CYP2C19 Gene Polymorphisms Research Articles

Impact of CYP2C19 and CYP2C9 gene polymorphisms on sodium valproate plasma concentration in patients with epilepsy

BackgroundValproic acid (VPA) is a broad spectrum anticonvulsant drug, which could be partially metabolised by cytochrome P450 (CYP) 2C9 and 2C19 enzymes. This study was designed to investigate the relationship...

Association between CYP2C19 gene polymorphisms and susceptibility to high-altitude pulmonary edema.

High-altitude pulmonary edema (HAPE) is caused by the interaction of both genetic and environmental risk factors. In this study, we aimed to explore whether three single nucleotide polymorphisms (SNPs) in CYP2C19 gene influenced the HAPE susceptibility in the Chinese Han population. We recruited 238 cases and 230 controls between January 2018 and October 2018 from the Affiliated Hospital of Xizang Minzu University. The relationship between CYP2C19 gene polymorphisms and HAPE was studied by association analysis. Genotyping was performed using the Agena MassARRAY platform and the statistical analysis was performed using Chi-squared test, independent sample t test, genetic model analysis and haplotype analysis. The main finding of our study showed that rs4494250 in CYP2C19 gene was associated with an increased risk of HAPE at age>32years in the log-additive model (OR=1.80, 95% CI=1.05-3.09, P=0.033). Also, it was observed to be associated with a reduced risk of HAPE at age≤2years in the dominant model (A/G-A/A vs G/G, OR=0.55, 95% CI=0.31-0.97, P=0.038) and in the log-additive model (OR=0.58, 95% CI=0.35-0.96, P=0.033). Our findings demonstrated that CYP2C19 genetic variants were associated with risk of developing HAPE in Han Chinese population.

CYP2C19, PON1, and ABCB1 gene polymorphisms in Han and Uygur populations with coronary artery disease in Northwestern Xinjiang, China, From 2014 Through 2019.

The morbidity of coronary artery disease (CAD) in the Uygur population of Xinjiang was much higher than the national average. Clopidogrel is the most commonly used medication worldwide in dual antiplatelet therapy for CAD, and the response of clopidogrel is affected by CYP2C19, PON1, and ABCB1 genetic polymorphisms. The distribution of CYP2C19∗17, ABCB1, and PON1 genetic polymorphisms in Han and Uygur populations with CAD of Xinjiang has not been investigated.This study aimed to investigate the frequencies of CYP2C19, PON1, and ABCB1 genetic polymorphisms, and to identify the metabolizer phenotype of CYP2C19 in Han and Uygur populations with CAD in Northwestern Xinjiang, China. We identified 602 Han and 527 Uygur patients from 2014 through 2019 and studied genotypes for selected allele polymorphisms using sequencing by hybridization.There were significantly different allele frequencies and genotype frequencies between the 2 ethnic groups in terms of CYP2C19∗2, ∗3, ∗17, ABCB1 and PON1, (P < .05). For CYP2C19∗17, the frequency of TT genotype was 2.5% in Uygur patients, but it was undetectable in Han patients. In both the intermediate and poor metabolizer groups, the genotypes polymorphisms CYP2C19∗2, ∗3, ∗17 were significantly less common in Uygur patients than in Han patients (P < .001). By contrast, the proportion of ultra-metabolizers as defined by CYP2C19∗2, ∗3, ∗17 polymorphisms significantly higher in Uygur patients (18.6%) than in Han patients (1.7%, P < .001). The CYP2C19∗2 frequency was significantly different between Han patients and Han healthy groups (P < .001), while the CYP2C19∗3 frequency was significantly different between Uygur patients and Uygur healthy groups (P < .001).Our study supports the notion of interethnic differences in terms of CYP2C19, PON1, and ABCB1 polymorphisms and CYP2C19 genotype-defined clopidogrel metabolic groups. These finding could provide valuable data and insights into personalized CAD treatment for the Uygur and Han populations in Xinjiang.

Association between CYP2C19 gene polymorphisms and lipid metabolism in Chinese patients with ischemic stroke.

