CYP2C19 Gene Polymorphisms Research Articles

Impact of CYP2C19 gene polymorphisms on clinical outcomes in patients with myocardial infarction during 60 months of follow-up

Objective: To evaluate the effect of CYP2C19 gene polymorphisms on clinical outcomes in patients after successful revascularization for acute myocardial infarction with and without ST segment elevation during clopidogrel therapy for 60 months of follow-up.Methods: From 2011 to 2012, 363 patients with acute myocardial infarction who underwent coronary revascularization were included in the study. In the postoperative period, the patients underwent genetic analysis for the CYP2C19 gene polymorphism. All patients received dual antiplatelet therapy with aspirin and clopidogrel. The 60-month follow-up period assessed the primary composite endpoint of the cumulative incidence of all-cause mortality, recurrent myocardial infarction, and stroke.Results: At 60 months after the initial intervention, 71 patients had a composite primary endpoint event (all-cause death, recurrent myocardial infarction, or stroke): 50 (20%, 95% CI 16–25) in the group patients with "wild genotype" and 21 patients of the "loss of function (LOF) *2+*3" group (19%, 95% CI 13–27). No significant relationship was observe between carriage of LOF alleles of the CYP2C19 and the primary endpoint during the 60-month follow-up (HR 0.99, 95% CI 0.59–1.65, P = .965), as well as between carriage of the homozygous CYP2C19 variant (*2/*2) and the development of myocardial infarction during the same period (HR 1.26, 95% CI 0.30–5.20, P = .752).Conclusion: No correlation was observed between the CYP2C19 gene polymorphisms (*2, *3 alleles) and the incidence of ischemic events in patients with myocardial infarction after myocardial revascularization throughout a 60-month follow-up period. Received 27 November 2022. Revised 25 September 2023. Accepted 26 September 2023. Funding: The study did not have sponsorship. Conflict of interest: The authors declare no conflict of interest. Contribution of the authorsConception and study design: I.O. GrazhdankinData collection and analysis: I.O. GrazhdankinStatistical analysis: V.L. LukinovDrafting the article: I.O. Grazhdankin, A.A. Prokhorikhin, V.I. Baystrukov, E.I. Kretov, V.L. LukinovCritical revision of the article: A.M. ChernyavskiyFinal approval of the version to be published: I.O. Grazhdankin, A.A. Prokhorikhin, V.I. Baystrukov, E.I. Kretov, A.M. Chernyavskiy, V.L. Lukinov

The combination of CYP2C19 polymorphism and inflammatory cell ratios in prognosis cardiac adverse events after acute coronary syndrome

BackgroundCYP2C19 gene polymorphism combination with inflammatory cell ratios was significant in the prognosis of coronary heart disease. Materials and methodsA cross-sectional analysis study, with 6 months follow-up on 142 patients with acute coronary syndrome. Patients were analyzed for CYP2C19 gene polymorphisms by real-time polymerase chain reaction (PCR) and complete blood count to determine inflammatory cell ratios and recorded cardiovascular events (CEs) after following up to 6 months. ResultsFor 90-day CEs, CYP2C19 gene polymorphism (Hazard Ratio (HR): 1.965, 95 % Confidence Interval (CI): 1.012–3.814), the combination of a neutrophil and lymphocyte ratio (NLR) ≥ 2.982 (HR: 13.001, 95 % CI: 1.37–97.304) or a platelet to lymphocyte ratio (PLR) ≥ 162.42 (HR: 2.878, 95 % CI: 1.212–6.835) was independent predictors of CEs. For 180-day CEs, CYP2C19 gene polymorphism combination with NLR ≥3.02 (HR: 13.946, 95 % CI: 1.833–106.121) or PLR ≥160.38 (HR: 5.349, 95 % CI: 1.379–20.745) or monocyte to lymphocyte ratio (MLR) ≥ 0.3 (HR: 4.699, 95 % CI: 1.032–31.393) were independent predictors of CEs. ConclusionNLR, PLR or MLR combined with CYP2C19 gene polymorphism were stronger independent predictors of cardiovascular events in patients with acute coronary syndromes compared to CYP2C19 gene polymorphism and inflammatory cell ratios separately. CYP2C19 polymorphism and high NLR was the strongest predictor of both CEs at 90 days and 180 days.

Association Study of Esomeprazole Pharmacokinetics and CYP2C19 Gene Polymorphisms.

