Metabolizer Genotype Research Articles

Association between effectiveness of tuberculosis treatment and cytochrome P-4502E1 polymorphism of the patients.

The risk of antituberculosis (TB) drug-induced liver injury could be determined by patients' genotype polymorphism of the xenobiotic-metabolizing enzymes. To find the meaning of cytochrome P-4502E1 (CYP2E1) polymorphism in TB patients. Corresponding of CYP2E1 polymorphism in TB patients with the level of isoniazid and rifampicin as well as for the outcome and toxicity development during inpatient TB treatment. CYP2E1 genotype was detected with the help of polymerase chain reaction and endonuclease analysis. The level of rifampicin, isoniazid, diene conjugates (DC), and catalase activity in the blood was determined spectrophotometrically. We have considered medical records at the beginning and at the end of inpatient treatment. Kruskal-Wallis, ANOVA, and Chi-square tests were used in this study. The concentration of rifampicin 6 h after its intake was 17.6% higher in carriers of slow metabolizer (SM) CYP2E1 genotype than in patients with rapid metabolizer (RM) genotype that proved a participation of hepatic enzyme CYP2E1 in metabolism of rifampicin. According to obtained results in TB patients with RM genotype, the indexes of cytolysis (alanine aminotransferase, aspartate aminotransferase) and bile stasis (gamma-glutathione transferase) were higher comparatively to SM genotype both before and after inpatient treatment. This correlated with a higher concentration of DC in the blood (+8.6%) and lower plasma catalase activity (-50.0%) in the patients with RM genotype comparatively with the patients with SM genotypes. Polymorphism of CYP2E1 genotype is an important criterion for the development of hepatotoxicity before and during TB treatment while increased rifampicin level has no influence on it.

CYP2C19⁎2 Polymorphism in Chilean Patients with In-Stent Restenosis Development and Controls.

Clopidogrel is an antiplatelet drug especially used in patients undergoing percutaneous coronary interventions (PCI). Polymorphisms within CYP2C19 can result in important interindividual variations regarding therapeutic efficacy. Therefore, we aimed to evaluate the impact of the CYP2C19⁎2 variant (rs4244285) on in-stent restenosis occurrence in Chilean patients who underwent PCI and received clopidogrel. A total of 77 cases with stenosis >50% in the angioplasty site (62.75 ± 9.8 years, 80.5% males) and 86 controls (65.45 ± 9.8 years, 72.1% males) were studied. The polymorphism was genotyped using TaqMan® Drug Metabolism Genotyping Assays. Overall, CYP2C19⁎2 allele frequency was 8.3%. Diabetes, chronic lesions, and bare metal stents (BMS) were observed more often in cases than in controls (p = 0.05, p = 0.04, and p = 0.02, resp.). Genotypic frequencies did not differ significantly between the groups (p = 0.15). Nonetheless, the mutated allele was observed in a greater proportion in patients without in-stent restenosis (p = 0.055). There was no significant association between the rs4244285 variant and the occurrence of in-stent restenosis after PCI (OR = 0.44; 95% CI: 0.19 to 1.04; p = 0.06). In summary, no association was identified between the CYP2C19⁎2 variant and the development of coronary in-stent restenosis.

Do Genetic Contributors to Warfarin Responsiveness or Common Thrombophilias Influence the Risk of Major Bleeding in Patients on Extended Duration Vitamin K Antagonist (VKA) for Venous Thromboembolic Disease?