ObjectiveThe CYP2C19 genetic variation may be involved in the development of atherosclerotic cardiovascular disease (ASCVD). Serum lipid levels are important risk factors for ASCVD, but the effect of the CYP2C19 gene on serum lipid metabolism remains unclear. This retrospective cohort study investigated the relationship between the CYP2C19 gene polymorphism and serum lipid levels in patients with ischemic stroke (IS).MethodsIS patients (n = 230) and control subjects (n = 100) were enrolled. All patients were diagnosed with IS via clinical manifestations and brain magnetic resonance imaging. All patients were genotyped.ResultsTriglyceride (TG), total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-c), and apolipoprotein B (ApoB) levels were significantly higher and high-density lipoprotein-cholesterol (HDL-c) and apolipoprotein A1 (ApoA1) levels were significantly lower in the IS group compared with the control group. Lower ApoA1 levels and higher ApoB levels were significant predictive factors for IS. Patients with higher ApoB levels had a higher risk of IS recurrence. Compared with extensive metabolizers, intermediate and poor CYP2C19 metabolizers had a higher risk of IS recurrence.ConclusionsOur study indicates CYP2C19 gene polymorphisms are related to lipid metabolism in patients with IS. IS patients who are poor CYP2C19 metabolizers may have a higher risk of disease recurrence.

An association between the rs1799853 and rs1057910 polymorphisms of CYP2C9, the rs4244285 polymorphism of CYP2C19 and the prevalence rates of drug-resistant epilepsy in children

Objective Epilepsy is a neurologically based disease. Literature data indicate a certain association between the polymorphism of these genes, which participate in the metabolism of drugs (CYP), and drug-resistant epilepsy. Aim The reports describe studies in which an association was evaluated between the rs1799853 (430C > T) and rs1057910 (1075A > C) polymorphisms of CYP2C9 gene and the rs4244285 (c.681G > A) polymorphism of CYP2C19 gene on one hand and the incidence of drug-resistant epilepsy in children on the other. Material and methods The above-mentioned polymorphisms were assessed by the PCR-RFLP technique in a group of patients with drug-resistant (n = 106) and drug-responsive (n = 80) epilepsy, as well as in non-epileptic children (n = 97), all of them hospitalised at the Department of Neurology of the Institute-Polish Mother’s Memorial Hospital in Lodz. Results It was demonstrated that CT genotype of the rs1799853 polymorphism of CYP2C9 gene and GA genotype of the rs4244285 polymorphism of CYP2C19 gene caused an enhanced risk of epilepsy. It was also shown that the occurrence of C-G-A haplotype, when referred to the rs1799853 polymorphism of CYP2C9 gene and the rs4244285 polymorphism of CYP2C19 gene, could be associated with a decreased risk of epilepsy occurrence. In case of the rs1799853 polymorphism in CYP2C9 gene, the occurrence of T allele four times increases the risk of drug-resistance in patients with diagnosed epilepsy. Conclusion The obtained results indicated that the rs1799853 and rs1057910 polymorphisms of CYP2C9 gene and the rs4244285 polymorphism of CYP2C19 gene could be associated with the occurrence of drug-resistant epilepsy in children.

Pharmacogenetics of the safety of phenazepam in alcohol withdrawal syndrome: haplotype and combinatorial analyses of polymorphic variants in the pharmacokinetic factor genes

Phenazepam is a benzodiazepine tranquilizer that is widely used in Russia. The drug is metabolized by cytochrome P450 3A (CYP3A) isozymes. Since their substrates have an affinity for P-glycoprotein, the polymorphic variants in the ABCB1 gene may affect the safety of this drug. Objective: to analyze associations between the CYP3A5, CYP2C9, CYP2C19, CYP2D6 and ABCB1 gene polymorphisms and the safety of phenazepam treatment for alcohol withdrawal syndrome (AWS). Patients and methods. The investigation enrolled 102 patients diagnosed with uncomplicated AWS (IDC-10 code F10.30). All the patients were followed up for 6 days within which they took phenazepam. 5-ml venous blood samples were collected from each patient for genotyping. The carriage of CYP3A4*22, CYP3A5*3, CYP2C19*2, CYP2C19*17, CYP2C9*2, ABCB1 3435C>T, 1236C>T, and 2677G>T/A polymorphic variants was determined by a real-time polymerase chain reaction assay. Therapy safety was evaluated using the UKU Side-Effect Rating Scale on day 6. Statistical analysis was carried out with SPSS Statistics 21.0. Haplotype and combinatorial analyses were performed using SNPStats. Results and discussion. The greater subjective severity of adverse reactions (ARs) was shown for the homozygotes of ABCB1 1236C>T CC (odds ratio (OR), 2.154; 95% confidence interval (CI), 1.271–3.650; p=0.014) and ABCB1 2677G>T GG (OR, 2.154; 95% CI, 1.271–3.650; p=0.014). On the contrary, a combinatorial analysis revealed the role of ABCB1 3435C>T, 1236C>T, and 2677G>T polymorphic alleles as predictors for the greater subjective severity of ARs. The following statistically significant polymorphic variant combinations were ABCB1 3435-1236–2677 and T-T-T-CYP3A5*3 isozymes (OR=5.03; 95% CI, 1.65–15.34; p=0.0056); T-T-T-CYP2C9*1 (OR=3.61; 95% CI, 1.31–9.92; p=0.015); T-T-T-CYP2C19*1 (OR=2.52; 95% CI, 1.05–6.08; p=0.042). Attention disorders were also established to be associated with the carriage of T-T-T-CYP2D6*1 (OR=2.58; 95 CI, 1.08–6.13; p=0.035). Conclusion. The carriage of ABCB1 3435-2677-1236 (T-T-T) haplotype is significantly associated with the greater severity of ARs in phenazepam-treated patients with AWS.

