CYP2C19 Gene Research Articles

Analysis of the Guiding Role of CYP2C19 Gene Combined With Platelet Function Detection in Antiplatelet Therapy in Patients With Complex Coronary Artery Disease After PCI.

ObjectiveTo explore the influence of CYP2C19 gene combined with platelet function test on clinical prognosis of patients with complex coronary artery disease receiving antiplatelet therapy after PCI.MethodsA total of 200 patients undergoing PCI in our hospital due to complex coronary artery disease from February 2019 to February 2021 were selected and divided into the control group and the observation group according to whether CYP2C19 gene detection was performed. The control group was treated with dual antiplatelet therapy of classical aspirin combined with clopidogrel, and the observation group was treated with individual antiplatelet therapy. The patients in the two groups were followed up for 1 year after PCI, and their quality of life was assessed using the Seattle Angina Questionnaire (SAQ score). The occurrence of major adverse cardiovascular events (MACE) during the follow-up period was also recorded.ResultsThe incidence of total MACE events in the observation group was slightly less than that in the control group, and the difference was statistically significant (P = 0.040). In particular, the observation group was superior to the control group in reducing the readmission rate of recurrent unstable angina pectoris, and the difference was statistically significant (P = 0.023). The location of coronary culprit lesions with recurrent ischemic events was commonly seen in non-interventional target lesions (interventional/non-interventional target sites: 12.9%: 77.1%). The SAQ score in the observation group was larger than that in the control group, and the difference was statistically significant (P = 0.012). There was no statistical difference in the incidence of major bleeding between the two groups (P = 0.352).ConclusionUsing CYP2C19 genotype combined with platelet function test to guide individualized antiplatelet therapy after complex coronary artery PCI is beneficial to reducing ischemic events in a short period (1 year), mainly due to reducing the risk of readmission for recurrent unstable angina pectoris, and improving the quality of daily life of patients without increasing the risk of massive hemorrhage, which can improve clinical prognosis.

A study of microRNA-223 in evaluating platelet reactivity in patients with acute ischemic stroke.

To investigate the relationship between plasma microRNA-223 expression and platelet reactivity in patients with acute ischemic stroke (AIS) and to evaluate its predictive value in clopidogrel resistance or high on-treatment platelet reactivity (HTPR). A total of 120 patients with acute ischemic stroke were screened in this study, and 60 patients were included in the acute ischemic stroke group according to the inclusion criteria and platelet reactivity after clopidogrel treatment. control group was 60 non-ischemic stroke patients hospitalized. The levels of phosphorylation of vasodilator-stimulated phosphoprotein (VASP) and adenosine diphosphate-induced platelet aggregation (ADP-PAg) in platelets were detected by flow cytometry. The expression level of plasma microRNA-223 was detected before and after clopidogrel treatment using quantitative real-time polymerase chain reaction (PcR). The AIS group was then divided into the clopidogrel non-HTPR and the clopidogrel HTPR groups based on the relative inhibition rate. We found that: 1) the VASP platelet reactivity index (PRI) was positively correlated with ADP-PAg; 2) before administration, the plasma microRNA-223 expression level and VASP-PRI were higher in the AIS group than in the control group; 3) after administration, the expression level of microRNA-223 was negatively correlated with VASP-PRI; 4) before and after treatment, the plasma microRNA-223 expression level in the clopidogrel HTPR group was lower than in the non-AIS patients; 5) before treatment, there was an interaction between the expression level of microRNA-223 in the plasma and the cYP2c19 loss-of-function (LOF) allele. The study showed that decreased plasma microRNA-223 expression levels in AIS patients indicate an increased risk of clopidogrel HTPR. carrying cYP2c19 LOF alleles may result in the microRNA-223 expression being more distinct. The combined detection of plasma microRNA-223 and cYP2c19 gene polymorphisms may be effective in predicting the occurrence of clopidogrel HTPR in patients with AIS.

