Frequencies Of CYP2C9 Research Articles

Dose regimens for Chinese adult liver transplant recipients according to the genetic polymorphisms of CYP2C9, CYP2C19, and CYP3A5 in recipients and donors.

Genetic polymorphisms of the P450 2C9 enzyme (CYP2C9), CYP2C19 and CYP3A5 gene are known to affect the metabolism of many drugs applied in liver transplant recipients, such as warfarin, voriconazole, and tacrolimus. The aim of this study was to recommend dose regimens for the liver recipients based on CYP2C9, CYP2C19, and CYP3A5 genotypic combinations of liver transplant recipients and their donors. 91 adult Han Chinese liver transplant recipients who underwent orthotopic liver transplantation at Tianjin First Central Hospital, China, between 2013 and 2014 were included in this study. CYP2C9*2, CYP2C9*3, CYP2C19* 2, CYP2C19*3 and CYP3A5*3, in both liver recipients and their grafted liver were tested by polymerase chain reaction-restriction fragment length polymorphism. The dose regimens for the liver recipients were recommended based on CYP genotypic combinations of the recipients and their donors. In the liver transplant recipients, the frequencies of CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3, and CYP3A5*3 were found to be 2.75%, 4.40%, 0%, 24.18%, and 75.27%, respectively. Allele frequencies were significantly different for CYP2C9*2, CYP2C19*2, and CYP2C19* 3 (p < 0.001) when comparing the recipients with Chinese, Eastern Asians and Caucasians populations. Most dose regimens of drugs, especially of immunosuppressive drugs, should be adjusted according to the variant metabolism activity affected by the genetic polymorphisms in both recipients and their grafted liver. The dose regimens would present considerable intraand inter-patient variability in liver transplant recipients since the genetic polymorphisms of P450 enzyme in their grafted liver might complicate the metabolism of drugs in liver transplant recipients. Giving careful consideration to the CYP genotypic combinations of transplant recipients and donors in clinical dose regimens could optimize outcomes.

Investigating the Role of Plasma Glucose Concentration as a Phenotypic Marker for CYP2C9 Genetic Variants, in the Diabetic Population of Gujarat.

The present study was aimed to investigate the role of plasma glucose concentration as a phenotypic marker and to study the frequency distribution of CYP2C9 genetic variants in Gujarat state diabetic population. One hundred and nine unrelated diabetes mellitus patients treated with sulfonylureas were genotyped for CYP2C9*2 and CYP2C9*3 alleles. Their pre- and posttreatment postprandial blood glucose levels were recorded and mean glucose drop per milligram of drug values were calculated and further used as an index for phenotypic correlation. The frequencies of CYP2C9*1, CYP2C9*2 and CYP2C9*3 alleles in the Gujarat state diabetic population were 0.84, 0.07 and 0.09, respectively. The distribution of CYP2C9*1/*1, CYP2C9*1/*2, CYP2C9*1/*3, CYP2C9*2/*2, CYP2C9*2/*3 and CYP2C9*3/*3 genotypes were 0.73, 0.08, 0.13, 0.0, 0.06 and 0.0, respectively. Patients with CYP2C9*1/*2 genotype did not show any significant difference in the mean glucose drop per milligram of drug values when compared with wild-type patients in glipizide-treatment group. Patients with CYP2C9*1/*3 genotype showed greater mean glucose drop per milligram of drug values than patients with CYP2C9*1/*1 wild-type genotype for both glipizide and glimepiride while patients with CYP2C9*2/*3 genotype showed greater drop than patients with CYP2C9*1/*1 genotype only in the glipizide-treatment group. The presence of CYP2C9*3 allele significantly affected plasma glucose drop per milligram of drug values in patients taking glipizide and glimepiride, while effects of CYP2C9*2 allele were insignificant. Further studies are needed to confirm the effects of CYP2C9*2 allele on plasma glucose drop per milligram of drug values. However, plasma glucose concentration is a complex physiological marker that cannot be used to establish perfect genotype-phenotype correlation. Hence studies exploring robust phenotypic markers must be initiated.

