CYP2C19 Gene Research Articles

Assessing the Performance of In silico Tools and Molecular Dynamics Simulations for Predicting Pharmacogenetic Variant Impact.

The ability of freely available in silico tools to predict the effect of non-synonymous single nucleotide polymorphisms (nsSNPs) in pharmacogenes on protein function is not well defined. We assessed the performance of seven sequence-based (SIFT, PolyPhen2, mutation accessor, FATHMM, PhD-SNP, MutPred2, and SNPs & Go) and five structure-based (mCSM, SDM, DDGun, CupSat, and MAESTROweb) tools in predicting the impact of 118 nsSNPs in the CYP2C19, CYP2C9, CYP2B6, CYP2D6, and DPYD genes with known function (24 normal, one increased, 42 decreased, and 51 no-function). Sequence-based tools had a higher median (IQR) positive predictive value (89% [89-94%] vs. 12% [10-15%], P < 0.001) and lower negative predictive value (30% [24-34%] vs. 90% [80-93%], P < 0.001) than structure-based tools. Accuracy did not significantly differ between sequence-based (59% [37-67%]) and structure-based (34% [23-44%]) tools (P = 0.070). Notably, the no-function CYP2C9*3 allele and decreased function CYP2C9*8 allele were predicted incorrectly as tolerated by 100% of sequenced-based tools and as stabilizing by 60% and 20% of structure-based tools, respectively. As a case study, we performed mutational analysis for the CYP2C9*1, *3 (I359L), and *8 (R150H) proteins through molecular dynamic (MD) simulations using S-warfarin as the substrate. The I359L variant increased the distance of the major metabolic site of S-warfarin to the oxy-ferryl center of CYP2C9, and I359L and R150H caused shifts in the conformation of S-warfarin to a position less favorable for metabolism. These data suggest that MD simulations may better capture the impact of nsSNPs in pharmacogenes than other tools.

Analysis of the effect of CYP2C19 gene properties on the anti-platelet aggregation of clopidogrel after carotid artery stenting under network pharmacology

Antiplatelet therapy is an important factor influencing the postterm patency rate of carotid artery stenting (CAS). Clopidogrel is a platelet aggregation inhibitor mediated by the adenosine diphosphate receptor and is affected by CYP2C19 gene polymorphisms in vivo. When the CYP2C19 gene has a nonfunctional mutation, the activity of the encoded enzyme will be weakened or lost, which directly affects the metabolism of clopidogrel and ultimately weakens its antiplatelet aggregation ability. Therefore, based on network pharmacology, analyzing the influence of CYP2C19 gene polymorphisms on the antiplatelet therapeutic effect of clopidogrel after CAS is highly important for the formulation of individualized clinical drug regimens. The effect of the CYP2C19 gene polymorphism on the antiplatelet aggregation of clopidogrel after CAS was analyzed based on network pharmacology. A total of 100 patients with ischemic cerebrovascular disease who were confirmed by the neurology department and required CAS treatment were studied. CYP2C19 genotyping was performed on all patients via a gene chip. All patients were classified into the wild-type (WT) group (*1/*1), heterozygous mutation (HTM) group (CYP2C19*1/*2, CYP2C19*1/*3), and homozygous mutation (HMM) group (CYP2C19*2/*2, CYP2C19*2/*3, and CYP2C19*3/*3). High-performance liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS) was used to detect the blood concentration of clopidogrel and the plasma clopidogrel clearance (CL) rate in different groups of patients before and after clopidogrel treatment. The platelet aggregation rate of patients with different genotypes was measured by turbidimetry. The incidences of clopidogrel resistance (CR) and stent thrombosis in different groups after three months of treatment were analyzed. The results showed that among the different CYP2C19 genotypes, patients from the HTM group accounted for the most patients, while patients from the HTM group accounted for the least patients. Similarly, the clopidogrel CL of patients in the HMM group was lower than that of patients in the WT group and HTM group (P < 0.01). The platelet inhibition rate of patients in the HMM group was evidently inferior to that of patients in the WT group and HTM group (P < 0.01). The incidence of CR and stent thrombosis in the WT group was notably lower than that in the HTM and HMM groups (P < 0.01). These results indicate that the CYP2C19 gene can affect CR occurrence and stent thrombosis after CAS by influencing clopidogrel metabolism and platelet count.