Impact of CYP2C19 metaboliser status on SSRI response: a retrospective study of 9500 participants of the Australian Genetics of Depression Study

BackgroundVariation within the CYP2C19 gene has been linked to differential metabolism of selective serotonin reuptake inhibitors (SSRIs). Pharmacogenetic recommendations based on the effect of CYP2C19 variants have been made available and are used increasingly by clinical practitioners. Nonetheless, the underlying assumption linking differential metabolism to efficacy or adverse side effects remains understudied. Here, we aim to fill this gap by studying CYP2C19 polymorphisms and inferred metabolism and patient-reported antidepressant response in a sample of 9531 Australian adults who have taken SSRIs.MethodsMetaboliser status was inferred for participants based on CYP2C19 alleles. Primary analysis consisted of assessing differences in treatment efficacy and tolerability between normal (reference) and: ultrarapid, rapid, intermediate and poor metabolisers.ResultsAcross medications, poor metabolisers reported a higher efficacy, whereas rapid metabolisers reported higher tolerability. When stratified by drug, associations between metaboliser status and efficacy did not survive multiple testing correction. Intermediate metabolisers were at greater odds of reporting any side effect for sertraline and higher number of side effects across medications and for sertraline.ConclusionsThe effects between metaboliser status and treatment efficacy, tolerability and side effects were in the expected direction. Our power analysis suggests we would detect moderate to large effects, at least nominally. Reduced power may also be explained by heterogeneity in antidepressant dosages or concomitant medications, which we did not measure. The fact that we identify slower metabolisers to be at higher risk of side effects even without adjusting for clinical titration, and the nominally significant associations consistent with the expected metabolic effects provide new evidence for the link between CYP2C19 metabolism and SSRI response. Nonetheless, longitudinal and interventional designs such as randomized clinical trials that stratify by metaboliser status are necessary to establish the effects of CYP2C19 metabolism on SSRI treatment efficacy or adverse effects.

Genetic Analysis of CYP2C9 with Reference to Drug Response in Epilepsy Patients of Pakistan.

Epilepsy is a major global issue. Epilepsy patients are treated with AED (antiepileptic drugs). Interindividual variability in drug response has been documented in several studies. The resistance to drug response may be attributed to genetic polymorphism. The current study was undertaken to investigate the CYP2C9 gene polymorphism associated with antiepileptic drug (AED) resistance in the Pakistani population. The current study included 337 individuals including 100 control subjects, 110 drug-resistant subjects, and 127 drug responders. Genomic DNA was isolated from blood, and amplification of rs1799853 (430C > T) and rs1057910 was carried out by polymerase chain reaction. Genotypes of CYP2C9 SNPs were determined by Sanger's sequencing. Astounding results were observed in the current study that none of the well-known reported SNPs of CYP2C9 was found in our Pakistani cohorts. However, a novel missense variant (c.374G > A) was found only in drug-resistant patients of the current study. According to the in silico analysis performed by PolyPhen-2, it was observed that this nonsynonymous substitution is likely to be pathogenic. The results of our study demonstrated that rs1799853 and rs1057910 may be involved in drug resistance in the Pakistani population. However, some other variants on CYP2C9 may play a critical role in AED resistance that needs to be explored.

Bioinformatics screening the novel and promising targets of curcumin in hepatocellular carcinoma chemotherapy and prognosis

BackgroundThe aim of present study was to screen the novel and promising targets of curcumin in hepatocellular carcinoma diagnosis and chemotherapy.MethodsPotential targets of curcumin were screened from SwissTargetPrediction, ParmMapper and drugbank databases. Potential aberrant genes of hepatocellular carcinoma were screened from Genecards databases. Fifty paired hepatocellular carcinoma patients’ gene expression profiles from the GEO database were used to test potential targets of curcumin. Besides, GO analysis, KEGG pathway enrichment analysis and PPI network construction were used to explore the underlying mechanism of candidate hub genes. ROC analysis and Kaplan-Meier analysis were used to evaluate the diagnostic and prognostic value of candidate hub genes, respectively. Real-time PCR was used to verify the results of bioinformatics analysis.ResultsBioinformatics analysis results suggested that AURKA, CDK1, CCNB1, TOP2A, CYP2B6, CYP2C9, and CYP3A4 genes served as candidate hub genes. AURKA, CDK1, CCNB1 and TOP2A were significantly upregulated and correlated with poor prognosis in hepatocellular carcinoma, AUC values of which were 95.7, 96.9, 98.1 and 96.1% respectively. There was not significant correlation between the expression of CYP2B6 and prognosis of hepatocellular carcinoma, while CYP2C9 and CYP3A4 genes were significantly downregulated and correlated with poor prognosis in hepatocellular carcinoma. AUC values of CYP2B6, CYP2C9, and CYP3A4 were 96.0, 97.0 and 88.0% respectively. In vitro, we further confirmed that curcumin significantly downregulated the expression of AURKA, CDK1, and TOP2A genes, while significantly upregulated the expression of CYP2B6, CYP2C9, and CYP3A4 genes.ConclusionsOur results provided a novel panel of AURKA, CDK1, TOP2A, CYP2C9, and CYP3A4 candidate genes for curcumin related chemotherapy of hepatocellular carcinoma.

