Frequencies Of CYP2C9 Research Articles

The Influence of Genetic Polymorphisms on Warfarin Dosage Requirements in Cardiac Valve Surgery Patients

Aim: Warfarin, a widely prescribed anticoagulant, exhibits considerable variability in patient response, making its clinical use challenging due to a narrow therapeutic window. This study aimed to evaluate the prevalence of CYP2C9 and VKORC1 gene polymorphisms in a cohort of 87 Turkish patients who underwent cardiac valve surgery and received warfarin therapy, as well as to assess their impact on warfarin dosage requirements. Methods: The frequencies of CYP2C9 and VKORC1 polymorphisms were analyzed, and patients were stratified based on the presence or absence of mutations affecting warfarin dosing. Results: Revealed that patients carrying at least one CYP2C9 or VKORC1 polymorphism required a significantly lower weekly warfarin dose to achieve the optimal international normalized ratio (INR). Conclusion: This study highlights the critical role of genetic factors in determining warfarin dosage and supports the integration of pharmacogenetic testing into clinical practice to personalize warfarin therapy. Such an approach has the potential to enhance treatment outcomes and minimize the risk of adverse events. Further research involving larger sample sizes and diverse patient populations is warranted to validate these findings and refine the current understanding of the genetic determinants of warfarin dosing.

Frequency of CYP2C19, P2RY12, ITGB3, ITGA2, and eNOS3 gene polymorphism in patients with myocardial infarction

The aim of the study was to assess the distribution of polymorphic variants G681A (*2) of the CYP2C19 gene, H1/H2 of the P2RY12 gene, T1565C of the ITGB3 gene, C807T of the ITGA2 gene, and T786C of the eNOS3 gene in the population of the Grodno region, and to study their associations with myocardial infarction (MI). The study of the population consists of 493 people, including 400 patients with MI aged 31 to 74 years and 93 people of the control group aged 32 to 60 years. Research data (clinical and genotyping performed by polymerase chain reaction) were analyzed using STATISTICA 10.0 software. The prevalence of carriage of genotypes associated with high residual platelet reactivity and variability in response to dual antiplatelet therapy among patients with MI was 25.2 % for the G681A polymorphic locus of the CYP2C19 gene (GA + AA), and for the H1/H2 polymorphic locus of the P2RY12 gene (H1/H2 + H2/H2) – 40.0 %, for the C807T polymorphic locus of the ITGA2 gene (CT + TT) – 65.8, for the T1565C polymorphic locus of the ITGB3 gene (TC + CC) – 25.5, for the polymorphic locus T786C of the eNOS gene (TC + CC) – 69.2 %. Among the individuals of the control group, the frequency of occurrence of these genotypes was 18.3, 46.2, 60.2, 37.6, 48.4 %, respectively. In patients with MI, compared to the control group, the TT genotype of the eNOS gene was less common (χ2 = 13.6, p = 0.0002), the CC genotype of the eNOS gene (χ2 = 5.4, p = 0.02) and the allele 786C of the eNOS gene (χ2 = 15.1, p = 0.0001) were more often detected. The carriage of the 786C allele of the eNOS gene increased the risk of MI in the studied population (OR = 2.0, 95 % CI: 1.41‒2.82, p = 0.0001). Gender differences were not found in the distribution of genotypes and alleles within the studied groups. There were no differences in carriage by the number of combinations of minor alleles between the control group and patients with MI. The most common combinations of minor alleles in both groups were comparable.

Frequencies of CYP2C19 and CYP2D6 gene variants in a German inpatient sample with mood and anxiety disorders

Objectives Previous results demonstrated that CYP2D6 and CYP2C19 gene variants affect serum concentrations of antidepressants. We implemented a PGx service determining gene variants in CYP2D6 and CYP2C19 in our clinical routine care and report on our first patient cohort. Methods We analysed CYP2D6 and CYP2C19 allele, genotype, and phenotype frequencies, and actionable pharmacogenetic variants in this German psychiatric inpatient cohort. Two-tailed z-test was used to investigate for differences in CYP2D6 and CYP2C19 phenotypes and actionable/non-actionable genetic variant frequencies between our cohort and reference cohorts. Results Out of the 154 patients included, 44.8% of patients were classified as CYP2D6 normal metabolizer, 38.3% as intermediate metabolizers, 8.4% as poor metabolizers, and 2.6% as ultrarapid metabolizers. As for CYP2C19, 40.9% of patients were classified as normal metabolizers, 19.5% as intermediate metabolizers, 2.6% as poor metabolizers, 31.2% as rapid metabolizers, and 5.8% as ultrarapid metabolizers. Approximately, 80% of patients had at least one actionable PGx variant. Conclusion There is a high prevalence of actionable PGx variants in psychiatric inpatients which may affect treatment response. Physicians should refer to PGx-informed dosing guidelines in carriers of these variants. Pre-emptive PGx testing in general may facilitate precision medicine also for other drugs metabolised by CYP2D6 and/or CYP2C19.