Genetic polymorphisms analysis of drug-metabolizing enzyme CYP2C9 in the Uyghur population

Genetic variations in cytochrome P450 2C9 are known to contribute to interindividual and interethnic variability in response to clinical drugs, but little is known about the genetic variation of CYP2C9 in the Uyghur population.We directly sequenced the whole CYP2C9 gene in 96 unrelated, healthy Uyghur from Xinjiang Uygur Autonomous Region of China and screened for genetic variants in the promoter, exons, introns and 3′-UTR.Thirty five previously reported alleles and six genotypes were detected in this study. The allele frequencies of CYP2C9*1, *2, *11, *12, *29 and *33 were 89.58, 7.81, 0.52, 0.52, 1.04 and 0.52%, respectively. We detected one non-synonymous novel variant at position 329 from Arg to Cys and this mutation is predicted to be intolerant by SIFT.Our results provide basic information about CYP2C9 alleles in Uyghur, which may help to optimize pharmacotherapy effectiveness by providing personalized medicine to this ethnic group.

High allele frequency of CYP2C9*3 (rs1057910) in a Negrito’s subtribe population in Malaysia; Aboriginal people of Jahai

Background: CYP2C9 gene polymorphisms modulate inter-individual variations in the human body’s responses to various endogenous and exogenous drug substrates. To date, little is known about the CYP2C9 gene polymorphisms among the aboriginal populations of the world, including those in Malaysia.Aim: To characterise and compare the CYP2C9 polymorphisms (CYP2C9*2, CYP2C9*3, CYP2C9*4 and CYP2C9*5) between one of Malaysia’s aboriginal populations, Jahai, with the national major ethnic, Malay. To also compare the allele frequencies from these two populations with available data of other aboriginal populations around the world.Subjects and methods: The extracted DNA of 155 Jahais and 183 Malays was genotyped for CYP2C9 polymorphisms using a nested multiplex allele-specific polymerase chain reaction technique. The results were confirmed by DNA direct sequencing.Results: Genotyping results revealed that CYP2C9*2, CYP2C9*4 and CYP2C9*5 were absent in Jahais, while only the latter two were absent in Malays. The CYP2C9*3 allelic frequency in Jahais was 36.2%, making them the most frequent carriers of the allele thus far reported in any ethnic group from Southeast Asia.Conclusions: The high frequency of CYP2C9*3 and the absence of CYP2C9*2 in Jahais suggest that genetic drift may be occurring in this ethnic group. This is the first study to determine the CYP2C9 polymorphisms in an aboriginal population in Malaysia.

Lower CYP2C9 activity in Turkish patients with Behçet's disease compared to healthy subjects: a down-regulation due to inflammation?

We previously reported on a Swedish patient with Behçet's disease (BD) who was an ultra-rapid metaboliser of drugs catalysed by CYP2C9. Was this extreme metabolism caused by the disease? This study aims to compare the genotype/phenotype of CYP2C9 in patients with BD and healthy subjects. As the occurrence of BD is high in Turkey, all subjects were recruited from this country. Genotyping of CYP2C9 was performed using standard PCR-RFLP and allele-specific PCR methods. Phenotyping of CYP2C9 was performed by administration of a 50-mg single oral dose of losartan and by calculating the urinary metabolic ratio (MR) of probe drug to its metabolite E-3174. Quantitation was performed by HPLC. The frequency of CYP2C9*2 and *3 was not significantly different between the Behçet's disease patients (12.5 and 8.7%) and the healthy subjects (8.9 and 8.2%). The geometric mean losartan MR was higher in the 52 patients (1.75) than in the 96 healthy subjects (1.02) (p = 0.002; t-test). Within the genotypes *1/*1, there was a significant difference of MR between patients and healthy subjects (P = 0.006). All but three of the Behçet's disease patients were treated with colchicine. In nine subsequent patients, we found no significant effect of 2 weeks of treatment with colchicine on the CYP2C9 MR. Contrary to expectation, the CYP2C9 activity was lower in Turkish BD patients compared to healthy subjects. As this seems not to be due to colchicine treatment, our hypothesis is that inflammation related to BD might have caused the down-regulation of the CYP2C9 activity due to immune cytokine reactions. The ultra-rapid metabolism of CYP2C9 substrate drugs in the Swedish patient was not due to her BD.