Effects of CYP2C19, CYP2C9 and CYP3A4 gene polymorphisms on plasma voriconazole levels in Chinese pediatric patients.

Voriconazole is the most commonly used antifungal agent in clinical application. Previous studies suggested that voriconazole was extensively metabolized by CYP450 enzyme system, including CYP2C19, CYP2C9 and CYP3A4, which contributed to the individual variability of the pharmacokinetic process of voriconazole. This study aimed to investigate the effects of CYP2C19, CYP2C9 and CYP3A4 gene polymorphisms on plasma voriconazole concentrations in Chinese pediatric patients. This study prospectively evaluated pediatric patients administrating voriconazole for the treatment or prophylaxis of invasive fungal infections from October 2018 to July 2020. Seven single-nucleotide polymorphisms in CYP2C19 (CYP2C19*2, CYP2C19*3, and CYP2C19*17), CYP2C9 (CYP2C9*3, CYP2C9*13) and CYP3A4 (CYP3A4*22, rs4646437) were detected by real-time fluorescent PCR with TaqMan probes. The voriconazole trough plasma concentration was determined by UPLC-MS/MS. A total of 68 pediatric patients were enrolled in this study. Our results showed that voriconazole plasma concentrations of patients with CYP2C19*2 or CYP2C19*3 allele were significantly higher than that with wild-type carriers (P < 0.0001, P = 0.004, respectively). However, CYP2C9*3 and CYP3A4 rs4646437 were not significantly associated with voriconazole plasma levels. The CYP2C19*17, CYP2C9*13 and CYP3A4*22 alleles were not observed in our study. Additionally, multiple linear regression analysis indicated that CYP2C19*2 and CYP2C19*3 alleles remained predictors of voriconazole plasma concentration (r2 = 0.428; P < 0.0001). For CYP2C19 metabolizer phenotype, trough concentration of voriconazole was significantly lower in NM group compared with IM (P < 0.0001) and PM (P = 0.004) groups. Voriconazole plasma levels in pediatric patients are mainly affected by CYP2C19 gene polymorphisms.

Influence of Clinically Significant Genes on Antiplatelet Effect of Clopidogrel and Clinical Outcomes in Patients with Acute Coronary Syndrome and Atrial Fibrillation