Association of CYP2C9*2 Allele with Sulphonylurea-Induced Hypoglycaemia in Type 2 Diabetes Mellitus Patients: A Pharmacogenetic Study in Pakistani Pashtun Population.

Polymorphism in cytochrome P450 (CYP) 2C9 enzyme is known to cause significant inter-individual differences in drug response and occurrence of adverse drug reactions. Different alleles of the CYP2C9 gene have been identified, but the notable alleles responsible for reduced enzyme activity are CYP2C9*2 and CYP2C9*3. No pharmacogenetic data are available on CYP2C9*2 and CYP2C9*3 alleles in the Pakistani population. In Pakistan, pharmacogenetics, which examines the relationship between genetic factors and drug response, are in the early stages of development. We, for the first time, investigated the association between the CYP2C9 variant alleles CYP2C9*2 and CYP2C9*3 and the incidence of hypoglycaemia in patients with Type 2 diabetes mellitus (T2DM) receiving sulphonylurea medications. A total of n = 400 individuals of Pashtun ethnicity were recruited from 10 different districts of Khyber Pakhtunkhwa, Pakistan to participate in the study. The study participants were divided into two distinct groups: the case group (n = 200) and the control group (n = 200). The case group consisted of individuals with T2DM who were receiving sulphonylurea medications and experienced hypoglycaemia with it, whereas the control group included individuals with T2DM who were receiving sulphonylurea medication but did not experience sulphonylurea-induced hypoglycaemia (SIH). Blood samples were obtained from study participants following informed consent. DNA was isolated from whole blood samples using a Wiz-Prep DNA extraction kit. Following DNA isolation, CYP2C9 alleles were genotyped using MassARRAY sequencing platform at the Centre of Genomics at the Rehman Medical Institute (RMI). The frequency of CYP2C9*2 (low-activity allele) was more frequent in the diabetic patients with SIH compared to the control group (17.5% vs. 6.0%, p = 0.021). The frequency of its corresponding genotype CYP2C9*1/*2 was higher in cases compared to the control group (10% vs. 6% with p = 0.036); the same was true for genotype CYP2C9*2/*2 (7% vs. 3.5% with p = 0.028). Logistic regression analysis evidenced potential association of CYP2C9*2 allele and its genotypes with SIH. When adjusted for confounding factors such as age, weight, sex, mean daily dose of sulphonylurea, and triglyceride level, the association between the CYP2C9*2 allele and hypoglycaemia remained consistent. Confounding factors played no role in SIH (insignificant p-value) because both groups (cases and controls) were closely matched in term of age, weight, sex, mean daily dose of sulphonylurea, and triglyceride levels. Our study suggests that genetic information about a patient's CYP2C9 gene/enzyme can potentially assist physicians in prescribing the most suitable and safest drug, based on their genetic make-up.

Integrated analysis of clinical and genetic factors on the interindividual variation of warfarin anticoagulation efficacy in clinical practice

AimThe anticoagulation effect of warfarin is usually evaluated by percentage of time in therapeutic range (PTTR), which is negatively correlated with the risk of warfarin adverse reactions. This study aimed to explore the effects of genetic and nongenetic factors on anticoagulation efficacy of warfarin during different therapeutic range.MethodsWe conducted an observational retrospective study aiming at evaluating the impact of clinical and genetic factors on PTTR from initial to more than six months treatment. This analysis included patients with heart valve replace (HVR) surgery who underwent long-term or life-long time treatment with standard-dose warfarin for anticoagulation control in Second Xiangya Hospital. All patients were followed for at least 6 months. We genotyped single nucleotide polymorphisms in VKORC1 and CYP2C9 associated with altered warfarin dose requirements and tested their associations with PTTR.ResultsA total of 629 patients with intact clinical data and available genotype data were enrolled in this study, and only 38.63% patients achieved good anticoagulation control (PTTR > 0.6). Clinical factors, including male gender, older age, overweight, AVR surgery and stroke history, were associated with higher PTTR. Patients with VKORC1 -1639AA genotype had significantly higher PTTR level compared with GA/GG genotype carriers only in the first month of treatment. Patients with CYP2C9*3 allele had higher PTTR compared with CYP2C9*1*1 carriers. Moreover, compared with VKORC1 -1639 AG/GG carriers, INR > 4 was more likely to be present in patients with AA genotype. The frequency of CYP2C9*1*3 in patients with INR > 4 was significantly higher than these without INR > 4.ConclusionWe confirmed the relevant factors of warfarin anticoagulation control, including genetic factors (VKORC1 -1639G > A and CYP2C9*3 polymorphisms) and clinical factors (male gender, older age, overweight, AVR surgery and stroke history), which could be helpful to individualize warfarin dosage and improve warfarin anticoagulation control during different treatment period.