To investigate the association between esomeprazole pharmacokinetics and CYP2C19 gene polymorphisms in a cohort of 95 healthy Chinese participants. A cohort of 95 participants was assembled and stratified into 2 distinct groups, receiving either 20 or 40mg of esomeprazole through oral administration. The subjects encompassed 17 poor metabolizers, 47 intermediate metabolizers, and 31 rapid metabolizers, and their genotypes were ascertained using the polymerase chain reaction-restriction fragment length polymorphism technique. Esomeprazole plasma concentrations were quantified employing a high-performance liquid chromatography-ultraviolet method. Pharmacokinetic parameters were computed via Phoenix WinNonlin 6.1 software, while SPSS 26.0 facilitated statistical analysis to contrast the pharmacokinetics and the CYP2C19 genotypes. In the aftermath of administering 20 or 40mg esomeprazole, marked differences were discerned between terminal elimination half-life, maximum concentration/dose, and area under the plasma concentration-time curve from time zero to infinity/dose of esomeprazole (P<.05), with the exception of time to maximum concentration. The findings of this investigation signify a significant association between esomeprazole metabolism and CYP2C19 gene polymorphisms. There were no unprecedented adverse events documented subsequent to the administration of 20 and 40mg esomeprazole dosages. Esomeprazole has manifested promising safety and tolerability profiles in pertinent clinical trials.

CYP2C19*17 association with higher plasma 4-hydroxy tamoxifen in Pakistani (estrogen-positive) breast cancer patients.

Breast cancer (BC) continues to be the most common cancer in the women worldwide. Since estrogen receptor (ER)-positive BC accounts for the majority of newly diagnosed cases, endocrine therapy is advised to utilize either tamoxifen (Tam) or aromatase inhibitors. The use of Tam as a monotherapy or in conjunction with an aromatase inhibitor following two or three years of endocrine therapy has long been recommended. When used adjuvantly, Tam medication reduces BC mortality and relapses, while it extends survival times in metastatic BC when used in conjunction with other treatments. Unfortunately, the efficiency of Tam varies considerably. This study was conducted to explore the influence of genetic polymorphisms in CYP2C19 gene on Tam's pharmacogenetics and pharmacokinetics in estrogen-positive BC patients. Data from healthy, unrelated individuals (n = 410; control group) and ER-positive BC patients (n = 430) receiving 20 mg of Tam per day were recruited. Steady-state plasma concentrations of Tam and its three metabolites were quantified using the high-performance liquid chromatography in the patients. The CYP2C19 polymorphisms were genotyped using an Amplification Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR) approach. More than 65% of healthy individuals were extensive metabolizers (*1/*1) for CYP2C19, whereas more than 70% of ER-positive BC patients were rapid and ultrarapid metabolizers (*1/17*, *17/17*). The polymorphism CYP2C19*17 is significantly associated with higher 4-hydroxytamoxifen (4-OH-Tam). Patients with the *17/*17 genotype exhibited 1- to 1.5-fold higher 4-OH-Tam, which was also high in patients with the *1/*2 and *2/*2 genotypes.

Influence of polymorphisms in CYP2C9, VKORC1, MDR1 and APOE genes on the warfarin maintenance dose in Brazilian patients.

Background: Polymorphisms in the CYP2C9, VKORC1, MDR1 and APOE genes may impact warfarin dose. Aim: To investigate the influence of sociodemographic and clinical factors and polymorphisms *1, *2 and *3 for CYP2C9, -1639G>A for VKORC1, 3435C>T for MDR1, and ϵ2, ϵ3 and ϵ4 for APOE genes on the mean weekly warfarin maintenance dose in adults. Methods: This cross-sectional study recruited a calculated sample of 315 patients in three anticoagulation clinics in Brazil. A model containing the variables significantly associated with warfarin dose was estimated. Results: The mean age of patients was 64.1±13.1 years, with 173 (54.9%) women. Age, use of amiodarone, genotype VKORC1 GA, genotype VKORC1 AA, genotypes CYP2C9*1/*2 or *1/*3 and genotypes CYP2C9*2/*2 or *2/*3 or *3/*3 were associated with a reduced warfarin dose. Conclusion: This study pointed out factors that could impact the management of oral anticoagulation.

Integration of CRISPR/Cas13a and V-Shape PCR for Rapid, Sensitive, and Specific Genotyping of CYP2C19 Gene Polymorphisms.