Efficacy of P2Y12 receptor inhibitors in myocardial infarction in individuals carrying different CYP2C19 genotypes living in the northern region of Russia

Aim. To evaluate the efficacy of P2Y12 receptor inhibitors (clopidogrel and ticagrelor) in patients with myocardial infarction (MI) living in the northern region of Russia (Khanty-Mansi Autonomous Okrug — Yugra), depending on the carriage of various CYP2C19 allelic variants.Material and methods. This prospective observational study included 218 patients with acute MI who underwent percutaneous coronary intervention (PCI). The patients also underwent determination of allelic variants of the CYP2C19 gene. Patient were divided into groups receiving clopidogrel (n=164, 75%) and ticagrelor (n=54, 25%). Using biostatistical analysis methods, a comparison of clinical and genetic characteristics was performed, as well as an assessment of the risk of ischemic events between the groups in the long-term (108 months, 9 years) post-infarction period.Results. Reduced (*1/*2, *2/*2, *1/*3) and increased (*1/*17, *17/*17) metabolizer CYP2C19 genotypes, as well as severe comorbidity, are reliable independent predictors of composite outcome (cardiovascular death, recurrent acute coronary syndrome, coronary stent/bypass thrombosis, myocardial revascularization, acute ischemic cerebrovascular accident) during a long-term (9 years) follow-up. The advantages of ticagrelor over clopidogrel in terms of the effect on the incidence of ischemic events in the long-term period were established without a significant difference for bleeding both in the general cohort of patients and among carriers of CYP2C19 allelic variants (*1/*2, *2/*2, *1/*3) and (*1/*17,*17/*17) in patients with MI.Conclusion. Ticagrelor is significantly more effective than clopidogrel in reducing the risk of ischemic events in the general cohort of patients, as well as in carriers of reduced (*1/*2, *2/*2, *1/*3) and increased (*1/*17, *17/*17) metabolizer CYP2C19 genotypes during 9-year follow-up after the index MI.

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.

#707 Effectiveness of a personalized approach to the treatment of patients with chronic coronary syndrome with type 2 diabetes and renal dysfunction

Abstract Background and Aims To evaluate the effectiveness of complex personalized treatment of patients with chronic coronary syndrome (CCS) with type 2 diabetes mellitus (T2DM). Method We observed patients with chronic stable angina pectoris III (FC) (Group I, 16) and CV IV FC (Group II, 18) with T2DM who underwent planned stenting of the coronary arteries (SCA). At baseline and after 3 and 6 months, we studied cholesterol, LDL cholesterol and HDL cholesterol, triglycerides (TG), ALT and AST, total bilirubin (TB), polymorphism of the CYP2C19 and 9p21 genes (rs 2383206 and rs 10757272), assessed myocardial viability (ECHOCG, MSCT), an ultrasound of the liver was performed. Against the background of basic therapy (antiplatelet agents, statins, beta blockers, ACE inhibitors), patients received a herbal hepatoprotector. Results Initial lipid parameters in patients with CCS and T2DM: cholesterol—6.9 mmol/l; LDL cholesterol –3.6; HDL cholesterol –1.1; TG –2.5 mmol/l. Parameters of global and regional systolic function were reduced. At the end of observation, lipid content: cholesterol—5.0; LDL cholesterol—2.3; HDL cholesterol –1.18; TG—1.61 mmol/l. Statins and antiplatelet agents were well tolerated, and there were no cases of withdrawal. Enzyme activity (ALT, AST), OB content were within normal values. The genetic studies carried out helped to select the most effective and safe doses of antiplatelet drugs and statins and significantly reduced the risk of complications and drug resistance. The hepatoprotector had a beneficial effect on the condition and function of the liver and improved the tolerability of medications. A personalized approach to the treatment of CCS was carried out taking into account the results of genetic testing with the selection of optimal doses of drugs. When the genotypes of CYP2C19*17 (rs 12248560) CC, ST and TT were distributed, the dose of antiplatelet agents was increased, and when the genotypes of the CYP2C19 gene (rs 4244285) GG, AG and AA were distributed, they were reduced. Assessment of myocardial viability, selection of doses of statins and antiplatelet agents according to individual characteristics, as well as a hepatoprotector increased the effectiveness and safety of treatment. SCA and basic treatment had an impact on the pathogenetic links of CCS, which is especially important in the treatment of patients with concomitant T2DM. Conclusion A personalized approach to the treatment of patients with CCS with T2DM who require SCA, taking into account the functional state and viability of the myocardium, the pharmacogenetic characteristics of the drugs, increases the effectiveness of revascularization, prevents the development of resistance, side effects and complications.

