CYP2C19 Polymorphisms Research Articles

N-acetyltransferase 2 (NAT2) and Cytochrome 2C9 (CYP2C9) Genes Polymorphisms in Type 2 Diabetes Mellitus Patients in Yaoundé, Cameroon

Although several environmental factors influence the onset of type 2 Diabetes Mellitus (T2DM), genetic factors contribute to an individual vulnerability to this disease. This study was aimed at studying CYP2C9*3 single nucleotide polymorphism (SNP) and NAT2 gene polymorphisms, and their correlation, if any, in the susceptibility to type 2 diabetes in Yaoundé, Cameroon. This was a case-control study involving 70 participants living in Yaoundé, Cameroon. DNA was extracted by Chelex 100 method. Polymorphisms of NAT2 gene and CYP2C9*3 SNP were assessed using Polymerase Chain Reaction – Restriction Fragment Length Polymorphism (PCR-RFLP). NAT2 gene characterization revealed the predominance of NAT2*5 alleles (35%) and slow metabolizing phenotype (72.9%). CYP2C9 gene characterization revealed the predominance of the wild-type allele (54%) and intermediate metabolizing phenotype (91%). Individuals with the “NAT2 slow metabolizer” phenotype were more likely to have T2DM while those with “intermediate metabolizer” phenotype were less likely to develop this disease (OR = 3.9740, P = 0.0009 and OR = 0.1406, P = 0.0044, respectively). CYP2C9*3 had no discernable predisposition to T2DM (OR= 0.1765, P= 0.1981). This study demonstrates that the NAT2 slow metabolizer phenotype could be associated with the development of T2DM in Yaoundé, Cameroon.

Study on the associations between liver damage and antituberculosis drug rifampicin and relative metabolic enzyme gene polymorphisms

ABSTRACT The occurrence of antituberculosis drug-induced liver injury affects the effectiveness of antituberculosis treatments. Understanding the mechanism and risk factors of such liver injury may improve the outcomes of those patients who received antituberculosis treatments. In this study, 2,255 pulmonary tuberculosis patients were included. Their medical records were reviewed, questionnaire surveys, liver function tests at the end of February (including patients with uncomfortable symptoms during the intensive treatment period), and blood samples were saved. Afterward, cases of liver damage were determined using Chinese liver damage criteria. The genotype of all participants was determined using the PCR-LDR method. Finally, the association between genetic polymorphism and ATB-DILI susceptibility was assessed using the univariate Logistic regression models. Among the 2,255 tuberculosis patients who received rifampicin, 612 (27.1%) had antituberculosis drug-induced liver injury. We observed higher proportions of older age, male, and lower levels of AST, ALT, and TBil among patients with liver injury. Results of univariate of logistic regression models showed that patients with CYP2C19 were more likely to have liver injury compared with no such genotypes patients (all P < 0.05). Patients with tuberculosis with older age and genetic polymorphism of CYP3A4, CYP2C9, and CYP2C19 who received long-term rifampicin treatment were more likely to have antituberculosis drug-induced liver injury. It is important for healthcare providers to carefully evaluate and monitor rifampicin use for these patients.

CYP2C19 polymorphisms and clopidogrel efficacy in the secondary prevention of ischemic stroke: a retrospective observational study

The relationship between cytochrome P450 2C19 (CYP2C19) polymorphisms and clopidogrel efficacy in patients with percutaneous coronary intervention (PCI) has been widely studied. However, the relationship between CYP2C19 polymorphisms and the response to clopidogrel in patients treated for ischemic stroke (IS) remains controversial. What's more, few data address the relevance of CYP2C19 polymorphisms in patients taking clopidogrel for secondary prevention of ischemic stroke. This study investigates whether carrying CYP2C19 loss-of-function (LOF) alleles affects the risk of recurrent stroke in IS patients. One hundred twenty-two IS patients were CYP2C19 genotype screened and enrolled in the study from January 2016 to December 2017. Those with stroke recurrence, stroke sequelae, or bleeding diseases were excluded. The remaining 89 patients were divided into the following 2 groups: non-carriers of CYP2C19 LOF alleles (n=38) and carriers (n=51) of CYP2C19 LOF alleles. The variables that could influence the rate of recurrent stroke were assessed in a multivariate analysis to determine the independent risk factors. The CYP2C19*2 and *3 alleles frequencies among the 122 patients were 31.97% and 4.10%, respectively. Carriers of LOF alleles had a more significant history of hypertension compared with non-carriers [n=43/51 (86.7%) versus n=23/38 (60.5%), P=0.01]. In addition, the inclusion rate of aspirin in discharge medication was significantly higher for carriers than for non-carriers [n=19/51 (37.3%) versus n=5/38 (13.2%), P=0.01]. CYP2C19 LOF alleles were significantly associated with an increased risk of recurrent stroke [odds ratio (OR): 7.586; 95% confidence interval (CI): 1.346-42.770, P=0.022]. CYP2C19 LOF alleles may increase the risk of recurrent IS. The polymorphisms of CYP2C19 may be predictors of a poor functional outcome in patients with recurrent stroke. Instead of clopidogrel, aspirin can be prescribed as a secondary preventative measure against stroke in carriers of CYP2C19 LOF alleles.