The Relation between CYP2C9 Gene Polymorphism and Warfarin Dosing in an Iranian Population

Background: Warfarin is a common anticoagulant agent which is widely used in many countries. However, Warfarin is one of those drugs which requires close monitoring and dosing while inappropriate could lead to hemorrhagic epoxides. Achieving a desirable international normalized ratio (INR) range depends on various demographic factors and genetic factors are now becoming an emerging area of interest in cardiovascular research. CYP2C9 is a gene encoding a member of cytochrome P450 enzyme which metabolizes many drugs. Genetic variation in this gene has been linked to abruption in Warfarin drug response. In present study the effect of genetic polymorphisms in CYP2C9 gene and its response to Warfarin is investigated. Methods: Total of 95 patients who had cardiovascular diseases and were using Warfarin for at least 3 months were enrolled in this cross sectional study. Their DNA was extracted and the genetic polymorphisms in CYP2C9 gene (RS1799853 as CYP2C*2 and RS1057910 as CYP2C9*3) were evaluated by using polymerase chain reaction and sequencing. Kruskal-Wallis test were used for comparing the Warfarin values between the genotype groups. The SPSS software 22v was used for data analysis. Results: Among the study population the prevalence of genotypes were as follow: CC/AA: 61.1, CT/AA: 17.9, CT/AC: 1.1, CC/AC: 3.6, TT/AA: 2.3, CC/CC: 0%. The CC/AA and CC/AC variants were related to Warfarin dose (P

Influence of CYP2C19 genotype on antiplatelet treatment outcomes after percutaneous coronary intervention in patients with coronary heart disease.

The aim of the study was to compare the clinical efficacy and safety of ticagrelor and clopidogrel in patients with coronary heart disease one year after percutaneous coronary intervention (PCI), and to explore their association with the CYP2C19 gene polymorphism. A total of 971 patients with coronary heart disease who were hospitalized and underwent PCI from April 2016 to May 2017 were studied. All 971 patients were divided into three subgroups according to CYP2C19 gene types as fast metabolizing, slow metabolizing and very slow metabolizing type. Patients were also classified according to the oral antiplatelet aggregation drugs they received: clopidogrel group and ticagrelor group. The incidence of major adverse cardiac events (MACE) and bleeding events in the clopidogrel-treated and ticagrelor-treated groups and in patients with fast, slow, and very slow CYP2C19 metabolisms were compared. Binary logistic regression analysis was carried out to analyze the risk factors associated with MACEs and hemorrhagic events. Patients on ticagrelor had a greater number of bleeding complications compared to those on clopidogrel (P<0.001), with no difference in MACE between the two groups (P=0.399). The incidence of MACE was significantly higher in very slow metabolizing patients receiving clopidogrel (P<0.001) while the incidence of bleeding complications was significantly higher in fast metabolizing patients receiving ticagrelor (P<0.001). The regression analysis revealed that the CYP2C19 gene mutation, a dual-antiplatelet therapy, and a stroke history were all significantly associated with MACE. By contrast, a dual-antiplatelet therapy and a stroke history were significantly associated with bleeding events. Findings of the present study indicated that clopidogrel and ticagrelor were equally efficacious post-PCI. Efficacy of clopidogrel was reduced in patients with very slow CYP2C19 genotype while bleeding complications were higher in patients with fast CYP2C19 genotype receiving ticagrelor. CYP2C19 genotyping may be used to provide guidance to optimize individual antiplatelet treatment.

