CYP4F2 Gene Polymorphisms Research Articles

Comparative study of the CYP2C19, CYP2C9, CYP4F2 gene polymorphisms impact on the clinical and laboratory characteristics of acute coronary syndrome patients

Coronary heart disease (CHD) is one of the most common causes of death worldwide. The pharmacokinetic properties of drugs used to treat coronary heart disease depend on genetic factors, including the genotype of CYP2C19, CYP2C9 and CYP4F2. However, existing studies of the genetic basis of the response to treatment in patients with acute coronary syndrome (ACS) have contradictory results, requiring a more detailed study. Goal. In this study, we studied the distribution of the genotypes of CYP2C19*2, CYP2C9*2 and CYP4F2*3 among 59 patients diagnosed with ACS who received dual antiplatelet therapy. Methods. The polymerase chain reaction (PCR) method was used to determine the genotypes of CYP2C19, CYP2C9 and CYP4F2. A correlation analysis of the results of genotype carriage and clinical and laboratory parameters of patients was carried out. Results. The distribution of CYP2C9*2 genotypes was as follows: wild genotype (CC) was found with a frequency of 78 % (45 patients), heterozygotes (CT) — 22 % (12 patients), homozygotes (TT) were not detected. The CYP4F2*3 genotype was distributed as follows: 56.14 % (32 patients) had a wild genotype (CC), 31.5 % (18 patients) were heterozygotes with reduced enzyme activity (CT), 12.36 % (7 patients) were homozygotes for the T (TT) allele. The distribution of alleles and genotypes of CYP2C9 did not correspond to the Hardy-Weinberg equation (χ2 = 21.55; p = 0.044), while the distribution of alleles and genotypes of CYP4F2 corresponded to it (χ2 = 3.61; p = 0.0574). Conclusion. The study showed a high prevalence of the genotypes CYP2C9*2 (CT) and CYP4F2*3 (CT and TT) among patients with acute coronary syndrome. The carriage of CYP2C19*2 was significantly associated with adverse cardiovascular events in patients. These results suggest that genetic testing can provide valuable information for risk stratification and personalized treatment of patients with acute coronary syndrome

Genetic Variants of CYP4F2 Associated with Ischemic Stroke Susceptibility in the Han Population from Southern China.

The pathophysiological mechanism of ischemic stroke is complex. Traditional risk factors cannot fully or only partially explain the occurrence and development of IS. Genetic factors are getting more and more attention. Our study aimed to explore the association between CYP4F2 gene polymorphism and susceptibility to IS. A total of 1322 volunteers were enrolled to perform an association analysis through SNPStats online software. Using FPRP (false-positive report probability) to detect whether the result is a noteworthy finding. The interaction of SNP-SNP in IS risk was assessed by multi-factor dimensionality reduction. Statistical analysis of this study was mainly completed by SPSS 22.0 software. Mutant allele "A" (OR = 1.24) and genotype "AA" (OR = 1.49) or "GA" (OR = 1.26) of CYP4F2-rs2108622 are risk genetic factors for IS. Rs2108622 is significantly associated with an increased risk of IS among subjects who are females, aging >60 years old, with BMI ≥24 kg/m2, and smoking or drinking volunteers. CYP4F2-rs3093106 and -rs3093105 are associated with susceptibility to IS among smoking, drinking subjects, or IS patients complicated with hypertension. CYP4F2-rs2108622, -rs3093106, and -rs3093105 are associated with an increased risk of IS.

Genetic polymorphisms in CYP4F2 may be associated with lung cancer risk among females and no-smoking Chinese population.