P.0574 Effect of CYP2C19 polymorphisms on antidepressant prescription patterns and treatment emergent mania in bipolar disorder patients

P.0574 Effect of CYP2C19 polymorphisms on antidepressant prescription patterns and treatment emergent mania in bipolar disorder patients

Effect of CYP2C19 polymorphisms on serum valproic level acid in Chinese Han patients with schizophrenia

Valproic acid is an anticonvulsant, which is also widely used for treating psychiatric disorders. Some clinical trials have demonstrated benefits of valproic acid augmentation therapy in schizophrenia. Interindividual variability in valproic acid dose and serum concentration may reflect functional consequences of genetic polymorphisms in genes encoding drug-metabolizing enzymes. The aim of this study was to determine the relationship between serum concentrations of valproic acid and single nucleotide polymorphisms of the cytochrome P450 (CYP) 2C19 gene in patients with schizophrenia. All patients had been receiving fixed dose of valproic acid for at least 2 weeks. The daily doses were 0.5–1.5 g. No other drugs except olanzapine were coadministered. Serum concentrations of valproic acid were measured using the ultra-high performance liquid chromatography method with mass-spectrometric detection. The CYP2C19 (CYP2C19*2 G681A rs4244285 and CYP2C19*3 G636A rs4986893) genotypes were identified by real-time PCR analyses. The mean concentration/dose ratios of valproic acid were significantly higher in patients with CYP2C19 *1/*2 genotype (P < 0.01) or CYP2C19 *2/*3 genotype (P < 0.01) than in those with CYP2C12 *1/*1 genotype. The mean concentration/dose ratios of valproic acid were significantly higher in patients with 1 (P < 0.01) or 2 (P < 0.01) mutated alleles for CYP2C19 than in those without mutated alleles. And the post hoc analysis revealed that the result has acceptable statistical (power (1 – β) = 0.8486 at type I level of 0.05) to support the observed significant associations for CYP2C19 SNPs and serum C/D ratios of valproic acid. The findings of this study suggest that the genetic polymorphisms of CYP2C19 significantly affect the steady-state serum concentrations of valproic acid in Chinese Han population. The determination of the CYP2C19 genotypes may be useful for dosing adjustment in schizophrenia patients on valproic acid therapy.

DO VKORC1 AND CYP2C9 MUTATIONS LEAD TO WARFARIN RESISTANCE?

The objective of this study was to determine the influence of VKORC1 and CYP2C9 polymorphisms on warfarin resistant patients. Warfarin resistance is described as the inability to prolong the prothrombin time or raise the INR up to the 2 therapeutic range when the drug is given at typically doses. Polymorphisms may play a role as some VKORC1 and CYP2C9 variant alleles are known to be associated with these circumstances. 28 patients who were taking warfarin more than 15 mg/day and had INR values below 2.1 and had thromboembolic events while using warfarin were enrolled in this study. Heterozygote mutation in the VKORC1 gene was identified in 15 of 28 patients. Seven patients had heterozygote mutation of the CYP2C9 gene, and that may correspond to the ultrarapid metabolism of warfarin. VKORC1 and CYP2C9 polymorphism contribute to the difference in dose requirement amongst the patients, but other additional possible factors may play a role in different races. We suggest that medicians may use this tests before starting warfarin therapy and shape the treatment course according to this results.

