjusted R²=0.15 (estimation´s standard error=4.5) and the genetic approach improved the dose forecast up to 30% (estimation´s standard error=4.6). Again, the best model combined clinical and genetic factors (R² = 0.48; estimation´s standard error=4) which provided the best results of doses estimates within 20% of the real dose in patients taking lower (≤ 7 mg/week) or higher (≥ 25 mg/week) acenocoumarol doses. In conclusion, we developed a prediction algorithm using clinical data and three polymorphisms in VKORC1, CYP2C9* and CYP4F2 genes that provided a steady acenocoumarol dose for about 50% of patients in the Validation Cohort. Such algorithm was especially useful to patients who need higher or lower acenocoumarol doses, those patients with higher time required until their stabilisation and are more prone to suffer a treatment derived complication.

A NOVEL POLYMORPHISM OF THE CYP4F2 GENE IS ASSOCIATED WITH ACUTE CORONARY SYNDROME

ObjectivesCYP4F2 is responsible for metabolising arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE), which plays a crucial role in the regulation of cardiovascular homeostasis. The present study aimed to evaluate whether or...

A multiplex assay to detect variations in the CYP2C9, VKORC1, CYP4F2 and APOE genes involved in acenocoumarol metabolism

ObjectivesWe have developed a genotyping system to determine the alleles of genes related to interindividual variability in acenocoumarol dosage requirements. This genotyping system is intended for routine clinical use and therefore it is essential that it be simple, fast and inexpensive. Design and methodsWe developed a PCR multiplex SNaPshot reaction that targets 6 SNPs (single nucleotide polymorphisms) in CYP2C9, CYP4F2, VKORC1 and APOE genes, which are associated with acenocoumarol dose requirements. ResultsWe tested the multiplex in 152 samples and found it to be 100% concordant with the results of other methods. ConclusionsWe successfully produced a reliable multiplex system for simultaneously typing 6 SNPs. This system may be used as a model for accurate, simple and inexpensive genotyping of SNPs related to dose requirements. This information allows the prediction of drug efficiency in patients prior to treatment with acenocoumarol and the prevention of adverse drug reactions.

Warfarin pharmacogenetics: development of a dosing algorithm for Omani patients

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 3673G>A polymorphism emerged as the single most important predictor of warfarin dose variability, even in this admixed population (partial R(2)=0.45).

Effects of CYP4F2 Gene Polymorphisms on Warfarin Clearance and Sensitivity in Korean Patients With Mechanical Cardiac Valves

Recently, a single nucleotide polymorphism of CYP4F2 (rs2108622) was reported to have a significant relationship with the stable warfarin dose. However, the underlying mechanism of CYP4F2 effects on the stable warfarin dose has not been studied. This study aimed to examine the effects of cytochrome P450 (CYP) 4F2 gene on warfarin clearance and sensitivity in Korean patients with mechanical heart valves. One hundred ninety-one patients with mechanical heart valves who were on anticoagulation therapy with warfarin and maintained international normalized ratio levels of 2-3 for 3 consecutive times were followed up, retrospectively. Warfarin enantiomer concentrations were determined by a validated high-performance liquid chromatography method. Genotypes of vitamin K epoxide reductase complex subunit 1, CYP2C9, CYP2C19, CYP4F2, human microsomal epoxide hydroxylase, calumenin, and γ-glutamyl carboxylase were determined. From multiple linear regression models, vitamin K epoxide reductase complex subunit 1, CYP2C9, CYP4F2, and age were found to have significant effects on warfarin stable dose. The stable warfarin daily doses of patients with the CC, CT, and TT genotypes in the CYP4F2 gene were 5.34 ± 2.04, 5.33 ± 1.64, and 6.55 ± 2.12 mg, respectively. The higher dose requirements in patients with TT alleles in CYP4F2 were attributable to a low warfarin sensitivity (international normalized ratio/warfarin plasma concentration); the warfarin sensitivity in CC, CT, and TT genotypes was 2.1 ± 1.2, 1.0 ± 0.4, and 0.8 ± 0.6, respectively. The similarity between the dose requirements of patients with CT and CC alleles was explained through the combined result of warfarin sensitivity and clearance outcomes. Apparent plasma (S)- and (R)-warfarin clearances were found to be 37.7% and 34.1% lower in CT genotype patients than in CC genotype patients, respectively. The dose variability in CYP4F2 genotypes was attributable to both warfarin clearance and sensitivity differences.

