CYP4F2 Research Articles

Nonalcoholic fatty liver disease impairs the cytochrome P-450-dependent metabolism of α-tocopherol (vitamin E)

This study aims to investigate in in vivo and in vitro models of nonalcoholic fatty liver disease (NAFLD) the enzymatic metabolism of α-tocopherol (vitamin E) and its relationship to vitamin E-responsive genes with key role in the lipid metabolism and detoxification of the liver. The experimental models included mice fed a high-fat diet combined or not with fructose (HFD+F) and HepG2 human hepatocarcinoma cells treated with the lipogenic agents palmitate, oleate or fructose. CYP4F2 protein, a cytochrome P-450 isoform with proposed α-tocopherol ω-hydroxylase activity, decreased in HFD and even more in HFD+F mice liver; this finding was associated with increased hepatic levels of α-tocopherol and decreased formation of the corresponding long-chain metabolites α-13-hydroxy and α-13-carboxy chromanols. A decreased expression was also observed for PPAR-γ and SREBP-1 proteins, two vitamin E-responsive genes with key role in lipid metabolism and CYP4F2 gene regulation. A transient activation of CYP4F2 gene followed by a repression response was observed in HepG2 cells during the exposure to increasing levels of the lipogenic and cytotoxic agent palmitic acid; such gene repression effect was further exacerbated by the co-treatment with oleic acid and α-tocopherol and was also observed for PPAR-γ and the SREBP isoforms 1 and 2. Such gene response was associated with increased uptake and ω-hydroxylation of α-tocopherol, which suggests a minor role of CYP4F2 in the enzymatic metabolism of vitamin E in HepG2 cells. In conclusion, the liver metabolism and gene response of α-tocopherol are impaired in experimental NAFLD.

Effect of Genetic Variability in the CYP4F2, CYP4F11, and CYP4F12 Genes on Liver mRNA Levels and Warfarin Response

Genetic polymorphisms in the gene encoding cytochrome P450 (CYP) 4F2, a vitamin K oxidase, affect stable warfarin dose requirements and time to therapeutic INR. CYP4F2 is part of the CYP4F gene cluster, which is highly polymorphic and exhibits a high degree of linkage disequilibrium, making it difficult to define causal variants. Our objective was to examine the effect of genetic variability in the CYP4F gene cluster on expression of the individual CYP4F genes and warfarin response. mRNA levels of the CYP4F gene cluster were quantified in human liver samples (n = 149) obtained from a well-characterized liver bank and fine mapping of the CYP4F gene cluster encompassing CYP4F2, CYP4F11, and CYP4F12 was performed. Genome-wide association study (GWAS) data from a prospective cohort of warfarin-treated patients (n = 711) was also analyzed for genetic variations across the CYP4F gene cluster. In addition, SNP-gene expression in human liver tissues and interactions between CYP4F genes were explored in silico using publicly available data repositories. We found that SNPs in CYP4F2, CYP4F11, and CYP4F12 were associated with mRNA expression in the CYP4F gene cluster. In particular, CYP4F2 rs2108622 was associated with increased CYP4F2 expression while CYP4F11 rs1060467 was associated with decreased CYP4F2 expression. Interestingly, these CYP4F2 and CYP4F11 SNPs showed similar effects with warfarin stable dose where CYP4F11 rs1060467 was associated with a reduction in daily warfarin dose requirement (∼1 mg/day, Pc = 0.017), an effect opposite to that previously reported with CYP4F2 (rs2108622). However, inclusion of either or both of these SNPs in a pharmacogenetic algorithm consisting of age, body mass index (BMI), gender, baseline clotting factor II level, CYP2C9∗2 rs1799853, CYP2C9∗3 rs1057910, and VKORC1 rs9923231 improved warfarin dose variability only by 0.5–0.7% with an improvement in dose prediction accuracy of ∼1–2%. Although there is complex regulation across the CYP4F gene cluster, the opposing effects between the two SNPs in the CYP4F gene cluster appear to compensate for each other and their effect on warfarin dose requirement is unlikely to be clinically significant.