Introduction: The interindividual variability of the antiplatelet effect of clopidogrel is determined by multiple clinical and genetic factors. A lot of genotype-oriented studies have concentrated on the impact of CYP2C19 gene polymorphisms on platelet aggregation in patients receiving clopidogrel. However, the influence of this polymorphism may be only 12–20%, so other genetic markers should also be investigated. The aim of this work was to study the impact of carriage of CES1, PON1, ABCG2, CYP4F2, CYP3A4, IGTB3, P2Y12, PEAR1, and B4GALT2 polymorphisms on antiplatelet effect of clopidogrel and clinical outcomes in patients with acute coronary syndrome (ACS) and atrial fibrillation (AF). Methods: 103 patients who underwent ACS with or without percutaneous coronary intervention and concomitant nonvalvular AF were included in an open multicenter prospective study to assess efficacy and safety of combined antithrombotic therapy. The study assessed the frequency of different primary clinical outcomes (incidence of major bleeding, hospital mortality, cardiovascular mortality, stroke and transient ischemic attacks (TIAs), renal mortality) and secondary outcomes (resistance to therapy – high residual platelet reactivity, excessive platelet suppression). Residual platelet reactivity was examined using the VerifyNow system (Accumetrics, Latham, NY, USA). Results: None of the studied genetic markers had no statistically significant effect on the antiaggregant response to clopidogrel in patients with ACS and AF. However, CYP4F2 C(Val433Met) T, PEAR1 rs41273215 C>T were statistically significantly associated with an increased frequency of bleeding on antithrombotic therapy. B4GALT2 rs1061781 was statistically significantly associated with increased frequency of strokes and TIA. Conclusion: In our study, we determined that carriers of CYP4F2 gene polymorphisms C(Val433Met)T, PEAR1 rs41273215 C>T (CT+TT) were associated with lower safety of antithrombotic therapy in patients with ACS and AF. And, the B4GALT2 rs1061781 gene polymorphism was associated with a greater risk of insufficient efficacy of the therapy. The data obtained in our study may improve the understanding of the effect of less studied genetic markers on the efficacy and safety of antithrombotic therapy in patients with ACS and AF.

New associations of serum β-carotene, lycopene, and zeaxanthin concentrations with NR1H3, APOB, RDH12, AND CYP genes.

Variation in carotenoid bioavailability at individual and population levels might depend on host‐related factors where genetic variation has a part to play. It manifests itself through the proteins involved in carotenoid intestinal absorption and metabolism, blood lipoprotein transport, or tissue uptake. This study aims to identify novel SNPs which could be associated with carotenoid serum concentrations. A total of 265 self‐reported healthy individuals of Lithuanian origin were genotyped (Illumina HumanOmniExpress‐12v1.0 or v1.1 and Infinium OmniExpress‐24v1.2 arrays) and fasting blood serum concentrations of β‐ and α‐carotene, β‐cryptoxanthin, lycopene, lutein, and zeaxanthin were measured (Shimadzu Prominence HPLC system). According to the individual carotenoid concentrations, the cohort was subdivided into quartiles. Q1 and Q4 were used for the following association analysis. The set of 2883 SNPs in 109 potential candidate genes (assumed for a direct or indirect role in carotenoid bioavailability) was analyzed. Liver X receptor alpha (NR1H3) “transport” polymorphisms rs2279238 (p = 2.129 × 10−5) and rs11039155 (p = 2.984 × 10−5), and apolipoprotein B (APOB) “transport” polymorphism rs550619 (p = 4.844 × 10−5) were associated with higher zeaxanthin concentration. Retinol dehydrogenase 12 (RDH12) “functional partner” polymorphism rs756473 (p = 7.422 × 10−5) was associated with higher lycopene concentration. Twenty‐one cytochrome P450 (CYP2C9, CYP2C18, and CYP2C19) “metabolism” polymorphisms in locus 10q23.33 were significantly associated with higher β‐carotene concentration. To conclude, four novel genomic loci were found to be associated with carotenoid serum levels. Zeaxanthin, lycopene, and β‐carotene serum concentrations might depend on genetic variation in NR1H3, APOB, RDH12 and CYP2C9, CYP2C18, and CYP2C19 genes.