Effects of genetic polymorphisms of CYP2J2, CYP2C9, CYP2C19, CYP4F2, CYP4F3 and CYP4A11 enzymes in preeclampsia and gestational hypertension

IntroductionThe aim of this study was to investigate the effects of cytochrome P450 (CYP) 2J2, CYP2C9, CYP2C19 and CYP4F2, CYP4F3 and CYP4A11 genetic polymorphisms in preeclampsia and gestational hypertension (GHT) patients in a sample of Turkish population. Materials-methodsPatients (n = 168; 110 GHT and 58 preeclampsia) and healthy pregnant women (n = 155, controls) participated in the study. For genotyping, polymerase chain reaction (PCR) and restriction analysis (RFLP) were used. Substance levels were measured using LC-MS. ResultsPlasma DHET levels in GHT and preeclampsia patients were significantly lower than those in the control group (62.7%, 66.3% vs.100.0%, respectively, p < 0.0001). An increase in CYP2J2*7 allele frequency was observed in the preeclampsia group, as compared to GHT group (12.1% vs. 4.5%; odds ratio, O.R. = 2.88, p < 0.01). The frequencies of CYP2C19*2 and*17 alleles were higher in GHT group as compared to the control group (17.7% vs. 11.6%, O.R. = 1.99, p < 0.01; and 28.6% vs.18.4%, O.R. = 2.03, p < 0.01, respectively). An increased frequency of CYP4F3 rs3794987 G allele was found in GHT group as compared to the control group (48.0% vs. 38.0%; O.R. = 1.53, p < 0.01). DiscussionDHET plasma levels were significantly reduced in hypertensive pregnant groups as compared to the control group. The allele frequency distributions for CYP2J2*7, CYP2C19 *2, *17 and CYP4F3 rs3794987 were significantly different in hypertensive pregnant patients as compared to the healthy control subjects. Our results may suggest that investigated genetic polymorphisms may be useful in diagnosis and clinical management of GHT and preeclampsia patients.

CYP2C19 gene polymorphism in Ningxia.

Poor metabolizer (PM)status of CYP2C19 can bea predisposing factor for developing gastric cancer inH. pylori-infected patients. It is unclear whether PM status of CYP2C19 canalso be a potential factor forH.pyloriinfection in healthy people. We used high-throughput sequencing to detect single nucleotide polymorphisms (SNPs) at just three loci, rs4244285 (CYP2C19*2), rs4986893 (CYP2C19*3) and rs12248560 (CYP2C19*17), to identify the exact CYP2C19 alleles corresponding to the mutated sites. We determined CYP2C19 genotypes of 1050 subjects from 5 cities of Ningxia from September 2019 to September 2020 and evaluated the potential correlation between H.pylori and CYP2C19 gene polymorphisms. Clinical data were analyzed using χ2 tests. The frequency of CYP2C19*17 in Hui (3.7%) was higher as compared to Han (1.4%) in Ningxia (p = 0.001). The frequency of CYP2C19*1/*17 of Hui (4.7%) was higher as compared to Han (1.6%) in Ningxia (p = 0.004). The frequency of CYP2C19*3/*17 of Hui (1%) was higher as compared to Han (0%) in Ningxia (p = 0.023). The frequencies of alleles (p = 0.142) and genotypes (p = 0.928) were not found to be significantly different among the different BMI groups. The frequencies of four alleles betweenH. pyloripositive and negative groups were not found to be statistically different (p = 0.794). The frequencies of the different genotypes betweenH. pyloripositive and negative groups were not statistically different (p = 0.974), and no statistical difference was observed between the different metabolic phenotypes (p = 0.494). There were regional differences observed in CYP2C19*17 distribution in Ningxia. The frequency of CYP2C19*17 in Hui was higher than in Han of Ningxia. No significant relationship was found between CYP2C19 gene polymorphism and susceptibility to H. pylori infection.

