CYP2C19 Polymorphisms in Indonesia: Comparison among Ethnicities and the Association with Clinical Outcomes.
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SUBMITTER: Miftahussurur M
PROVIDER: S-EPMC8067412 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The CYP2C19 gene plays a detrimental role in the metabolism of clopidogrel. This study aimed to investigate the association between CYP2C19 polymorphisms and the clinical efficacy of clopidogrel therapy in patients who have undergone carotid artery stenting (CAS). CYP2C19 genotype screening was performed on 959 ischemic stroke patients. Of these patients, 241 who had undergone CAS were enrolled in the study. They were all followed up for 1 year after stent surgery, and the primary clinical end-points were ischemic events. The frequencies of the CYP2C19*2 and *3 alleles among the 959 patients were 31.80% and 5.06%, respectively. Regarding the 241 participants who had undergone CAS, multivariate Cox regression analysis showed that the CYP2C19 loss-of-function (LOF) alleles (*2 and *3) were risk factors for post-CAS prognosis. Within 1 year of follow-up, the patients carrying the CYP2C19 LOF alleles were more likely to experience ischemic events than those carrying none. The occurrence of ischemic events did not significantly differ between the *2 and *3 allele carriers. Our results suggest that CYP2C19 LOF alleles (*2 and *3) significantly impact the prognosis of patients on clopidogrel therapy after CAS and that the CYP2C19*2 and CYP2C19*3 alleles have the same effects on prognosis.
| S-EPMC4853775 | biostudies-other
Project description:BackgroundChoosing the most effective chemotherapeutic agent with safest side effect profile is a common challenge in cancer treatment. Although there are standardized chemotherapy protocols in place, protocol changes made after extensive clinical trials demonstrate significant improvement in the efficacy and tolerability of certain drugs. The pharmacokinetics, pharmacodynamics, and tolerance of anti-cancer medications are all highly individualized. A driving force behind these differences lies within a person's genetic makeup.Recent findingsPharmacogenomics, the study of how an individual's genes impact the processing and action of a drug, can optimize drug responsiveness and reduce toxicities by creating a customized medication regimen. However, these differences are rarely considered in the initial determination of standardized chemotherapeutic protocols and treatment algorithms. Because pharmacoethnicity is influenced by both genetic and nongenetic variables, clinical data highlighting disparities in the frequency of polymorphisms between different ethnicities is steadily growing. Recent data suggests that ethnic variations in the expression of allelic variants may result in different pharmacokinetic properties of the anti-cancer medication. In this article, the clinical outcomes of various chemotherapy classes in patients of different ethnicities were reviewed.ConclusionGenetic and nongenetic variables contribute to the interindividual variability in response to chemotherapeutic drugs. Considering pharmacoethnicity in the initial determination of standard chemotherapeutic protocols and treatment algorithms can lead to better clinical outcomes of patients of different ethnicities.
| S-EPMC10440845 | biostudies-literature
Project description:OBJECTIVE:To determine whether cytochrome P450 (CYP)2C19 haplotype associates with lansoprazole-associated adverse event frequency. STUDY DESIGN:Respiratory adverse events from a clinical trial of lansoprazole in children with asthma were analyzed for associations with extensive or poor metabolizer (PM) phenotype based on CYP2C19 haplotypes. Carriers of CYP2C19*2, *3, *8, or *9 alleles were PMs; carriers of 2 wild-type alleles were extensive metabolizers (EMs). Plasma concentrations of lansoprazole were determined in PM and EM phenotypes. RESULTS:The frequency of upper respiratory infection among PMs (n = 45) was higher than that among EMs (n = 91), which in turn was higher than that in placebo subjects (n = 135; P = .0039). The frequency of sore throat (ST) was similarly distributed among EMs and PMs (P = .0015). The OR (95% CI) for upper respiratory infections in PMs was 2.46 (1.02-5.96) (P = .046); for EMs, the OR (95% CI) was 1.55 (0.86-2.79). The OR (95% CI) for ST in EMs and PMs was 2.94 (1.23-7.05, P = .016) vs 1.97 (1.09-3.55, P = .024), respectively. Mean ± SD plasma concentrations of lansoprazole were higher in PMs than in EMs: 207 ± 179 ng/mL vs 132 ± 141 ng/mL (P = .04). CONCLUSIONS:Lansoprazole-associated upper respiratory infections and ST in children are related in part to CYP2C19 haplotype. Our data suggest that lansoprazole-associated adverse events in children may be mitigated by adjusting the conventional dose in PMs. Additional studies are required to replicate our findings.