Rapid detection of single nucleotide polymorphisms (SNPs) in the CYP2C19 gene is of great significance for clopidogrel-accurate medicine. CRISPR/Cas systems have been increasingly used in SNP detection due to their single-nucleotide mismatch specificity. PCR, as a powerful amplification tool, has been incorporated into the CRISPR/Cas system to improve the sensitivity. However, the complicated three-step temperature control of the conventional PCR impeded rapid detection. The "V" shape PCR can shorten about 2/3 of the amplification time compared with conventional PCR. Herein, we present a new system termed the "V" shape PCR-coupled CRISPR/Cas13a (denoted as VPC) system, achieving the rapid, sensitive, and specific genotyping of CYP2C19 gene polymorphisms. The wild- and mutant-type alleles in CYP2C19*2, CYP2C19*3, and CYP2C19*17 genes can be discriminated by using the rationally programmed crRNA. A limit of detection (LOD) of 102 copies/μL was obtained within 45 min. In addition, the clinical applicability was demonstrated by genotyping SNPs in CYP2C19*2, CYP2C19*3, and CYP2C19*17 genes from clinical blood samples and buccal swabs within 1 h. Finally, we conducted the HPV16 and HPV18 detections to validate the generality of the VPC strategy.

Analysis of the association of CYP450 gene polymorphisms with ischemic stroke

To assess the association of cytochrome P450 (CYP450) gene polymorphisms with the occurrence of ischemic stroke (IS). From January 2020 to August 2022, 390 IS patients treated at the Zhengzhou Seventh People's Hospital were enrolled as the study group, and 410 healthy individuals undergoing physical examination during the same period were enrolled as the control group. Clinical data of all subjects were collected, which included age, sex, body mass index (BMI), smoking history and results of laboratory tests. Chi-square test and independent sample t test were used for comparing the clinical data. Multivariate logistic regression analysis was used to analyze the non-hereditary independent risk factors for IS. Fasting blood samples of the subjects were collected, and the genotypes of rs4244285, rs4986893, rs12248560 of the CYP2C19 gene and rs776746 of the CYP3A5 gene were determined by Sanger sequencing. The frequency of each genotype was calculated by using SNPStats online software. The association between the genotype and IS under the dominant, recessive and additive models was analyzed. The levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL-C), apolipoprotein B (Apo-B) and homocysteine (Hcy) of the case group were significantly higher than those of the control group, whilst the levels of high density lipoprotein (HDL-C) and Apo-A1 (APO-A1) were significantly lower (P < 0.05). Multivariate Logistic regression analysis showed that TC (95%CI = 1.13-1.92, P = 0.02), LD-C (95%CI = 1.03-2.25, P = 0.03), Apo-A1 (95%CI = 1.05-2.08, P = 0.04), Apo-B (95%CI = 1.7-4.22, P < 0.01) and Hcy (95%CI = 1.12-1.83, P = 0.04) were non-genetic independent risk factors for the occurrence of IS. Analysis of the association between the genetic polymorphisms and the risk of IS showed that the AA genotype at rs4244285 of the CYP2C19 gene, the AG genotype and A allele at rs4986893 of the CYP2C19 gene, and the GG genotype and G allele at rs776746 of the CYP3A5 gene were significantly associated with IS. Under the recessive/additive model, dominant model and dominant/additive model, polymorphisms of the rs4244285, rs4986893 and rs776746 loci were also significantly associated with the IS. TC, LDL-C, Apo-A1, Apo-B and Hcy can all affect the occurrence of IS, and CYP2C19 and CYP3A5 gene polymorphisms are closely associated with the IS. Above finding has confirmed that the CYP450 gene polymorphisms can increase the risk of IS, which may provide a reference for the clinical diagnosis.

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.

Influence of CYP2C19 genetic variants and smoking on dual antiplatelet efficacy in patients with coronary artery disease.