Pharmacogenetics of CYP2C19*17: Functional and Clinical Implications of CYP2C19*17 - rs12248560 (c.-806C&gt;T) in the Development of Type 2 Diabetes

The prevalence of diabetes mellitus (DM) is increasing worldwide including Saudi Arabia. DM increases mortality rate, morbidity and vascular complications, accompanied by poor general health status and low quality of life. CYP2C19*17 polymorphism in CYP2C19 gene is associated with the clinical outcome of drugs that are substrates of CYP2C19. CYP2C19*17 confers reduced susceptibility to certain illnesses. This research was conducted to develop a robust method to genotype the rs12248560 single nucleotide variation (SNV). We enrolled 206 subjects: 100 subjects were clinically confirmed cases of type 2 diabetes (T2D), and 106 subjects were healthy controls in this study. Samples from all subjects were screened for the CYP2C19 rs12248560 (c.-806C&gt;T) by the amplification-refractory mutation system PCR (ARMS-PCR). The frequencies of CYP2C19*17 TT, CT, CC genotypes in T2D cases were 12%, 21%, and 67%, respectively whereas those in healthy controls were 70.75%, 26.41%, and 2.83%, respectively. The difference was significant (p &lt; 0.035). T allele (fT) prevalence was found to be substantially greater in T2D cases compared to healthy controls (0.22 vs. 0.16). Results indicated that the CYP2C19*17 - TT genotype is associated with increased susceptibility to T2D with OR = 4.47, RR = 2.64, (p &lt; 0.024). Moreover, the ARMS-based assay proved to be an easy method for the determination of CYP2C19*17 genotypes with reduced cost and good accuracy. In addition, this result helps in the detection and stratification of the individuals who are at risk for the development of T2D. Nevertheless, this finding needs to be validated in molecular genetic studies with increased specimen size and in different ethnicities.

ЧАСТОТА АЛЛЕЛЕЙ И ГЕНОТИПОВ ПО АЛЛЕЛЬНЫМ ВАРИАНТАМ CYP2С9*2 И CYP2С9*3 СРЕДИ БОЛЬНЫХ С БОЛЕВЫМ СИНДРОМОМ, ПРИНИМАВШИХ НЕСТЕРОИДНЫЕ ПРОТИВОВОСПАЛИТЕЛЬНЫЕ СРЕДСТВА

Abstract. Introduction. The most clinically significant polymorphic markers of the CYP2C9 gene are the amino acid substitutions of CYP2C9*2. One of the types of human cytochrome P450 – cytochrome CYP2C19 plays an important role in the metabolism of certain drugs, including proton pump inhibitors. The genetic polymorphism of СУР2С19 has pronounced interindividual differences. The significance of genetic polymorphism is determined when the occurrence of variant alleles is more than 1% in the population. Aim. The aim of the study was to improve the principles of pharmacotherapy of nonsteroidal anti-inflammatory drugs depending on the frequency of alleles and genotypes according to allelic variants of CYP2С9*2 and CYP2С9*3 in patients with pain syndrome, who took nonsteroidal anti-inflammatory drugs. Material and methods. The study included 69 patients with pain syndrome. The study of the association between the carrier of genotypes according to the CYP2С9*2 and CYP2С9*3 alleles and the development of gastropathies with the use of anti-inflammatory drugs was carried out by conducting a prospective case-control study. Molecular genetic studies were carried out on the basis of the Laboratory of Medical Genetics, the Research Institute of Hematology and Blood Transfusion of the Ministry of Health of the Republic of Uzbekistan. Results and discussion. Our data suggest that the carriage of allelic variants of CYP2C9*2 and CYP2C9*3 should be considered as a risk factor for the development of gastropathies when using anti-inflammatory drugs. It can be assumed that in order to reduce the risk of adverse drug reactions when using anti-inflammatory drugs in this category of patients, their joint administration with proton pump inhibitors is necessary. Conclusion. Significantly significant differences in the frequencies of CYP2C9 and CYP2C19 alleles between groups of patients with and without complications from the gastrointestinal tract while taking anti-inflammatory drugs and proton pump inhibitors. Therefore, it is necessary to further study the frequencies of alleles and genotypes according to the allelic variants of CYP2С9*2 and CYP2С9*3 among patients with pain syndrome who took anti-inflammatory drugs.