The impact of CYP2C19 genotypes on steady-state plasma concentration of escitalopram in South Indian population with Major Depressive Disorder

Background: Among depressed patients, escitalopram plasma levels differed between those who were considered as extensive metabolizers and poor metabolizers of CYP2C19. However, the majority of research utilized the dose-response relationship. Consequently, we investigated the effect of variations in the CYP2C19 gene on the levels of drug in the bloodstream of individuals suffering from Major Depressive Disorder (MDD) in south India. Methods: A total of 109 individuals with MDD who were prescribed escitalopram at doses of 5, 10, 15, or 20 mg daily participated in this research. We used HPLC with SPD-10AVP UV-Visible detector to measure the escitalopram concentrations in the blood. The polymorphisms of the CYP2C19 were determined by employing the PCR techniques. Results: Our study found that 55% of the subjects were intermediate metabolizers, followed by extensive (19.3%), poor (17.4%), and ultra-rapid (8.3%). The significant correlation is identified between the steady state plasma concentration and Sex with (P - Value &amp;lt; 0.05), insignificant correlation was seen in Age and BMI with (P - Value &amp;gt; 0.05). The majority of gene variants seen in the study population were CYP2C19*1/*2, accounting for 49 individuals (44.9%). Conclusion: These findings showed that sex had a substantial impact on the CYP2C19 genetic variation. Medication administration to individuals with CYP2C19PM requires special caution.

Prediction models of persistent taxane-induced peripheral neuropathy among breast cancer survivors using whole-exome sequencing

Persistent taxane-induced peripheral neuropathy (TIPN) is highly prevalent among early-stage breast cancer survivors (ESBCS) and has detrimental effect on quality of life. We leveraged logistic regression models to develop and validate polygenic prediction models to estimate the risk of persistent PN symptoms in a training cohort and validation cohort taking clinical risk factors into account. Based on 337 whole-exome sequenced ESBCS two of five prediction models for individual PN symptoms obtained AUC results above 60% when validated. Using the model for numbness in feet (35 SNVs) in the test cohort, 73% survivors were correctly predicted. For tingling in feet (55 SNVs) 70% were correctly predicted. Both models included SNVs from the ADAMTS20, APT6V0A2, CCDC88C, CYP2C8, EPHA5, NR1H3, PSKH2/APTV0D2, and SCN10A genes. For cramps in feet, difficulty climbing stairs and difficulty opening a jar the validation was unsuccessful. Polygenic prediction models including clinical risk factors can estimate the risk of persistent taxane-induced numbness in feet and tingling in feet in ESBCS.

Impact of CYP2C19 Gene Variants on Long-Term Treatment with Atorvastatin in Patients with Acute Coronary Syndromes.