The Frequency of Cyp2c19 Genetic Polymorphisms In Russian Patients With Peptic Ulcer Treated With Proton Pump Inhibitors

The Frequency oF cyP2c19 GeneTic PolymorPhisms in russiAn PATienTs WiTh PePTic ulcer TreATed WiTh ProTon PumP inhibiTors N.P. Denisenko; D.A. Sychev; Zh.M. Sizova; A.V. Grachev; and K.A. Velikolug Russian Medical Academy of Post-Graduate Education, Moscow, Russia; I.M. Sechenov First Moscow State Medical University, Moscow, Russia; SM-Clinic, Moscow, Russia; and Out-patient department No. 51 branch 3, Moscow, Russia Introduction: Proton pump inhibitors, which are widely used as acid-inhibitory agents for the treatment of peptic ulcer, are mainly metabolized by 2C19 isoenzyme of cytochrome P450 (CYP2C19). CYP2C19 has genetic polymorphisms, associated with extensive, poor, intermediate or ultrarapid metabolism of proton pump inhibitors. Genetic polymorphism of CYP2C19 could be of clinical concern in the treatment of peptic ulcer with proton pump inhibitors. The aim of the study – to investigate the frequencies of CYP2C19*2, CYP2C19*3 and CYP2C19*17 alleles and genotypes in Russian patients with peptic ulcer. Materials and Methods: The study involved 971 patients with peptic ulcer from the European part of Russia (Moscow), 428 male (44%) and 543 female (56%). The mean age was 44.6 ± 11.9 years (range 15–88 y). DNA isolated from blood samples was used for the analysis of CYP2C19 genetic polymorphisms (CYP2C19*2, *3, *17 alleles) by real-time polymerase chain reaction. Results: Regarding CYP2C19 genotype, 317 patients (32.65%) out of 971 were CYP2C19*1/*1 carriers classified as extensive metabolizers. Three hundred eighty-six (39.75%) with CYP2C19*1/*17 or CYP2C19*17/*17 genotype were ultrarapid metabolizers. Two hundred fifty-one people (25.85%) were intermediate metabolizers with CYP2C19*1/*2, CYP2C19*2/*17, CYP2C19*1/*3, CYP2C19*3/*17 genotypes. Seventeen patients (1.75%) with CYP2C19*2/*2, CYP2C19*3/*3, CYP2C19*2/*3 genotypes were poor metabolizers. The allele frequencies were the following: CYP2C19*2 – 0.140, CYP2C19*3 – 0.006, CYP2C19*17 – 0.274. Conclusion: There is a high frequency of CYP2C19 genotypes associated with modified response on proton pump inhibitors in Russian patients with peptic ulcer. Genotyping for CYP2C19 polymorphisms is suggested to be a useful tool for personalized dosing of proton pump inhibitors.

Allele Frequency Distributions of the Drug Metabolizer Genes &lt;i&gt;CYP2C9*2&lt;/i&gt;, &lt;i&gt;CYP2C9*3&lt;/i&gt;, and &lt;i&gt;CYP2C19*17&lt;/i&gt; in the Buginese Population of Indonesia

The present study is part of the genetic mapping of Indonesia focusing on drug metabolizing enzymes, which started with the Buginese population of Makassar, South Sulawesi. The two CYP450 gene subfamilies, i.e. CYP2C9 and CYP2C19 are of interest as they exhibit wide inter-individual variation in expression, which influence the drug metabolism capacity. The CYP2C9 alleles of interest in this study were CYP2C9*2 and *3, and of CYP2C19 was CYP2C19*17. The study aimed to determine the frequencies of the CYP2C9 genotype, which contains *1, *2 and *3 alleles, and the CYP2C19 genotype, which comprises the *1 and *17 alleles in the Buginese. Ninety six Buginese subjects, comprising 48 males and 48 females were studied. CYP2C9 and CYP2C19 alleles were detected by a PCR-RFLP assay method. Results showed that there was no CYP2C9*2 allele present, while the frequencies of CYP2C9*3 and CYP2C19*17 overall were 1.56 % and 4.68 %, respectively. The frequency of the CYP2C9*3 allele in females was 2.08%, and not statistically different from that in males (1.05%). The frequency of the CYP2C19*17 allele in females (8.33%), was significantly different (P<0.05) from that in males (1.05%). No subject carried the CYP2C9*2/*2, CYP2C9*3/*3, CYP2C19*17/*17, or CYP2C9*3/CYP2C19*17 genotype. The study is the first to describe the drug metabolizing enzyme polymorphisms, CYP2C9 and CYP2C19, in the Indonesian Buginese population.

Effects of cytochrome P450 2C19 and paraoxonase 1 polymorphisms on antiplatelet response to clopidogrel therapy in patients with coronary artery disease.