The association between GGCX, miR-133 genetic polymorphisms and warfarin stable dosage in Han Chinese patients with mechanical heart valve replacement.

Warfarin is a widely used anticoagulant with a narrow therapeutic index. Polymorphisms in the VKORC1, CYP2C9 and CYP4F2 genes have been verified to correlate with warfarin stable dosage (WSD). Whether any other genes or variants affect the dosage is unknown. The aim of our study was to investigate the relationship between GGCX, miR-133 variants and the WSD in Han Chinese patientswith mechanical heart valve replacement (MHVR). A total of 231 patients were enrolled in the study. Blood samples were collected for genotyping. The average WSD among subjects with different GGCX or miR-133 genotypes was compared. Regression analyses were performed to test for any association of genetic polymorphisms with WSD. The warfarin dosage in patients with the GGCX rs699664 TT and rs12714145 TT genotypes was 3.77±0.93 (95% CI: 3.35-4.19) mg/d and 3.70±1.00 (95% CI: 3.32-4.09) mg/d, respectively. The GGCX rs699664 and rs12714145 genotypes were significantly associated with WSD (P<.05). But they were ruled out in the multivariate regression analysis. There were no significant differences in the average warfarin stable dosage between subjects with MIR133B rs142410335 wild-type and variant genotypes (P>.05). The genotypes of GGCX rs699644 and rs12714145 were significantly associated with WSD (P<.05), but their contributions were not significant after accounting for other factors. MIR133B rs142410335 makes no significant contributions to warfarin stable dosage in Han Chinese patientswith MHVR neither in univariate regression nor in multivariate regression analyses.

Influence of NR3C1 and VDR polymorphisms on stable warfarin dose in patients with mechanical cardiac valves

ObjectivesThe aim of this study was to evaluate the associations between polymorphisms of VKORC1, CYP2C9, CYP4F2, NR3C1 and VDR genes and stable warfarin doses in Korean patients with mechanical heart valves. MethodsSeventeen single-nucleotide polymorphisms (SNPs) in 204 patients with stable warfarin dose were analyzed: VKORC1 (rs9934438), CYP2C9 (rs1057910), CYP4F2 (rs2108622), NR3C1 (rs41423247, rs1800445, rs56149945, rs10052957, rs6198, rs33388, rs6196, and rs244465), and VDR (rs1544410, rs11568820, rs731236, rs757343, rs7975232, and rs2228570). Statistical analyses were conducted to evaluate the associations of gene variations with stable warfarin dose. Number needed to genotype was obtained by calculating the percentage of patients whose predicted dose was at least 20% higher or lower than the actual stable dose. ResultsThe combined genotypes of rs7975232 and rs2228570 of the VDR gene revealed a significant association with stable warfarin dose, along with VKORC1, CYP2C9, and CYP4F2 polymorphisms. Patients with the genotype combination GT,TT/CT,CC of VDR rs7975232/rs2228570 required significantly higher stable warfarin dose (5.79±2.02mg) than those with the other genotypic combinations (5.19±1.78mg, p=0.034). Multivariate analysis showed that VDR rs7975232/rs2228570 explained 2.0% of the 47.5% variability in overall warfarin dose. Adding VDR SNP combinations to the base model including non-genetic variables (age, sex, and body weight) and genetic variables (VKORC1 rs9934438, CYP2C9 rs1057910, and CYP4F2 rs2108622) gave a number needed to genotype of 41. ConclusionsThis study showed that stable warfarin dose is associated with VDR SNPs along with VKORC1, CYP2C9, and CYP4F2 SNPs.

Pathway-analysis of published genome-wide association studies of lung cancer: A potential role for the CYP4F3 locus.