Genetic polymorphism of clopidogrel metabolism related gene CYP2C19 gene in Chinese from Foshan area of Guangdong Province

ABSTRACT Background: The CYP2C19 gene is highly polymorphic, and CYP2C19 is involved in the broad interindividual variability of the clinical efficacy of certain clinical medications, such as clopidogrel. However, data on the CYP2C19 genotype in the Chinese population of the Foshan area of Guangdong Province are scarce. The purpose of this study was to determine CYP2C19 genetic polymorphisms in patients in the Foshan area and to compare the CYP2C19 genotype frequencies in different populations to determine the allele distribution pattern to identify the most appropriate prescription. Methods: The CYP2C19 gene was detected in 1231 patients on a gene chip platform, and the genotype frequencies of CYP2C19 in Foshan populations from different populations were compared. Results: The frequencies of CYP2C19*1, *2 and *3 in the Foshan population were 63.89%, 30.46% and 5.65%, respectively. For the three metabolic types, the frequency associated with the rapid metabolism type (*1/*1) was 41.51 [95% confidence interval (CI) 40.11 to 42.91%]; that for the intermediate metabolism type (*1/*2, *1/*3) was 44.76% (95% CI 43.34 to 46.18) and that for the slow metabolism type (*2/*2, *2/*3, *3/*3) was 13.73% (95% CI 12.75 to 14.71%). In the Foshan population, the frequencies of the CYP2C19 *2 and *3 alleles were similar to those previously reported for Chinese and other Asian populations. Conclusion: Our study is a report on the genetic basis of CYP2C19 polymorphism in the Foshan population. Our results will potentially contribute to the improvement of pharmacotherapy effectiveness by providing personalized medicine for the Foshan population.

The Dynamic Effect of Non-CYP3A4-Metabolized and CYP3A4-Metabolized Statins on Clopidogrel Resistance in Patients With Cerebral Infarction.

Objective: To explore the treatment effect of statins used together with clopidogrel on cerebral infarction (CI). Methods: One hundred and thirty non-clopidogrel resistant patients were divided into a dynamic clopidogrel resistant (DCR) group and a continuous Non clopidogrel resistance (NCR) group. Patients were randomly assigned to AC group (atorvastatin 40 mg/d + clopidogrel, 51 patients) and RC group (rosuvastatin 20 mg/d + clopidogrel, 47 patients). The patient’s platelet aggregation rate (PAR) was measured on visit 0 (baseline), visit 1 (1 week after clopidogrel alone treatment), and visits 2 to 4 (one, three, and 6 months after clopidogrel plus statins treatment). The platelet reactivity index (PRI) was assessed on visits 0, 2, and 4, and clopidogrel thiol metabolite (H4) levels was measured on visits 2 and 4. DNA sequencing was used to determine CYP3A4, CYP2C9, and CYP2C19 genotypes in all patients. Results: PAR, PRI, and H4 levels, DCR ratio, and the genotype frequencies of CYP2C9*3εC, CYP2C19*2εA, and CYP2C19*3εA of both groups were similar (p > 0.05). CYP2C19εA *2 and *3 were independent risk factors for DCR (p < 0.05). Conclusion: Clopidogrel combined with atorvastatin does not affect platelet inhibition and does not increase the incidence of DCR. The incidence of DCR in the Chinese population is high and is related to CYP2C19εA.

Association of CYP2C19*2/3 gene polymorphism with lung cancer in Moroccan population