Our study aimed to explore the potential association of CYP4F2 gene polymorphisms with lung cancer (LC) risk. The five variants in CYP4F2 were genotyped using Agena MassARRAY in 507 cases and 505 controls. Genetic models and haplotypes based on logistic regression analysis were used to evaluate the potential association between CYP4F2 polymorphisms and LC susceptibility. This study observed that rs12459936 was linked to an increased risk of LC in no-smoking participants (allele: OR = 1.38, p = 0.035; homozygote: OR = 2.00, p = 0.035; additive: OR = 1.40, p = 0.034) and females (allele: OR = 1.64, p = 0.002; homozygote: OR = 2.57, p = 0.006; heterozygous: OR = 2.56, p = 0.001; dominant: OR = 2.56, p < 0.002; additive: OR = 1.67, p = 0.002). Adversely, there was a significantly decreased LC risk for rs3093110 in no-smoking participants (heterozygous: OR = 0.56, p = 0.027; dominant: OR = 0.58, p = 0.035), rs3093193 (allele: OR = 0.66, p = 0.016; homozygote: OR = 0.33, p = 0.011; recessive: OR = 0.38, p = 0.021; additive: OR = 0.64, p = 0.014), rs3093144 (recessive: OR = 0.20, p = 0.045), and rs3093110 (allele: OR = 0.54, p = 0.010; heterozygous: OR = 0.50, p = 0.014; dominant: OR = 0.49, p = 0.010; additive: OR = 0.54, p = 0.011) in females. The study demonstrated that CYP4F2 variants were associated with LC susceptibility, with evidence suggesting that this connection may be affected by gender and smoking status.

Suggestive evidence of CYP4F2 gene polymorphisms with HAPE susceptibility in the Chinese Han population.

High altitude pulmonary edema (HAPE) is a common respiratory disease in the high altitude area, which is rapid and harmful. We firstly conducted a case-control study to assess the potential association of CYP4F2 gene polymorphisms with HAPE susceptibility in the Chinese Han population. The study recruited 238 patients with HAPE and 230 healthy controls in Northwest China. Genomic DNA was extracted from blood samples, and gene polymorphisms were detected using the Agena MassARRAY platform. Odds ratios (ORs), 95% confidence intervals (95% CIs), and P-value were used to evaluate the relationship between HAPE risk and CYP4F2 gene polymorphisms. Multi-factor dimension reduction (MDR) was used to assess the optimal interaction of CYP4F2 gene polymorphisms on HAPE risk. We found rs3093193 was shown to reduce the risk of HAPE (OR = 0.70, 95% CI = 0.52-0.93, P = 0.014), while rs12459936 was increased the susceptibility to HAPE (OR = 2.08, 95% CI = 1.33-3.26, P = 0.001). Age stratified analysis revealed that rs3093193 and rs12459936 were correlated with HAPE risk in people at age > 32 years old, and rs3093193 and rs3093110 were correlated with the HAPE risk in people at age ≤ 32 years old. Gender stratification analysis was found that rs3093193, rs12459936, and rs3093110 were all related to HAPE risk in males. A combination of rs12459936 and rs3093110 was the best multi-loci model with the highest testing accuracy. Our study is the first to provide the association between CYP4F2 gene polymorphisms and HAPE risk in the Chinese Han population.

The influence of clinical and genetic factors on the stability of warfarin’s anticoagulant effect in patients with atrial fibrillation

The aim. To investigate the influence of clinical and genetic factors on the stability of warfarin’s anticoagulant effect in patients with atrial fibrillation (AF) during the year. Materials and methods. The study involved 60 patients with AF, age 70.50 (64.25; 76.25) years (32 men and 28 women). Coagulogram indexes with International Normalized Ratio (INR) were determined using Coag Chrome 3003 monthly; the CHA2DS2-VASC, HAS-BLED, SAMe-TT2R2 scales scores were evaluated; the calculation of TTR was performed using the Rosendaal method. CYP2C9, CYP4F2, VKORC1 genes polymorphisms were determined using multiplex real time polymerase chain reaction in CFX-96 thermocycler (BioRad). Results. Median TTR in groups of patients with SAMe-TT2R2 score &lt;2 (n = 33) and ≥2 (n = 27) did not differ significantly (74 % versus 68 % respectively, P &gt; 0.05). There were significantly more patients with TTR &lt;70 % in the group with predicted labile INR (59.36 % versus 30.30 %; χ2 = 5.07, P &lt; 0.05). SAMe-TT2R2 score ≥2 increased the risk of poor INR control by 1.96 times (CI 1.05–3.63). No association of TTR with CYP2C9, CYP4F2 and VKORC1 gene polymorphisms was found. Episodes of excessive hypocoagulation (INR &gt;4) were detected in 21 (40 %) patients during the year. Excessive hypocoagulation was significantly more common in patients carrying the allele A of the VKORC1 gene in comparison with non-carriers (51.43 % versus 24.00 %; χ2 = 4.57, P &lt; 0.05). The presence of mutant allele A was associated with 2.14-fold higher risk of excessive hypocoagulation (RR = 2.14; CI 1.06–4.69). Taking amiodarone (χ2 = 3.13; P &lt; 0.05) had a significant effect on the development of excessive hypocoagulation with a relative risk RR = 1.83 (CI 1.01–3.35). Conclusions. SAMe-TT2R2 score can be useful to predict poor INR control, while VKORC1 genotype estimating – to predict excessive hypocoagulation episodes. An integrated approach using clinical and genetic methods is needed to determine the potential efficacy and safety of warfarin therapy.