This study aimed to investigate the effects of smoking and CYP2C19 gene polymorphism on antiplatelet therapy to specify the most optimized and accurate antiplatelet therapy for different populations. This study included 6,353 patients with coronary artery disease (CAD). In total, 2,256 (35.5%) were smokers and 4,097 (64.5%) were non-smokers. Patients carrying a CYP2C19*2 or *3 allele were considered loss-of-function (LOF) allele carriers. The medical history of patients who had undergone percutaneous coronary intervention (PCI) at Beijing Anzhen Hospital was recorded. The primary endpoint was major adverse cardiovascular or cerebrovascular events (MACCE) during the 6-month follow-up period. A Cox regression model was used to assess the interactions between antiplatelet efficacy and CYP2C19 LOF allele carrier status, stratified by smoking status. Compared to clopidogrel plus aspirin, ticagrelor plus aspirin reduced the MACCE recurrence risk in non-smokers (carrier: 6.0 vs. 2.0%, hazard ratio 0.298, 95% confidence interval 0.204-0.635, P < 0.0001; non-carrier: 5.8 vs. 2.1%, hazard ratio 0.358, 95% confidence interval 0.189-0.678, P = 0.002), and not in smokers. Similar results were discovered regarding the recurrence rate for hospitalization for ischemic cardiac events in non-smokers. No apparent difference was discovered in the bleeding events in either group. There were no significant associations between antiplatelet medication and CYP2C19 LOF allele carrier status for the MACCE recurrence risk among smokers (P = 0.943, respectively) or non-smokers (P = 0.774, respectively). In patients with CAD after PCI, ticagrelor plus aspirin lowered the MACCE recurrence risk in CYP2C19 LOF allele carriers and non-carriers compared with clopidogrel plus aspirin alone among non-smokers. The efficacy of antiplatelet therapy varies between CYP2C19 LOF allele carrier status. No significant interaction between CYP2C19 LOF allele carrier status and antiplatelet effectiveness was observed. However, caution should be used to interpret our results considering the many limitations of our investigation.

Pharmacokinetics and bioequivalence evaluation of omeprazole and sodium bicarbonate dry suspensions in healthy Chinese volunteers

Omeprazole and sodium bicarbonate dry suspension are effective treatments for acid-related disorders. This study compared the bioequivalence and safety of the two formulations of omeprazole and sodium bicarbonate powder and assessed how CYP2C19 gene polymorphisms affect pharmacokinetics (PK). A single-center, randomized, single-dose, 2-sequence and 2-period crossover method was performed in forty healthy Chinese subjects. Blood samples were collected after a single dose for PK (AUC0–∞, AUC0–t, and Cmax) analysis. The concentrations of Omeprazole in human plasma were determined by HPLC–MS/MS. Besides, the gene polymorphisms of CYP2C19 were assessed by Sanger sequencing. The geometric mean ratios (90% confidence interval) [GMR (95% CI)] of Test/Reference preparation for Cmax: 95.2% (88.48%, 102.43%), AUC0–t: 97.47% (94.4%, 101.02%), AUC0–∞: 97.68% (94.27%, 101.21%) were within the range of 80.00–125.00%. The non-parametric test showed no statistical difference in Tmax between the two groups (p > 0.05). All drugs were well tolerated, no severe adverse reactions occurred, and no significant differences in adverse events between the two drugs. For CYP2C19 gene polymorphisms, the results showed that of 40 subjects, 12 subjects were extensive metabolizers, 24 were intermediate metabolizers, and 4 were poor metabolizers, the frequency of metabolic genotypes were 30%, 60%, and 10%. And the allele distributions for CYP2C19 were *1, *2, and *3 at 60%, 38.75%, and 1.25%. Both the CYP2C19 alleles and metabolic genotypes were consistent with other studies in Chinese. The results of PK parameters showed that different genotypes of CYP2C19 lead to significant differences in t1/2, AUC0–t, AUC0–∞ and Cmax, but no significant differences in Tmax in each group. At the same time, we confirmed that the PK parameters of the test and reference had no differences between the males and females. This study has shown that the pharmacokinetic parameters of the two formulations are not significantly different, which showed bioequivalence and exemplary safety. CYP2C19 gene polymorphism significantly differed in the PK parameters of omeprazole sodium bicarbonate powder.

ASSOCIATION BETWEEN CYP2C19 GENE POLYMORPHISMS AND CARDIOVASCULAR RISK FACTORS IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION

This study aims to investigate CYP2C19 gene polymorphisms and the association between gene polymorphisms with cardiovascular risk factors and major adverse cardiovascular events (MACE) in patients with acute myocardial infarction (AMI). A prospective cross-sectional analysis study involved 86 AMI patients enrolled and assessed CYP2C19 gene polymorphisms with MACE evaluated after three months of AMI treatment. CYP2C19*1*1 genotype accounted for the highest prevalence at 54.7%, which means normal metabolizers phenotype prevalence was the highest. The prevalence of patients with circumflex artery stenting, medical history of taking clopidogrel, percutaneous coronary intervention (PCI), and hypertension in patients with CYP2C19 polymorphism was significantly higher than in those without CYP2C19 polymorphism, 35.9 vs. 10.6, 46.2 vs. 14.9,10.3 vs., and 9.49 vs. 74.5, respectively (p&lt;0.05). In patients with CYP2C19 polymorphisms, using a combination of clopidogrel and aspirin regimen had a 13.6% of cardiovascular mortality, while using ticagrelor and aspirin regimen was 0% (p&gt;0.05). The relationship between CYP2C19 gene polymorphisms and MACE after three months of AMI treatment was not associated. CYP2C19 gene polymorphism is associated with hypertension, medical history of PCI, taking clopidogrel, and circumflex artery stenting injury. This study established the relationship between CYP2C19 gene polymorphism and cardiovascular risk factors in patients with acute myocardial infarction who require testing for this gene polymorphism when suffering from acute myocardial infarction to have a medicine adaptation method. Keywords: Polymorphism, CYP2C19 , Acute Myocardial Infarction, Major Adverse Cardiovascular Events, Percutaneous Coronary Intervention DOI： https://doi.org/10.35741/issn.0258-2724.58.3.11

Efficacy and safety of vonoprazan-amoxicillin dual therapy for Helicobacter pylori first-line treatment: a single-center, randomized, controlled trial.

With the increase in antibiotic resistance, the success rate of Helicobacter pylori (H. pylori) eradication therapy has declined in recent years. Vonoprazan-amoxicillin (VA) dual therapy has been reported to be a promising regimen. To compare the efficacy and safety of VA dual therapy and bismuth quadruple therapy containing amoxicillin and clarithromycin for H. pylori first-line eradication, and to further analyze the effects of clarithromycin resistance on eradication rate. This study was a single-center, open-label, randomized controlled trial. Treatment-naïve H. pylori-infected patients were randomly allocated 1:1 to the VA group (vonoprazan 20 mg twice daily and amoxicillin 750 mg four times daily, for 14 days) or the RBAC group (rabeprazole 10 mg, bismuth potassium citrate 220 mg, amoxicillin 1000 mg and clarithromycin 500 mg twice daily, for 14 days). H. pylori clarithromycin resistance and CYP2C19 gene polymorphisms were detected with real-time polymerase chain reaction (PCR) technique. The eradication rates and adverse events were analyzed. A total of 151 patients were enrolled. The intention-to-treat (ITT), modified intention-to-treat (mITT), and per-protocol (PP) eradication rates and their 95% confidence intervals (95% CIs) were 94.6% (86.0-98.3%), 98.6% (91.3-99.9%), and 98.5% (90.9-99.9%) for VA group and 87.0% (77.0-93.3%), 91.8% (82.3-96.6%), and 93% (83.7-97.4%) for RBAC group. The eradication rate of the VA group was noninferior to the RBAC group in ITT, mITT, and PP analyses (p < 0.0001). In patients infected with strains of clarithromycin resistance point mutation, the eradication rate of the RBAC group decreased to lower than 90%, but the difference from the VA group did not achieve statistical significance (ITT eradication rate: 81.5% in the RBAC group and 96.2% in the VA group, p = 0.192). The incidence of adverse events in the VA group was 39.2%, which was significantly lower than that in the RBAC group (79.2%, p = 0.000). The efficacy of VA dual therapy is noninferior to RBAC in H. pylori first-line eradication, with fewer adverse reactions. This study was registered at the Chinese Clinical Trial Registry (ChiCTR2100052550) on 30 October 2021.

Fibrinogen-Aα THR312ALA Polymorphism is Associated to Chronic Thromboembolic Pulmonary Hypertension in Turkey.

