Frequencies Of CYP2C9 Research Articles

Allele and Genotype Frequencies of CYP2C19 in Patients with Drug-Eluting Stents Following Percutaneous Coronary Intervention in Southwest of Iran

Background: Clopidogrel is a platelet inhibitor drug widely used in patients undergoing percutaneous coronary intervention (PCI) for the prevention of stent thrombosis. Genetic variation within CYP2C19 gene causes variable clopidogrel response. The FDA has recommended CYP2C19 genotyping in the patients taking clopidogrel, especially in the population with high prevalence rates of CYP2C19 *2 and *3 alleles. Objectives: The aim of this study was to determine the prevalence of CYP2C19 gene polymorphisms in the population received Drug-Eluting Stents following PCI in the southwest of Iran. Methods: This cross-sectional study was conducted on 102 patients undergoing PCI. Demographic characteristics and risk factors of patients were collected using a questionnaire and CYP2C19 genotyping was carried out by PCR-RFLP. Then CYP2C19 allele and genotype frequencies were determined and analyzed using χ2 test. Results: Data analysis showed that the frequencies of CYP2C19*1, CYP2C19*2, and CYP2C19*3 allele were 79.4%, 15.2%, and 5.4%, respectively. The frequency of CYP2C19*1/*1 genotype was 60.8%. Moreover, CYP2C19*1/*2, CYP2C19*1/*3, CYP2C19*2/*3 heterozygote genotypes were shown in 28.4%, 8.8%, and 2.0% of the subjects, respectively. None of the patients had CYP2C19*2/*2 or CYP2C19*3/*3 genotypes. Conclusions: The results of this study showed a high prevalence of CYP2C19*2 polymorphism in the population lived in the southwest of Iran. The frequency of CYP2C19*1/*2 genotype is compatible with the majority of the Iranian population and more similar to Caucasian populations.

The impact of cytochrome 450 and Paraoxonase polymorphisms on clopidogrel resistance and major adverse cardiac events in coronary heart disease patients after percutaneous coronary intervention

BackgroundClopidogrel is an inactive prodrug, it catalyzed into its active form by Cytochrome 450 and Paraoxonase-1(PON-1). polymorphisms of genes encoding these enzymes will affect the efficacy of Clopidogrel. The main objective of our study was to investigate the association of CYP2C19*2, CYP2C19*3 and PON-1Q192R polymorphisms with Clopidogrel resistance and major adverse cardiac events in Jin Hua district in the middle of Zhe Jiang Province in China.MethodsOne hundred sixty coronary heart disease patients with percutaneous coronary intervention, who were followed-up for 1 year, were enrolled in our study. These patients were co-administered aspirin 100 mg/d and clopidogrel 75 mg/d following a loading dose of 300 mg. The ADP-induced platelet aggregation rate was measured by Platelet aggregator. Genotypes of CYP2C19*2, CYP2C19*3, PON-1Q192R were determined using Sanger sequencing in all patients. Various clinical data were collected.ResultsThe frequencies of CYP2C19*2, CYP2C19*3 and PON-1Q192R homozygous mutant genotypes were significantly lower in non-responders than those in responders. After for all variables, CYP2C19*2, CYP2C19*3 and PON-1Q192R independently increased the risk of clopidogrel resistance with adjusted ORs 46.65(95% CI,1.77–25.04; p = 0.005); 22.74(95% CI, 3.11–166.27; p = 0.002); 5.69 (95% CI,1.06–30.47; p = 0.042). Over a follow-up of 12 months, the incidence of major adverse cardiac events (MACE) in CYP2C19*1/*2, *1/*3, *2/*2, *2/*3 was significantly higher than no mutant genotype (18/40vs.2/63,3/9vs.2/63, 11/6vs.2/63, 7/1vs2/63, respectively). There was no significant correlation between PON-1Q192R mutant allele and MACE.ConclusionOur study was first time to report on CYP2C19 and PON-1 polymorphisms in Jin Hua population in the middle of Zhe Jiang province in China. The carriage of CYP2C19*2 or *3 mutant allele significantly reduced the platelet response to clopidogrel and increase the MACE. The carriage of PON-1 mutant allele also significantly reduced the platelet response to clopidogrel, but would not increase the major adverse cardiac events after 1 year follow-up.Trial registrationChiCTR, ChiCTR1800018316. Registered 11 September 2018 – prospective registered, http://www.chictr.org.cn/edit.aspx?pid=30927&htm=4.