The fatty acids (FAs) metabolism is suggested to play a pivotal role in the development of lung cancer, and we explored that by conducting a pathway-based analysis. We performed a meta-analysis of published datasets of six genome wide association studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium, which included 12 160 cases with lung cancer and 16 838 cancer-free controls. A total of 30 722 single-nucleotide polymorphisms (SNPs) from 317 genes relevant to FA metabolic pathways were identified. An additional dataset from the Harvard Lung Cancer Study with 984 cases and 970 healthy controls was also added to the final meta-analysis. In the initial meta-analysis, 26 of 28 SNPs that passed false discovery rate multiple tests were mapped to the CYP4F3 gene. Among the 26 top ranked hits was a proxy SNP, CYP4F3 rs4646904 (P = 8.65 × 10-6 , FDR = 0.018), which is suggested to change splicing pattern/efficiency and to be associated with gene expression levels. However, after adding data of rs4646904 from the Harvard GWAS, the significance in the combined analysis was reduced to P = 3.52 × 10-3 [odds ratio (OR) = 1.07, 95% confidence interval (95%CI) = 1.03-1.12]. Interestingly, the small Harvard dataset also pointed to the same direction of the association in subgroups of smokers (OR = 1.07) and contributed to a combined OR of 1.13 (95% CI = 1.06-1.20, P = 6.70 × 10-5 ). The results suggest that a potentially functional SNP in CYP4F3 (rs4646904) may contribute to the etiology of lung cancer, especially in smokers. Additional mechanistic studies are warranted to unravel the potential biological significance of the finding.

CYP4F2 repression and a modified alpha-tocopherol (vitamin E) metabolism are two independent consequences of ethanol toxicity in human hepatocytes

The expression of CYP4F2, a form of cytochrome P-450 with proposed role in α-tocopherol and long-chain fatty acid metabolism, was explored in HepG2 and HepaRG human hepatocytes during ethanol toxicity.Cytotoxicity, ROS production, and JNK and ERK1/2 kinase signaling increased in a dose and time-dependent manner during ethanol treatments; CYP4F2 gene expression decreased, while other CYP4F forms, namely 4F11 and 12, increased along with 3A4 and 2E1 isoforms. α-Tocopherol antagonized the cytotoxicity and CYP4F2 gene repression effect of ethanol in HepG2 cells. Ethanol stimulated the tocopherol-ω-hydroxylase activity and the other steps of vitamin E metabolism, which points to a minor role of CYP4F2 in this metabolism of human hepatocytes. PPAR-γ and SREBP-1c followed the same expression pattern of CYP4F2 in response to ethanol and α-tocopherol treatments. Moreover, the pharmacological inhibition of PPAR-γ synergized with ethanol in decreasing CYP4F2 protein expression, which suggests a role of this nuclear receptor in CYP4F2 transcriptional regulation.In conclusion, ethanol toxicity modifies the CYP expression pattern of human hepatic cells impairing CYP4F2 transcription and protein expression. These changes were associated with a lowered expression of the fatty acid biosynthesis regulators PPAR-γ and SREBP-1c, and with an increased enzymatic catabolism of vitamin E. CYP4F2 gene repression and a sustained vitamin E metabolism appear to be independent effects of ethanol toxicity in human hepatocytes.

Pharmacogenetics-based warfarin dose prediction algorithm for patients with heart valve replacement in Southeast China