The correlation between recurrent risk and CYP2C19 gene polymorphisms in patients with ischemic stroke treated with clopidogrel for prevention.

Background:To explore the correlation between recurrent risk and CYP2C19 gene polymorphisms in patients with ischemic stroke (IS) treated with clopidogrel for prevention.Methods:A total of 289 patients with IS treated with clopidogrel regularly were enrolled in this study, and stroke recurrence of all patients were recorded by follow-up. The correlation between CYP2C19 gene polymorphism and stroke recurrence in patients taking clopidogrel regularly was analyzed.Results:After a mean follow-up period of 6 months, there were 289 patients who took clopidogrel regularly, and 41 of which occurred recurrent stroke. Patients of poor metabolizer and intermediate metabolizer had higher risk of recurrent stroke comparing with patients of extensive metabolize, and the odds ratios were 2.88 (95% confidence interval [CI] 1.31–6.33, P = .068) and 3.00 (95% CI 1.09–8.22, P = .027), respectively. The recurrence risk of ∗2 (G681A)A allele carriers was 3.30 times that of G allele carriers (P = .0065). The recurrence rate of stroke in patients carrying heterozygous and homozygous ∗2 allele mutant was 1.96 times (P = .071) and 3.30 times (P = .012) that of patients with wild-type genes. Multifactor logistic regression analysis result indicated carrying loss of function (LOF) allele was an independent risk factor of stroke recurrence.Conclusion:For patients with IS treated with clopidogrel regularly for secondary prevention, poor metabolizer, and intermediate metabolizer patients had higher risk of recurrent stroke comparing with extensive metabolize ones. Carrying CYP2C19 LOF allele is an independent risk factor of stroke recurrence in patients with IS.

The value of cytochrome P4502C19 gene assay for anti-platelet therapy after PCI in stable angina patients with left main coronary artery lesions

To evaluate the efficacy and safety of different antiplatelet therapies for stable angina patients with complicated left main coronary artery lesions and intermediate metabolizer Cytochrome P450 2C19 gene (CYP2C19) undergoing PCI. A total of 247 patients diagnosed with stable angina in cardiology department of Fujian union hospital from February 2015 to February 2017 were retrospectively analyzed, among them, the elective PCI were performed on the left main coronary artery and the CYP2C19 gene poly-morphism were intermediate metabolize, they were divided into ticagrelor treatment group(aspirin combined with ticagrelor, n=95)and clopidogrel treatment group(aspirin combined with clopidogrel, n=152) according to the different antiplatelet treatment programs. Both groups were given aspirin 300 mg and clopidogrel 300 mg orally before PCI; the ticagrelor group were given the maintenance dose of ticagrelor (90 mg orally, twice a day) after PCI, while those in clopidogrel group were clopidogrel 75 mg orally (once a day) after PCI; both groups were given the maintenance dose of aspirin (100 mg orally, once a day)after PCI. The major adverse cardiovascular events (MACE) were observed within 12 months after PCI. At 12 months after PCI, the incidence of MACE in the ticagrelor treatment group was significantly lower than that in the clopidogrel treatment group, the difference was statistically significant (2.1% vs 15.1%, P=0.001).There were no significant differences between the two groups in the restenosis rates of non- revascularized target vessel, recurrent rates of angina pectoris(but not myocardial infarction), recurrent rates of myocardial infarction, and revascularization rates of target vessel (P > 0.05). There were also no significant differences between the two groups in bleeding. For stable angina patients with complicated left main coronary artery lesions and intermediate metabolizer CYP2C19 gene, aspirin combined with ticagrelor antiplatelet therapy after PCI is effective, the effect of ticagrelor is better than clopidogrel on MACE, and ticagrelor does not seem to increase the risk of bleeding.