Global Distribution of CYP2C19 Risk Phenotypes Affecting Safety and Effectiveness of Medications

Background: Genetic variability of CYP2C19 may affect safety or effectiveness of many drugs as outlined in the CPIC dosing guidelines. Aim was to determine the predictive prevalence of high-risk phenotypes due to CYP2C19 variants collectively in the world population. It was also aimed to establish a correlation how the identified high-risk phenotypes may affect safety or effectiveness of drugs. Methods: Frequency of CYP2C19*2, *3 and *17 alleles were obtained from 1000 Genomes project Phase III in line with Fort Lauderdale principles. Phenotypes were assigned using international standardized consensus terms based on the carrier of characteristics alleles. The CYP2C19 pharmacogenomics information of drugs were obtained from international pharmacogenomics working groups. Association of predicted high-risk phenotypes with the safety or effectiveness of medications were gained from CPIC dosing guidelines. Findings: Following CPIC dosing guidelines, ultrarapid metabolizers and poor metabolizers were considered as being as high-risk phenotypes for at least ten clinically important medications. Meta-analysis of the prevalence of high-risk phenotypes showed that it was statistically significant ( P <0.0001) in different ethnic groups with pooled prevalence of 27.4% (95% CI 18%-37%). The present study suggests that African (37.2%; 95% CI 34%-41%) and European (35.4%; 95% CI 31%-40%) population are being at particularly higher risk of either sub therapeutic drug responses or toxicities. Interpretation: Approximately one third of the world population were predictively identified as being as high-risk phenotypes affecting safety or effectiveness of certain number of medications. Large scale clinical studies are warranted to assess clinical outcomes of these medications considering CYP2C19 pharmacogenomics effects. Funding Statement: The author stated there was no funding. Declaration of Interests: The author declares no conflict of interest. Ethics Approval Statement: Not required.

Abstract LB-B19: Investigating the effect of pharmacogenetic variations on voriconazole levels in pediatric cancer patients

Abstract Background: Voriconazole is a second-generation triazole antifungal with broad-spectrum activity against Aspergillosis, metabolized mainly by CYP2C19 in the liver. Despite the use of weight-based dosing, plasma voriconazole blood levels show inter-individual variability, which is attributed to many factors such as weight, age, food, drug interactions, and CYP2C19 polymorphism. Voriconazole metabolism in pediatrics has been reported to be profoundly impacted by CYP2C19 genotypes. Aim: To evaluate the frequencies of CYP2C19 variant alleles (*2, *3, and *17), genotypes, and phenotypes in Egyptian pediatric cancer patients and to investigate the correlation between CYP2C19 genetic variability and other factors with voriconazole plasma levels. Methods: This study was conducted on 100 pediatric cancer patients with probable fungal infection treated with voriconazole. DNA was extracted from blood samples and analyzed by the TaqMan SNP genotyping assay. Identified genotypes were classified accordingly into various predicted phenotypes. Results: Voriconazole plasma levels widely varied, with only 49.5% reaching therapeutic levels. Frequencies of CYP2C19*2 and *17 allelic variants were 10.6 and 18.3%, respectively, while allele *3 was not detected in the study population. A significant correlation was found between plasma levels and CYP2C19 phenotypes: ultra-rapid metabolizers had significantly lower plasma levels (P=0.003) relative to the extensive metabolizer genotype. Conclusion: Determination of CYP2C19 genotype at initiation of therapy, followed by drug monitoring, would serve as a valuable tool for the optimization of voriconazole therapy for pediatric cancer patients. It would also be an essential step in the advancement of precision medicine to optimize therapeutic efficacy and minimize toxicity. Citation Format: Dina Saeed, Lobna Shalaby, Mohamed Nagy, Ahmed ElZeiny, Tarek M. Mostafa, Marwa T. ElRakaiby, Mohammed M. Nooh, Alaa El-Haddad, Maggie Abbassi, Ramy K. Aziz. Investigating the effect of pharmacogenetic variations on voriconazole levels in pediatric cancer patients [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-B19. doi:10.1158/1535-7163.TARG-19-LB-B19

Possibilities of optimizing approaches to the treatment of resistant epilepsy in children using pharmacogenetic studies data