Influence of Clinically Significant Genes on Antiplatelet Effect of Clopidogrel and Clinical Outcomes in Patients with Acute Coronary Syndrome and Atrial Fibrillation

Introduction: The interindividual variability of the antiplatelet effect of clopidogrel is determined by multiple clinical and genetic factors. A lot of genotype-oriented studies have concentrated on the impact of CYP2C19 gene polymorphisms on platelet aggregation in patients receiving clopidogrel. However, the influence of this polymorphism may be only 12–20%, so other genetic markers should also be investigated. The aim of this work was to study the impact of carriage of CES1, PON1, ABCG2, CYP4F2, CYP3A4, IGTB3, P2Y12, PEAR1, and B4GALT2 polymorphisms on antiplatelet effect of clopidogrel and clinical outcomes in patients with acute coronary syndrome (ACS) and atrial fibrillation (AF). Methods: 103 patients who underwent ACS with or without percutaneous coronary intervention and concomitant nonvalvular AF were included in an open multicenter prospective study to assess efficacy and safety of combined antithrombotic therapy. The study assessed the frequency of different primary clinical outcomes (incidence of major bleeding, hospital mortality, cardiovascular mortality, stroke and transient ischemic attacks (TIAs), renal mortality) and secondary outcomes (resistance to therapy – high residual platelet reactivity, excessive platelet suppression). Residual platelet reactivity was examined using the VerifyNow system (Accumetrics, Latham, NY, USA). Results: None of the studied genetic markers had no statistically significant effect on the antiaggregant response to clopidogrel in patients with ACS and AF. However, CYP4F2 C(Val433Met) T, PEAR1 rs41273215 C>T were statistically significantly associated with an increased frequency of bleeding on antithrombotic therapy. B4GALT2 rs1061781 was statistically significantly associated with increased frequency of strokes and TIA. Conclusion: In our study, we determined that carriers of CYP4F2 gene polymorphisms C(Val433Met)T, PEAR1 rs41273215 C>T (CT+TT) were associated with lower safety of antithrombotic therapy in patients with ACS and AF. And, the B4GALT2 rs1061781 gene polymorphism was associated with a greater risk of insufficient efficacy of the therapy. The data obtained in our study may improve the understanding of the effect of less studied genetic markers on the efficacy and safety of antithrombotic therapy in patients with ACS and AF.

The Effect of CYP4 F2 Polymorphism on Initial Warfarin Dose in Patients with Heart Valve Replacement

To study the effect of cytochrome P-4504F2 ( CYP4 F2) gene polymorphism on the initial dose of warfarin in patients after mechanical heart valve replacement. We collected 350 patients receiving warfarin after mechanical heart valve replacement from January 2013 to December 2015 in our hospital. According to the international standardized ratio (INR) ≥2 at the initial stage after surgery, the patients were divided into two groups: INR≥2 group and INR<2 group. We selected the blood samples of all the 350 patients with testing the CYP4 F2 gene type of each patient, and analyzed the effect of CYP4 F2 gene polymorphism on the initial dose of warfarin after mechanical heart valve replacement (the average daily dose during hospitalization of patients 5-10 days after mechanical heart valve replacement). There was no statistical significance in the initial dose of warfarin among patients with different CYP4 F2 genotypes. However, warfarin dose was higher in CYP4 F2 TT genotype than in CYP4 F2 CC carriers ((3.37±0.68) mg vs. (2.94±0.74) mg, P<0.05) in INR≥2 group; In patients with the same genotype, the initial dose of warfarin in the CYP4 F2 CC ((4.02±0.58) mg vs. (2.94±0.74) mg) and CYP4 F2 CT genotypes ((4.15±0.88) mg vs. (3.18±0.82) mg) of INR<2 group was higher than that in INR≥2 group ( P<0.05). Gender, age, body mass index (BMI), comorbidities (hypertension, diabetes mellitus, coronary heart disease, atrial fibrillation), cytopigment P-450 2C9 ( CYP2 C9), CYP4 F2 and vitamin K peroxide-reductase complex 1 ( VKORC1) gene polymorphism and INR compliance were included in multiple linear regression analysis. The regression equation was as follows: warfarin initial dose (mg) =-8.634+0.352×BMI (kg/m 2) +1.102× CYP4 F2 genotype (CC or CT values 1, TT values 2) +2.147× VKORC1 (AA or AG values 1, GG values 2) +1.325×INR ( INR≥2 values 0, INR<2 values 1). The coefficient of determination ( R 2) of regression equation was 0.431 ( P<0.05). CYP4 F2 gene polymorphism may affect the initial dose of warfarin in patients after heart valve replacement, and this effect is also affected by body characteristics and other factors.