This study was designed to analyze the influence of polymorphisms in CYP2C9, VKORC1, CYP4F2, GGCX, and EPHX1 genes on the optimal warfarin dosage in patients who have undergone artificial heart valve replacement and establish an algorithm for use by physicians in Southeast China to predict each patient’s optimal steady-state warfarin dose. One-hundred and ninety-six patients scheduled for heart valve replacement in Southeast China were enrolled in this study. Five genotypes, CYP2C9, VKORC1, CYP4F2, GGCX and EPHX1, were detected using time-of-flight mass spectrometry. Correlations of clinical and genetic factors with optimal steady-state dose of warfarin were analyzed. There were significant correlations between the genotypes of CY2C9, VKORC1, CYP4F2 and the warfarin dosage (P = 0.000, 0.000 and 0.015). Multiple stepwise regression analysis was performed to obtain the following algorithm: [Dose (mg/day) = EXP(0.540 + 0.544 × VKORC1 - 0.392 × CYP2C9 + 0.342 × CYP4F2 + 0.474 × BSA - 0.005 × Age)]. This algorithm could predict 49.2% of the observed differences in optimal warfarin dosage among the enrolled patients. A retrospective validation study comparing this algorithm with the published algorithms used in patient populations of other races revealed that the obtained algorithm had the best accuracy (The smallest MRE: 21.11 ± 19.08 mg/day) and applicability (the largest RE proportion of patients in ideal rang: 58.3%). This study 1) defined the relative contributions of age, body surface area, and polymorphisms in CYP2C9, VKORC1, and CYP4F2 to the optimal steady-state dosage of warfarin; 2) established a dose prediction algorithm for populations in this region that takes into account the clinical, pharmacological and genetic polymorphism data; and 3) clarified the advantages of this algorithm over the established prediction equations. Our algorithm can assist clinicians in Southeast China in prescribing appropriate anticoagulation therapy.

Do Genetic Contributors to Warfarin Responsiveness or Common Thrombophilias Influence the Risk of Major Bleeding in Patients on Extended Duration Vitamin K Antagonist (VKA) for Venous Thromboembolic Disease?

Background: Recent studies have indicated that genetic factors such as polymorphisms in the CYP2C9 and the VKORC1 genes play an important role in vitamin K antagonist (VKA) response and perhaps bleeding. There are also data to suggest, especially for factor V Leiden, that thrombophilia may confer a decreased risk of bleeding (which could explain its persistence and high prevalence in the population). The influence of major genetic factors on risk of bleeding have not previously been evaluated in large prospective cohort studies of patients with VTE on extended (treatment after the first 3 to 6 months) VKA therapy.Aims: We sought to determine the effect of genetic variants that influence warfarin metabolism and thrombophilias on the rates of major bleeding during extended VKA therapy in patients with VTE disease.Methods: The Bleeding Risk study is a multicentre, multinational prospective cohort study of patients on extended VKA for unprovoked VTE, or provoked VTE with prior VTE. Patients were enrolled after at least 3 months of VKA. All major bleeding events during long term VKA were captured and adjudicated. A blood sample was taken from each patient at their first study visit and analysed in a central lab to identify the following genetic variant types: CYP2C9*2 (C/T), CYP2C9*3 (T/G), 1639G-A (G/A), Factor V Leiden (G/A: FVL), CYP4F2 (G/A), and Prothrombin gene 20210 variant (PGV). Rates of major bleeding were then evaluated for patients with each genetic variant in isolation and in combination.Results: 2290 of the 2514 patients enrolled at 12 sites have contributed over 7000 years of observation and were included in this analysis. The mean patient age was 60.2±14.7 years, 64% were male, 92% Caucasian, average BMI was 31.3, and 9% of patients were on antiplatelet agents. Patients were followed for a mean of 2.8 years (range, 0.1 to 6.8 years. 121 patients (4.8%) experienced at least one episode of major bleeding. The annual rate of bleeding was 1.7 per 100 patient-years of observation. The CYP2C9*2 variant heterozygous/homozygous versus wildtype (476 patients vs 1584) was protective against bleeding (Incidence risk ratio 0.5, p =0.01), CYP2C9*3 variant heterozygous/homozygous versus wildtype (215 patients vs 1845) was associated with major bleeding (Incidence risk ratio 2.0, p =0.01), VKORC1 and CYP4F2 had no association with major bleeding, and CYP2C9*3 variant heterozygous/homozygous in combination with wildtype CYP2C9*2 (186 patients) was associated with major bleeding (Incidence risk ratio 3.24, p =0.02). Both FVL (19% of patients) and PGV (8% of patients) had no effect on major bleeding, with p values > 0.35 for comparison of the wildtype to heterozygous/homozygous.Conclusion: This is the largest study we are aware of to determine if warfarin metabolic genotype variants and common thrombophilias influence major bleeding risk in patients followed long-term with extended duration VKA therapy for VTE. The thrombophilias do not influence bleeding risk but those with CYP2C9*3 hetero/homozygous inheritance had double the risk and CYP2C9*2 hetero/homozygous inheritance half the risk. There appears to be an interaction between the CYP2C9*2 and *3 genotypes. DisclosuresWells:BMS/Pfizer: Research Funding; Bayer Healthcare: Other: Speaker Fees and Advisory Board; Janssen Pharmaceuticals: Consultancy; Itreas: Other: Served on a Writing Committee. Kovacs:LEO Pharma: Honoraria; Bayer: Honoraria, Research Funding; Daiichi Sankyo Pharma: Research Funding; Pfizer: Honoraria, Research Funding. Anderson:Bayer Healthcare: Research Funding. Rodger:Canadian Agency for Drugs and Technologies in Health: Consultancy; Boehringer Ingelheim: Research Funding.