Clopidogrel is an antiplatelet prodrug that is recommended to reduce the risk of recurrent thrombosis in coronary artery disease (CAD) patients. Paraoxonase 1 (PON1) is suggested to be a rate-limiting enzyme in the conversion of 2-oxo-clopidogrel to active thiol metabolite with inconsistent results. Here, we sought to determine the associations of CYP2C19 and PON1 gene polymorphisms with clopidogrel response and their role in ADP-induced platelet aggregation. Clopidogrel response and platelet aggregation were determined using Multiplate aggregometer in 211 patients with established CAD who received 75 mg clopidogrel and 75–325 mg aspirin daily for at least 14 days. Polymorphisms in CYP2C19 and PON1 were genotyped and tested for association with clopidogrel resistance. Linkage disequilibrium (LD) and their epistatic interaction effects on ADP-induced platelet aggregation were analysed. The prevalence of clopidogrel resistance in this population was approximately 33.2% (n = 70). The frequencies of CYP2C19*2 and *3 were significantly higher in non-responder than those in responders. After adjusting for established risk factors, CYP2C19*2 and *3 alleles independently increased the risk of clopidogrel resistance with adjusted ORs 2.94 (95%CI, 1.65–5.26; p<0.001) and 11.26 (95%CI, 2.47–51.41; p = 0.002, respectively). Patients with *2 or *3 allele and combined with smoking, diabetes and increased platelet count had markedly increased risk of clopidogrel resistance. No association was observed between PON1 Q192R and clopidogrel resistance (adjusted OR = 1.13, 95%CI, 0.70–1.82; p = 0.622). Significantly higher platelet aggregation values were found in CYP2C19*2 and *3 patients when compared with *1/*1 allele carriers (p = 1.98×10−6). For PON1 Q192R genotypes, aggregation values were similar across all genotype groups (p = 0.359). There was no evidence of gene-gene interaction or LD between CYP2C19 and PON1 polymorphisms on ADP-induced platelet aggregation. Our findings indicated that only CYP2C19*2 and *3 alleles had an influence on clopidogrel resistance. The risk of clopidogrel resistance increased further with smoking, diabetes, and increased platelet count.

Variant recurrent risk among stroke patients with different CYP2C19 phenotypes and treated with clopidogrel

Polymorphisms of CYP2C19 have been associated with variant risk of subsequent cardiovascular events in survivors of myocardial infarction (MI) receiving clopidogrel. This study evaluated the impacts of CYP2C19 polymorphisms on stroke recurrence and other vascular events in a cohort of Chinese patients receiving clopidogrel. From Nanjing Stroke Registry Program, 625 consecutive patients with ischemic stroke were enrolled between May 2008 and April 2010. CYP2C19 variants (*2, *3, and *17) were genotyped. Clinical outcomes were determined with three monthly follow-up. The primary endpoint was a composite of vascular death, non-fatal ischemic stroke, and non-fatal MI. The second endpoint was bleeding events. The median exposure to clopidogrel was 13.2 (interquartile range, 8.9–18.0) months. Primary endpoint was observed in 85 (13.6%) patients and secondary endpoint in 13 (2.1%) patients. Frequencies of CYP2C19*1, *2, *3, and *17 alleles were 61.2, 34.0, 3.8, and 1.0%, respectively, in this patient cohort. CYP2C19 loss-of-function allele (*2 and *3, LOF) carriers were observed with higher risk of subsequent vascular events compared with non-carriers (17.2 versus 8.1%, HR = 2.16, 95% CI: 1.31–3.56, p = 0.003). After adjusted for age, sex, major cardiovascular risk factors, and drug agent, CYP2C19 LOF carrier was independently associated with primary endpoint (HR = 2.31, 95% CI: 1.39–3.84, p = 0.001). No significant association between CYP2C19 gain-of-function (*17, GOF) and clinical events was detected. In Chinese stroke survivors treated with clopidogrel, carriers of CYP2C19 LOF allele may have increased risk of recurrence.

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.

Genetic polymorphisms in warfarin and tacrolimus-related genes VKORC1, CYP2C9 and CYP3A5 in the Greek-Cypriot population