Background: Recent studies have indicated that genetic factors such as polymorphisms in the CYP2C9 and the VKORC1 genes play an important role in vitamin K antagonist (VKA) response and perhaps bleeding. There are also data to suggest, especially for factor V Leiden, that thrombophilia may confer a decreased risk of bleeding (which could explain its persistence and high prevalence in the population). The influence of major genetic factors on risk of bleeding have not previously been evaluated in large prospective cohort studies of patients with VTE on extended (treatment after the first 3 to 6 months) VKA therapy.Aims: We sought to determine the effect of genetic variants that influence warfarin metabolism and thrombophilias on the rates of major bleeding during extended VKA therapy in patients with VTE disease.Methods: The Bleeding Risk study is a multicentre, multinational prospective cohort study of patients on extended VKA for unprovoked VTE, or provoked VTE with prior VTE. Patients were enrolled after at least 3 months of VKA. All major bleeding events during long term VKA were captured and adjudicated. A blood sample was taken from each patient at their first study visit and analysed in a central lab to identify the following genetic variant types: CYP2C9*2 (C/T), CYP2C9*3 (T/G), 1639G-A (G/A), Factor V Leiden (G/A: FVL), CYP4F2 (G/A), and Prothrombin gene 20210 variant (PGV). Rates of major bleeding were then evaluated for patients with each genetic variant in isolation and in combination.Results: 2290 of the 2514 patients enrolled at 12 sites have contributed over 7000 years of observation and were included in this analysis. The mean patient age was 60.2±14.7 years, 64% were male, 92% Caucasian, average BMI was 31.3, and 9% of patients were on antiplatelet agents. Patients were followed for a mean of 2.8 years (range, 0.1 to 6.8 years. 121 patients (4.8%) experienced at least one episode of major bleeding. The annual rate of bleeding was 1.7 per 100 patient-years of observation. The CYP2C9*2 variant heterozygous/homozygous versus wildtype (476 patients vs 1584) was protective against bleeding (Incidence risk ratio 0.5, p =0.01), CYP2C9*3 variant heterozygous/homozygous versus wildtype (215 patients vs 1845) was associated with major bleeding (Incidence risk ratio 2.0, p =0.01), VKORC1 and CYP4F2 had no association with major bleeding, and CYP2C9*3 variant heterozygous/homozygous in combination with wildtype CYP2C9*2 (186 patients) was associated with major bleeding (Incidence risk ratio 3.24, p =0.02). Both FVL (19% of patients) and PGV (8% of patients) had no effect on major bleeding, with p values > 0.35 for comparison of the wildtype to heterozygous/homozygous.Conclusion: This is the largest study we are aware of to determine if warfarin metabolic genotype variants and common thrombophilias influence major bleeding risk in patients followed long-term with extended duration VKA therapy for VTE. The thrombophilias do not influence bleeding risk but those with CYP2C9*3 hetero/homozygous inheritance had double the risk and CYP2C9*2 hetero/homozygous inheritance half the risk. There appears to be an interaction between the CYP2C9*2 and *3 genotypes. DisclosuresWells:BMS/Pfizer: Research Funding; Bayer Healthcare: Other: Speaker Fees and Advisory Board; Janssen Pharmaceuticals: Consultancy; Itreas: Other: Served on a Writing Committee. Kovacs:LEO Pharma: Honoraria; Bayer: Honoraria, Research Funding; Daiichi Sankyo Pharma: Research Funding; Pfizer: Honoraria, Research Funding. Anderson:Bayer Healthcare: Research Funding. Rodger:Canadian Agency for Drugs and Technologies in Health: Consultancy; Boehringer Ingelheim: Research Funding.

CYP2C19 Genotype-Guided Dosing and Voriconazole Concentrations in Hematopoietic Stem Cell Transplant Patients (HSCT) Receiving Antifungal Prophylaxis