BackgroundAs it is the case for all kinds of cancer; lung cancer is a multifactorial disease. The interaction between both Exposures to different carcinogens and individual genetic backgrounds modulate the disease risk. Cytochrome P450 family is one of the main enzymes involved in the metabolism of these carcinogens. Therefore, polymorphisms of genes encoding for the cyp450 enzymes can be responsible for the inter-individual differences in lung cancer susceptibility. In this study, we chose to focus on the Cyp2c19, as one of the crucial cyp450 enzymes associated with metabolism of a number of drugs and xenobiotics and its association with the lung cancer risk. MethodsPeripheral blood from a total of 115 Moroccan patients diagnosed with lung cancer and 105 healthy subjects was collected. The genotyping of CYP2C19*2 and CYP2C19*3 polymorphisms was carried out using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technic. ResultsWe found that the frequency of both CYP2C19*2 (GA+AA) genotype and CYP2C19*A allele were significantly more frequent in lung cancer patients than that in control subjects (24.3% vs 13.3%; p = 0.04 and 14.35% vs 7.15%; p = 0.01 respectively). We also found that the CYP2C19*3 A allele was only found in lung cancer patient with a frequency of 10% (p = 0.007). Consequently, the frequency of the CYP2C19*3 (GA + AA) genotype was also significantly more prevalent in lung cancer patients than that in controls (20% vs 0.00%; p = 0.005). We also found that smoking is associated to a higher lung cancer risk in participants carrying CYP2C19*3 or CYP2C19*2 GG genotypes (p < 0.0001, OR = 26.42, 95%CI = 12.38–56.36) and (p < 0.0001, OR = 24,44, 95%CI = 11,13–53,65). While the binary logistic regression analysis demonstrates that interaction of CYP2C19*2 with smoking has no effect on the lung cancer risk, unlike the CYP2C19*3 which coexisted with smoking increases lung cancer risk even more. ConclusionThese findings indicate that the CYP2C19*2 and CYP2C19*3 polymorphisms are significantly associated with lung cancer in Moroccan population. In addition, that the coexistence of CYP2C19*3 with smoking increased lung cancer risk even more.

Frequencies of polymorphisms in genes affecting the pharmacokinetics of warfarin in the Zaporizhzhia region

The aim of the study: to establish the frequencies of polymorphisms in VKORC1, CYP2C9 and CYP4F2 genes among residents of the Zaporizhzhia region. Materials and methods. A total of 150 persons (62 male, 88 female) with a median age of 46 years (26; 58) undergoing preventive examination at the Medical Educational and Scientific Center “University Clinic” of Zaporizhzhia State Medical University (ZSMU). The CYP2C9, CYP4F2, VKORC1 genes polymorphisms in atrial fibrillation patients were determined in the Department of Molecular Genetic Studies of the ZSMU Medical Laboratory Center. Amplification of DNA fragments containing polymorphic regions was performed using multiplex real time polymerase chain reaction with Warfarin Pharmacogenetics kits (LLC NPO DNA Technology) in a CFX-96 thermocycler (BioRad) with a fluorescence detection scheme. Results. It was determined that among Zaporizhzhia region residents, the frequencies of CYP2C9*2 genotypes were: C/C – 77.3 %, C/T – 22.7 %, T/T – 0; CYP2C9*3 genotypes: A/A – 88.7 %, A/C – 10.7 %, C/C – 0.6 %; CYP4F2 genotypes: C/C – 56.0 %, C/T – 35.3 %, T/T – 8.7 %; VKORC1 genotypes: G/G – 38.0 %, G/A – 50.0 %, A/A – 12.0 %. There were no statistically significant differences in the distribution of genotype frequencies between males and females and between different age groups. The frequencies of CYP2C9, CYP4F2, VKORC1 genotypes in different populations were compared. Their variability in different geographic regions was established. Conclusions. CYP4F2 and VKORC1 genes polymorphisms are more common in the Zaporizhzhia region, while the prevalence of CYP2C9*2 and CYP2C9*3 genes polymorphisms is much lower. It is necessary to take into account the prevalence of genes polymorphisms that affect warfarin metabolism for each individual population to select its dose by pharmacogenetic testing.

Association between CYP2C19 polymorphisms and clinical outcomes in patients undergoing stent procedure for cerebral artery stenosis

We investigated the effect of CYP2C19 polymorphisms on the clinical outcomes of clopidogrel therapy in patients after stenting procedure for cerebral artery stenosis in northeast China. 568 patients performed CYP2C19 genotype screening in the neurosurgery department of our hospital; 154 patients were finally recruited according to the inclusion and exclusion criteria, and followed-up for 6 months. Ischemic events including (1) transient ischemic attack (TIA); (2) stent thrombosis; (3) ischemic stroke; and (4) death were defined as primary clinical endpoints. The frequencies of CYP2C19*1, *2 and *3 alleles in 568 patients were 63.1%, 31.1% and 5.8%, respectively. 154 patients were classified into extensive (65 patients; 42.2%), intermediate (66 patients; 42.9%), and poor (23 patients; 14.9%) metabolizer groups. A χ2 test showed a significant difference in primary clinical endpoints at 6 months (P = 0.04), and a multivariate Cox regression analysis indicated that the CYP2C19 loss-of-function (LOF) alleles associated with post-procedure prognosis. The Kaplan–Meier curve revealed that there was no significant difference in ischemic events between *2 and *3 alleles carriers. Our study verifies that CYP2C19 *2 and *3 have significant impact on the clinical outcomes of clopidogrel therapy in patients with stenting procedure for cerebral artery stenosis in China.