The impact of CYP4F2, ABCB1, and GGCX polymorphisms on bleeding episodes associated with acenocoumarol in Russian patients with atrial fibrillation.

Oral anticoagulants are commonly used to treat patients with thromboembolic pathology. Genetic variations could influence personal response to anticoagulant drugs. Acenocoumarol (AC) is a vitamin K antagonist used in anticoagulant therapy and as a prophylaxis measure in Europe. In this study, we assessed the effect of CYP4F2 rs2108622, ABCB1, and GGCX polymorphisms on the safety profile and regime dosing of AC in patients with nonvalvular atrial fibrillation. Fifty patients aged 40-70 years were included. All patients received AC in the dose of 1-6 mg daily with a target international normalized ratio of 2.0-3.0. Genotyping for polymorphism markers C3435T for the ABCB1 gene, rs2108622 for the CYP4F2 gene, and rs11676382 for the GGCX gene were designed using polymerase chain reaction and restriction fragment length polymorphism. Statistical analysis was performed using the Fisher exact test and the Mann-Whitney U test. We found that CYP4F2 rs2108622 CT carriers required a higher AC dose than CC (p=0.0366), and CT and TT carriers required a higher AC dose than CC (p=0.0314). We found that ABCB1 CT and TT genotypes are associated with a higher risk of bleeding. No influence of ABCB1 and GGCX polymorphisms on the doses of AC was established. CYP4F2 could still be a genetic factor responsible for the personal variability of AC metabolism.

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.

Effect of VKORC1, CYP2C9, CFP4F2, and GGCX Gene Polymorphisms on Warfarin Dose in Japanese Pediatric Patients.

Warfarin dosage requirements show considerable inter-individual variability. There are some reports of warfarin dose regimens correlating with single nucleotide polymorphisms (SNP) for CYP2C9, VKORC1 and other genes in adults. In children, however, reports are scarcer than in adults and the number of genes examined is more limited. We explored the effects of genetic variation on warfarin dose requirement in Japanese pediatric patients. A total of 45 patients who were prescribed warfarin at the Yokohama City University Hospital were included in this study. The influence of genetic polymorphisms on stable warfarin dosage requirement was investigated by genotyping SNPs of the VKORC1, CYP2C9, CYP4F2, and GGCX genes (rs9923231, rs1057910, rs2108622, and rs699664, respectively) in each patient. Patients with the TT genotype in rs9923231 in VKORC1 required significantly lower maintenance dosages than those with the TC genotype (p=0.001). Multiple regression analysis showed that, while VKORC1 status and patient height account for 78.2% of the variability in maintenance warfarin dosage, genetic polymorphisms in VKORC1 account for 27%, although polymorphisms in CYP4F2 and GGCX had no effect on dosage and the effect of CYP2C9 could not be evaluated. Polymorphisms in VKORC1 partially affected daily warfarin dosage requirements. VKORC1 genotype and height are the primary determinants influencing warfarin dosage in Japanese pediatric patients. Further studies with larger sample sizes are needed to confirm our results.