Background: Therapeutic drug monitoring of voriconazole is useful due to its unpredictable pharmacokinetics, narrow therapeutic index, and exposure-response relationship as sub-therapeutic initial troughs may cause a higher risk for invasive fungal infections (IFIs) and related mortality. Voriconazole is metabolized largely via cytochrome P450 2C19 (CYP2C19) and studies suggest that the greatest risk of sub-therapeutic voriconazole concentrations are in CYP2C19 rapid (RMs) and ultrarapid metabolizers (UMs). Herein we present interim results from the first prospective study investigating the impact of CYP2C19 genotype-guided voriconazole dosing on trough concentrations and clinical outcomes in adult allogeneic HSCT patients receiving voriconazole as antifungal prophylaxis.Methods: Buccal swabs were obtained on the day of admission from all patients scheduled for allogeneic HSCT. DNA was extracted using the Magmax DNA multi-sample kit and TaqMan® Drug Metabolism Genotyping Assays were used to detect single nucleotide polymorphisms in the CYP2C19 gene associated with *1, *2, *3 and *17 alleles. Patients harboring the *1/*17 (RM) or *17/*17 (UM) genotypes received oral voriconazole 300 mg twice daily post-transplant, whereas all other patients received the standard 200 mg twice daily dose. All patients started antifungal prophylaxis on day +1 post-transplant with IV micafungin until patients were able to tolerate oral medications, upon which voriconazole was initiated (approximately 7-10 days post-transplant) and continued until day +100 post-transplant. Trough levels were obtained at steady state (5-7 days after starting voriconazole) and subsequent doses were adjusted to target a pre-specified therapeutic range of 1.0-5.5 mg/L. The primary objective was the proportion of patients with sub-therapeutic voriconazole concentrations (<1.0 mg/L) at steady state. Secondary objectives included the proportion of patients within each phenotype category with sub-therapeutic concentrations at day 5-7, the proportion of patients with supratherapeutic concentrations at day 5-7, the incidence of voriconazole-related toxicities, and incidence of IFI.Results: Evaluable genotypes and trough levels were available for 26 patients at the time of analysis (46% female and 54% male; mean age 50 years) (8% UMs, 23% RMs, 46% normal [NMs], 19% intermediate [IMs] and 4% poor metabolizers [PMs] for CYP2C19). Patients had a primary diagnosis of either acute myeloid leukemia (N=9), lymphoma (N=7), myeloproliferative disease (N=4), acute lymphocytic leukemia (N=3), chronic myeloid leukemia (N=2), or plasma cell leukemia (N=1), and received either a busulfan and cyclophosphamide-based myeloablative regimen or fludarabine, cyclophosphamide, and total body irradiation-based reduced intensity regimen. The percentage of patients with sub-therapeutic voriconazole trough levels at day 5-7 was reduced from historically 50% to 30.8% with CYP2C19 genotype-guided dosing. The study was designed at the one-sided alpha = 0.05 significance level, and the observed results were statistically significant (P = 0.038). Of patients with sub-therapeutic initial trough concentrations (N=8), none were RMs or UMs compared to 80% in historical controls (P <0.001). Of these 8 patients, 5 were NMs and 3 were IMs. No supra-therapeutic trough concentrations were observed. There were no grade 3/4 drug-related adverse events and no patients experienced an IFI.Conclusion: CYP2C19 genotype-guided voriconazole dosing significantly reduced the percentage of patients with initial sub-therapeutic trough concentrations at day 5-7. Importantly, no RMs or UMs were sub-therapeutic when receiving a higher starting dose of 300 mg twice daily. Other factors may influence trough levels beyond CYP2C19 status, including body composition, compliance, food and drug interactions, other genetic factors, and timing of the level, as suggested by low troughs even in NM and IM patients. We anticipate enrolling a total of 60 evaluable patients to complete this study. Preliminary results suggest that CYP2C19 genotype-guided dosing improves the ability to achieve therapeutic concentrations sooner, thus minimizing the need for subsequent dose adjustments and additional trough levels (possibly reducing overall costs), and providing early adequate drug exposure in order to decrease the incidence of IFIs. [Display omitted] DisclosuresPatel:Janssen Pharmaceuticals: Consultancy, Research Funding; Myriad Genetics: Research Funding. Symanowski:Eli Lilly & Co: Consultancy; Ra Pharma: Consultancy; Caris Life Sciences: Consultancy; Endocyte: Consultancy. Avalos:Seattle Genetics: Membership on an entity’s Board of Directors or advisory committees.

Detection of CYP2C19 Genetic Variants in Malaysian Orang Asli from Massively Parallel Sequencing Data.

The human cytochrome P450 (CYP) is a superfamily of enzymes that have been a focus in research for decades due to their prominent role in drug metabolism. CYP2C is one of the major subfamilies which metabolize more than 10% of all clinically used drugs. In the context of CYP2C19, several key genetic variations that alter the enzyme’s activity have been identified and catalogued in the CYP allele nomenclature database. In this study, we investigated the presence of well-established variants as well as novel polymorphisms in the CYP2C19 gene of 62 Orang Asli from the Peninsular Malaysia. A total of 449 genetic variants were detected including 70 novel polymorphisms; 417 SNPs were located in introns, 23 in upstream, 7 in exons, and 2 in downstream regions. Five alleles and seven genotypes were inferred based on the polymorphisms that were found. Null alleles that were observed include CYP2C19*3 (6.5%), *2 (5.7%) and *35 (2.4%) whereas allele with increased function *17 was detected at a frequency of 4.8%. The normal metabolizer genotype was the most predominant (66.1%), followed by intermediate metabolizer (19.4%), rapid metabolizer (9.7%) and poor metabolizer (4.8%) genotypes. Findings from this study provide further insights into the CYP2C19 genetic profile of the Orang Asli as previously unreported variant alleles were detected through the use of massively parallel sequencing technology platform. The systematic and comprehensive analysis of CYP2C19 will allow uncharacterized variants that are present in the Orang Asli to be included in the genotyping panel in the future.