The effectiveness of lipid-lowering therapies may be insufficient in high-risk cardiovascular patients and depends on the genetic variability of drug-metabolizing enzymes. Customizing statin therapy, including treatment with atorvastatin, may improve clinical outcomes. Currently, there is a lack of guidelines allowing the prediction of the therapeutic efficacy of lipid-lowering statin therapy. This study aimed to determine the effects of clinically significant gene variants of CYP2C19 on atorvastatin therapy in patients with acute coronary syndromes. In total, 92 patients with a confirmed diagnosis of ST-elevation myocardial infarction (STEMI) or non-ST-elevation myocardial infarction (NSTEMI) were sequenced for target regions within the CYP2C19 gene on the Illumina Miniseq system. The CYP2C19 poor metabolizer phenotype (carriers of CYP2C19*2, CYP2C19*4, and CYP2C19*8 alleles) was detected in 29% of patients. These patients had significantly lower responses to treatment with atorvastatin than patients with the normal metabolizer phenotype. CYP2C19-metabolizing phenotype, patient age, and smoking increased the odds of undertreatment in patients (∆LDL-C (mmol/L) < 1). These results revealed that the CYP2C19 phenotype may significantly impact atorvastatin therapy personalization in patients requiring LDL lipid-lowering therapy.

Adherence to endocrine therapy with tamoxifen and satisfaction with follow-up of women with breast cancer by a gynecologist: A survey study

Background. Side effects of endocrine therapy with tamoxifen (TAM) reduce the quality of life of patients with breast cancer (BC) and adversely affect treatment compliance. Against the background of treatment of BC with TAM, the risk of developing endometrial hyperplasia (EH) increases. At the moment, algorithms for monitoring patients receiving TAM by an obstetrician-gynecologist have not been developed and approved. There are also divergent opinions of experts regarding the diagnosis and management of patients in the detection of EH. This article presents the results of the final stage of the study in 2017–2022 – a survey study. The purpose of this study was to assess adherence to endocrine therapy and satisfaction with observation by a gynecologist of women with BC after 5 years of observation and their relationship with the identified early associated polymorphisms of the CYP2D6, CYP3A5, CYP2C9 and ABCB1 genes. Materials and methods. 54 patients with BC, out of 120 who had previously passed the first pharmacogenetic stage of the study, were interviewed with specially designed questionnaire. Due to the small sample size, delta percentages (∆%) were used in each comparison group with a difference threshold of 5%. To assess associations with the studied genetic polymorphisms, previously obtained significant associations of adverse drug reactions with pharmacogenetics in the same patients were used. Results. The prevalence of all adverse drug reactions (ADRs), with the exception of EH, was higher in the group of patients who canceled TAM. Over 5 years of follow-up, 57.4% of patients were regularly observed by an obstetrician-gynecologist, 42.59% of patients visited a gynecologist less than once a year. Of all the respondents, 53.7% of patients are satisfied with the regularity and quality of dispensary observation by an oncologist, 33.33% of patients are satisfied with the regularity and quality of dispensary observation by an obstetrician-gynecologist. All studied ADRs (EH, hot flashes, asthenia, bone pain and dyspepsia) associated with various genetic polymorphisms, prevailed in the group of patients who stopped taking TAM due to drug intolerance (∆%: 25.72, 6.97, 4.81, 6.97 and 24.52 respectively) compared with the TAM-group. Conclusion. The results obtained confirm the role of the studied genetic polymorphisms in the development of ADRs of TAM, but only systemic (hot flashes, asthenia, bone pain and dyspepsia). With regard to endometrial hyperplasia, no significant differences were obtained, which requires more extensive studies.

Effect on emergence from anesthesia following induction with diazepam and its association with CYP2C9, CYP2C19 and CYP3A4 gene polymorphisms