BackgroundTwo variants in the gene encoding the cytochrome P450 2C9 enzyme (CYP2C9) are considered the most significant genetic risk factors associated with bleeding after warfarin prescription. A variant in the vitamin K epoxide reductase (VKORC1) has been also associated by several studies with warfarin response. Another variant in the P450 3A5 enzyme (CYP3A5) gene is known to affect the metabolism of many drugs, including tacrolimus.FindingsWe conducted a population genetic study in 148 unrelated healthy Greek-Cypriot volunteers (through PCR-RFLP assays), in order to determine the frequencies of the above pharmacogenetics variants and to compare allele frequencies with those in other major ethnic groups. The allele frequencies of CYP2C9*2, CYP2C9*3 and CYP3A5*3 were found to be 0.162, 0.112 and 0.943 respectively, whereas VKORC1 - 1639A was 0.534. The latter frequency differs significantly when compared with Caucasians, Asians and Africans (p < 0.001) and is still significant when compared with the geographically and culturally closely related to Greek-Cypriots, Hellenes of Greece (p = 0.01). Interestingly ~18% of our population are carriers of four or three risk alleles regarding warfarin sensitivity, therefore they have a high predisposition for bleeding after taking high or even normal warfarin doses.ConclusionsOur data show no significant difference in the frequency of CYP2C9 and CYP3A5 allelic variants when compared to the Caucasian population, but differ significantly when compared with Africans and Asians (p < 0.001). Also, the frequency of variant VKORC1 - 1639A differs between Greek-Cypriots and every other population we compared. Finally, about 1/5 Greek-Cypriots carry three or four risk alleles and ~50% of them carry at least two independent risk alleles regarding warfarin sensitivity, a potentially high risk for over-anticoagulation.

Interaction between smoking and CYP2C19*3 polymorphism increased risk of lung cancer in a Chinese population

Cytochrome P450 (CYP) 2C19 is expressed in vascular endothelium and metabolizes arachidonic acid to biologically active epoxyeicosatrienoic acids (EETs), which play a crucial role in either the detoxification or inactivation of potential carcinogens, or the bioactivation of some environmental procarcinogens to reactive DNA-binding metabolites. And smoking is a major risk factor for lung cancer. The purpose of this study is to explore the relationship between the interaction of CYP2C19*3 polymorphism and smoking and lung cancer in a Chinese population. In a Chinese case-control study of lung cancer patients (n=420) and healthy controls (n=420), we investigated the roles of CYP2C19*3 polymorphism in lung cancer risk using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. We found that the frequency of CYP2C19 (*)3 (AG + AA) genotype was significantly higher in lung cancer patients than that in control subjects (14.28 % versus 4.76 %; P<0.001). Multivariable logistic regression analysis showed that after adjustment of other risk factors, the A allele of CYP2C19*3 remains significantly associated with lung cancer. We also found that there was a significant interaction between CYP2C19 (*)3 and smoking in increasing the risk for lung cancer (OR 5.121, 95 % confidence interval [CI] 4.321-10.124; P=0.001). The interaction between CYP2C19 (*)3 polymorphism and smoking plays an important role in the mechanism of lung cancer in Chinese population.

Genetic polymorphisms of CYP2C8, CYP2C9 and CYP2C19 in Ecuadorian Mestizo and Spaniard populations: a comparative study

This study was designed to investigate the potential differences between Spaniards and Ecuadorian Mestizo people regarding CYP2C8, CYP2C9, and CYP2C19 genetic polymorphisms. DNA from 282 Spaniard and 297 Ecuadorian subjects were analyzed by either a previously reported pyrosequencing method (CY2C8*3, CYP2C9*2, CYP2C9*3, CYP2C19*2 and CYP2C19*3) or a nested PCR technique (CYP2C19*17). Whereas CYP2C19*17 allele distribution was higher in Ecuadorians than in Spaniards (P<0.001) and the frequency of CYP2C19*3 was similar in these two populations (P>0.05), the other allelic variants were detected at significantly lower frequencies in Ecuadorians than in Spaniards (P<0.05). According to the diplotype distributions, the prevalence of the presumed CYP2C9 and CYP2C8 extensive metabolizers was higher in Ecuadorians than in Spaniards (P<0.05). Individuals genotyped CYP2C19*1/*17 and *17/*17 who were considered as ultrarapid metabolizers were overrepresented in Ecuadorians in relation to Spaniards (P<0.001). By contrast, among Ecuadorians no poor metabolizers (PMs) of either CYP2C8 or CYP2C9 were found and only two individuals were CYP2C19 PMs. These data are compatible with a higher CYP2C8, CYP2C9, and CYP2C19 activity in Mestizo Ecuadorians as opposed to Spaniards, which could imply differences in dosage requirements for drugs metabolized by these cytochromes and should also be considered in allele-disease association studies.

Analysis of the CYP2C19 genetic polymorphism in Han and Uyghur patients with cardiovascular and cerebrovascular diseases in the Kashi area of Xinjiang.