The potential for non-adaptive origins of evolutionary innovations in central carbon metabolism.

BackgroundBiological systems are rife with examples of pre-adaptations or exaptations. They range from the molecular scale – lens crystallins, which originated from metabolic enzymes – to the macroscopic scale, such as feathers used in flying, which originally served thermal insulation or waterproofing. An important class of exaptations are novel and useful traits with non-adaptive origins. Whether such origins could be frequent cannot be answered with individual examples, because it is a question about a biological system’s potential for exaptation.We here take a step towards answering this question by analyzing central carbon metabolism, and novel traits that allow an organism to survive on novel sources of carbon and energy. We have previously applied flux balance analysis to this system and predicted the viability of 1015 metabolic genotypes on each of ten different carbon sources.ResultsWe here use this exhaustive genotype-phenotype map to ask whether a central carbon metabolism that is viable on a given, focal carbon source C – the equivalent of an adaptation in our framework – is usually or rarely viable on one or more other carbon sources C new – a potential exaptation. We show that most metabolic genotypes harbor potential exaptations, that is, they are viable on one or more carbon sources C new. The nature and number of these carbon sources depends on the focal carbon source C itself, and on the biochemical similarity between C and C new. Moreover, metabolisms that show a higher biomass yield on C, and that are more complex, i.e., they harbor more metabolic reactions, are viable on a greater number of carbon sources C new.ConclusionsA high potential for exaptation results from correlations between the phenotypes of different genotypes, and such correlations are frequent in central carbon metabolism. If they are similarly abundant in other metabolic or biological systems, innovations may frequently have non-adaptive (“exaptive”) origins.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-016-0343-7) contains supplementary material, which is available to authorized users.

Pharmacogenetics of efavirenz discontinuation for reported central nervous system symptoms appears to differ by race

Efavirenz frequently causes central nervous system (CNS) symptoms. We evaluated genetic associations with efavirenz discontinuation for CNS symptoms within 12 months of treatment initiation. Patients had initiated efavirenz-containing regimens at an HIV primary care clinic in the Southeastern United States and had at least 12 months of follow-up data. Polymorphisms in CYP2B6 and CYP2A6 defined efavirenz metabolizer categories. Genome-wide genotyping enabled adjustment for population stratification. Among 563 evaluable patients, 99 (17.5%) discontinued efavirenz within 12 months, 29 (5.1%) for CNS symptoms. The hazard ratio (HR) for efavirenz discontinuation for CNS symptoms in slow versus extensive metabolizers was 4.9 [95% confidence interval (CI): 1.9-12.4; P=0.001]. This HR in Whites was 6.5 (95% CI: 2.3-18.8; P=0.001) and 2.6 in Blacks (95% CI: 0.5-14.1; P=0.27). Considering only slow metabolizers, the HR in Whites versus Blacks was 3.1 (95% CI: 0.9-11.0; P=0.081). The positive predictive value of slow metabolizer genotypes for efavirenz discontinuation was 27% in Whites and 11% in Blacks. Slow metabolizer genotypes were associated significantly with efavirenz discontinuation for reported CNS symptoms. This association was considerably stronger in Whites than in Blacks.

Phenotypic innovation through recombination in genome-scale metabolic networks.

Recombination is an important source of metabolic innovation, especially in prokaryotes, which have evolved the ability to survive on many different sources of chemical elements and energy. Metabolic systems have a well-understood genotype-phenotype relationship, which permits a quantitative and biochemically principled understanding of how recombination creates novel phenotypes. Here, we investigate the power of recombination to create genome-scale metabolic reaction networks that enable an organism to survive in new chemical environments. To this end, we use flux balance analysis, an experimentally validated computational method that can predict metabolic phenotypes from metabolic genotypes. We show that recombination is much more likely to create novel metabolic abilities than random changes in chemical reactions of a metabolic network. We also find that phenotypic innovation is more likely when recombination occurs between parents that are genetically closely related, phenotypically highly diverse, and viable on few rather than many carbon sources. Survival on a new carbon source preferentially involves reactions that are superessential, that is, essential in many metabolic networks. We validate our observations with data from 61 reconstructed prokaryotic metabolic networks. Our systematic and quantitative analysis of metabolic systems helps understand how recombination creates innovation.