| S-EPMC7274090 | biostudies-literature
Project description:BackgroundClopidogrel is an antiplatelet drug used in the treatment of ischemic stroke. Safety and efficacy of clopidogrel has been confirmed in CAPRIE, PRoFESS trials. However, these studies focused on patients aged less than 75?years. CYP2C19 polymorphisms resulted in individual differences in clopidogrel response. Our objective was to determine whether elderly stroke patients aged over 75?years would benefit from CYP2C19-genotype-guided strategy for the secondary prevention of stroke.MethodsA retrospective analysis of patients aged 75?years or older with non-cardiogenic stroke who received 75?mg clopidogrel was performed. CYP2C19 genotype-guided group included noncarriers of CYP2C19*2 or CYP2C19*3 loss-of-function alleles (LoFA) and compared against the non-genotype-guided group which may carriers CYP2C19 LoFA or not. The primary endpoints were composite of stroke and myocardial infarction at 24?months' follow-up.ResultsTwo hundred one patients were included: 99 in the genotype-guided group and 102 in the non-genotype-guided group. Kaplan-Meier(KM)analysis showed that CYP2C19 gene polymorphism was associated with the rate of the primary endpoints (P?=?0.0031). The primary endpoints occurred in 13 patients (13.1%) in the genotype-guided group and in 30 patients (29.4%) in the non-genotype-guided group (hazard ratio(HR), 0.39; 95% confidence interval(CI), 0.20 to 0.75; p?=?0.004). Cox regression analysis showed that CYP2C19 genotype-guided strategy was a protective factor for the primary endpoints (HR, 0.39; 95% CI:0.20 to 0.74, P?=?0.004).ConclusionThe CYP2C19 genotype-guided strategy could reduce the occurrence of composite of stroke and myocardial infarction compared to a non-genotype-guided strategy for non-cardiogenic stroke patients aged 75?years or older who received clopidogrel.
| S-EPMC7941922 | biostudies-literature
Project description:Since its approval by the U.S. Food and Drug Administration in 2002, voriconazole has become a key component in the successful treatment of many invasive fungal infections including the most common, aspergillosis and candidiasis. Despite voriconazole's widespread use, optimizing its treatment in an individual can be challenging due to significant interpatient variability in plasma concentrations of the drug. Variability is due to nonlinear pharmacokinetics and the influence of patient characteristics such as age, sex, weight, liver disease, and genetic polymorphisms in the cytochrome P450 2C19 gene (CYP2C19) encoding for the CYP2C19 enzyme, the primary enzyme responsible for metabolism of voriconazole. CYP2C19 polymorphisms account for the largest portion of variability in voriconazole exposure, posing significant difficulty to clinicians in targeting therapeutic concentrations. In this review, we discuss the role of CYP2C19 polymorphisms and their influence on voriconazole's pharmacokinetics, adverse effects, and clinical efficacy. Given the association between CYP2C19 genotype and voriconazole concentrations, as well as the association between voriconazole concentrations and clinical outcomes, particularly efficacy, it seems reasonable to suggest a potential role for CYP2C19 genotype to guide initial voriconazole dose selection followed by therapeutic drug monitoring to increase the probability of achieving efficacy while avoiding toxicity.