Abstract 14311: Gene Guided Antiplatelet Therapy for Acute Coronary Syndrome: An Updated Meta-Analysis

Introduction: Clopidogrel has been the mainstay oral antiplatelet regimen to treat Acute Coronary syndrome (ACS) post percutaneous coronary intervention (PCI) with stents. However, there is marked inter-individual variability due to genetic polymorphisms in the hepatic cytochrome P450 (CYP) 2C19 in the antiplatelet effects of clopidogrel and a reduced response to this drug may be a risk factor for ischemic complications. There has been varied evidence in gene-guided antiplatelet therapy post PCI. An updated meta-analysis was conducted to study the effect of gene-guided antiplatelet therapy in ACS. Methods: A systematic literature review was performed in Embase, PubMed and SCOPUS for all the related articles until May 2021 yielding 180 publications. Nine studies fulfilled inclusion criteria including 8 randomized clinical trials and 1 observational study. The Mantel- Haenszel random-effects model was used to calculate odds ratio (OR) and 95% confidence intervals (CI). Outcomes analyzed were the composite major adverse cardiovascular events (MACE), stent thrombosis, myocardial infarction (MI), bleeding and cardiovascular (CV) death. Results: Gene guided antiplatelet therapy was performed in 7106 patients and conventional therapy in 3970 patients. The MACE events was significantly lower in gene-guided therapy arm (OR = 0.67, 95% CI [0.51 -0.87], P=0.003) driven by lower stent thrombosis (OR=0.47, 95% CI [0.25 -0.88], P=0.02) and lower MI in the gene guided therapy (OR=0.61, 95% CI [0.41 -0.92], P=0.02). The bleeding rates trended to be lower in the gene guided therapy as well (OR = 0.75, 95% CI [0.54-1.02], P=0.07). There is no significance difference in CV death. (OR=0.57, 95% CI [0.21-1.55]) Conclusions: Genotype guided antiplatelet therapy in ACS has lower adverse cardiovascular outcomes driven by lower stent thrombosis and MI with lower bleeding trends as well.

Valproic Acid After Neurosurgery Induces Elevated Risk of Liver Injury: A Prospective Nested Case-Control Study.

Valproic acid (VPA) has been widely used to prevent epileptic seizures after neurosurgery in China. We have found that the incidence of liver injury (LI) in patients using VPA after neurosurgery is higher than that in other patients. The objective of this study was to investigate the risk factors of LI in patients using VPA after neurosurgery. A nested case-control study was conducted in patients using VPA after neurosurgery between September 2019 and March 2021. Cases of LI were matched to controls by age and body mass index (BMI). Conditional logistic regression was used to estimate matched odds ratios representing the odds of LI. A receiver operating characteristic curve was used to analyze the optimal cutoff condition. A total of 248 people (62 LI and 186 control) were enrolled. Among patients with vs without LI, the matched odds ratio for trough concentration of VPA was significant (matched odds ratio [OR], 1.09; 95% confidence interval [CI]: 1.01-1.19). The course of treatment (OR: 1.17, 95% CI: 1.02-1.33), Glasgow score (OR: 0.26, 95% CI: 0.10-0.67), gene polymorphisms of CYP2C19 (OR: 2.09, 95% CI: 1.03-146.93), and UGT1A6 (OR: 34.61, 95% CI: 1.19-1003.23) were all related to the outcome. The optimal cutoff of the course of treatment was 10 days, while the trough concentration of VPA was determined to be 66.16 mg/L. Length of treatment, VPA trough concentration, and Glasgow score were associated with LI in patients after neurosurgery. A gene test may be necessary for people who are prescribed VPA for a long time.

Effect of major CYP2C19 genetic polymorphisms on Helicobacter pylori eradication based on different treatment regimens.

Helicobacter pylori (H. pylori) infection is a global issue. Its eradication in affected individuals is important to prevent several further complications that may occur if left untreated. Proton pump inhibitors (PPIs) serve an important role in the eradication regimens of H. pylori. PPIs are metabolized primarily through the CYP2C19 enzyme in the liver. Inter-individual variation in the response to eradication treatment may partly be due to variations in the metabolism of PPIs. The aim of this study was to determine whether there was any association between CYP2C19 genetic polymorphisms and the response to eradication therapy amongst Jordanians infected with H. pylori receiving lansoprazole-based regimens. The present study was approved by the Institutional Review Board of The University of Jordan Hospital. A total of 141 patients infected with H. pylori were genotyped for the polymorphisms CYP2C19*2 and CYP2C19*17 using the PCR-restriction fragment length polymorphism assay method. Patients received lansoprazole-based triple or sequential therapy. The assessment of eradication was performed using either a H. pylori stool antigen test or from feedback from patients regarding their improvement. Eradication rates were 84.6% and 64.5% in the intermediate-metabolizer and extensive-metabolizer group, respectively. This difference was not statistically significant. Moreover, no significant association was found between the carriers of the CYP2C19*17 polymorphism and the response to eradication therapy. These findings suggest that there was no significant association between the CYP2C19 genotype and the response to eradication therapy amongst Jordanians infected with H. pylori.