We conducted an observation of 83 children with therapy-resistant forms of epilepsy between the ages of 11 months and 18 years. The presence of CYP2C9, CYP2C19 and CYP3A4 gene polymorphisms was detected in 60 of the examined patients, that is, 72.29 % of them, 33 patients (39.76 %) had CYP2C19 gene polymorphisms, CYP2C9 gene polymorphisms had 17 (20.48 %) children, and 10 (12.05 %) of them had CYP3A4 gene polymorphisms. The frequency of CYP2C19*2 and CYP3A4*1B polymorphisms was signifi cantly higher than in the Ukrainian and other European populations, no statistical data signifi - cance of differences in the frequency of CYP2C9 gene polymorphisms compared with the Ukrainian population was found. CYP2C19 gene polymorphisms are signifi cantly more frequently recorded by us compared to the results obtained by researchers in Russia and Turkey in closely related studies. It is shown that children with cytochrome P450 gene polymorphisms are recommended: more frequent clinical, instrumental, and laboratory monitoring of patients to prevent side eff ects of therapy; monitoring (not a one-time study) of AED concentration in blood plasma. The necessity of conduction of pharmacogenetic research at the stage of debut of epilepsy in the case of suspicion of treatment-resistant form of the disease and in the case of ineffi - ciency or severe side eff ects of the fi rst assigned AED was demonstrated. Key words: children, treatment, resistant epilepsy, cytochrome P450, gene polymorphism.

CYP2C19 genetic polymorphism in the Vietnamese population

Background: Genetic polymorphism of CYP2C19 has been shown to affect enzyme activity and thereby contribute to inter-individual variability in drug metabolism and response. The complete genetic variation of CYP2C19 in Vietnam still remains obscure even though data of common alleles in Vietnamese Kinh have been reported.Aim: To establish the extent of CYP2C19 polymorphism in Vietnamese.Subjects and methods: The promoter and all nine exons of CYP2C19 in 100 healthy unrelated Vietnamese Kinh subjects were sequenced. Additionally, the CYP2C19 variants, *2, *3 and *17 were analysed by RFLP-PCR in 275 subjects of four minor ethnic groups in Vietnam (Tay, Muong, H’Mong and Nung).Results: In 100 Kinh subjects, the percentages of CYP2C19*1, CYP2C19*2, CYP2C19*3 and CYP2C19*17 alleles were 76%, 20.5%, 2.5% and 1%, respectively. Three novel variants in introns 2, 5 and 8 had no impact on mRNA splicing according to the Human Splicing Finder. The prevalence of CYP2C19*17 in Vietnamese Kinh was significantly lower compared with figures found in Western Asia and Europe, while CYP2C19*2 frequency was statistically higher than that in Western Asia and several countries in Europe. The frequency of CYP2C19*2 in Kinh was significantly lower than in the other four ethnic minorities.Conclusion: These results provide information on CYP2C19 polymorphism in the Vietnamese population, which could be useful for optimising drug therapies and precision medicine studies.

Frequency of CYP2C9 (*2, *3 and IVS8-109A>T) allelic variants, and their clinical implications, among Mexican patients with diabetes mellitus type 2 undergoing treatment with glibenclamide and metformin.

The majority of Mexican patients with diabetes mellitus type 2 (DMT2) (67.9-85.0%) are prescribed sulphonylureas (SUs), which are metabolized by cytochrome P450 2C9 (abbreviated as CYP2C9). SUs are a type of oral anti-diabetic compound which inhibit ATP-sensitive potassium channels, thus inducing glucose-independent insulin release by the β-pancreatic cells. The wide variability reported in SU responses has been attributed to the polymorphisms of CYP2C9. The present study aimed to describe CYP2C9 polymorphisms (*2, *3 and IVS8-109T) within a sample of Mexican patients with DMT2, while suggesting the potential clinical implications in terms of glibenclamide response variability. From a sample of 248 patients with DMT2 who initially consented to be studied, those ultimately included in the study were treated with glibenclamide (n=11), glibenclamide combined with metformin (n=112) or metformin (n=76), and were subsequently genotyped using a reverse transcription-quantitative polymerase chain reaction (PCR), end-point allelic discrimination and PCR amplifying enzymatic restriction fragment long polymorphism. Clinical data were gathered through medical record revision. The frequencies revealed were as follows: CYP2C9*1/*1, 87.5%; *1/*2, 6.5%; *1/*3, 5.2%; and CYP2C9, IVS8-109A>T, 16.1%. Glibenclamide significantly reduced the level of pre-prandial glucose (P<0.01) and the percentage of glycated hemoglobin (%HbA1c; P<0.01) for IVS8-109A>T compared with combined glibenclamide and metformin treatment. Concerning the various treatments with respect to the different genotypes, the percentages obtained were as follows: Glibenclamide A/A, HbA1c<6.5=33.3%; glibenclamide + metformin A/A, HbA1c<6.5=24.6%; glibenclamide A/T, HbA1c<6.5=33.3%; glibenclamide + metformin A/T, HbA1c<6.5=25%; glibenclamide T/T, HbA1c<6.5=100%; and glibenclamide + metformin T/T, HbA1c<6.5=12.5%. Altogether, these results revealed that, although genetically customized prescriptions remain a desirable goal to increase the chances of therapeutic success, within the studied population neither allelic variants nor dosages demonstrated a clear association with biomarker levels. A key limitation of the present study was the lack of ability to quantify either the plasma concentrations of SU or their metabolites; therefore, further, precise experimental and observational studies are required.