Introduction &amp; Objectives: Benzodiazepines are commonly used as adjuvants to IV anesthetic agents. Diazepam dosage varies widely depending on the desired endpoints. The rationale behind such inter-individual variability in drug responses has been attributed to genetically determined alterations in the enzyme activities. We assessed the emergence time in patients after induction of anesthesia with two different doses of diazepam and evaluated if any correlation exists between the emergence time and genetic polymorphism in drug metabolizers CYP2C19, CYP2C9, and CYP3A4 genes. Methodology: The study was conducted on randomly selected adult patients scheduled for elective surgery between 40-60 y of age with predefined inclusion and exclusion criteria. The patients were distributed into 2 groups, with group 1 receiving 0.2 mg/kg and group 2 given 0.3 mg/kg diazepam. Wake-up time after surgery was determined after a standardized verbal command played by a tape-recorder. Three ml blood in Ethylenediaminetetraacetic acid (EDTA) was collected before administering anesthesia. Results: Wake-up time between 8-18 min did not vary between the two groups. Comparatively persons having 2C19 2 took longer time to wake-up but this association was not statistically significant. However, CYP2C9 2 and 2 C9 3 and CYP3A4 genotypes had no influence on wake-up time. Conclusion: The pilot study suggests the emergence time from diazepam is longer in patients having 2C19 2 which confers slow-metabolizer phenotype. However, this study needs to be replicated in larger sample size to arrive at definitive conclusions before clinical applications. Abbreviations: BDZ- benzodiazepine; EDTA- Ethylenediaminetetraacetic acid; GA-General Anesthesia Key words: Diazepam; Emergence; Gene Polymorphism; Pharmacogenetics Citation: Mittal T, Badhe VK, Badhe DSD, Ahluwalia P, Mitta Bl, Mittal R. Effect on emergence from anesthesia following induction with diazepam and its association with CYP2C9, CYP2C19 and CYP3A4 gene polymorphisms. Anaesth. pain intensive care 2024;28(1):126-138. DOI: 10.35975/apic.v28i1.2380 Received: July 20, 2023; Reviewed: December 07, 2023; Accepted: December 07, 2023

Defining light transmission aggregometry cutoff values for clopidogrel and aspirin resistance in flow diversion treatment of intracranial aneurysms.

Concern about thromboembolic events after flow diversion (FD) warrants dual antiplatelet therapy for 3 to 6 months. Platelet function tests are routinely performed prior to the procedure to detect clopidogrel responsiveness, as resistance is associated with CYP2C19 gene polymorphisms. This study aimed to identify optimal cutoff values in light transmission aggregometry (LTA) for clopidogrel and aspirin as predictive indicators of thromboembolic complications. The authors conducted a retrospective analysis of aneurysms treated with FD between 2013 and 2023 at a single academic institution. Patients with LTA data for adenosine diphosphate (ADP) and arachidonic acid (ARA) were included, excluding those with aborted procedures. Receiver operating characteristic curves were plotted for ADP and ARA assays to determine optimal cutoff values. A total of 442 patients harboring 552 aneurysms treated in 485 procedures were selected for this analysis. Complete and near-complete aneurysm occlusion on the last radiological follow-up was achieved in 81.8% of aneurysms in a median last imaging follow-up of 13.9 months. A good functional outcome (modified Rankin Scale score ≤ 2) was achieved in 96.3% of patients on the last follow-up. Thromboembolic complications occurred in 4.9% of procedures, and intracranial hemorrhagic complications in 1.9%. For the ADP assay, a value ≥ 40% reached a sensitivity of 82.1% and a specificity of 42.9% with a positive likelihood ratio (LR) of 1.50. For the ARA assay, a value ≥ 13.5% reached a sensitivity of 82.1% and a specificity of 45.6% with a positive LR of 1.51. This study analyzed the largest FD-treated cohort in which optimal LTA platelet function thresholds for clopidogrel were evaluated and is the first to assess LTA values for aspirin. The authors found that values ≥ 40% for clopidogrel and ≥ 13.5% for aspirin were optimal for predicting thromboembolic complications after FD in treating aneurysms.

Pharmacogene expression during progression of metabolic dysfunction-associated steatotic liver disease: Studies on mRNA and protein levels and their relevance to drug treatment