Associations of rs4244285 in the CYP2C19 gene with multifactorial diseases

Xenobiotic metabolism system in the current populations is involved in the biotransformation of a wide range of endogenous substrates and various xenobiotics, which can contribute to developing the diseases of various organ systems, and, in some cases, comorbid conditions where increased biotransformation system activity is observed. In this regard, it is of great interest to study the involvement of polymorphism in xenobiotic metabolism genes in the development of both isolated pathology and various comorbid conditions.Aim. The goal of study was to investigate the involvement of rs4244285 in the CYP2C19 gene in the development of isolated pathology and comorbidities.Material and Methods. The frequencies of alleles and genotypes were studied in groups of patients with comorbid conditions including groups of coronary artery disease (CAD) with hypertension (HTN) (CAD_HTN, n = 133) and bronchial asthma (BA) with HTN (BA_HTN, n = 178), in group of isolated BA (n = 135), and in the population sample of the city of Tomsk (n = 377). Association analysis covered three initial groups of patients (CAD, BA, and BA_HTN) and subgroups assigned based on the presence of absence of HTN diagnosis taking into account comorbid conditions both in patient samples and in population control.Results and Discussion. The study demonstrated the predisposing eff ect of GA genotype on the development of comorbid BA and HTN (OR = 1.94, p = 0.038) and comorbid CAD and HTN (OR = 2.26, p = 0.009) compared to isolated BA. The AA genotype was observed 3.98 times less often in HTN patients than in normotensive individuals. However, the diff erences did not reach the level of statistical signifi cance due to the low occurrence of this genotype.Conclusion. The obtained results may be explained by the involvement of CYP2C19-metabolites of arachidonic acid in the regulation of vascular tone, which requires further study.

The Validation and Application of a Novel CYP2C19 Genotyping Approach Based on Capillary Electrophoresis in Chinese Han population.

CYP2C19 gene polymorphisms have been described to have an important influence on the drug metabolism observed in human populations. A series of PCR-based molecule detection methods are applied to identify CYP2C19 genotype. The aim of the study is to validate the novel CYP2C19 genotyping approach with other methods and reveal the allele frequency distribution of CYP2C19 in Chinese Han population. We applied a novel genotyping approach for CYP2C19 gene which was combining direct PCR and capillary electrophoresis (CE) technique. A series of fluorescent labeled primers were designed to amplify the particular DNA fragments which indicated the wild type of CYP2C19 genotype. The variants consist of CYP2C19*2, CYP2C19*3 and CYP2C19*17 alleles. Both the novel PCR-based CE method and real-time quantitative PCR (RT-qPCR) method were used to identify the CYP2C19 genotypes in 324 whole blood samples originated from Chinese Han population. According to the different criterions for judgement of two methods, we can obtain the CYP2C19 alleles and genotypes of the same participants. Kappa statistics was used to evaluate the consistency of the two results and the frequencies of CYP2C19 alleles. The genotypes in Chinese Han population were calculated using EXCEL. Furthermore, to ensure the accuracy and reliability of the CYP2C19 genotypes obtained by using the novel approach, Sanger sequencing was conducted to validate the CYP2C19 genotypes *1/*17 and *2/*3. Among the 324 specimens, 111 were *1/*1, 141 were *1/*2, 10 were *1/*3, 4 were *1/*17, 46 were *2/*2, 10 were *2*/3, 1 was *2/*17, and 1 was *3/*17. Allele distributions for CYP2C19 were *1, *2, *3, and *17 at 58.18%, 37.65%, 3.24%, and 0.93%, respectively. Both PCR-based CE method and RT-qPCR methods had good consistency in the genotypes of CYP2C19 polymorphism (Kappa value = 1.000, p < 0.05). The DNA sequences of CYP2C19 genotype *1/*17 were composed of c.681 G/G, c.636 G/G, and c.-806 C>T. In the same way, the DNA sequences of CYP2C19 genotype *2/*3 were composed of c.681 G>A, c.636 G>A, and c.-806 C/C. The variants including the CYP2C19*2 allele were the most common mutations in Chinese Han unrelated individuals. Both PCR-based CE method and RT-qPCR method had good consistency in the genotypes of CYP2C19 polymorphism. Nevertheless, because of more convenience and higher throughput, the novel PCR-based capillary electrophoresis approach showed to be more suitable for clinical gene screening.

The VKORC1 and CYP2C9 gene variants as pharmacogenetic factors in acenocoumarol therapy in Serbian patients - consideration of hypersensitivity and resistance