Allelic frequency of PON1 Q192R, CYP2C19*2 and CYP2C19*17 among Jordanian patients taking clopidogrel

Purpose: To investigate the influence of allelic frequencies of PON1 Q192R, CYP2C19*2 and CYP2C19*17 genetic polymorphisms on the response to clopidogrel among Jordanian patients. Methods: Polymorphisms in CYP2C19 were assessed among 148 patients using PCR-RFLP assay. Results: The CYP2C19*2, CYP2C19*17, and PON1 Q192R allele frequencies were 9.8, 28.72 and 28.7 %, respectively. On the genotyping side, the frequencies of CYP2C19*1/1* and CYP2C19*1/2* were 80.4 and 19.6 %, respectively, but none of the patients had CYP2C19*2/2* genotype. The genotype frequencies CYP2C19*17 were 47.97, 46.62 and 5.41 % for wild-type C-C, heterozygote C-T, and the mutant T-T, respectively. PON1 genotype was 42.7 % for QQ, and 57.8 % for QR. None of the patients had RR genotype. Conclusion: Relative to other populations, the observed allelic frequencies are consistent with the values reported for Caucasian and Middle Eastern populations. Keywords: CYP2C9 polymorphisms, Clopidogrel, Genotype, Allele frequency, PON1 genes

Effect of CYP2C9 and VKORC1 genetic polymorphisms on warfarin dose requirement in Central China Han populations

Purpose: To investigate the frequency of CYP2C9 and vitamin K epoxide reductase complex subunit 1 (VKORC1) and determine the effect of these genetic factors on weekly warfarin dose requirement in Central China Han populations.Methods: A total of 333 hospitalized patients with deep venous thrombosis after minimally invasive surgery were enrolled in this study. Genotypes of VKORC1 and CYP2C9 were analyzed by polymerase chain reaction (PCR)-DNA Chip method. Multiple linear regression analysis was used to explore the impact on weekly warfarin dose requirement.Results: The allele frequencies of VKORC1 -1639 G and VKORC1 -1639 A were 0.105 and 0.895, respectively, whereas no genotype of CYP2C9*1*2, CYP2C9*2*2 and CYP2C9*3*3 were found, and the allele frequencies of CYP2C9*1, CYP2C9*2 and CYP2C9*3 were 0.943, 0.015 and 0.042, respectively. Multiple linear regression analysis indicated that several factors including VKORC1 -1639 G>A, CYP2C9*2, CYP2C9*3, age, body mass index (BMI) and amiodarone use may explain the 47.2 % of individual variations in the weekly warfarin doses requirement.Conclusion: There is no significant difference in the frequency of VKORC1 (-1639 G>A), CYP2C9*2 and CYP2C9*3 compared to those of Asian populations, but there is significant difference when compared with those of Europeans and Caucasians. Considering VKORC1 -1639 G>A, CYP2C9*2, and CYP2C9*3 genetic polymorphisms as well as age, BMI and amiodarone use may explain the 47.2% of individual variations in the weekly warfarin doses requirement..Keywords: Warfarin, CYP2C9, VKORC1, Polymorphism, Body mass index, International normalized ratio

Abstract TP518: Ethnic Differences in Poor Metabolizer Alleles of 12 Pharmacogenomic Actionable Genes in Asian Indians