Metabolic dysfunction-associated steatotic liver disease (MASLD) is common worldwide. Genes and proteins contributing to drug disposition may show altered expression as MASLD progresses. To assess this further, we undertook transcriptomic and proteomic analysis of 137 pharmacogenes in liver biopsies from a large MASLD cohort.We performed sequencing on RNA from 216 liver biopsies (206 MASLD and 10 controls). Untargeted mass spectrometry proteomics was performed on a 103 biopsy subgroup. Selected RNA sequencing signals were replicated with an additional 187 biopsies.Comparison of advanced MASLD (fibrosis score 3/4) with milder disease (fibrosis score 0–2) by RNA sequencing showed significant alterations in expression of certain phase I, phase II and ABC transporters. For cytochromes P450, CYP2C19 showed the most significant decreased expression (30 % of that in mild disease) but significant decreased expression of other CYPs (including CYP2C8 and CYP2E1) also occurred. CYP2C19 also showed a significant decrease comparing the inflammatory form of MASLD (MASH) with non-MASH biopsies. Findings for CYP2C19 were confirmed in the replication cohort. Proteomics on the original discovery cohort confirmed decreased levels of several CYPs as MASLD advanced but this decrease was greatest for CYP2C19 where levels fell to 40 % control. This decrease may result in decreased CYP2C19 activity that could be problematic for prescription of drugs activated or metabolized by CYP2C19 as MASLD advances. More limited decreases for other P450s suggest fewer issues with non-CYP2C19 drug substrates. Negative correlations at RNA level between CYP2C19 and several cytokine genes provided initial insights into the mechanism underlying decreased expression.

The Influence of CYP2C19 Gene Polymorphism on Selective Serotonin Reuptake Inhibitors In Patients with Major Depressive Disorder: A Pharmacogenetic Prospecting Approach

Major Depressive Disorder (MDD) is a chronic disorder characterized by at least a two-week-long major depressive episode. Selective Serotonin Reuptake Inhibitors (SSRIs) remain the primary prescribed antidepressants to treat MDD. However, SSRIs themselves are found to be ineffective in some individuals or may even lead to adverse side effects. These variable responses have been linked to the drug being metabolized by CYP2C19, which exhibited various polymorphisms. Understanding how gene polymorphism affects drug metabolism is essential since these insights can revolutionize clinical practice, allowing for more precise and personalized treatment approaches that optimize efficacy while minimizing side effects. This issue is particularly pertinent in Indonesia, where research in this area lags behind the pressing need for such studies. In this review, the impact of CYP2C19 polymorphism on the effectiveness of SSRI class drugs, namely citalopram, escitalopram, and sertraline, are explored. Nine relevant articles related to the topic have been studied in Japan, China, Turkey, Russia, Scandinavia, and Australia. The results concluded that CYP2C19 polymorphism can influence the metabolism of SSRIs (citalopram, escitalopram, and sertraline) due to its variability in enzyme activities, which includes both loss-of-function (*2, *3) and gain-of-function (*17) polymorphisms. Consequently, these genetic variations can lead to significant changes in drug efficacy and safety changes within individual patients. This review sheds light on the importance of considering genetic factors when prescribing SSRIs for MDD in the future treatment strategies.

Genetic variability in stroke patients: CYP2C19 polymorphisms unraveled

ObjectiveTo study the distribution characteristics of CYP2C19 polymorphisms in patients suffering from stroke in Han Chinese patients.MethodPCR and DNA microarray chip technology were used to detect the CYP2C19 genotype of 549 patients with stroke, and the genotype, allele frequency and metabolic type of patients with different sexes, ages and types of infarctions and the independent risk factors for clopidogrel resistance were analyzed.ResultsSix genotypes were detected in these 549 patients. A total of 233 (42.44%) patients had the heterozygous allele *1/*2, which was the most prevalent, followed by the homozygous wild-type allele *1/*1 (191, 34.79%). A total of 30 (5.46%) patients possessed the heterozygous allele *1/*3, and 65 (11.84%) patients had the homozygous mutant allele *2/*2. Twenty-nine (5.28%) patients had the compound heterozygous mutant allele *2/*3, and only 1 patient had the homozygous mutant allele *3/*3. The distribution of genotypes, alleles, and metabolic types did not change significantly (P > 0.05) by sex, age, or type of stroke. In addition, no independent risk factors for clopidogrel resistance were found in this analysis.ConclusionThe distribution of CYP2C19 genotypes, allele frequencies, and metabolic types in patients with stroke in Han Chinese patients were not correlated with sex, age, or infarction type. The possibilities of hyperglycemia, hypercholesterolemia, hypertriglyceridemia, hypo-HDL-cholesterolemia, hyper-LDL-cholesterolemia and high blood pressure were not statistically associated with CYP2C19 genotypes. CYP2C19 gene polymorphism detection is recommended for patients who are available, and during treatment, the CYP2C19 genotype can be used to guide personalized precise medication use in patients with stroke.