Chronic thromboembolic pulmonary hypertension is a condition that occurs after mechanical obstruction of the pulmonary arteries by thrombus. Since the frequency and demographics of chronic thromboembolic pulmonary hypertension differ between countries, it is thought that genetic factors may play a role in its development. The aim of this study is to reveal the status of VKORC1, CYP2C9*3, CYP2C9*7, and fibrinogen-Aα THR312ALA gene polymorphisms in chronic thromboembolic pulmonary hypertension patients in Turkey. In this prospective cross-sectional study, a total of 46 chronic thromboembolic pulmonary hypertension patients and 106 healthy volunteers were included. Polymerase chain reaction-restriction fragment length polymorphism method was used to determine candidate gene polymorphisms for chronic thromboembolic pulmonary hypertension. The general population parameters of each locus were calculated, and the relationship between dominant, codominant, and recessive genotype models and chronic thromboembolic pulmonary hypertension was analyzed. For the fibrinogen-Aα gene, those with the THR/THR genotype were found to have a 13.51 (95% CI: 2.688-33.333) times less susceptibility rate to the disease than those with the ALA/THR genotype, the susceptibility of THR/ALA genotype to the disease was 5.026 (95% CI: 1.774-14.242) times more than those with ALA/ALA genotype. There was no difference between patient groups for VKORC1, CYP2C9*3 genes (P >.05). Since the CYP2C9*7 patient group was monomorphic for the ILE allele, the patient/control odds ratio and 95% CI could not be calculated. This study shows that there is an association between the fibrinogen-Aα gene ALA polymorphism at the amino acid position of 312 and the development of chronic thromboembolic pulmonary hypertension, but not between the CYP2C9 and VKORC1 gene polymorphisms.

Variants in CYP2J2 and CYP2C9 Contribute to Susceptibility of Lung Cancer.

Cytochrome P450 (CYP) enzymes are involved in the metabolism of xenobiotic and carcinogen. In the study, we evaluated the association of CYP2J2 and CYP2C9 variants with lung cancer. Five polymorphisms in CYP2J2 and four polymorphisms in CYP2C9 were genotyped in 507 lung cancer patients and 505 controls with Agena MassARRAY platform. The linkage of variants with lung cancer risk was evaluated by odds ratio (OR) and 95% confidence interval (CI) in genetic models and haplotype analyses. We found that CYP2C9 rs1934967 alleles were associated with lung cancer risk (P < 0.05). In stratified analysis, rs2280274 (women, non-smoker, non-drinker and lymphatic metastasis), rs11207535 (non-smoker and non-drinker), rs10889159 (non-smoker and non-drinker) of CYP2J2, whereas rs1934967 (age ≤ 60m, BMI > 24, squamous carcinoma) of CYP2C9 decreased lung cancer risk (P < 0.05). In addition, the results of linkage disequilibrium (LD) analysis showed that rs2280274|rs4388726 - TG (with adjustment: P = 0.042) of CYP2J2 and rs10509679|rs1934967|rs1934968|rs9332220 - GTGG (without adjustment: P = 0.044) of CYP2C9 were linked with a significantly decreased lung cancer risk. Our results indicated genetic variants in CYP2J2 and CYP2C9 might contribute to the susceptibility of lung cancer in Chinese population.

Impact of CYP2C19 gene polymorphisms on warfarin dose requirement: a systematic review and meta-analysis.

Background: Various genetic factors influence warfarin maintenance dose. Methods: Aliterature search was performedon PubMed, Embase and the Cochrane Library, and a meta-analysis to analyze the impact of CYP2C19 polymorphisms on warfarin maintenance dose wasconducted. Results: From nine studies encompassing 1393 patients, threeCYP2C19 SNPs wereidentified: rs4244285, rs4986893 and rs3814637. Warfarin maintenance dose was significantly reduced by 10% in individuals with the rs4986893 A allele compared with the GG carriers and was 34%, 16% and 18% lower in patients with rs3814637 TT and CT genotypes and T allele, respectively, than that in CC carriers. No significant dose difference was observed among the rs4244285 genotypes. Conclusion: CYP2C19 rs4986893 and rs3814637 are associated with significantly reduced warfarin dose requirements.

Clinical genetic counselling and rehabilitation treatment of a patient with Guillain–Barré syndrome after COVID-19