CYP2C8 and CYP2E1 genetic variants increase risk of tuberculosis in northwest Chinese Han population.

Tuberculosis (TB) is a chronic infectious disease which remains a main cause of death worldwide, and arises more and more concerns in recent years. CytochromeP450 (CYP450) is involved in the metabolism of many exogenous and endogenous compounds, and its polymorphism is associated with many diseases. The objective of our study was to explore the relationship between CYP450 polymorphisms and TB susceptibility in Northwest Chinese Han population. 506TB patients and 506 controls were recruited for our study, and their DNA were extracted. Six single nucleotide polymorphisms (SNPs) were selected for genotype. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated to evaluate the correlation between SNPs and TB risk. The genotype "TA" of CYP2C8 rs2275620 was related to an increased risk of TB in the co-dominant model (OR=1.33, 95%CI =1.00-1.76, p=0.049). In females, CYP2E1 rs2070672 was related to an increased TB susceptibility (co-dominant: OR=1.62, 95%CI=1.04-2.52, p=0.032; dominant: OR=1.66, 95%CI=1.08-2.56, p=0.020; additive: OR=1.60, 95%CI=1.08-2.36, p=0.018), and CYP2E1 rs2515641 was also associated with an increased risk of TB (co-dominant: OR=1.90, 95%CI=1.19-3.04, p=0.007; dominant: OR=1.94, 95%CI=1.23-3.05, p=0.004; additive: OR=1.80, 95%CI=1.20-2.71, p=0.005) in women. But there was no statistical significance between haplotypes and TB risk (p>0.05). Our research showed CYP2C8 and CYP2E1 polymorphisms are associated with an increased risk of TB in Northwest Chinese Han population, which may provide a crucial help on defining new therapeutic strategies for chemoprevention.

CYP2C19 Loss-of-function Polymorphisms are Associated with Reduced Risk of Sulfonylurea Treatment Failure in Chinese Patients with Type 2 Diabetes.

Sulfonylureas (SUs) are predominantly metabolized by cytochrome p450 2C9 (CYP2C9) and cytochrome p450 2C19 (CYP2C19) enzymes. CYP2C9 polymorphisms are associated with greater treatment response and hypoglycemic risk in SU users. However, there are no large scale pharmacogenetic studies investigating the effect of loss‐of‐function alleles CYP2C19*2 and CYP2C19*3, which occur frequently in East Asians. Retrospective pharmacogenetic analysis was performed in 11,495 genotyped patients who were enrolled in the Hong Kong Diabetes Register between 1995 and 2017, with follow‐up to December 31, 2019. The associations of CYP2C19 polymorphisms with SU treatment failure, early HbA1c response, and severe hypoglycemia were analyzed by Cox regression or logistic regression assuming an additive genetic model. There were 2341 incident SU users that were identified (mean age 59 years, median diabetes duration 9 years), of which 324 were CYP2C19 poor metabolizers (CYP2C19 *2/*2 or *2/*3 or *3/*3). CYP2C19 poor metabolizers had lower risk of SU treatment failure (hazard ratio 0.83, 95% confidence interval (CI) 0.72–0.97, P = 0.018) and were more likely to reach the HbA1c treatment target < 7% (odds ratio 1.52, 95% CI 1.02–2.27, P = 0.039) than wild‐type carriers (CYP2C19 *1/*1) following adjustment for multiple covariates. There were no significant differences in severe hypoglycemia rates among different CYP2C19 genotype groups. CYP2C19 polymorphisms should be considered during personalization of SU therapy.

Clinical Outcomes After Percutaneous Coronary Intervention Over Time on the Basis of CYP2C19 Polymorphisms.