Introduction/Objective. Coumarin therapy represents one of the best models for applying pharmacogenetics. The contribution of factors influencing coumarin therapy can vary significantly between ethnic groups, which justifies conducting population-specific studies. The aim of this study was to analyze the influence of the most important genetic factors (VKORC1 and CYP2C9 genes) that affect coumarin therapy in patients from Serbia. Methods. A retrospective study involving 207 patients on acenocoumarol therapy was conducted. Genetic analyses were performed by direct sequencing. Influence on acenocoumarol dose of variants (VKORC1, CYP2C9*2, CYP2C9*3) causing hypersensitivity and VKORC1 variants causing resistance to acenocoumarol were analyzed. Multiple regression analysis was used to design a mathematical model for predicting individual drug dosage based on clinical-demographic and genetic data. Results. The study confirmed significant influence of the analyzed genetic factors on acenocoumarol maintenance dose. We designed mathematical model for predicting individual acenocoumarol dose and its unadjusted R2 was 61.8. In the testing cohort, our model gave R2 value of 42.6 and showed better prediction in comparison with model given by other authors. In the analyzed patients, nine different variants in the VKORC1 coding region were found. Among carriers of these variants 78% were completely resistant, and it was not possible to achieve therapeutic effect even with high doses of acenocoumarol. Conclusions. Population-specific model for prediction individual dose of acenocoumarol, may show advantages over protocols that are used in a generalized manner. Also, VKORC1 variants which cause coumarin resistance should be considered when planning therapy.

Assessment of susceptibility to phthalate and DINCH exposure through CYP and UGT single nucleotide polymorphisms

Single nucleotide polymorphisms (SNPs) of cytochrome P450 (CYPs) and UDP-glucuronosyltransferase (UGTs) genes have been proposed to influence phthalates and 1,2-cyclo-hexanedicarboxylic acid diisononyl ester (DINCH) biotransformation but have not been investigated on a populational level. We investigated the role of SNPs in CYP2C9, CYP2C19, CYP2D6, UGT2B15, and UGT1A7 genes in the biotransformation of phthalates (DEHP, DEP, DiBP, DnBP, BBzP, DiNP, DidP) and DINCH by determining their urine metabolites. From the Slovenian study population of 274 men and 289 lactating primiparous women we obtained data on phthalate and DINCH urine metabolite levels (MEHP, 5OH-MEHP, 5oxo-MEHP, 5cx-MEPP, MEP, MiBP, MnBP, MBzP, cx-MINP, OH-MiDP, MCHP, MnPeP, MnOP, 5OH-MINCH, 5oxo-MINCH), SNP genotypes (rs1057910=CYP2C9*3, rs1799853=CYP2C9*2, rs4244285=CYP2C19*2, rs12248560=CYP2C19*17, rs3892097=CYP2D6*4, rs1902023=UGT2B15*2, and rs11692021=UGT1A7*3) and questionnaires. Associations of SNPs with levels of metabolites and their ratios were assessed by multiple linear regression and ordinary logistic regression analyses. Significant associations were observed for CYP2C9*2, CYP2C9*3, CYP2C19*17, and UGT1A7*3 SNPs. The most pronounced was the influence of CYP2C9*2 and *3 on the reduced DEHP biotransformation, with lower levels of metabolites and their ratios in men and women. In contrast, carriers of CYP2C19*17 showed higher urine levels of DEHP metabolites in both genders, and in women also in higher DiNP, DiDP, and DINCH metabolite levels. The presence of UGT1A7*3 was associated with increased metabolite levels of DINCH in men and of DiBP and DBzP in women. Statistical models explained up to 27% of variability in metabolite levels or their ratios. Our observations confirm the effect of CYP2C9*2 and *3 SNPs towards reduced DEHP biotransformation. We show that CYP2C9*2, CYP2C9*3, CYP2C19*17, and UGT1A7*3 SNPs might represent biomarkers of susceptibility or resilience in phthalates and DINCH exposure that have been so far unrecognised.