CYP gene expressions in obesity-associated metabolic syndrome

The contribution of cytochrome P450 (CYP) gene expressions in metabolic syndrome (MetS) has not been elucidated, and was the aim of this study. A total of 51 MetS patients and 41 healthy controls with similar age and sex were included to this study. mRNA from blood samples was extracted, and real-time polymerase chain reaction was performed for gene expressions using a dynamic array system. We observed marked suppressions in CYP2A6 (p=0.0123), CYP4F2 (p=0.0005), CYP3A5 (p=0.0003), and CYP17A1 (p<0.0001) gene expressions in MetS patients. This is the first study to provide evidence that depressed expressions of CYP2A6, CYP4F2, CYP3A5, and CYP17A1 genes may play a role in MetS.

Risk factors for post-transplant diabetes mellitus in renal transplant: Role of genetic variability in the CYP450-mediated arachidonic acid metabolism

Arachidonic acid (AA) is metabolized by cytochrome P450 (CYP) enzymes to epoxyeicosatrienoic acids (EETs) and 20-hidroxyeicosatetraenoic acid (20-HETE), which play an important role both in renal transplant and diabetes mellitus (DM). We searched for associations between polymorphisms in this metabolic pathway and the risk of post-transplant diabetes mellitus (PTDM) in kidney recipients. One-hundred-sixty-four patients were genotyped for common SNPs in this route, namely CYP2C8*3, CYP2C8*4, CYP2C9*2, CYP2C9*3, CYP2J2*7, CYP4A11 F434S and CYP4F2 V433M. Demographic and clinical parameters were retrospectively collected at four time-points in the first year after grafting.Thirty-four patients (20.73%) developed PTDM, which was more prevalent among older patients [OR for older age = 1.06 (1.03–1.10), p < 0.001] and in those with higher body mass index (BMI) [OR for higher average BMI in the first year = 1.13 (1.04–1.23); p < 0.01]. Creatinine clearance [OR = 0.97 (0.95–0.99); p < 0.01] and exposure to tacrolimus [OR = 3.25 (1.15–9.19); p < 0.05] were also relevant for PTDM risk. With regard to genetic variants, logistic regression analysis controlling for significant demographic and clinical variables showed that the V433M polymorphism in CYP4F2, responsible for 20-HETE synthesis, was an independent risk factor for PTDM [OR = 3.94 (1.08–14.33); p < 0.05].We have shown that a genetic variant in the CYP4F2 gene, the main gene implicated in 20-HETE synthesis, is associated with the risk for PTDM. Our findings suggest that genes in the metabolic pathways of AA may become good candidates in genetic association studies for PTDM.

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

Interethnic variability of CYP4F2 (V433M) in admixed population of Roma and Hungarians

AimsPharmacogenetic based dosing recommendations are provided in FDA-approved warfarin label for Caucasians. Evidence of notable difference in dosing algorithms of under-represented populations forced us to explore the genetic variability of CYP4F2 gene in Roma and Hungarian populations. Patients and methods484 Roma, 493 Hungarian untreated subjects were genotyped for the CYP4F2*3 (rs2108622) variant by PCR-RFLP assay. Results and discussionWe firstly report, that frequencies of the CYP4F2 rs2108622 GG, GA, AA genotypes and A allele in the Roma population were 46.5%, 42.6%, 10.9% and 32.2%; in Hungarians 50.1%, 42.2%, 7.7% and 22.8%, respectively. Bearing of two minor alleles of CYP4F2 missense variant (AA genotype) modestly explains inter-ethnic differences of studied populations (p<0.08). CYP4F2*3 (V433M) risk allele frequency of Roma (0.32) was in higher range, and of Hungarians (0.23) in lower range, as compared with other world populations. ConclusionsRoma have an elevated chance for higher mean warfarin dose, besides a decreased risk of major bleeding events in long-term warfarin use.