The aim of this study was to investigate the association between CYP2C19 gene polymorphisms and the risk of cardiovascular events in the early stage and subsequent period after percutaneous coronary intervention (PCI) among patients who received clopidogrel. Between October 2015 and January 2017, CYP2C19 genotyped patients who were treated with clopidogrel after PCI were enrolled in this study. Included patients were categorized as non-loss-of-function metabolizers, intermediate metabolizers, and poor metabolizers based on CYP2C19 genotype. The primary outcome was a composite of any-cause mortality, nonfatal myocardial infarction, nonfatal ischemic stroke, and stent thrombosis occurring during exposure to clopidogrel. The rates of clinical outcome events were compared between CYP2C19 phenotypes. Landmark analyses were processed at 90 days and 1 year post-PCI. Of 1341 patients, 161 (12.0%) had 2 copies of loss-of-function (LOF) alleles, 621(46.3%) had one LOF allele, and 559 (41.7%) had no LOF allele. At the 3-month follow-up, the primary outcome events were more frequent in carriers of 2 LOF alleles (5.6%) than in noncarriers (1.8%) [adjusted hazard ratio (HR) 2.944, 95% confidence interval, 1.184-7.321, P = 0.020). A similar finding was observed among in patients with acute coronary syndrome indications at the index PCI (adjusted HR 3.046, 95% confidence interval, 1.237-7.501, P = 0.015). These differences did not persist within the subsequent 9 months of follow-up, among either all comers or subjects with acute coronary syndrome. In conclusion, these data demonstrate a higher risk for ischemic events in patients with 2 CYP2C19 LOF alleles who are prescribed clopidogrel, seen at 3 months after PCI, that is not sustained for 12 months.

Effect of genetic polymorphisms and haplotypes on the efficacy and safety of postoperative analgesia with ketoprofen in patients with coronary artery disease after cardiac surgery

Abstract Background Most cardiac surgeries are associated with post-sternotomy pain syndrome. Pain causes elevation of blood pressure, heart rate and may be associated with hemodynamic instability, respiratory infections, and other postoperative complications. Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used analgesics in cardiac surgery. The majority of NSAIDs are metabolized by cytochrome P-450. The mechanism of action of NSAIDs is associated with blocking of prostaglandin-endoperoxide synthase (PTGS). Individual variabilities and gene polymorphisms may affect ketoprofen exposure, efficacy and safety. Purpose Evaluation of the influence of CYP2C9 - CYP2D6 and PTGS-2 rs20417 – PTGS-1 rs12353214 haplotypes on the efficacy and safety of postoperative analgesia with ketoprofen in patients with coronary artery disease after cardiac surgery. Methods The study included 90 patients. Pain intensity assessment was measured by the Numeric Rating Scale (NRS). Dyspeptic symptoms were evaluated using the Gastrointestinal Symptom Rating Scale (GSRS). Acute kidney injury was determined by Kidney Disease Improving Global Outcomes criteria. Genotyping of polymorphisms CYP2C9*3 (1075A&amp;gt;C) rs1057910, CYP2D6*4 (1846G&amp;gt;A) rs3892097, PTGS-2 (G&amp;gt;C) rs20417, PTGS-1 (C&amp;gt;T) rs12353214 was performed. Results The study revealed the following haplotypes: (1) CYP2C9*3 rs1057910 (AA) – CYP2D6*4 rs3892097 (GG), (2) CYP2C9*3 rs1057910 (AC) – CYP2D6*4 rs3892097 (GA), (3) PTGS-2 rs20417 (GG) – PTGS-1 rs12353214 (CT), (4) PTGS-2 rs20417 (CC) – PTGS-1 rs12353214 (CC). Pain intensity by the NRS score was significantly higher in patients with AA-GG haplotype compared to AC-GA haplotype for CYP2C9*3 - CYP2D6*4: 7,13±2,14 and 5±1,52 (p=0,009); 7,06±1,99 and 4,86±1,57 (p=0,007); 4,96±1,83 and 3,29±1,79 (p=0,04); 4,57±1,66 and 2,86±1,57 (p=0,02), on days 1, 2, 3 and 5 in the postoperative period, respectively. There were no significant differences in pain intensity by the NRS in patients with PTGS-2 rs20417 – PTGS-1 rs12353214 haplotypes. Also there were no significant differences in GSRS score and acute kidney injury frequency in patients with AA-GG and AC-GA haplotypes for CYP2C9*3 – CYP2D6*4 and GG-CT and CC-CC haplotypes for PTGS-2 rs20417 – PTGS-1 rs12353214. Conclusion CYP2C9*3 - CYP2D6*4 haplotypes affect efficacy of postoperative analgesia with ketoprofen in patients with coronary artery disease after cardiac surgery. Further studies are needed to develop genotype-guided postoperative pain management. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This study was financially supported by RF President's grant for scientific schools, project No. NSh 2698.2020.7 Pain intensity by NRSDyspepsia symptoms by GSRS