A191 EFFICIENCY OF TAILORED ERADICATION REGIMEN BASED ON ANTIBIOTIC SUSCEPTIBILITY AND CYP2C19 GENOTYPE TESTING IN CHILDREN WITH REFRACTORY HELICOBACTER PYLORI INFECTION

Abstract Background Refractory helicobacter pylori (Hp) is a challenging problem for pediatric population. Whether Hp culture and CYP2C19 genotype need to be done together still remains contraversial. Aims To explore the efficiency of tailored eradication therapy based on helicobacter pylori culture, susceptibility and CYP2C19 genotype in children who failed to empirical Hp eradication strategy in Baoding region(China). Methods This study is an observational cohort study. A total of 156 children with Hp infection who failed to amoxicillin + clarithromycin +omeprazole triple regimen in Baoding Children’s Hospital were selected as study subjects, and 92 of them underwent Hp culture and CYP2C19 genetic testing. 75 cases with successful Hp culture were defined as successful culture group and were treated according to antibiotics sensitivity and genotype results. 17 cases with failed culture were defined as culture failure group and were treated only based on the results of CYP2C19 genotype. 64 children who did not agree to perform Hp culture and CYP2C19 gene testing were defined as the empirical eradication therapy group and were treated with quadruple therapy (amoxicillin + metronidazole + omeprazole + bismuth). Antibiotics resistance, CYP2C19 gene polymorphism and therapeutic efficiency between the three groups were compared and analyzed. Results Results of Hp culture and antibiotics susceptibility: among the 75 children with successful culture, 72 (96%) were resistant to clarithromycin, 3 (4%) were resistant to metronidazole, 5 (7%) were resistant to levofloxacin, 5 (7%) were resistant to rifampicin, 1 (1%) was resistant to tetracycline, and there was no resistance to amoxicillin and furazolidone. Results of CYP2C19 genotype test: among the 92 patients who underwent genotype test, 43 were Extensive Metabolizer (EM) (47%), 9 were Poor Metabolizer (PM) (10%), and 40 were Intermediate Metabolizer (IM) (44%). Efficiency results: eradication rate in the successful culture group, culture failure group and empirical eradication therapy group was 99% (74/75),88%(15/17) and 72%(46/64), respectively. The eradication rate of children in the culture failure group and the empirical eradication therapy group were both lower than that in the successful culture group,and there were no difference between empirical eradication therapy group and culture failure group(p=0.283). Conclusions Tailored treatment based on Hp culture + antibiotics susceptibility and CYP2C19 genotype detection should be performed in children with refractory Hp infection. Hp culture + antibiotics susceptibility plays a more important role than CYP2C19 genotype. Funding Agencies None

Clinical study on traditional Chinese medicine constitution types and CYP2C19 gene polymorphism in acute cerebral infarction

Objective To investigate the correlation between Traditional Chinese medicine (TCM) constitution classification and clopidogrel-related CYP2C19 gene polymorphism of acute cerebral infarction patients. Methods A cross-sectional method was used in this study. Patients with acute cerebral infarction were screened and enrolled according to our inclusion and exclusion criteria. TCM constitution were evaluated in patients with acute cerebral infarction. Digital fluorescence hybridization Technology was used to test genotypes of CYP2C19 and Hardy-Weinberg’s equilibrium was used to examine CYP2C19 gene polymorphism of the patients. Binary logistic regression analysis method was used to explore the relationship between TCM constitution types and clopidogrel-related CYP2C19 gene polymorphism in acute cerebral infarction. Results Among the 100 patients with acute cerebral infarction, 18 belong to Yang-deficiency constitution (18 cases, 18%), 30 Yin-deficiency (30 cases, 30%), 18 belong to Qi-deficiency constitution (18 cases, 18%), 51 belong to phlegm-dampness constitution(51 cases, 51%), 14 belong to damp-heat constitution (14 cases, 14%), 2 belong to special constitution (2 cases, 2%), blood-stasis constitution (27 cases, 27%), Qi stagnation constitution (4 cases, 4%), and normal constitution (11 cases, 11%). The CYP2C19*2 gene polymorphism distribution: CYP2C19*2 (A/A, mutant homozygous) (21 cases, 21%), CYP2C19*2 (A/G, mutant heterozygote) (33 cases, 33%), CYP2C19*2 (G/G) (normal homozygous) (46 cases, 46%). The mutant allele frequency was 0.375. Binary logistic regression analysis showed that compared with A/A genotype, the G/G genotype of CYP2C19*2 in acute cerebral infarction was correlated with phlegm-dampness constitution (OR=5.105, 95% CI: 1.308-19.928, P<0.05) and blood-stasis constitution (OR=12.557, 95% CI: 1.741-90.558, P<0.05). Conclusions The proportion of phlegm-dampness constitution is the highest in patients with acute cerebral infarction. The mutation rate of clopidogrel-related CYP2C19*2 was significantly higher than that of CYP2C19*3 clopidogrel-related CYP2C19*2 gene polymorphism might be related to phlegm-dampness constitution and blood-stasis constitution. Key words: Brain infarction; Constitutional type (TCM); Clopidogrel; CYP2C19 gene polymorphism; Cross-sectional study