Relationship Between CYP2C8*2 and &amp;lt;i&amp;gt;Pfmdr1&amp;lt;/i&amp;gt; N86Y Polymorphisms in Patients with Uncomplicated Malaria in Yaounde, Centre Region of Cameroon

<i>Background: Plasmodium falciparum</i> malaria is a major public health problem in Cameroon. It remains endemic and is the leading cause of morbidity and mortality in the most vulnerable groups, including children under five and pregnant women. The fight against plasmodium today faces not only diversity, preventive struggles, but also the spread of resistant parasites to available antimalarials. Several factors, among others, genetic factors, and the immune system predispose patients to develop resistances. The parasite's resistance to antimalarial would continue to be an obstacle to the management of malaria in Cameroon. This study aimed to determine the frequency of the mutation affecting the gene <I>CYP2C8</I> (<I>CYP2C8</I>*2) and its influence on the mutation N86Y of the plasmodial gene <i>Pfmdr1</i> in children under 15 years of age suffering from non-complicated malaria in Yaounde. <i>Methods:</i> This was a population based, retrospective study in a Cameroonian population. Archived whole blood samples collected from One hundred children infected with <i>Plasmodium falciparum</i> malaria were randomly selected. Blood samples spotted on filter papers were used for DNA (plasmodial and human) extraction performed by the chelex-100 method. The <i>PfmdrI</i> marker was established by the nested PCR and gene involved in the metabolism of antimalarial by conventional PCR. The RFLP-PCR technique allowed the detection of the polymorphism of these mutations. The restriction enzyme <i>bclI</i> was used for the polymorphisms of the cyp2C8 gene and the restriction enzyme <i>AflIII</i> for <i>PfmdrI</i>. <i>Results:</i> the mutant allele CYP2C8*2 had a frequency of 38%. For the <i>Pfmdr1 </i>gene, 57% of isolates were detected with the mutant 86Y. The application of the Khi2 statistical test showed that patients with the mutant allele CYP2C8*2 were more likely to be infected with the <i>pfmdrI</i>-86Y mutant strain (OR: 2,446; P: 0.030). <i>Conclusion: </i>This study reported that the mutant allele CYP2C8*2 influences the emergence of <i>Pfmdr1</i> 86Y mutants.

Associations of CYP2C19 and F2R genetic polymorphisms with platelet reactivity in Chinese ischemic stroke patients receiving clopidogrel therapy.

Genetic variation has been considered a major contributor to the high variability in the response to dual antiplatelet therapy in patients with acute ischemic stroke or transient ischemic attack. Recently, incidences of ischemic stroke are increasing rapidly in China. We aimed to evaluate the influence of potential determinants on the response of antiplatelet therapy and adverse events in Chinese ischemic stroke patients receiving clopidogrel-aspirin treatment. Based on the clopidogrel drug response pathway and the coagulation and anticoagulation function, we systematically selected 34 genetic polymorphisms in 12 candidate genes. Three hundred and eight patients were divided into 2 groups according to their degree of inhibition of platelet aggregation. Multivariate analysis was then performed to assess the influence of demographic, clinical and genetic factors on platelet reactivity in Chinese ischemic stroke patients. We found that polymorphisms in CYP2C19 and F2R genes were still significantly associated with platelet reactivity in Chinese ischemic stroke patients (P = 0.037 and 0.015). The newly identified rs168753 in F2R gene may influence the efficacy to clopidogrel-aspirin therapy for ischemic stroke patients. We also found that ischemic stroke patients with low level of inhibition of platelet aggregation had higher risk of recurrent ischemic events (P = 0.001). Together, these results emphasized the necessity of genotype-directed antiplatelet therapy and facilitated to minimize adverse ischemic events.

Polymorphisms in CYP2C8 Gene in Pakistani Population and Their Frequencies in Various Ethnic Groups

Cytochrome P4502C8 represents 7% of the hepatic cytochrome system and metabolizes around 5% of drugs in phase I processes. It also plays a significant role in the metabolism of endogenous compounds. More than 20 single nucleotide polymorphisms (SNPs) have been reported, mainly in exon 3, 5, and 8. Some of the SNP’s lead to decreased enzyme activity and may have impact on drug metabolism. This research study aims to determine the frequencies of the most common SNPs of the CYP2C8 gene (CYP2C8*2, *3, *4) in the Pakistani population. A cross-sectional study consisting of 391 healthy humans was conducted after taking informed consent. DNA was extracted using commercial kits, and allelic and genotype frequencies were determined after PCR amplification, restriction fragment length polymorphism, and gel electrophoresis. The rate of minor allele was found to be 11.64% for CYP2C8*2, 14.71% for CYP2C8*3, and 1.53% for CYP2C8*4. Comparison with the 1000 Genome project reveals that the allelic frequencies of CYP2C8*4 in Pakistani population were similar to other South Asian populations while the frequencies of CYP2C8*2 and CYP2C8*3 as significantly different from other South Asian populations. A significant interethnic variation was also observed among Pakistani ethnicities. The CYP2C8*2 allele was highest in the Sindhi population, CYP2C8*3 in the Pashtoon population and CYP2C8*4 in the Balochi population. These data suggest that the frequency of poor metabolizers of CYP2C8 is high enough in the Pakistani population to warrant further genotype-phenotype correlations studies on individual drugs metabolized by CYP2C8 enzyme.