CYP2C19 & UGT1A6 genetic polymorphisms and the impact on Valproic acid-induced weight gain in people with epilepsy: Prospective genetic association study

ObjectivesTo study the association between CYP2C19*2 (681 G > A) and UGT1A6*2 (552A > C) polymorphisms on Valproic acid (VPA)-induced weight gain in People with epilepsy (PWE). MethodsWe recruited PWE on VPA monotherapy and genotyped for CYP2C19 and UGT1A6 polymorphisms. Association between CYP2C19 polymorphism and weight gain was the primary outcome parameter. We followed them up monthly for six months and recorded Body mass index (BMI), drug compliance, side effects, food frequency, physical activity. ResultsOf 108 participants recruited, we assessed the association between the polymorphism and weight gain in 101 PWE for CYP2C19*2 and 103 PWE for UGT1A6*2 polymorphism. The proportion of participants with weight gain was higher in those with poor and intermediate metabolizer genotypes of CYP2C19 (*1/*2 and *2/*2) compared to extensive metabolizers (*1/*1) [53.3 % vs 31.7 %, RR 1.68, 95 % CI (1.01–2.79), P = 0.03]. However, CYP2C19*2 allele did not show an increased risk of weight gain over the CYP2C19*1 allele. No association could be demonstrated with UGT1A6 genotypes and weight gain. In logistic regression analysis, CYP2C19*2 carrier genotype was the independent predictor of weight gain. OR 2.89 [95% CI (1.07–7.84)]. There were no significant association with serum TSH, fT4, testosterone, and valproate levels with CYP2C19 or UGT1A6 polymorphisms. SignificancePeople with epilepsy carrying CYP2C19 polymorphisms (*1/*2) and (*2/*2) had 3 times higher risk of VPA-induced weight gain compared to wild type (*1/*1).

The correlation between platelet responsiveness to clopidogrel and CYP2C19 polymorphism in patients with peripheral vascular disease.

Several patients undergoing endovascular intervention and bypass surgery present with high platelet reactivity following clopidogrel treatment. We aimed to determine the frequency of the genetic polymorphism of CYP2C19*2 and the contribution of this polymorphism along with other clinical parameters to clopidogrel response in an Egyptian population. A total of 50 patients receiving clopidogrel at a maintenance dose of 75 mg daily post vascular intervention from January 1, 2019, to May 30, 2020, were enrolled in this study. Clopidogrel resistance was determined through platelet aggregation analysis using Chrono-Log® platelet aggregometer. Single-nucleotide polymorphism (SNP) genotyping was performed using quantitative real-time polymerase chain reaction (QRT-PCR). The incidence of clopidogrel resistance among this Egyptian population is about 22%. Univariate analysis demonstrated that CYP2C19*2 genotype (p = 0.001), high body mass index (BMI; p = 0.025), diabetes (p = 0.037), high fasting blood glucose (FBG) level (p = 0.037), and high glycosylated hemoglobin (HbA1c) level (p = 0.004) were significantly associated with clopidogrel resistance. Multivariate analysis showed that CYP2C19*2 genotype (odds ratio (OR), 927.71; 95% confidence interval (CI), 1.915-449496.2; p = 0.030) and high BMI (OR, 1.789; 95% CI, 1.044-3.064; p = 0.034) were the most powerful predictors of clopidogrel resistance. Clopidogrel resistance in patients with peripheral vascular disease is associated with the presence of CYP2C19*2 allele, obesity, and diabetes; these factors should be considered prior to clopidogrel administration.