Association of genetic variants at CETP, AGER, and CYP4F2 locus with the risk of atrophic age-related macular degeneration.

BackgroundAge‐related macular degeneration (AMD) is the leading cause of blindness in the elderly individuals. The etiology of AMD includes environmental and genetic factors.MethodsWe aimed to determine the association between CETP (rs5882; rs708272; rs3764261; rs1800775; rs2303790), AGER (rs1800624; rs1800625), and CYP4F2 (rs1558139) gene polymorphisms and development of atrophic AMD. About 52 patients with atrophic AMD and 800 healthy control subjects were evaluated. The genotyping of single‐nucleotide polymorphisms in CETP, AGER, and CYP4F2 was carried out using the real‐time‐PCR method.ResultsGenetic risk models in the analysis of CETP rs5882 revealed statistically significant variables with increased risk of atrophic AMD in the codominant (p < .001), dominant (p < .001), recessive (p < .001), and additive (p < .001) models with the highest 25.4‐fold increased risk of atrophic AMD in the codominant model (p < .001). The AGER rs1800625 was associated with a highly increased risk of atrophic AMD in the codominant (p < .001), recessive (p < .001), and additive (p < .001) genetic models.ConclusionWe identified two polymorphisms with a higher risk of atrophic AMD (CETP rs5882 and AGER rs1800625).

CYP4F2 and CYP3A5 gene polymorphisms and lung cancer in Chinese Han population

This study aimed to explore whether the polymorphisms of CYP4F2 and CYP3A5 are correlated with the risk of lung cancer development. A case–control study was conducted among 510 patients with pathologically confirmed lung cancer as the case group and 504 healthy individuals as the control group. Four single-nucleotide polymorphisms of the CYP4F2 and CYP3A5 genes were genotyped, and their correlations with the risk of lung cancer were examined using Chi-square test and logistic regression analysis. Stratified analysis found that the rs3093105 and rs3093106 loci of CYP4F2 gene were significantly associated with lower risk of lung cancer (P = 0.012, OR 0.64, 95% CI 0.45–0.91). The correlation was related to patients’ age and sex and pathological type of lung cancer. Similarly, the rs10242455 loci of CYP3A5 gene showed a statistical significance between the case group and the control group (P = 0.018, OR 0.71, 95% CI 0.53–0.94), which also was associated with reduced risk of squamous cell lung cancer in the dominant and additive models (dominant: OR 0.66, 95% CI 0.46–0.94, P = 0.021; additive: OR 0.71, 95% CI 0.53–0.95, P = 0.023). CYP4F2 and CYP3A5 gene polymorphisms are associated with the reduced risk of non-small cell lung cancer, and its correlation is related to patients’ age and sex and pathological type of lung cancer.