Frequency of CYP2C19*2 Allele in Patients with Acute Coronary Syndrome: A Cross-sectional Study from Central Kerala, India

Introduction: Ischaemic Heart Diseases (IHD) are increasing at an alarming rate globally. Pharmacotherapy, the mainstay of management of IHD, has Dual Antiplatelet Therapy (DAPT) at its crux. DAPT, comprising of clopidogrel and aspirin, is used often for 12 months in medically managed Acute Coronary Syndrome (ACS). Clopidogrel being a prodrug, needs to be activated after ingestion, mainly by Cytochrome family of enzymes, for the desired pharmacological effects. Abnormal enzymes that convert clopidogrel to its active form can reduce the effectiveness of the drug. Therefore, Single Nucleotide Polymorphisms (SNPs) of the enzymes involved, would predispose the patient to therapy failure and recurrence of the illness. This study aims at identifying the presence of a genetic variant associated with clopidogrel responsiveness in patients with ACS. Aim: To estimate the frequency of CYP2C19*2 allele in patients with ACS presenting to Government Medical College, Thrissur, Kerala, India. Materials and Methods: Present study was a cross-sectional study done among 60 patients who presented to Government Medical College, Thrissur with ACS, between June 2018 to June 2019. Having obtained informed consent from the participants blood samples were collected in Ethylene diamine tetra-acetic Acid (EDTA) tubes. Samples were used to look for presence of CYP2C19*2 allele by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). Results: Out of 60 patients 38 were males and 22 were females. Most common age group was 61-65 years. The frequency of CYP2C19*2 allele was 41% in the study population and the variant genotype (AA/AG) was present in 62%. Conclusion: The variant genotype was found to be present in a high frequency in the study population implying the high risk for therapy failure in the study population. This asserts the need to probe the matter further, as the gene is also implicated in the metabolism of several other drugs. The introduction of pharmacogenomic testing prior to initiation of therapy may be therefore recommended for better treatment outcome. However, to validate the same, further studies with larger sample size may be necessary.

Variations in the frequencies of polymorphisms in the CYP2C9 gene in six major ethnicities of Pakistan

Genetic variation in cytochrome P450 (CYP) 2C9 is known to cause significant inter-individual differences in drug response and adverse effects. The frequencies of CYP2C9*2 and CYP2C9*3, both of which are responsible for the low activity of the enzyme, are not known in the Pakistani population. Therefore, we screened various ethnic groups residing in Pakistan for these polymorphisms. A total of 467 healthy human volunteers were recruited from six major ethnicities of Pakistan after written informed consent. Our results indicate that about 20% of the Pakistani population has a genotype containing at least one low activity allele. Ethnic Punjabi and Pathan populations had the highest frequencies of wild type genotypes while Urdu, Seraiki, and Sindhi populations showed higher rates of both low activity genotypes. The Baloch population showed the highest rates of low activity genotypes with less than 50% of the samples showing wild type genotypes, suggesting that more than half of the Baloch population possesses low activity genotypes. The frequencies found in various ethnic groups in Pakistan were comparable with ethnicities in the South Asian region except for the Baloch population. These results suggest that pharmacogenetics screening for low activity genotypes may be a helpful tool for clinicians while prescribing medications metabolized by CYP2C9.

Global distribution of CYP2C19 risk phenotypes affecting safety and effectiveness of medications.

Genetic variability of CYP2C19 may affect safety or efficacy of many clinically important medications as outlined in the clinical pharmacogenetics implementation consortium (CPIC) dosing guidelines. To determine the predictive prevalence of high-risk phenotypes due to CYP2C19 genetic variants collectively in the world population and to establish a correlation how the identified high-risk phenotypes may affect safety or effectiveness of drugs, this study was conducted. 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. Association of predicted high-risk phenotypes with the safety or effectiveness of medications was gained from CPIC dosing guidelines. Ultrarapid 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 due to combined effects of CYP2C19*2, *3 and *17 variants. Large scale clinical studies are warranted to assess clinical outcomes of these medications considering CYP2C19 pharmacogenomics effects.