Associations of Gene Polymorphisms and Prognosis in Highly Adherent to Treatment Patients After Myocardial Infarction

Aim. To evaluate the influence of genetic factors on the risk of developing a combined endpoint, during a one-year supervision of patients, who had myocardial infarction and highly adherent to drug therapy.Material and methods. The research included 250 patients with high adherence to treatment with myocardial infarction, using the method of polymerase chain reaction we determined the polymorphisms Thr174Met and Met235Thr in the AGT gene, Arg389Gly and Ser49Gly in the ADRB1 gene, Ser447Ter in the LPL gene and Leu28Pro in the APOE gene, Trp212Ter and G681A in the CYP2C19 gene, and then we evaluated their influence on the prognosis.Results. A significant influence on the risk of developing combined endpoint was noticed for the polymorphism of CYP2C19 (G681A) gene. For the GA genotype of the CYP2C19 gene (G6881A), the OR of developing an unsuccessful outcome was 1.97 (95 % CI 1.05 — 3.69) (P = 0.03). For сarrier-state of A allele the OR was 1.46 (95 % CI 1.06 — 3.64) (P = 0.03). Conclusion. The results received indicate the need for individual approach for the choice of drugs from the group of inhibitors P2Y12-receptors for dual antiplatelet therapy, and if clopidogrel is chosen it is necessary to resolve the issue of pharmacogenetic testing for CYP2C19.

Genetic polymorphism of CYP2C19 and subcortical variability in the human adult brain

Pharmacogenetic studies have shown involvement of cytochrome P450 enzymes in the metabolism of psychotropic drugs. However, expression and activity on endogenous substrates in the brain may underlie a constitutive role of these enzymes beyond drug metabolism. CYP2C19, which is expressed in the human fetal brain during neurodevelopment, shows affinity for endogenous compounds including monoaminergic neurotransmitters, steroid hormones, and endocannabinoids. In this study (N = 608), we looked at the genetic polymorphism of CYP2C19 and its potential associations with structural phenotypes of subcortical brain volume with structural imaging. Using two independent volume estimation techniques, we found converging evidence for a positive association between CYP2C19 activity scores, as inferred from the genotype, and basal ganglia and hippocampal volume. This association was present only in female individuals, raising the possibility that effects on brain morphology may arise through a mechanism involving the metabolism of estrogen steroids.

The CYP2C19 polymorphisms effects on H. pylori cure rate in proton pump inhibitor-based therapeutic regimens: An updated meta-analysis

IntroductionCYP2C19 genotypes induce H. pylori eradication rate in the patients receiving PPI-based treatment regimens. The present study aimed to evaluate the effect of CYP2C19 variants on the H. pylori eradication rate in naive patients treated with PPI-based anti-H. pylori therapies. MethodsA computer-assisted comprehensive literature search was done in the Scopus, Pubmed, Embase, and the Cochran Register of Controlled Trials (CENTRAL) databases, for the relevant studies to be collected with no limitation in the language and publication date. All statistic analyses were performed using Comprehensive meta-analysis software. Eradication rate of H. pylori in different CYP2C19 genotypes was measured via event rate; In addition, we pooled the data by the odds ratio with 95% CI to evaluate the effect of CYP2C19 polymorphisms on the changes in the rates of H. pylori eradication as well as sup-grouping analysis for individual PPIs. Publication bias also was assessed via Begg's p-value, Egger's p-value, and funnel the plot. ResultsThe number of studies included in the present one was 38 studies with 7079 data from the patients. H. pylori eradication rates in HomEMs, HetEMs and PMs were 77%, 82.7% and 85.4%, respectively. We observed a significant difference in H. pylori eradication rates between the HomEMs vs. HetEMs (OR: 0.69; 95% CI: 0.57–0.85), HomEMs vs. PMs (OR: 0.57; 95% CI: 0.46–0.72), as well as HetEMs vs. PMs (OR: 0.70; 95% CI: 0.56–0.87). However, the subgroup analysis was performed due to significant heterogeneity. A significantly lower eradication rate in HomEMs vs. HetEMs (OR: 0.34; 95% CI: 0.22–0.52) and HomEMs vs. PMs (OR: 0.22; 95% CI: 0.10–0.47) for Omeprazole as well as HomEMs vs. HetEMs (OR: 0.56; 95% CI: 0.39–0.82) for Lansoprazole or HomEMs vs. PMs (0.57; 95% CI: 0.33–1.00) were observed for Esomeprazole. ConclusionThe H. pylori eradication rate in HomEM, HetEM, and PM was 77%, 82.7%, and 85.4% respectively. Moreover, the clinical efficacy of Omeprazole, Lansoprazole, and Esomeprazole-based first-line therapies is significantly dependent on the CYP2C19 genotype status, while polymorphisms of this gene have no significant effect on the efficacy of Pantoprazole and Rabeprazole-based diets.