| S-EPMC4082739 | biostudies-other
Project description:ObjectivesThis study sought to evaluate the influence of the genetic polymorphisms on platelet reactivity and clinical outcomes in acute ischemic stroke patients taking clopidogrel.BackgroundLittle research has been published on relationships between genetic polymorphisms, platelet reactivity, and clinical outcomes in stroke patients treated with clopidogrel.MethodsPatients hospitalized in Changhai Hospital with acute ischemic stroke were randomly enrolled into treatment with a 75-mg daily maintenance dose of clopidogrel. Genotyping was detected by the MassARRAY iPLEX genotyping system (Sequenom Inc, San Diego, CA), and platelet reactivity was evaluated by the VerifyNow P2Y12 test (Accumetrics Inc., San Diego, CA). Sixteen single nucleotide polymorphisms (SNPs) within 9 genes were selected and high on-clopidogrel platelet reactivity (HPR) was defined as P2Y12 reaction units (PRU) value ≥230. The primary endpoint was ischemic events, including major adverse cardiac events (MACE), recurrence of stroke, transient ischemic attack (TIA), and the composite of vascular death, and the secondary endpoint was bleeding.ResultsOf the 345 patients recruited, 275 (79.7%) patients were followed up for 1 year and 122 (35.4%) patients were categorized as HPR. Among the SNPs selected, only the CYP2C19*2 allele and the CYP2C19*3 allele were statistically significantly associated with PRU (P < 0.001 and P = 0.003, respectively). Similarly, the prevalence of HPR was associated with CYP2C19*2 and CYP2C19*3 (P < 0.001 and P = 0.001, respectively). During the 1 year of follow-up, a total of 64 (23.3%) cases of clinical events occurred, including 60 ischemic events and 4 bleeding events. There were no correlation between CYP2C19 variant alleles and clinical outcomes (P > 0.05), but a statistically significant relevance was found between the HPR and the ischemic events in 1 year of follow-up (P = 0.001).ConclusionsCYP2C19*2 and CYP2C19*3 had a significant impact on clopidogrel response, but was not associated with ischemic events during 1 year of follow-up in patients with acute ischemic stroke. HPR was an independent risk factor for ischemic events, and the VerifyNow P2Y12 test may be available to guide individualized antiplatelet therapies in stroke patients in China.
| S-EPMC6493114 | biostudies-literature
Project description:The aggregated risk of recurrent stroke in stroke/transient ischemic attack (TIA) patients carrying CYP2C19 LoF alleles who take clopidogrel has not been investigated recently, and the available research is limited. This study aimed to perform an updated meta-analysis to assess the association between CYP2C19 LoF alleles and the risk of recurrent stroke in patients taking clopidogrel. Databases were searched for the literature on eligible studies. The end points were recurrent stroke, composite vascular events, and bleeding events. Odds ratios (ORs) were calculated using RevMan software, where p < 0.05 was considered statistically significant. Patients carrying CYP2C19 LoF alleles who were treated with clopidogrel had a significantly increased risk of recurrent ischemic stroke compared with non-carriers (OR 2.18, 96% CI 1.80-2.63; p < 0.00001). The risk of recurrent stroke was only significantly different in Asian patients (OR 2.29, 96% CI 1.88-2.80; p < 0.00001) but not in patients of other ethnicities; however, there were a limited number of studies in other ethnic groups. Both observational studies (OR 2.83, 96% CI 2.20-3.65; p < 0.00001) and RCTs (OR 1.48, 96% CI 1.10-1.98; p = 0.009) found associations with a significantly increased risk of recurrent ischemic stroke. Asian stroke patients or TIA patients carrying CYP2C19 LoF alleles and taking clopidogrel were at a significantly higher risk of recurrent ischemic stroke than non-carriers. Significantly increased risk of recurrent ischemic stroke was found in both observational studies and RCTs.
| S-EPMC10997845 | biostudies-literature
Project description:ObjectiveThe outcomes of sepsis and septic shock patients are heterogonous, with avariable response despite standardized care. The aim of this study was toexplore the racial differences in septic shock outcomes, and theirassociation with genetic polymorphisms and cytokine levels in an Asianpopulation.Materials and methodsThis was an observational cohort study with Intensive Care units of a 500bedded tertiary care hospital in Singapore. 198 patients (73 Chinese, 73Malay and 52 Indian and others) admitted to the Khoo Teck Puat HospitalIntensive Care Unit between August 2016 and June 2017, with a diagnosis ofsevere sepsis (according to) were enrolled. Plasma interlukin-6 (IL-6),interlukin-10 (IL-10) and tumour necrosis factor-a (TNFa) were measuredusing a highly sensitive quantitative sandwich enzyme-linked immunosorbentassay (ELISA) (BioVendor, Modrice, Czech Republic). The gene panel studiedincluded 16 genes.ResultsThe rs7038903 common variant in SVEP1 gene showed significant associationwith sepsis severity independent of other variants in ordinal logistic andlinear regression model (p = 0.001 and p = 0.002 respectively). Moreover, the association between rs7038903 and increased hazard for death remained significant after further adjusting for cytokines level. Interestingly, significant differences were seen in plasma IL6 inindividuals with or without rs7038903 C allele (28pg/ml (IQR 12-86) vs90pg/ml (IQR 49-155); P=0.022) in patients with severe sepsis in the Malayethnic group.ConclusionOur study shows a promising polymorphism in SVEP1 gene (rs7038903) which isassociated with sepsis shock and 28 days mortality, independent of age, gender, and method of diagnosis and SOFA score. Collectively, while our findings so far have shown the additional value or measuring cytokines andgenetic markers in sepsis outcomes in the local population, further largescare studies are needed in a heterogeneous septic population with arigorous analysis to know the significance of our findings.How to cite this articleSiddiqui S, Gurung RL et al. Genetic Polymorphisms and Cytokine Profile of Different Ethnicities in Septic Shock Patients, and their Association with Mortality. Indian J Crit Care Med 2019;29(3):135-138.