Introduction: Diversity in drug response related to cardiovascular and other diseases is attributed to both genetic and non-genetic factors. However, there is a paucity of genetic information across ethnically and genetically diverse populations. Here, we have analyzed 20 SNPs from 12 pharmacogenomics genes in Punjabi Sikhs of Asian Indian origin (N= 1,616), as part of the Sikh Diabetes Study (SDS)/Asian Indian Diabetic Heart Study (AIDHS). Methods: Samples were genotyped using the Human 660W Quad Bead Chip panel (Illumina, Valencia, CA). We compared the allelic associations with poor metabolism (PM) phenotype across other HapMap populations. Results: Indians had a significantly higher frequency of CYP2C9*3 (12% SDS, 13% GIH (Gujarati Indians) vs. 5% in Europeans (CEU) (p genotype = 0.008) and ‘T’ allele of CYP4F2 (36%) SDS, (43%) GIH vs. (21%) in CEU (p genotype =7.8x10 -7 ); both associated with a higher risk of bleeding with warfarin. The PM phenotype of the CYP1A2*1F allele for slow metabolism of caffeine and carcinogens was significantly higher in Indians (SDS 43%, GIH 51%) compared to CEU 29% (p genotype =0.01). While the frequency of ‘T’ risk allele MTHFR (C677T) was significantly lower in Indians compared to Europeans (0.19 SDS, 0.16 GIH vs. 0.31 CEU), the low activity ‘C’ allele of MTHFR was strikingly higher in SDS (44%) compared to GIH (39%) and CEU (34%) (p genotype =4.9x10 -3 ). These variants in MTHFR affect the metabolism of cholesterol-lowering (statins), 5-fluorouracil, and methotrexate-based cancer drugs. Conclusion: This is a first large study reporting a significant ethnic difference in the frequency of PM phenotype in Indian Sikhs compared to other global populations. Our findings underscore the need for establishing a global benchmark by conducting pre-emptive genotyping in drug metabolizing genes before beginning therapeutic intervention.

Aspirin and Clopidogrel Resistance in Indian Patients with Ischemic Stroke and its Associations with Gene Polymorphisms: A Pilot Study.

Introduction:Antiplatelet resistance is one of the urgent issues in current stroke care. One-third to one-half of the patients who experience a recurrent stroke is already on antiplatelet medications. We studied resistance to aspirin and clopidogrel in Indian stroke patients and its association with gene polymorphisms.Methods:Platelet function testing by light transmission aggregometry was performed on 65 patients with ischemic stroke who were stable on dual antiplatelet therapy (clopidogrel 75 mg OD and aspirin 75 mg OD) along with 65 age-matched controls. Aspirin resistance was considered as mean platelet aggregation ≥70% with 10 μM adenosine diphosphate (ADP) and ≥20% with 0.75 mM arachidonic acid. Clopidogrel resistance was defined as <10% decrease from the baseline in platelet aggregation in response to ADP 10 μM and semi-response as <30% decrease from the baseline. Polymorphisms CYP2C19 * 2 and GPIIb/IIIa (PLA1/A2) were genotyped by polymerase chain reaction-restriction fragment length polymorphism.Results:We found 64.6% (42/65) patients with inadequate response to clopidogrel (15.4% [10/65] resistant and 49.2% [32/65] semi-responders) and 4.6% (3/65) patients with inadequate response to aspirin (3.1% [2/65] resistant and 1.5% [1/65] semi-responder). The frequency of CYP2C19*2 mutant genotype was significantly higher in clopidogrel nonresponders compared to responders (P = 0.014). Clopidogrel nonresponsiveness was much higher in small vessel stroke.Conclusion:Unlike aspirin, a high proportion of nonresponders to clopidogrel was identified. In an interim analysis on 65 Indian patients, a significant association was found between CYP2C19*2 and clopidogrel nonresponsiveness.

The Effect of CYP2C19 and Nongenetic Factors on Clopidogrel Responsiveness in the MENA Region: A Systematic Review.