The authors present a clinical case of rehabilitation after the development of GuillainBarr syndrome, an acute autoimmune inflammatory polyradiculoneuropathy, in a patient who underwent a SARS CoV-2 infection. The patient previously manifested with severe comorbidities (arterial hypertension, hypercholesterolemia, type 2 diabetes mellitus, stenosing atherosclerosis of brachiocephalic arteries). A diagnostic panel of single nucleotide gene polymorphisms associated with risk factors of cardiovascular diseases, metabolic disorders, immunopathology, pharmacogenetics was applied using PCR-RT Genetic Passport test system, and the results were interpreted in order to predict potential complications, adverse drug reactions and the choice of biomarkers for preventive measures. We have compared clinical manifestations, comorbid background and the identified genotype features, as follows: minor homo- and heterozygous variants of ACE, AGT, CYP1A2, NOS3, PPARD, EDN, PALLD, SNX19 genes associated with predisposition to cardiovascular diseases, increasing the risk of dysregulation of blood pressure, development of endothelial dysfunction. The following gene variants were revealed: FXII, ITGA2, ITGB3, MTHFR, MTRR, MTR, PAI-1 that increase the risk of venous and arterial thrombosis, along with gene variants of ADRB3, FTO, INSIG2, KCNG11, LEP, PPARD, TCF7L2, ApoC3, PON1 associated with carbohydrate and lipid metabolism disorders; polymorphisms in the genes determining the immune response, i.e., IL4, IL6, IL8, IL10, CDH1, BDNF1, CRP, CCR5 (with del32 allele considered a risk factor of severe SARS-CoV-2), homozygous polymorphism of a gene of FCGR2 associated with risk of antigen-antibody-complement-mediated cytotoxicity, circulation arrest, deposition of immune complexes in endothelium of microvessels, decreased antithrombotic effects and increased procoagulant activity. Pharmacogenetic study revealed a variant of the CYP4F2 gene, a CYP2C19 gene polymorphism associated with delayed metabolism of a number of pharmaceuticals which requires higher drug dosage, or choosing a drug with a different mechanism of action; gene variants of CYP1A2, GSTP1, GSTT1 reducing efficiency of the cellular detoxification system; NAT2*5 and NAT2*6 variants determining a decrease in appropriate enzyme activities when administering a standard dose of drugs with slowdown of their detoxification, accumulation of toxic metabolites causing clinical adverse effects (hepatotoxicity, dyspepsia, lupus-like syndrome, polyneuritis). Based on the genotype that determines pathogenesis of the multifactorial pathology (including immune-mediated complications of COVID-19), a personalized approach is recommended to the patient, in terms of treatment and prevention of complications. On the basis of testing the biochemical, immunological and blood coagulation biomarkers, an adequate choice of pharmaceuticals is recommended for the patient.

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.

CYP2C19 polymorphisms and lipoproteins associated with clopidogrel resistance in children with Kawasaki disease in China: A prospective study.

BackgroundCYP2C19 genetic variation and clinical factors have been proved to be related with clopidogrel resistance (CR) in adults, while the presence of CR in children with Kawasaki disease (KD) was seldom reported. Our objective was to evaluate KD patients’ response to clopidogrel treatment and determine whether CYP2C19 gene polymorphisms and laboratory indicators are associated with CR in this population.MethodsThis was a prospective and single-center study. We recruited children with KD hospitalized in the cardiology department at the Children’s Hospital Capital Institute of Pediatrics between January 2019 and October 2021, and the distribution of the CYP2C19 gene polymorphisms was assessed. According to the light transmission aggregometry (LTA) test results, KD patients who were treated with clopidogrel were divided into CR group and non-CR (NCR) group. We also analyzed the influence of CYP2C19 gene polymorphisms and laboratory indicators on CR in children with KD.Results(1) A total of 346 children with KD were evaluated for the genotypic and phenotypic distributions of CYP2C19. Loss-of-function (LOF) mutated allele was included in 56.9% of CYP2C19 genotypes, and their corresponding phenotypes were intermediate metabolizers (46.2%) and poor metabolizers (10.7%). (2) The incidence of CR in this study population was 31.4%. The multivariate logistic regression showed that carrying CYP2C19 LOF allele (OR, 3.922; 95%CI, 1.504–10.282; P = 0.005) and high levels of low-density lipoprotein (OR, 1.675; 95%CI, 1.069–2.623; P = 0.024) were independent risk factor for CR, while low levels of high-density lipoprotein (OR, 0.120; 95%CI, 0.020, 0.734; P = 0.022) was an independent protective factor for CR. The area under the receiver operator characteristic curve of the multivariate logistic regression model (including high-density lipoprotein, low-density lipoprotein, and CYP2C19 LOF allele carriers) for predicting CR was 0.769 (95% CI, 0.674–0.863; P < 0.001). The sensitivity and specificity were 70.3 and 74.0%, respectively.ConclusionCarrying CYP2C19 LOF allele, low levels of high-density lipoprotein, and high levels of low-density lipoprotein were independent risk factors for CR in children with KD in China. This may benefit pediatricians in choosing appropriate individualized antiplatelet therapy.