| S-EPMC6487620 | biostudies-literature
Project description:ObjectiveThe CYP2C19 genetic variation may be involved in the development of atherosclerotic cardiovascular disease (ASCVD). Serum lipid levels are important risk factors for ASCVD, but the effect of the CYP2C19 gene on serum lipid metabolism remains unclear. This retrospective cohort study investigated the relationship between the CYP2C19 gene polymorphism and serum lipid levels in patients with ischemic stroke (IS).MethodsIS patients (n = 230) and control subjects (n = 100) were enrolled. All patients were diagnosed with IS via clinical manifestations and brain magnetic resonance imaging. All patients were genotyped.ResultsTriglyceride (TG), total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-c), and apolipoprotein B (ApoB) levels were significantly higher and high-density lipoprotein-cholesterol (HDL-c) and apolipoprotein A1 (ApoA1) levels were significantly lower in the IS group compared with the control group. Lower ApoA1 levels and higher ApoB levels were significant predictive factors for IS. Patients with higher ApoB levels had a higher risk of IS recurrence. Compared with extensive metabolizers, intermediate and poor CYP2C19 metabolizers had a higher risk of IS recurrence.ConclusionsOur study indicates CYP2C19 gene polymorphisms are related to lipid metabolism in patients with IS. IS patients who are poor CYP2C19 metabolizers may have a higher risk of disease recurrence.
| S-EPMC7350049 | biostudies-literature
Project description:BackgroundCytochrome P450 2C19 is responsible for the metabolism of many drugs, including the activation of clopidogrel. The allele CYP2C19*17 is associated with ultra-rapid metabolizer phenotypes by increasing gene transcription. This study tests to what extent CYP2C19*17 enhances CYP2C19 expression in human liver and whether additional regulatory variants contribute to variation in CYP2C19 expression.MethodsCYP2C19 mRNA was measured with quantitative real-time PCR (qRT-PCR), enzyme activity as metabolic velocity with S-mephenytoin as the substrate and allelic mRNA expression ratio with SNaPshot in human livers. CYP2C19 transcribed exons and a 4kb promoter region were sequenced using IonTorrent PGM or Sanger sequencing and screened for polymorphisms associated with total hepatic CYP2C19 mRNA, enzyme activity and allelic mRNA ratios.ResultsLivers heterozygote and homozygous for CYP2C19*17 had mRNA levels 1.8-fold (p=0.028) and 2.9-fold (p=0.006), respectively, above homozygous reference allele livers. CYP2C19*17 heterozygotes were also associated with increased allelic mRNA expression (allelic ratio ~1.8-fold, SD±0.6, p<0.005), whereas CYP2C19 enzyme activity was elevated 2.3-fold, with borderline significance (p=0.06) in CYP2C19*17 carriers. One liver sample of African ancestry displayed a 2-fold allelic expression ratio, and another sample, a ~12-fold increase in metabolic velocity. Neither case was accounted for by *17, which indicates the presence of additional regulatory variants.ConclusionsOur findings confirm *17 as a regulatory polymorphism enhancing hepatic CYP2C19 expression 2-fold with potential to compensate for the loss of function allele CYP2C19*2. Additional regulatory factors may also enhance CYP2C19 expression in African American populations.
| S-EPMC3755489 | biostudies-literature