Clopidogrel is the cornerstone antiplatelet used in the treatment and prevention of thrombotic events. Some studies examined the effect of CYP2C19 polymorphism and nongenetic factors on clopidogrel response in the Middle East and North Africa (MENA) region. However, the consistency among these studies is yet unknown. This study aims to estimate the prevalence of CYP2C19 genetic variants in MENA region and to evaluate the effect of these variants as well as the nongenetic factors on clopidogrel responsiveness. A systematic literature search was performed to identify relevant articles. Only observational studies were included. A total of 20 studies in 8 different populations were included. The CYP2C19*2 variant is the most prevalent loss-of-function (LOF) allele in the MENA region (1.7%-35%). The frequency of CYP2C19*17 ranged from 5.3% to 26.9%. Of the 9 studies, 6 found an association between carriers of at least 1 LOF allele and clopidogrel resistance. Older age, high body mass index, females, and the use of calcium channel blockers were associated with clopidogrel resistance as well. Association between the CYP2C19*2 allele and clopidogrel resistance is common among MENA populations. Future studies should focus on having larger sample sizes to detect other minor variant alleles and their effect on bleeding and cardiovascular outcomes.

Genotype and Allele Frequencies of CYP2C9, VKORC1, CYP2C19 and PON1 in Chinese Han Population Detected in our Hospital

Warfarin and clopidogrel are commonly used anticoagulant and antiplatelet drugs, and their response and/or toxicity were significant influenced by genetic polymorphism of drug metabolizing enzymes transporters and drug targets...

Evaluation of CYP2C9- and VKORC1-based pharmacogenetic algorithm for warfarin dose in Gaza-Palestine.

Aim:To evaluate applicability of CYP2C9*2, *3 and VKORC1–1639G > A based algorithm to predict warfarin stable dose (WSD) in a group of Palestinian patients.Patients & methods:Warfarin doses were retrospectively calculated for 101 Palestinian patients under warfarin therapy using three models. Performance of the three models was assessed in 47 patients found to take WSD.Results:Frequency of CYP2C9*2, *3 and VKORC1–1639G > A alleles is 13.6, 0.0 and 46.5% respectively. The international warfarin pharmacogenetics consortium algorithm was more reliable (MAE = 8.9 ± 1.4; R2 = 0.350) than both the clinical algorithm (MAE = 10.4 ± 1.4; R2 = 0.128;) and the fixed-dose algorithm (MAE = 11.1 ± 1.7).Conclusion:The international warfarin pharmacogenetics consortium algorithm can be reliably applied for predicting the WSD in Palestinian population.

The effect of CYP2C9*2, CYP2C9*3, and VKORC1-1639 G>A polymorphism in patients under warfarin therapy in city of Kermanshah.

Polymorphism in the genes encoding CYP2C9 enzyme and VKORC1 reductase significantly influence warfarin dose requirement since patients with CYP2C9*2, CYP2C9*3 and VKORC1 mutant alleles require lower warfarin maintenance doses. Studies have reported the ethnic variations in the frequency of these genes within the various populations in Iran and other parts of the world. However, no such study has been done yet on Kurdish population in Kermanshah. From Kurdish population of Kermanshah province in Iran, a total of 110 patients who had heart surgery and taking warfarin, were genotyped for polymorphisms of VKORC1-1639 G>A, CYP2C9*2, and CYP2C9*3. Polymorphism genotyping was performed by sequencing as well as polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) using restriction enzymes of MspI, AVAII and KpnI, respectively. The frequencies of VKORC1-1639 GG, GA, and AA genotypes were 42%, 36%, and 22%, respectively and for CYP2C9 1*/1*, 1*/2*, 2*/2*, 1*/3*, 3*/3*, 2*/3* were 71%, 17%, 5.4%, 1.8%, 4.5%, and 0%, respectively. The frequency of VKORC1-1639A allele was 42.3% and the frequencies of CYP2C9*2 and *3 alleles were 14% and 5.4%, respectively. It was indicated that low warfarin dose requirements are strongly associated with the presence of CYP2C9 and VKORC1-1639 variant alleles. Our results confirmed the supply to understand the distribution of genomic biomarkers related to the drugs metabolism for future planning health programs.