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.

Distribution of CYP2D6 and CYP2C19 gene polymorphisms in Han and Uygur populations with breast cancer in Xinjiang, China.

The aim of this study was to investigate the frequency distribution of the cytochrome P450 (CYP450) enzymes, CYP2D6 and CYP2C19, and the form of tamoxifen metabolisation in premenopausal patients with breast cancer in the Han and Uygur ethnic groups of Xinjiang to guide rational clinical drug use. A total of 125 Han patients and 121 Uygur patients with premenopausal hormone-receptor-positive breast cancer treated at the Xinjiang Uygur Autonomous Region Cancer Hospital between 1 June 2011 and 1 December 2013 were selected. The common mutation sites in CYP450 were analysed using TaqMan® minor groove binder technology. Genetic testing was performed to determine other metabolic types of tamoxifen, and the genotypes and metabolic types were compared using a Chi-squared test. Between the Han and Uygur groups, there were significant differences in the frequencies of the CYP2D6 (*10/*10) and CYP2C19 (*1/*1) genotypes, with P-values of 0.002 and 0.015, respectively. Genotypes of CYP2D6 (*1/*1), CYP2D6 (*1/*5), CYP2D6 (*5/*5), CYP2D6 (*5/*10) and CYP2C19 (*3/*3) were expressed in the two patient groups, and the difference was not statistically significant (P > 0.05). In the Han patients, the proportions of extensive, intermediate and poor metabolisers of tamoxifen were 72, 24 and 4%, respectively, whereas those in the Uygur patients were 76.9, 17.4 and 5.7%, respectively, with no significant difference (P > 0.05). In conclusion, There were partial differences in the CYP2D6 and CYP2C19 gene polymorphisms of CYP450 between the Han and Uygur patients with premenopausal breast cancer, but there was no significant difference between the CYP2D6 and CYP2C19 phenotypes. Further research is needed to determine the relationship between the enzyme genetic differences of CYP450 and the pharmacokinetics and efficacy of tamoxifen. Although there were some differences in genotypes, these did not result in differences in the predicted tamoxifen metabolisation phenotype between the Han and Uygur patients with breast cancer. Therefore, the doses should be adjusted according to the individual genotype data.

CYP2C19 gene variants and major depressive disorder: integrative review

Major depressive disorder (MDD) is a multifactorial condition common in the general population, treated with different antidepressants. Several genes are involved in the metabolism of these antidepressants, including CYP2C19. Consequently, functional polymorphisms in these genes affect these drugs' metabolism. Through an integrative review, this research aimed to verify the CYP2C19 gene polymorphisms' influence on antidepressant metabolism, evaluate their frequency in patients affected by MDD, verify clinical and demographic characteristics of studied populations, and identify possible associations of this gene with MDD. The database used to search for articles was Biblioteca Virtual em Saúde - BVS, and four articles were selected. Polymorphisms in the CYP2C19 gene may contribute to the metabolism of some antidepressants, such as citalopram, but not others, such as venlafaxine and sertraline. Interestingly, the drug sertraline can influence the levels of lipid profile parameters. In addition, some polymorphisms may be relatively frequent depending on the populations, such as Asians. No CYP2C19 polymorphisms associated with MDD development were observed.

Proton-Pump Inhibitors in Eosinophilic Esophagitis: A Review Focused on the Role of Pharmacogenetics.