Correlation between CYP2C9 gene polymorphism and warfarin dose in Chinese Han population with coronary heart disease.

This study aimed to explore the correlation between CYP2C9 gene polymorphism and warfarin dose in Chinese Han patients with coronary heart disease. The selection was made to the analysis of blood coagulation test of Chinese Han ethnic group, 200 cases of coronary heart disease patients as target group, the patients were satisfied taking warfarin INR target (in the range of 2.0 ~ 3.0), the other to select 200 cases proved by physical examination health as health group. The warfarin dose and the clinical laboratory INR after warfarin administration were taken, and the DNA of the patients was extracted and tested. The CYP2C9 genotype and allele frequency of patients in the standard group were observed, and the basic information and gene test results of the healthy group and the standard group were compared. Patients in the standard group were grouped according to the CYP2C9 and VKORC1 genotype, and the warfarin dosage was compared respectively. The number of cases of anticoagulant overdose in patients with different genotypes in the target group at the initial stage of warfarin treatment was compared. Results showed that CYP2C9*1/*2, *2/*2, *2/*3, *3/*3 genotypes were not found by detecting CYP2C9 genotype and allele frequency in the standard group. There were no significant differences in genotype and allele frequency between the standard group and the healthy group (P BBB 0 0.05). The mean daily dose of the CYP2C9*1/*3 genotype was lower than the mean daily dose of warfarin required by the CYP2C9*1/*1 genotype, and the difference was statistically significant (P < 0.05). There were significant differences in the incidence of anticoagulation overdose at the initial stage of treatment among different CYP2C9 genotypes (P < 0.05), and the incidence of an anticoagulation overdose in group *1/*3 was significantly higher than that in group *1/*1. In general, There was a correlation between CYP2C9 gene polymorphism and warfarin dose in Chinese Han population with coronary heart disease. Compared with the wilD-type (*1/*1) enzyme, the metabolic ability of warfarin in mutant CYP2C9 enzyme (mainly *1/*3 in Chinese population) decreases, and the patients were sensitive to warfarin treatment, and the dose required decreases.

Prevalence of CYP2C19 Gene Polymorphism in Patients with Coronary Artery Disease Undergoing Percutaneous Coronary Intervention.

Prevalence of CYP2C19 Gene Polymorphism in Patients with Coronary Artery Disease Undergoing Percutaneous Coronary Intervention.

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.

Pharmacogenomic analysis of a genetically distinct Indigenous population.

Indigenous Australians face a disproportionately severe burden of chronic disease relative to other Australians, with elevated rates of morbidity and mortality. While genomics technologies are slowly gaining momentum in personalised treatments for many, a lack of pharmacogenomic research in Indigenous peoples could delay adoption. Appropriately implementing pharmacogenomics in clinical care necessitates an understanding of the frequencies of pharmacologically relevant genetic variants within Indigenous populations. We analysed whole-genome sequence data from 187 individuals from the Tiwi Islands and characterised the pharmacogenomic landscape of this population. Specifically, we compared variant profiles and allelic distributions of previously described pharmacologically significant genes and variants with other population groups. We identified 22 translationally relevant pharmacogenomic variants and 18 clinically actionable guidelines with implications for drug dosing and treatment of conditions including heart disease, diabetes and cancer. We specifically observed increased poor and intermediate metabolizer phenotypes in the CYP2C9 (PM:19%, IM:44%) and CYP2C19 (PM:18%, IM:44%) genes.

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.