BackgroundThe aim of this study was to analyze the CYP2C19 genetic polymorphism among Han and Uyghur patients with cardiovascular and cerebrovascular diseases in the Kashi area of Xinjiang.Material/MethodsWe enrolled 1020 patients with cardiovascular and cerebrovascular diseases, including 220 Han subjects and 800 Uyghur subjects. We used the gene chip method to detect polymorphisms in CYP2C19. The allele frequencies of CYP2C19 and the metabolic phenotype frequencies were then compared between the 2 ethnic groups.ResultsThe frequency of CYP2C19 *1 was 0.6454 in Han subjects and 0.7869 in Uyghur subjects, and the difference was statistically significant (P<0.05). The frequency of CYP2C19 *2 was 0.3273 in Han subjects and 0.1837 in Uyghur subjects (P<0.05). The frequency of the homozygous extensive metabolizer phenotype was 42.72% and 62.13% in Han and Uyghur subjects, respectively (P<0.01). The frequency of the heterozygous extensive metabolizer phenotype was 43.64% and 33.13% in Han and Uyghur subjects, respectively (P<0.01). The frequency of poor metabolizers in Han and Uyghur subjects was 13.64% and 4.76%, respectively (P<0.01).ConclusionsAmong patients with cardiovascular and cerebrovascular diseases located in the Kashgar Prefecture of Xinjiang, there is a differential distribution of CYP2C19 genotypes between the Han and Uyghur populations. Uyghur patients showed higher frequencies of extensive metabolizer genotypes than Han patients, while Han patients showed higher frequencies of poor metabolizer genotypes than Uyghur patients.

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.

The Effect of Genetic Polymorphisms of Cytochrome P450 CYP2C9, CYP2C19, and CYP2D6 on Drug-Resistant Epilepsy in Turkish Children

Despite the availability of several antiepileptic drugs, drug resistance remains one of the major challenges in epilepsy therapy. Genetic factors are known to play a significant role in the prognosis and treatment of epilepsy. The aim of this study was to determine the frequencies of alleles for CYP2C9, CYP2C19, and CYP2D6 genes in Turkish children with epilepsy, and to investigate the relationship between the genetic polymorphism of these genes with multiple drug resistance in epilepsy patients. We genotyped 132 epileptic patients (60 drug resistant and 72 drug responsive) and 55 healthy controls for six single nucleotide polymorphisms (SNPs) in CYP2C9, CYP2C19, and CYP2D6. Genotype, allele, and haplotype frequencies were compared between groups. The frequencies of CYP2C9*3/*3 genotype and CYP2C9*3 allele, and the haplotype CCGG (CYP2C9*2 C>T, CYP2C9*3 A>C, and CYP2C19*2 G>A, CYP2C19* G>A) were significantly higher in drug-resistant versus -responsive patients. Our results demonstrated the important role of the CYP2C9*3 allelic variant in preventing epilepsy patients from developing drug resistance. These data suggest that CYP2C9, CYP2C19, and CYP2D6 SNPs and haplotypes may affect the response to antiepileptic drugs.

The Frequency of CYP2C9, VKORC1, and CYP4F2 Polymorphisms in Russian Patients With High Thrombotic Risk

VKORC1, CYP2C9, and CYP4F2 are known to be responsible for the metabolism of warfarin. The aim was to explore the frequencies of these genotypes in the Russian population and compare the results with those for other populations. In total, 91 Caucasian subjects with a mean age of 66.17 years (SD, 10.9) were recruited into the study. Of them, 40 patients (48.2%) were men. In order to obtain necessary clinical data, the medical records of the patients were reviewed. Blood (5 mL) was taken from each subject, and DNA was isolated and used for identification of the CYP2C9 allele *1, *2, *3, -1639G/A VKORC1, and CYP4F2 V433M rs2108622 C>T, using the real-time polymerase chain reaction-restriction fragment length polymorphism assay. The CYP2C9*1/*1 genotype was detected in 67.0%, CYP2C9*1/*2 in 9.9%, CYP2C9*1/*3 in 11.0%, CYP2C9*2/*2 in 2.2%, CYP2C9*2/*3 in 8.8%, and CYP2C9*3/*3 in 1.1% of the patients. The results for VKORC1 were as follows: 49.5% (GG), 28.6% (GA), and 22.0% (AA); meanwhile, those for the genotype CYP4F2 were 57.1% (CC), 34.1% (CT), and 7.7% (TT). No significant deviations from the Hardy-Weinberg equilibrium were observed. The frequency of the polymorphisms in the Russian population was found to differ from Asian and close to Caucasian. There were no significant interethnic variations in the frequency of CYP4F2 among Russian, Asian, and Caucasian populations. The frequency of CYP2C9, CYP4F2, and VKORC1 polymorphisms in Russian patients is comparable with other European ethnic groups.