CYP2C19 gene polymorphisms among Moroccan patients with breast cancer disease: A case-control study

BackgroundCytochrome P450 2C19 (CYP2C19) enzyme is implicated in the metabolism pathway of many exogenous and endogenous substrates, including estrogens. The expression and activity of CYP2C19 are influenced by its genetic variability. Therefore, functional polymorphisms of CYP2C19 gene are expected to affect the catabolism of estrogens and consequently are associated with susceptibility to develop breast cancer. AimsUsing a case-control study, we investigated CYP2C19 polymorphisms: CYP2C19*2(rs4244285), CYP2C19*3(rs4986893) and CYP2C19*17(rs12248560) in Moroccan Breast Cancer patients compared to healthy women controls. We also tested association of these polymorphisms with several characteristics of these patients. MethodsCYP2C19 polymorphisms were genotyped in 440 subjects, including 220 histologically confirmed Breast Cancer patients and 220 healthy women controls. For each polymorphism, association between genotypes and Breast Cancer risk was evaluated as odds ratios with 95% confidence intervals adjusted for age and menopausal status. Furthermore, association of each CYP2C19 polymorphisms with tumor characteristics of Breast Cancer cases was investigated. ResultsNone of the CYP2C19 variants was significantly associated with Breast Cancer risk. However, carriers of CYP2C19*3 allele A showed an association with Triple-Negative Breast Cancer subtypes (P=0.02). ConclusionOur results highlighted a possible implication of CYP2C19*3 polymorphism and triple negative Breast Cancer through an unidentified mechanism. Further studies with more triple negative samples are needed to support this finding.

Effects of CYP2C9 and VKORC1 genetic polymorphisms in Chinese Han population on maintenance dosage of warfarin

Objective To analyze CYP2C9 and VKORC1 gene polymorphisms in Chinese Han population and their correlation with the maintenance dosage of warfarin. Methods From October 2017 to April 2018, 458 Chinese Han patients (213 males and 245 females, aged from 26 to 94 years old) who underwent coagulation analysis in Peking University People′s Hospital were included in this retrospective study. PCR-Fluorescent probe method was applied to detect CYP2C9*3 and VKORC1-1639A>G gene polymorphisms in 458 patients, and among them, 130 patients who took warfarin for anticoagulant therapy and reached the international standard ratio of prothrombin time (INR) within the range of 2.0-3.0 were recorded. The basic information, dosage of warfarin and INR were also recorded. The statistical analysis data were compared with the reference table of recommended dosage of warfarin for different genotypes of patients recommended by FDA and the formula of predicted dosage of warfarin was simply verified by SPSS. Results Among the 458 patients who took anticoagulant therapy, the genotype frequencies of CYP2C9*1/*1(AA), CYP2C9*1/*3(AC) and CYP2C9*3/*3(CC) were 90.8%, 8.5%, and 0.7%; the genotype frequencies of VKORC1-1639GG and VKORC1-1639AG were 0.9% and 14.2%; the genotype frequencies of VKORC1-1639AA was 84.9%. After INR was reached, the results showed that the variant CYP2C9*1/*3 and CYP2C9*3/*3 required lower daily maintain dosage [(2.92±1.29) mg] than wild-type CYP2C9*1/*1 patients did [(3.91±1.63) mg], with statistically significant difference (P=0.018). And variant VKORC1-AA required lower daily maintain dosage [(3.68±1.64) mg] than variant VKORC1-AG patients did [(4.54±1.29) mg], with statistically significant difference (P=0.001). The application dosage of warfarin in patients with different VKORC1+CYP2C9 genotypes was consistent with the recommended dosage of the FDA reference table. The prediction accuracy of miao 2007 formula was lower than that of IWPC formula, and 94.1% of patients′ dosages of warfarin were underestimated. Conclusion Patients with CYP2C9*3 or VKORC1-AA genotype required lower warfarin dosage. The CYP2C9 and VKORC1 gene polymorphisms had a certain correlation with maintenance dosage of warfarin. Key words: Warfarin; Polymorphism, genetic; Cytochrome P-450 CYP2C9; Vitamin K epoxide reductases; Dose-respanse relationship,drug

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.