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.

Association of the CYP4F2 rs2108622 genetic polymorphism with hypertension: a meta-analysis.

Previous case-control studies on the relationship between the CYP4F2 gene rs2108622 polymorphism and hypertension have produced contrasting results. In this study, we aimed to further evaluate the relationship between the CYP4F2 gene rs2108622 polymorphism and hypertension. We selected four case-control studies related to the CYP4F2 gene rs2108622 polymorphism and hypertension by searching PubMed, EMBase, the Chinese Biomedical Literature Database, and the Wanfang database. We utilized the Cochran Q-test and the I2 index to measure the heterogeneity across studies. To merge the odds ratio (OR) and the 95% confidence interval (95%CI), we utilized the fixed and random-effect models during the analyses. The present study included 1878 patients with hypertension and 1512 healthy control subjects. By meta-analysis, we did not find any association of the CYP4F2 gene rs2108622 polymorphism with hypertension in either genotype or allele distribution [AA+AG vs GG: OR = 1.18, 95%CI (0.91-1.54), P = 0.21; GG+AG vs AA: OR = 0.91, 95%CI (0.80-1.05), P = 0.20; A allele vs G allele: OR = 1.04, 95%CI (0.93-1.16), P = 0.53]. We concluded that the CYP4F2 gene rs2108622 polymorphism was not associated with hypertension.

Genetic epidemiology of pharmacogenetic variations in CYP2C9, CYP4F2 and VKORC1 genes associated with warfarin dosage in the Indian population.

Warfarin, a widely used anticoagulant, exhibits large interindividual variability in dose requirements. CYP2C9 and VKORC1 polymorphisms in various ethnic groups have been extensively studied as genetic markers associated with variable drug response. However, allele frequencies of these variants have not been assessed in major ethnic groups in the Indian population. To study the functional variants known to affect warfarin dosing, we reanalyzed genotype microarray datasets generated as a part of genome-wide association studies as well as data from the Indian Genome Variation database. We examined data from 2680 individuals across 24 ethnically diverse Indian subpopulations. Allelic distribution of VKORC1 (-1639G>A) showed a greater degree of variation across Indian subpopulations, with frequencies as low as 6.5% in an out-group subpopulation to >70% in Tibeto-Burmans. Risk allele frequency of CYP4F2*3 (V433M) was higher in north Indians (0.30-0.44), as compared with other world populations, such as African-American (0.12), Caucasian (0.34) and Hispanic (0.23). TheVKORC1 variant (-1639A) was shown to be prevalent amongst Tibeto-Burmans, whereas CYP2C9 (R144C, I359L) and CYP4F2 (V433M) variants were observed in considerable variability amongst Indo-Europeans. The frequency of CYP2C9*3 (I359L) in north Indians was found to be higher than in most Asian populations. Furthermore, geographical distribution patterns of these variants in north India showed an increased trend of warfarin extensive metabolizers from the Himalayan to Gangetic region. Combined allele frequency (CYP2C9*3 and CYP4F2*3) data suggest that poor metabolizers varied in the range of 0.38-1.85% in Indo-Europeans. Based on genotypic distribution, the majority of the Indian subpopulation might require higher doses for stable anticoagulation, whereas careful assessment is required for Tibeto-Burmans who are expected to have intermediate dose requirement. This is the largest global genetic epidemiological study examining variants associated with warfarin that could potentially be valuable to clinicians in optimizing dosage strategies.