Pharmacodynamic effect of adjunctive cilostazol vs. high-dos clopidogrel in acute coronary syndrome patients according to the CYP2C19 genotype (ACCEL-GENOTYPE) study

Purpose: Cilostazol use in ACS patients has been reduced the risks of ischemic events and restenosis in East Asians. Compared with Caucasians, East Asians have higher frequency of CYP2C19 loss-of-function allele (*2 and *3). We compared the pharmacodynamic effect of adjunctive cilostazol vs. high-dose clopidogrel in PCI-treated East Asians with ACS according to the CYP2C19 genotype. Methods: ACS patients were assigned to either clopidogrel 150 mg/d (DOUBLE group; n=139) or cilostazol 100 mg twice a day + clopidogrel 75 mg/d (TRIPLE group; n=136) on top of aspirin. Platelet aggregation (PA) was measured at baseline and at least 30-day follow-up with light transmittance aggregometery (20 μM ADP and 6 μg/ml collagen). PAs were adjusted with known clinical covariates. CYP2C19*2 or *3 genotype was determined. Primary endpoint was the level of 20 μM ADP-induced PA at follow-up. HPR was defined as 20 μM ADP-induced PA >59%. Results: During standard-dose clopidogrel treatment, platelet measurements did not differ according to individual CYP2C19 genotype between the groups (Fig. 1A). PA levels and HPR risk increased across the CYP2C19 genotype (p≤0.174). At follow-up, the TRIPLE vs. DOUBLE group showed significantly lower level of PAs irrespective of the CYP2C19 genotype (Fig. 1B). In the DOUBLE group, the risk of HPR was observed in 27.3% of patients and increased across the CYP2C19 genotype (adjusted p=0.042), whereas the effect of TRIPLE regimen was not significantly influenced with the CYP2C19 genotype (adjusted p=0.289). Similar trend was observed for collagen-induced PA. ![Figure][1] Figure 1 Conclusion: In PCI-treated East Asians presented with ACS, adjunctive cilostazol exhibited favorable platelet measurements compared with high-dose clopidogrel irrespective of the CYP2C19 genotype. [1]: pending:yes

PP159—C677T Polymorphism of Methylenetetrahydrofolate Reductase and Homocysteine Concentration in Patients with Essential Hypertension

e68 Volume 35 Number 8S Among Costa Ricans, CYP2C9*2 was also lower in the AM than in the CRM population (P < 0.05). Moreover, the frequency of CYP2C9*3 in the CRM, AM and AC groups was 3.6%, 2.1% and 3.3%, respectively. CYP2C9*6 was not detected. Conclusion: Present data support that the CYP2C9*2 frequency is lower in Amerindian populations than Caucasians, suggesting the importance of pharmacogenetic studies for optimizing drug dosages in different populations according to their ancestry. Funding Sources: This study was supported by the University of Costa Rica (CCG, GJA and RB), AEXCID Cooperacion Extremena of Junta de Extremadura (11A002), Consejeria de Empleo, Empresa e Innovacion and Fondo Social Europeo (FSE) Grant PD10199 (MEGN) and the Network Red Iberoamericana de Farmacogenetica y Farmacogenomica. PI10/02758. Disclosure of Interest: None declared.

PP149— The Ceiba Cocktail for Drug Hydroxylation Phenotyping in Hispanic Populations