Comparison of the effect of clarithromycin triple therapy with or without N-acetylcysteine in the eradication of Helicobacter pylori: a randomized controlled trial.

Background:Whether adjunctive N-acetylcysteine (NAC) may improve the efficacy of triple therapy in the first-line treatment of Helicobacter pylori infection remains unknown. Our aim was to compare the efficacy of 14-day triple therapy with or without NAC for the first-line treatment of H. pylori.Material and methods:Between 1 January 2014 and 30 June 2018, 680 patients with H. pylori infection naïve to treatment were enrolled in this multicenter, open-label, randomized trial. Patients were randomly assigned to receive triple therapy with NAC [NAC-T14, dexlansoprazole 60 mg four times daily (q.d.); amoxicillin 1 g twice daily (b.i.d.), clarithromycin 500 mg b.i.d., NAC 600 mg b.i.d.] for 14 days, or triple therapy alone (T14, dexlansoprazole 60 mg q.d.; amoxicillin 1 g b.i.d., clarithromycin 500 mg b.i.d.) for 14 days. Our primary outcome was the eradication rates by intention to treat (ITT). Antibiotic resistance and CYP2C19 gene polymorphism were determined.Results:The ITT analysis demonstrated H. pylori eradication rates in NAC-T14 and T14 were 81.7% [276/338, 95% confidence interval (CI): 77.5–85.8%] and 84.3% (285/338, 95% CI 80.4–88.2%), respectively. In 646 participants who adhered to their assigned therapy, the eradication rates were 85.7% and 88.0% with NAC-T14 and T14 therapies, respectively. There were no differences in compliance or adverse effects. The eradication rates in subjects with clarithromycin-resistant, amoxicillin-resistant, or either clarithromycin/amoxicillin resistant strains were 45.2%, 57.9%, and 52.2%, respectively, for NAC-T14, and were 66.7%, 76.9%, and 70.0%, respectively, for T14. The efficacy of NAC-T14 and T14 was not affected by CYP2C19 polymorphism.Conclusion:Add-on NAC to triple therapy was not superior to triple therapy alone for first-line H. pylori eradication [ClinicalTrials.gov identifier: NCT02249546].

&lt;p&gt;The Effect of &lt;em&gt;UGT1A9&lt;/em&gt;, &lt;em&gt;CYP2B6&lt;/em&gt; and &lt;em&gt;CYP2C9&lt;/em&gt; Genes Polymorphism on Propofol Pharmacokinetics in Children&lt;/p&gt;

PurposeThis study was conducted to determine the effect of UGT1A9 98T>C, CYP2B6 516G>T and CYP2C9 430C>T genetic polymorphisms on the pharmacokinetics of propofol in children of different sexes and ages who undergone total intravenous anesthesia (ТIVA) and deep sedation during diagnostic and therapeutic procedures.Patients and MethodsThe prospective study included 94 children, ASA I-II status, 1 to 17 years of age, who undergone standard anesthetic protocol for TIVA, which implied the continuous use of propofol. Before the administration of propofol, venous blood was sampled to determine the presence of genetic variations in UGT1A9, CYP2B6 and CYP2C9 gene using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). From each patient included in the study blood samples were taken: 10 mins after the induction of anesthesia, immediately before the discontinuation of the propofol infusion, 10 mins after discontinuation of the propofol infusion and 20 mins after discontinuation of the propofol infusion to determine the pharmacokinetics of the drug in the plasma of the subjects The plasma propofol concentration was determined by HPLC analytical technique.ResultsUGT1A9 genotype is an independent predictor of the propofol concentration in children immediately after the end of the continuous infusion and 10 mins afterwards. In the carriers of the polymorphic UGT1A9 C allele, the propofol distribution constant was higher. The carriers of the polymorphic CYP2B6 T allele received a significantly lower overall and initial dose of propofol. Unlike polymorphism of the UGT1A9 gene, the tested CYP2C9 and CYP2B6 gene polymorphisms are not independent predictors of the pharmacokinetics of propofol.ConclusionFurther investigations of UGT1A9, CYP2B6 and CYP2C9 and other genes that participate in propofol metabolism as well as detailed analyses of the general conditions, administered therapies and associated diseases could explain the large interindividual variability of propofol metabolism in children.