Rapid detection of CYP2C9, CYP2C19,CYP4F2,VKORC1 and ABCB1 gene polymorphisms by liquid phase chip technology

Objective To establish a method for simultaneous and rapid detecting of the polymorphisms in Cytochrome P450 2C9 (CYP2C9), CYP2C19, CYP4F2, Vitamin K epoxide reductase (VKORC1) and ATP-binding cassette subfamily B member1 (ABCB1) gene, which were associated with warfarin and clopidogrel, based on liquid phase chip technology. Methods Method establishment. The eight gene sequences near targeted sites related to warfarin and clopidogrel were found in Genbank, and the specific primers and probes were designed. Through multiple PCR amplification, followed by allele specific primer extension (ASPE), and MagPlex-Tag microspheres hybridization, the suspension array Luminex 200 system step-by-step, the genotypes were determined by fluorescence signal. The reaction system was optimized and its methodological evaluation was performed. 260 patients with antithrombotic therapy from Dongguan houjie hospital were recruited in this study form June 2017 to December 2018. The eight genotypes of the 260 patients were detected by the established method, and the results were compared with the sequencing results. Results The results of 260 samples showed that allelic median fluorescence intensity (MFI) ratios of homozygotes (mutant/wild-type) were all greater than 0.9 or less than 0.1, and all the allelic MFI ratios of heterozygotes were between 0.3 and 0.6. The within run and between run coefficients of variance for allelic MFI ratios were lower than 6.4% and 10.9%, respectively. The minimum DNA template requirements was 0.75ng. The genotypes of 260 patients determined by the established method were completely concordant with the sequencing results. Conclusion A method was established successfully for rapid detecting the genotypes which associated with warfarin and clopidogrel based on liquid phase chip technology. Key words: Liquid phase chip technology; Allele-specific primer extension; Warfarin; Clopidogrel; Single nucleotide polymorphism

Significance of CYP4F2 polymorphism on oral anticoagulation therapy with acenocoumarol in South Indian patients with mechanical heart valves

BackgroundThe coumarin group of oral anticoagulants has a narrow therapeutic range and wide inter-individual variability. Polymorphism of VKORC1 and CYP2C9 genes are the major genetic determinants of the drug-dose response. Our study aimed to investigate the role of CYP4F2 (1347 G > A) polymorphism on the acenocoumarol daily dose requirement, and its interaction with VKORC1 and CYP2C9 polymorphism. Methods301 Rheumatic Heart Disease (RHD) patients with mechanical cardiac valves were recruited. Genotyping for CYP4F2, VKORC1 and CYP2C9 was done by PCR-RFLP. CYP4F2 genotype distribution GG, GA and AA was 23.5%, 51.5% and 25% respectively. The mean daily dose requirement for variant homozygous patients (AA) was 0.46 folds more when compared to wild type (GG) (Adjusted OR 0.46; 0.21–0.99, p = .048). However, on combined genotype analysis of CYP4F2, VKORC1 and CYP2C9 there was no significant difference in mean dose requirement. ConclusionThe homozygous genotype (AA) of CYP4F2 gene was more prevalent in our study cohort. No significant association was found between CYP4F2 gene polymorphism and acenocoumarol mean dose requirement, both when analyzed individually and in combination with VKORC1 and CYP2C9 polymorphisms.

Erratum to: Effect of VKORC1, CYP2C9, CYP4F2, and GGCX Gene Polymorphisms on Warfarin Dose in Japanese Pediatric Patients.

Erratum to: Effect of VKORC1, CYP2C9, CYP4F2, and GGCX Gene Polymorphisms on Warfarin Dose in Japanese Pediatric Patients.

GW26-e2203 Haplotype-Based Case-Control Study of the Human CYP4F2 Gene and Essential Hypertension in the Chinese Han population

CYP4F2 is responsible for metabolizing arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE), which plays a crucial part in the regulation of blood pressure in humans. The aim of the present study was to assess the association between the human CYP4F2 gene polymorphism and essential

CYP4F2 gene single nucleotide polymorphism is associated with ischemic stroke.

The objective of this study was to explore the relationship between CYP4F2 gene polymorphism and ischemic stroke (IS) in the Han Chinese population. We performed a case-control study to genotype four single nucleotide polymorphisms (SNPs) (rs2108622, rs3093100, rs3093105, rs3093135) in the CYF4F2 gene. The genotype and haplotype distributions were compared between the case and control groups. We found that the GG genotype of rs2108622 in the CYP4F2 gene was associated with risk of IS (P = 0.023). Haplotype analysis indicated that the GGGT haplotype comprising rs2108622-rs3093100-rs3093105-rs3093135 was associated with IS, which suggests that the GGGT haplotype may be a risk factor for IS (P = 0.012). CYP4F2 gene polymorphism might increase the risk of IS in the Chinese population.

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.

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...

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

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...

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.