Statins increase cytochrome P450 4F3-mediated eicosanoids production in human liver cells: A PXR dependent mechanism

In the present study, the ability of lovastatin, a competitive inhibitor of HMG-CoA reductase, to regulate the gene expression and function of Cytochrome P450 4F3B (CYP4F3B) was examined in the well differentiated HepaRG human hepatoma cell line. Statins induced CYP4F3B mRNA, protein and the production of 20-hydroxyeicosatetraenoic acid (20-HETE), a product of arachidonic acid metabolism and a peroxisome proliferator activated receptor (PPAR) ligand. This response was not dependent on cholesterol shortage or on sterol regulatory element binding protein activation. By both a pharmacological and a siRNA approaches, we demonstrated that recruitment of the Pregnane X Receptor (PXR) was required to mediate CYP4F3 induction by lovastatin. Furthermore, the CYP4F3 gene promoter was transcriptionally activated by PXR, and responded to lovastatin. Finally, the expression of fatty acid-responsive genes was increased in response to the statin or 20-HETE in a CYP4F3-dependent way. We propose that metabolites produced by CYP4F3 could modulate lipid metabolism in response to lovastatin. These results suggest the existence of a novel pathway, operating in liver cells, through which statins could lower lipid levels.

Effects of CYP4F2 Polymorphism on Response to Warfarin During Induction Phase: A Prospective, Open-Label, Observational Cohort Study

BackgroundThe cytochrome P450 (CYP) 4F2 isozyme has been reported to metabolize vitamin K1 in vitro, and the V433M polymorphism in the CYP4F2 gene has been associated with reduced vitamin K1 metabolism and the need for a higher maintenance dosage in patients receiving warfarin. ObjectiveThe purpose of the present study was to evaluate the effects of V433M polymorphism on warfarin response during the induction phase. MethodsWarfarin-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. ResultsThe 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 >3 was >4-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 >10-fold lower than in the other carriers. Both of these findings had a nominal P value of <0.05. After adjustment for false discovery rate, none of the findings remained significant at a threshold q value of <0.05. 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. ConclusionsThese 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.

Integrating interacting drugs and genetic variations to improve the predictability of warfarin maintenance dose in Chinese patients

Compared with genetic factors, drug interactions are largely unexplored in pharmacogenetic studies. This study sought to systematically investigate the effects of VKORC1, STX4A, CYP2C9, CYP4F2, CYP3A4, and GGCX gene polymorphisms and interacting drugs on warfarin maintenance dose. A retrospective study of 845 Chinese patients after heart valve replacement receiving long-term warfarin maintenance therapy was conducted. Thirteen polymorphisms in the six genes were genotyped, and 36 drugs that may interact with warfarin were investigated. Single-nucleotide polymorphism association analysis showed that VKORC1, CYP2C9 and CYP4F2 variations were highly associated with the warfarin maintenance dose. Among 36 drugs that may interact with warfarin, fluconazole, amiodarone, and omeprazole were associated with the requirement for 45.8, 16.7, and 16.7% lower median warfarin dose (all P<0.05 with a false discovery rate <0.05). The final pharmacogenetic equation explained 43.65% of interindividual variation of warfarin maintenance dose with age, body surface area, VKORC1 g.3588G>A, CYP2C9*3, CYP4F2 c.1297G>A, amiodarone, fluconazole, and diltiazem accounting for 1.97, 2.74, 24.12, 3.94, 1.64, 5.92, 2.47, and 0.84% of variation. The present study indicated that VKORC1, CYP4F2, and CYP2C9 genotypes and interacting drugs had a significant impact on the warfarin maintenance dose in Chinese patients with heart valve replacement and demonstrated that integrating interacting drugs can largely improve the predictability of the dose algorithm.