P25 Polymorphism of CYP2C19 is associated with poor platelet response to clopidogrel and indirectly affect TIMIi-flow among asian patients with STEMI undergoing primary PCI

Abstract Background The platelet response to clopidogrel treatment is very important in patients with myocardial infarction undergoing primary PCI. Asian populations have been shown to have higher proportion of CYP2C19 gene polymorphism that may alter biotransformation of clopidogrel, than Caucasians. However, It is unclear whether platelet reactivity measured by P2Y12 reaction unit (PRU) is affected by CYP2C19 polymorphism, and whether it will impair coronary flow among Asian patients with STEMI after primary PCI. Purpose: We sought to define whether polymorphisms on CYP2C19 genes will affect platelet reactivity response to Clopidgrel therapy, and whether subsequently it will affect the TIMI flow in Asian patients with STEMI undergoing primary PCI. Method: We studied 90 patients with STEMI receiving 600 mg loading dose of clopidogrel prior to primary PCI. High-on-treatment platelet reactivity was evaluated using the VerifyNow Assay. Patients with platelet reactivity more than 208 PRU are categorized as non-responders to Clopidogrel. Genotyping of CYP2C19 was performed by real-time polymerase chain reaction (PCR). Post primary PCI TIMI flow was categorized into good (TIMI flow 3), and impaired (TIMI flow &amp;lt;3). Results: Among all 90 patients (median age = 54.5 years old; 93.3% male), there were 36.6 % patients with CYP2C19 polymorhisms, carrying *2 or *3 alleles. Platelet reactivity test revealed 23.4% of all patients were Clopidogrel non-responders. Multivariate analysis showed CYP2C19 polymorphism is associated with Clopidogrel non-reponders (OR 4.7, p = 0.030), along with other factors such as: Diabetes, Renal impairment, and use of proton pump inhibitor drugs. After successful stent implantation during primary PCI, there were 24.4% patients still with TIMI flow &amp;lt; 3. There was no direct correlation between CYP2C19 polymorphism and TIMI flow &amp;lt; 3 after primary PCI. However, we found significant association between Clopidogrel non-reponders and TMI flow &amp;lt; 3 after primary PCI in those STEMI patients (OR 3.3, p = 0.046). Conclusions: In Asian patients with STEMI receiving clopidogrel prior to primary PCI, the CYP2C19 polymorphisms is associated with poor platelet response to Clopidogrel therapy. The Clopidogrel non-responders is associated with impaired TIMI flow after primary PCI.

(Frequency of CYP2C19 Gene Polymorphisms (SNP) and its Impact on Clinical Outcome in Ischemic Heart Disease Patients Taking Clopidogrel after percutaneous coronary intervention (PCI

كلوبيدوجريل ، أحد مشتقات ثينوبيريدين عن طريق الفم قادر على تثبيط تنشيط الصفائح الدموية. Clopidogrel هو دواء أولي يتم تحويله إلى عقار نشط بواسطة السيتوكروم الكبدي CYP2C19 و CYP2C19 * 2 و CYP2C19 * 3 الأليلات متعددة الأشكال التي تعتبر من الأليلات متعددة الأشكال التي تؤدي إلى فقدان الوظيفة مما يؤدي إلى تقليل الاستجابة للكلوبيدوجريل. هدفت دراستنا إلى الكشف عن تواتر تعدد الجينات CYP2C19 وتأثيرها على النتائج السريرية في مرضى نقص تروية القلب الذين يتناولون عقار كلوبيدوجريل. الأم والطرق: تم جمع عينات الدم من 102 مريض بأمراض القلب الإقفارية وتم تحديد الأليلات التكرارية بواسطة تفاعل البوليميراز المتسلسل وتبع جميع المرضى التقييم السريري والفحوصات القلبية الغازية وغير الغازية. كان تردد CYP2C19 * 1 49٪ ، CYP2C19 * 2 كان 15٪ و CYP2C19 * 3 كان 1٪ ، CYP2C19 * 17 كان 34٪ ، المرضى الذين يعانون من نوبات إقفارية متكررة 37 مريضًا (35.8٪) ، من هؤلاء المرضى ، كان 10 مرضى مستقلب طبيعي (27٪) ، و 27 مريضاً كانوا مستقلبات غير طبيعية (73٪) بقيمة p- 0.047 لاحتشاء عضلة القلب و 0.020 للذبحة الصدرية غير المستقرة. خاتمة:. تم العثور على علاقة لا معنوية بين CYP2C19 تعدد الأشكال والنوبات الإقفارية المتكررة في هذه الدراسة ودراسات متعددة المراكز مطلوبة لتأكيد هذه النتائج.

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

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