PP149— The Ceiba CoCkTail foR DRug hyDRoxylaTion PhenoTyPing in hisPaniC PoPulaTions F. De Andres; M.E.G. Naranjo; M. Sosa-Macias; B.P. Lazalde Ramos; E. Tarazona-Santos; A. LLerena; and CEIBA Consortium CICAB, Clinical Research Centre, Extremadura University Hospital, BADAJOZ, Spain; Centro Interdisciplinario de Investigacion para el Desarrollo Integral Regional del IPN Unidad Durango, CIIDIR-IPN, Durango; Laboratorio de Medicina Molecular, Unidad Academica de Medicina Humana y Ciencias de la Salud, Universidad Autonoma de Zacatecas, Zacatecas, Mexico; and Departamento de Biologia Geral, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil Introduction: Interethnic variability of drug metabolism has been demonstrated across Iberoamerican populations by the CEIBA Consortium. Drug-metabolizing enzymes genotype just predicts actual drug metabolic activity (phenotype) in the cases of poor metabolizers. For example, only 30% of ultrarapid metabolizers can be predicted from genotyping (Llerena et al., 2012). Moreover, according to EMA recommendations, development of phenotyping procedures for drug interactions studies and clinical research recommended (EMA, 2013). Therefore, a novel cocktail approach to measure metabolic activity (metabolic ratios) of the main CYP enzymes in just one experiment is developed and validated to be used in the study of Latin-American populations. Patients (or Materials) and Methods: Subjects were given low oral doses of 100-mg caffeine, 25-mg losartan, 20-mg omeprazole, and 30-mg dextromethorphan. Blood samples were taken 4 hours after administering the drugs to assay the following metabolic ratios in plasma: CYP1A2 (caffeine/paraxanthine), CYP2C9 (losartan /E-3174), CYP2C19 (omeprazole/5-hydroxyomeprazole), CYP2D6 (dextromethorphan/ dextrorphan), and CYP3A4 (dextromethorphan/3-methoxymorphinan). Solid phase extraction was utilized for analyte extraction and LC-MS/MS to quantify the probe drugs and metabolites. Results: Recovery values > 80% were obtained for all analytes, and no carryover or relative matrix effects were observed. The analytes were separated and detected in 9 minutes and the method was fully validated, with lower limits of quantification ranging from 0.3 ng mL–1 for 5-hydroxyomeprazole to 3.2 ng mL–1 for paraxanthine. The correlation coefficient (r2) values obtained were over 0.995 for all analytes. According to the EMA guideline on bioanalytical method validation, precision and accuracy values below 15% were achieved. Conclusion: The method was proven to be useful to measure targeted analytes for the evaluation of CYPs hydroxylation capacity in just a single experiment. Funding Sources: Supported by AEXCID-Cooperacion Extremena of Junta de Extremadura (11IA002) to Sociedad Ibero-Americana de Farmacogenetica-SIFF, and coordinated by the RIBEF network (Red Iberoamericana de Farmacogenetica y Farmacogenomica; www. ribef.com). Disclosure of Interest: None declared. PP151—PRevalenCe of CaRRiage CyP2C9, vkoRC1 anD CyP4f2 PolymoRPhisms in Russian PaTienTs WiTh high ThRomboTiC Risk PResCRibeD WaRfaRin ComPaReD WiTh oTheR eThniC gRouPs D. Ivashchenko; D. Sychev; I. Rusin; A. Grachev; and T. Beloshickaya Clinical Pharmacology, I.M. Sechenov First Moscow State Medical University; Cardiology; and Medical Genetic, SM-Clinic, Moscow, Russian Federation Introduction: VKORC1, CYP2C9, and CYP4F2 responsible for the metabolism of warfarin. Personal and ethnic differences in the genetic profile reveals in determining the outcome of a drug therapy. Aim: to explore the frequencies of CYP2C9, VCORC1, and CYP4F2 genotypes in Russians, compare results with ones for other nations Patients (or Materials) and Methods: A total 91 Caucasian subjects were recruited into the study. Forty (48.2%) patients were male and age was 66.17 (10.9) years. All patients had indications to receive warfarin. Medical records for the patients group were reviewed for the relevant clinical data. 5 ml of blood was taken from each subject, and DNA was isolated and used for identification of the CYP2C9 allele *1, *2, *3; G-1639A VCORC1; CYP4F2 V433M rs2108622 C > T using real-time polymerase chain reaction-restriction fragment length polymorphism assay. Results were compared with other ethnic groups and statistically analyzed with chi-square test. Results: We described the prevalence of CYP2C9 polymorphisms *1/*1 (67%), *1/*2 (9,9%), *1/*3 (11%), *2/*2 (2,2%), *2/*3 (8,8%), same for VKORC1 GG (49,5%), GA (28,6%), AA (22,%) and CYP4F2 CC (57,1%), CT (34,1%), TT (7,7%). No significant deviantions from Hardy-Wainberg equilibrium were observed (p 0.05). Conclusion: Prevalence of carriage of CYP2C9, VKORC1 polymorphisms in Russian patients with high thrombotic risk is closed to Caucasians and distinguish from Asians but no for CYP4F2. Disclosure of Interest: None declared.