Effect of &lt;i&gt;CYP2C9&lt;/i&gt;*3 gene polymorphism on lipid-lowering efficacy of fluvastatin in a Chinese hyperlipidemic population

Purpose: To investigate the frequency of gene CYP2C9 *3 in Chinese populations, and to analyze the impact of CYP2C9 *3 genetic polymorphism on the cholesterol-lowering effect of fluvastatin in a Chinese hyperlipidemic population. Methods: CYP2C 9 genotype was determined by polymerase chain reaction - restriction fragment length polymorphism (PCR - RFLP) in 270 unrelated hyperlipidemic patients who were treated with 80mg fluvastatin monotherapy daily for 4 weeks and 250 healthy controls. Clinical data were collected prior to treatment with fluvastatin and 4 weeks after. Results: In 270 hyperlipidemic patients, the frequency of CYP2C9 *3 was 3.70 % which is significantly higher than in 250 healthy controls (2.60 %) ( p < 0.01). After oral intake of fluvastatin 80 mg daily for 4 weeks, CYP2C9 *1/*3 genotype was associated with a decrease in LDL-C levels (by 33.9 % in CYP2C9 *1/*3 versus 24.5 % for CYP2C9 *1/*1, p < 0.05) and with reduction of TC (by 36.4 % in CYP2C9 *1/*3 versus 19.4 % in CYP2C9 *1/*1, p < 0.05). Conclusion: The frequency of CYP2C9 *3 is 3.17 % in Chinese populations, and those who carry CYP2C9 *3 mutation have a high risk of hyperlipidemia. CYP2C9 *3 seems to increase the lipid-lowering effects of fluvastatin. Keywords: Hyperlipidemia, Gene, CYP2C9 , Polymorphism, Polymerase chain reaction, Restriction fragment length polymorphism, Fluvastatin

Частота носительства клинически значимых аллелей гена CYP2C19 у пациентов с острым коронарным синдромом из Центральной, Восточной, Северной Сибири и Московского региона.

&lt;b&gt;Цель.&lt;/b&gt; Важным аспектом современной кардиологической практики является резистентность к клопидогрелу – блокатору P2Y12-рецепторов, назначаемому в составе двойной антиагрегантной терапии для профилактика тромбозов установленного стента у пациентов, перенесших острый коронарный синдром (ОКС). Целью данного исследования является изучение в Сибирском и Московском регионах частоты «медленных» аллелей гена CYP2C19, ассоциированных с резистентностью к клопидогрелу, и «быстрых» аллелей, связанных с риском кровотечений. &lt;br /&gt; &lt;b&gt;Материал и методы.&lt;/b&gt; В исследование включены 512 жителей крупных городов Центральной (Новосибирск, Кемерово), Восточной (Иркутск), Северной (Сургут) Сибири и Московского региона с ОКС, перенесших чрескожное коронарное вмешательство. Средний возраст пациентов составил 63,9±10,9 года. Доля мужчин – 80% (409 человек), женщин – 20% (103 человека). Всем больным в составе комплексной медикаментозной терапии была назначена двойная антиагрегантная терапия. Пациенты получали клопидогрел в дозе 300 мг – нагрузочная, 75 мг – поддерживающая. Всем пациентам было проведено фармакогенетическое тестирование при помощи полимеразной цепной реакции в реальном времени для определения аллелей CYP2C19*2, CYP2C19*3 и CYP2C19*17. &lt;br /&gt; &lt;b&gt;Результаты.&lt;/b&gt; Среди пациентов Северной, Центральной, Восточной Сибири и Московского региона частота носительства аллельных вариантов CYP2C19*2 – CYP2C19*3 – CYP2C19*17 составила 14,9 – 0,5 – 33,3%, 11,05 – 0,0 – 17,1%, 10,6 – 2,85 – 22,2%, 8 – 0,0 – 15,4% соответственно. При оценке достоверности различий по частоте носительства «медленных» и «быстрых» аллельных вариантов гена CYP2C19 между пациентами русской этнической группы из 4 разных регионов с помощью критерия Фишера достоверные различия получены только между пациентами из Центральной и Восточной Сибири по CYP2C19*3 (р=0,001, отношение шансов (ОШ) 1,05 (95% доверительный интервал (ДИ) 1,01–1,09). &lt;br /&gt; &lt;b&gt;Заключение.&lt;/b&gt; Частота минорной аллели CYP2C19*2 составила 8,0–14,9% в разных регионах, однако различия оказались недостоверны. Частота аллели CYP2C19*3 составила 0,5–2,8%, при этом частота данной аллели статистически значимо различалась в Восточной и Центральной Сибири. Частота аллели CYP2C19*17 составила 15,4–33,3%.