Impact of &lt;i&gt;CYP2C19&lt;/i&gt; gene polymorphisms on clinical outcomes in patients with myocardial infarction during 12-month follow-up

Highlights. CYP2C19 gene polymorphisms in patients with acute myocardial infarction are common in clinical practice. The article assesses the role of genetic predisposition in the development of ischemic and hemorrhagic events during dual antiplatelet therapy (aspirin and clopidogrel) within the first 12 months after revascularization for acute myocardial infarction.Aim. To evaluate the impact of CYP2C19 gene *1, *2, *3, *17 alleles polymorphism on 12-month clinical outcomes in patients who underwent coronary revascularization due to acute myocardial infarction and took clopidogrel.Methods. 363 patients with acute myocardial infarction undergoing percutaneous coronary intervention were enrolled in the prospectively study in 2010–2012. CYP2C19 gene *1, *2, *3, *17 alleles polymorphism analysis was performed in all study participants. Dual antiplatelet therapy, consisting of aspirin and clopidogrel, was prescribed for 12 months. The follow-up period was 12 months, the incidence of cardiovascular death, non-fatal myocardial infarction, stroke and bleeding was assessed.Results. 12 months after inclusion in the study, the incidence of composite endpoint (defined as cardiovascular death, non-fatal myocardial infarction and stroke) was observed in 18 patients (7% [5%; 11%]; 95% CI) with wild-type CYP2C19 gene and in 12 patients (11% [6%; 18%]; 95% CI) with lost-of-function *2+*3 alleles, with no statistical difference (OR = 1.6 [0.7; 3.6], 95% CI; p = 0.301). Presence of any LOF-alleles did not predict composite endpoint events (OR = 1.56 [0.71; 3.34], 95% CI, p&lt;0.253). Multivariable logistic regression analysis revealed that CYP2C19*2 homozygotes have higher risk of composite endpoint (OR = 6.34, 95% CI [1.57; 22.23], p&lt;0.005) and myocardial infarction (OR = 5.45, 95% CI [1.14; 19.97], p&lt;0.016) compared to *2 heterozygotes and wild-type carriers. 14 patients had major bleedings, required blood transfusion or hospitalization. Patient’s age, increase in creatinine level and gain-of-function (GOF) CYP2C19*17 homozygotic carriage were identified as the predictors of major bleeding during follow-up period.Conclusion. In this study CYP2C19 LOF alleles polymorphism except the CYP2C19*2 homozygotic carriage demonstrated no impact on the incidence of ischemic events during 12-month follow-up in patients with acute MI who underwent successful revascularization. CYP2C19*17 homozygotes demonstrated increased risk of major bleeding only in young individuals with elevated blood creatinine levels.

Therapeutic drug monitoring and CYP2C19 genotyping guide the application of voriconazole in children

BackgroundThis study used therapeutic drug monitoring (TDM) and CYP2C19 gene polymorphism analysis to explore the efficacy and safety of different doses of voriconazole (VCZ) for the clinical treatment of pediatric patients, with the aim of providing guidelines for individualized antifungal therapy in children.MethodsOur study enrolled 94 children with 253 VCZ concentrations. The genotyping of CYP2C19 was performed by polymerase chain reaction (PCR)-pyrosequencing. VCZ trough concentration (Ctrough) was detected by high-performance liquid chromatography-tandem mass spectrometry. SPSS 23.0 was used to analyze the correlations between VCZ concentration, CYP2C19 phenotype, adverse effects (AEs), and drug-drug interactions.ResultsA total of 94 children aged between 1 and 18 years (median age 6 years) were enrolled in the study. In total, 42.6% of patients reached the therapeutic range at initial dosing, while the remaining patients reached the therapeutic range after the adjustment of the dose or dosing interval. CYP2C19 gene polymorphism was performed in 59 patients. Among these patients, 24 (40.7%) had the normal metabolizer (NM) phenotype, 26 (44.1%) had the intermediate metabolizer (IM) phenotype, and 9 (15.3%) had the poor metabolizer (PM) phenotype. No cases of the rapid metabolizer (RM) or ultrarapid metabolizer (UM) phenotypes were found. The initial VCZ Ctrough was significantly higher in patients with the PM and IM phenotypes than in those with the NM phenotype. The combination of immunosuppressive drugs (ISDs) did not affect VCZ Ctrough. The incidence of AEs was 25.5%, and liver function damage (46.2%) and gastrointestinal reactions (19.2%) were the most common.ConclusionsOur study showed significant individual differences of VCZ metabolism in children. Combining TDM with CYP2C19 gene polymorphism has important guiding significance for individualized antifungal therapy in pediatric patients.