Differential Impact of Cytochrome 2C19 Allelic Variants on Three Different Platelet Function Tests in Clopidogrel-Treated Patients.

On-treatment platelet reactivity in clopidogrel-treated patients can be measured with several platelet function tests (PFTs). However, the agreement between different PFTs is only slight to moderate. Polymorphisms of the CYP2C19 gene have an impact on the metabolization of clopidogrel and, thereby, have an impact on on-treatment platelet reactivity. The aim of the current study is to evaluate the differential effects of the CYP2C19 genotype on three different PFTs. Methods: From a prospective cohort study, we included patients treated with clopidogrel following percutaneous coronary intervention (PCI). One month after PCI, we simultaneously performed three different PFTs; light transmission aggregometry (LTA), VerifyNow P2Y12, and Multiplate. In whole EDTA blood, genotyping of the CYP2C19 polymorphisms was performed. Results: We included 308 patients treated with clopidogrel in combination with aspirin (69.5%) and/or anticoagulants (33.8%) and, based on CYP2C19 genotyping, classified them as either extensive (36.4%), rapid (34.7%), intermediate (26.0%), or poor metabolizers (2.9%). On-treatment platelet reactivity as measured by LTA and VerifyNow is significantly affected by CYP2C19 metabolizer status (p < 0.01); as metabolizer status changes from rapid, via extensive and intermediate, to poor, the mean platelet reactivity increases accordingly (p < 0.01). On the contrary, for Multiplate, no such ordering of metabolizer groups was found (p = 0.10). Conclusions: For VerifyNow and LTA, the on-treatment platelet reactivity in clopidogrel-treated patients correlates well with the underlying CYP2C19 polymorphism. For Multiplate, no major effect of genetic background could be shown, and effects of other (patient-related) variables prevail. Thus, besides differences in test principles and the influence of patient-related factors, the disagreement between PFTs is partly explained by differential effects of the CYP2C19 genotype.

Evaluation of the Influence of &lt;i&gt;CYP2C9* 2, CYP2C9*3&lt;/i&gt; Gene Polymorphisms on the Efficacy and Safety of Postoperative Analgesia with Ketoprofen in Patients after Cardiac Surgery

Aim. The aim of the study was to evaluate the efficacy and safety of ketoprofen as an analgesic therapy in patients with CYP2C9*2 (430C&gt;T) rs179985 and CYP2C9*3 (1075A&gt;C) rs1057910 gene polymorphisms after cardiac surgery.Material and methods. The study included 90 patients. Postoperative analgesia was perfomed by ketoprofen 100 mg intramuscularly twice daily. The evaluation of pain was determined daily by Numeric Rating Scale for 5 days after cardiac surgery. The safety of ketoprofen was determined by assessing the severity of gastroenterological symptoms using the Gastrointestinal Symptom Rating Scale questionnaire and determining the frequency of episodes of acute kidney injury. The material for DNA was venous blood. To determine the single nucleotide genetic polymorphisms CYP2C9*2 (430C&gt;T) rs179985 and CYP2C9*3 (1075A&gt;C) rs1057910, the real-time polymerase chain reaction was used.Results. In patients with the AA genotype of CYP2C9*3 polymorphism, the intensity of pain on the numeric rating scale scale (points) was significantly higher than in patients with the AC genotype: 7 [6; 8] vs 6 [5; 6] (р=0,003), 7 [6; 8] vs 6 [5; 6] (р=0,04), 6 [5; 7] vs 5 [4; 5] (р=0,04), 5 [3; 6] vs 3 [3; 4] points (р=0,02) on days 1, 2, 3 and 5 of the postoperative period, respectively. The severity of gastroenterological symptoms was higher in patients with a heterozygous CT genotype for the allelic variant CYP2C9*2 than in patients with a wild CС genotype and amounted to 19 [19; 22] vs 18 [16; 20] points, respectively, (p=0,04). The distribution of genotypes for CYP2C9*2 polymorphisms and CYP2C9*3 polymorphisms between the groups of acute renal injury did not differ significantly.Conclusion. Associations of polymorphisms CYP2C9*3 with a lower intensity of pain syndrome and CYP2C9*2 with a greater severity of gastroenterological symptoms were revealed.