Proton-pump inhibitors (PPIs) are the most administered first-line treatment for eosinophilic esophagitis (EoE). However, only around half of EoE patients respond histologically to a double dosage of PPI. In addition, 70% of responders maintain EoE in remission after tapering the PPI dose. In order to avoid endoscopy with biopsies-the only accurate method of assessing PPI response-efforts have been made to identify PPI responder patients. The clinical or endoscopic features and biomarkers evaluated so far, however, have not proven to be sufficient in predicting PPI response. Although new approaches based on omics technologies have uncovered promising biomarkers, the specialized and complex procedures required are difficult to implement in clinical settings. Alternatively, PPI pharmacogenetics based on identifying variations in CYP2C19 and STAT6 genes have shown promising results in EoE, and could easily be performed in most laboratories. Other genetic variations have also been associated with PPI response and may explain those cases not related to CYP2C19 or STAT6. Here, we provide an overview of PPI treatment in EoE and evidence of how genetic variations in CYP2C19 and other genes could affect PPI effectiveness, and also discuss studies evaluating the role of pharmacogenetics in predicting PPI response in patients with EoE.

Personalized approach to outpatient management of patients taking tamoxifen by gynecologists

BACKGROUND: 30% of women with luminal breast cancer receiving adjuvant tamoxifen experience disease recurrence within 15 years. This demonstrates the wide variability in clinical response to tamoxifen. Both nongenetic (age, gender, body mass index, duration of drug use) and genetic factors have been described to influence the high variability of response to tamoxifen. Differences in the genes encoding the enzymes CYP2D6, CYP2C, and CYP3A (CYP2D6*4, CYP3A5*3, CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3) and the ABCB1 gene (C3435T) may also be the main factors of susceptibility to the occurrence of undesirable effects when taking tamoxifen, which in turn may lead to decreased patient adherence to therapy.&#x0D; AIM: The aim of this study was to create a concept and an algorithm for a personalized approach to outpatient management of patients taking tamoxifen by a gynecologist in connection with the carriage of polymorphisms of cytochrome P450 and drug transporter genes.&#x0D; MATERIALS AND METHODS: In 2017–2018, the outpatient records of 230 patients with breast cancer were analyzed retrospectively. A single-stage pharmacogenetic study of 120 women with stage I–III luminal breast cancer taking tamoxifen was conducted prospectively for the presence of cytochrome P450 gene polymorphisms using the polymerase chain reaction method and assessing associations with adverse drug reactions, and 54 patients were interviewed after five-year follow-up to assess adherence and satisfaction with medical supervision.&#x0D; RESULTS: The likelihood of developing endometrial hyperplasia has been shown to increase while taking tamoxifen with increasing average age, body mass index, duration of tamoxifen use, and postmenopause. Significant associations have been identified between the carriage of the CYP2D6, CYP2C9, CYP2C19, CYP3A5, and ABCB1 gene polymorphisms and the development of adverse drug reactions. Predictive models have been developed to determine the risk of adverse drug reactions. All studied adverse drug reactions associated with various genetic polymorphisms predominated in the group of patients who stopped taking tamoxifen due to poor intolerance. Gynecologists regularly observed 57.4% of patients. Moreover, the higher the adherence to therapy was, the higher was the regularity of observation by a gynecologist.&#x0D; CONCLUSIONS: A plan for outpatient management of patients receiving adjuvant endocrine therapy with tamoxifen by a gynecologist has been developed.

Pharmacogenetic Approaches in Personalized Medicine for Postoperative Pain Management.

Despite technical and pharmacological advancements in recent years, including optimized therapies and personalized medicine, postoperative pain management remains challenging and sometimes undertreated. This review aims to summarize and update how genotype-guided therapeutics within personalized medicine can enhance postoperative pain management. Several studies in the area have demonstrated that genotype-guided therapy has the ability to lower opioid consumption and improve postoperative pain. Gene mutations, primarily OPRM1, CYP2D6, CYP2C9, COMT and ABCB1, have been shown to exert nuanced influences on analgesic response and related pharmacological outcomes. This review underscores the integration of pharmacogenetic-guided personalized medicine into perioperative care, particularly when there is uncertainty regarding opioid prescriptions. This approach leads to superior outcomes in terms of postoperative pain relief and reduced morbidity for numerous patients.