Screening for CYP2C19 Gene variants in a healthy Jordanian population

Purpose: To genotype healthy Jordanian population from three different provinces (Amman, Zarqa and Irbid) for cytochrome P4502C19 and to identify the allelic distribution of CYP2C19 variants in comparison with other findings around the world. Methods: Healthy Jordanian volunteers were recruited from government hospitals. Two hundred and sixty volunteers were included in the study regardless of sex and age. CYP2C19*2, *3,*4, *5, and *6 alleles were studied using polymerase chain reaction-restriction fragment length polymorphism (PCRRFLP) technique. Results: The results show that the Jordanian population tested exhibited 9 genotypes out of the 21 expected CYP2C19 genotypes. CYP2C19*1/*1 and *2/*2 genotypes were the most prominent in the sample population, while CYP2C19*2/*5 was the least prevalent genotype. The frequencies of the CYP2C19 variants did not deviate from Hardy-Weinberg equilibrium. Allele frequency of CYP2C19*2 in the Jordanian population was statistically different from that found in most Europeans, North and South Americans, Africans, and some Asian ethnic communities but not with South-East Asian populations (China, Chinese-Taiwanese, and Philippines) and Australian Aborigines. Conclusion: The findings of this study confirm the importance of CYP2C19 genotyping prior to drug therapy administration to achieve optimal dosage and cost-effective therapy. Keywords: Cytochrome P450, RFLP-PCR, Allele frequency, Pharmacogenetics, Optimal dosage, Costeffective therapy

Genetic variability of CYP2C9*2 and CYP2C9*3 in seven indigenous groups from Mexico.

CYP2C9 is one of the major drug metabolizing enzymes, however, little is known about polymorphisms in CYP2C9 gene and pharmacological implications in Mexican indigenous populations. Thus, frequencies of CYP2C9*2 and CYP2C9*3 alleles were evaluated in indigenous groups located in northwest (Cora), center (Mazahua and Teenek), south (Chatino and Mixteco) and southeast (Chontal and Maya) regions Mexico. Allelic discrimination was performed by real-time PCR. CYP2C9*2 allele was found only in Chontal and Maya groups, despite the low contribution of Caucasian component in these populations. CYP2C9*3 allele was present in all populations except in Mazahua, showing a wide genetic variability in the studied populations. Interestingly, we found significant differences between indigenous groups in CYP2C9*3 allele, even in groups located at the same region and belonging to the same linguistic family. These results contribute to laying the pharmacogenetic bases in Mexico, in addition to improving treatment, taking into account the genetic interethnic differences.

Genetic and Non-Genetic Factors Association with Warfarin Long Term Therapy Stability in Sudan

Anticoagulation with warfarin is characterized by a wide inter-individual variations in dose requirements and INR (International Normalised Ratio) stability, as there are evidences that warfarin response variability is associated with CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) and VKORC1 (Vitamin K epoxide reductase complex1) genetic polymorphisms. Carriers of CYP2C9*2 and VKORC11639G&amp;gt;A variant alleles are at greater risk of unstable anticoagulation therapy. Objectives: This retrospective case control study was directed to analyze the impact of genetic and non-genetic factors on warfarin therapy in Sudanese out-patients who were on long term warfarin therapy. Method: 118 Sudanese outpatients receiving warfarin treatment for at least six months, were interviewed for their non-genetic factors that included age, sex, indication for warfarin therapy, compliance, Vitamin K rich foods intake and concomitant drug therapy, in addition to their blood samples which were taken for DNA extraction and genotyping of CYP2C9*2 and VKORC11639G&amp;gt;A gene polymorphisms to study the genetic factors. INR stability % index was calculated, accordingly patients were classified into 2 groups, stable and unstable groups. Results: The frequencies of VKORC11639G&amp;gt;A alleles in Sudanese out-patients who were on long term warfarin therapy were 70.3% and 29.7% for the VKORC1/G and VKORC1/A alleles respectively. The frequencies of CYP2C9*2 alleles in Sudanese out-patients were 92.4% and 7.6% for CYP2C9*1 and CYP2C9*2 alleles respectively. Variables associated with low INR stability were VKCOR1/AA genotype (p-value = 0.028) and sex (p = 0.017). Variables that showed no association with INR stability were age (p-value = 0.259), compliance (p-value = 0.058). Vitamin K rich foods intake (p- value = 0.743), and mean stable warfarin dose (p-value = 0.439). Conclusion: Polymorphism in warfarin drug target gene VKORC1-11639G&amp;gt;A and sex are important elements of INR stability in Sudanese out- patients on long term warfarin therapy.