The effect of a single nucleotide polymorphism of the CYP4F2 gene on blood pressure and 20-hydroxyeicosatetraenoic acid excretion after weight loss

Genetic background partly determines the efficacy of interventions to lower blood pressure (BP). The CYP4F2 and CYP4A11 enzymes are renal 20-hydroxyeicosatetraenoic acid (20-HETE) synthases that regulate BP. Gene variants of CYP4F2 and CYP4A11 associate with hypertension and stroke. We showed that a gene variant of CYP4F2 but not CYP4A11 was associated with increased 20-HETE excretion and BP. To compare BP and 20-HETE responses in carriers of the CYP4F2 1347G/A polymorphism and controls CYP4F2-GG (wildtype), during weight loss. Volunteers genotyped as CYP4F2GA/AA (n = 26) and controls genotyped as CYP4F2 GG (n = 27) were counselled to reduce weight for 12 weeks, followed by 4 weeks of weight stabilization. Weight, 24-h BP, pulse pressure and urinary 20-HETE were measured at baseline, 12 and 16 weeks. At baseline, SBP was (+1.7 mmHg, P = 0.047) in the CYP4F2 GA/AA genotype. Compared with baseline, weight fell by 3.9 kg, P = 0.0001, in both genotypes, and was maintained to 16 weeks. SBP fell by (-7.6 mmHg, P = 0.004) in both genotypes after 12 weeks. However, after weight stabilization, SBP was +3.6 mmHg, P = 0.004 in CYP4F2 GA/AA genotype. DBP and heart rate changed similarly over time. Pulse pressure fell with weight loss (P < 0.001), but was elevated in the CYP4F2 GA/AA genotype at all time-points (+3.1 mmHg, P < 0.001). Urinary 20-HETE was similar at baseline and 12 weeks but elevated in the CYP4F2 GA/AA genotype (P = 0.017) after weight stabilization. Maintenance of lower BP after weight loss is more difficult for carriers of the CYP4F2 G1347A polymorphism and may be related to increased arterial stiffness and increased 20-HETE synthesis.

Genome at juncture of early human migration: a systematic analysis of two whole genomes and thirteen exomes from Kuwaiti population subgroup of inferred Saudi Arabian tribe ancestry.

Population of the State of Kuwait is composed of three genetic subgroups of inferred Persian, Saudi Arabian tribe and Bedouin ancestry. The Saudi Arabian tribe subgroup traces its origin to the Najd region of Saudi Arabia. By sequencing two whole genomes and thirteen exomes from this subgroup at high coverage (>40X), we identify 4,950,724 Single Nucleotide Polymorphisms (SNPs), 515,802 indels and 39,762 structural variations. Of the identified variants, 10,098 (8.3%) exomic SNPs, 139,923 (2.9%) non-exomic SNPs, 5,256 (54.3%) exomic indels, and 374,959 (74.08%) non-exomic indels are ‘novel’. Up to 8,070 (79.9%) of the reported novel biallelic exomic SNPs are seen in low frequency (minor allele frequency <5%). We observe 5,462 known and 1,004 novel potentially deleterious nonsynonymous SNPs. Allele frequencies of common SNPs from the 15 exomes is significantly correlated with those from genotype data of a larger cohort of 48 individuals (Pearson correlation coefficient, 0.91; p <2.2×10−16). A set of 2,485 SNPs show significantly different allele frequencies when compared to populations from other continents. Two notable variants having risk alleles in high frequencies in this subgroup are: a nonsynonymous deleterious SNP (rs2108622 [19:g.15990431C>T] from CYP4F2 gene [MIM:*604426]) associated with warfarin dosage levels [MIM:#122700] required to elicit normal anticoagulant response; and a 3′ UTR SNP (rs6151429 [22:g.51063477T>C]) from ARSA gene [MIM:*607574]) associated with Metachromatic Leukodystrophy [MIM:#250100]. Hemoglobin Riyadh variant (identified for the first time in a Saudi Arabian woman) is observed in the exome data. The mitochondrial haplogroup profiles of the 15 individuals are consistent with the haplogroup diversity seen in Saudi Arabian natives, who are believed to have received substantial gene flow from Africa and eastern provenance. We present the first genome resource imperative for designing future genetic studies in Saudi Arabian tribe subgroup. The full-length genome sequences and the identified variants are available at ftp://dgr.dasmaninstitute.org and http://dgr.dasmaninstitute.org/DGR/gb.html.