Quality of oral anticoagulation control in Chinese patients with non-valvular atrial fibrillation: a prospective controlled study

Objective The sex, age, medical history, treatment, tobacco use, race risk (SAMe-TT2R2) Score; the sex, age, medical history, treatment, tobacco use, genotype combination (SAMe-TT2G2) Score; and the so-called modified SAMe-TT2R2 scores have been proposed to predict the anticoagulation quality for patients with non-valvular atrial fibrillation (NVAF). The data from a prospective controlled study is used to validate the SAMe-TT2R2 and SAMe-TT2G2 scores in Chinese NVAF patients treated with warfarin and to evaluate the association of factors with time in therapeutic range (TTR) to predict the quality of oral anticoagulation control. Methods A total of 379 patients with NVAF under warfarin treatment for a three-month follow-up were included in this prospective, multicenter study. The quality of oral anticoagulation control was evaluated by the TTR. The TTR was dichotomized for binary logistic regression analysis, using a cutoff point for classification as an inadequate (TTR < 65.0%) control. Results The 379 NVAF patients had a mean TTR of 58.35 ± 26.33% and median SAMe-TT2R2 and SAMe-TT2G2 scores of 3 and 2, respectively. The discrimination performances of the SAMe-TT2R2 and SAMe-TT2G2 scores for inadequate anticoagulation control (TTR < 65.0%) were poor (c-index < 0.60). The gene frequency of CYP2C9*3 was 3.2% and that of VKORC1-1639 G > A was 89.3%. Genetic variation of CYP2C9*3 and VKORC1-1639 G > A did not affect TTR after initial treatment. The condition TTR < 65.0% was associated with an age below 60 without genotype-guided warfarin dose initiation and concomitant torasemide. Conclusions A warfarin-dosing algorithm used for initial treatment of patients older than 60 helps to achieve a better quality of oral anticoagulation control, whereas concomitant torasemide can produce a negative effect. These findings provide useful information for future investigations on the quality of oral anticoagulation control in Chinese anticoagulation clinical practice.

Major CYP450 Polymorphism among Saudi Patients.

Cytochrome P450 (CYP) contributes to a huge collection of medicinal products' Phase I metabolization. We aimed to summarize and investigate the current evidence regarding the frequency of CYP2D6, CYP2C9, CYP2C19, and MDR1 in Saudi Arabia. A computerized search in four databases was done using the relevant keywords. The screening process was done in two steps; title and abstract screening and full-text screening. Data of demographic and characteristics of included studies and patients were extracted and tabulated. Ten studies were eligible for our criteria and were included in this systematic review. The age of participants ranged between 17-65 years. Only two subjects showed PM phenotype of CYP2C19 in the Saudi population. The most frequent alleles were CYP2C19*1 (62.9%), CYP2C19*2 (11.2%-32%), and CYP2C19*17 (25.7%). The CYP2C19m1 was observed in 97 cases of extensive metabolizing (EM) phenotype CYP2C19. Concerning the CYP2C9, the most frequent alleles were CYP2C9*1 and CYP2C9*2, and the most frequent genotype was CYP2C9*1*1. The CYP2D6*41 allele and C1236T MDR1 were the most frequent allele in this population. The current evidence suggests that Saudi resembled European in the frequency of CYP2C19, Caucasians in both the incidence of CYP2C9 and CYP2C19m1, and the absence of CYP2C19m2. The CYP2D6*41 allele frequency in Saudi is relatively high. We recommend further research to evaluate the basic and clinical relevance of gene polymorphism in such ethnicity.

Interethnic differences in the prevalence of main cardiovascular pharmacogenetic biomarkers.

Background: The aim of this study was to determine the prevalence of CYP2C9, VKORC1, CYP2C19, ABCB1, CYP2D6 and SLCO1B1 genes polymorphisms among residents of the Volga region (Chuvash and Mari) and northernCaucasus (Kabardins and Ossetians). Materials & methods: The study involved 845 apparently healthy volunteers of both sexes of the four different ethnic groups living in the Russian Federation: 238 from the Chuvash ethnic group, 206 Mari, 157 Kabardins and 244 Ossetians. Results: Significant differences were identified in allele frequency of CYP2C9, VKORC1, CYP2C19, ABCB1, CYP2D6 and SLCO1B1 genes polymorphisms between the Chuvash and Kabardins, Chuvash and Ossetians, Mari and Kabardians, Mari and Ossetians.