Influence of CYP2C19 genetic polymorphisms on clinical outcomes of intracranial aneurysms treated with stent-assisted coiling

ObjectiveTo investigate the influence of CYP2C19 genetic polymorphisms on clinical outcomes of intracranial aneurysms treated with stent-assisted coiling.MethodsBetween September 2014 and October 2015, we prospectively recruited 215 patients with intracranial...

Prevalence of CYP2D6*2, CYP2D6*4, CYP2D6*10, and CYP3A5*3 in Thai breast cancer patients undergoing tamoxifen treatment.

BackgroundTamoxifen (TAM) is used in breast cancer treatment, but interindividual variabilities in TAM-metabolizing enzymes exist and have been linked to single nucleotide polymorphisms in the respective encoding genes. The different alleles and genotypes of these genes have been presented for Caucasians and Asians. This study aimed to explore the prevalence of the incomplete functional alleles and genotypes of the CYP2D6 and CYP3A5 genes in Thai breast cancer patients undergoing TAM treatment.Patients and methodsIn total, 134 Thai breast cancer patients were randomly invited to join the Thai Tamoxifen Project. Their blood samples were collected and extracted for individual DNA. The alleles and genotypes were determined by real-time polymerase chain reaction with TaqMan® Drug Metabolism Genotyping Assays.ResultsThe patients were aged from 27.0 years to 82.0 years with a body mass index range from 15.4 to 40.0, with the majority (103/134) in the early stage (stages 0–II) of breast cancer. The median duration of TAM administration was 17.2 months (interquartile range 16.1 months). Most (53%) of the patients were premenopausal with an estrogen receptor (ER) and progesterone receptor (PR) status of ER+/PR+ (71.7%), ER+/PR− (26.9%), ER−/PR+ (0.7%), and ER−/PR− (0.7%). The allele frequencies of CYP2D6*1, CYP2D6*2, CYP2D6*4, CYP2D6*10, CYP3A5*1, and CYP3A5*3 were 72.9%, 3.2%, 1.1%, 22.8%, 37.3%, and 62.7%, respectively, while the genotype frequencies of CYP2D6*1/*1, CYP2D6*1/*2, CYP2D6*2/*2, CYP2D6*4/*4, CYP2D6*1/*10, CYP2D6*2/*10, CYP2D6*4/*10, CYP2D6*10/*10, CYP3A5*1/*1, CYP3A5*1/*3, and CYP3A5*3/*3 were 9.7%, 2.2%, 3.7%, 1.5%, 15.7%, 9.7%, 3.7%, 53.7%, 13.4%, 47.8%, and 38.8%, respectively.ConclusionThe majority (97.8%) of Thai breast cancer patients undergoing TAM treatment carry at least one incomplete functional allele, including 20.9% of the patients who carry only incomplete functional alleles for both the CYP2D6 and CYP3A5 genes. This research indicates the high prevalence of these defective alleles that are involved in TAM-metabolic pathways that might further affect TAM treatment.

Cell-to-cell heterogeneity emerges as consequence of metabolic cooperation in a synthetic yeast community.

Cells that grow together respond heterogeneously to stress even when they are genetically similar. Metabolism, a key determinant of cellular stress tolerance, may be one source of this phenotypic heterogeneity, however, this relationship is largely unclear. We used self‐establishing metabolically cooperating (SeMeCo) yeast communities, in which metabolic cooperation can be followed on the basis of genotype, as a model to dissect the role of metabolic cooperation in single‐cell heterogeneity. Cells within SeMeCo communities showed to be highly heterogeneous in their stress tolerance, while the survival of each cell under heat or oxidative stress, was strongly determined by its metabolic specialization. This heterogeneity emerged for all metabolite exchange interactions studied (histidine, leucine, uracil, and methionine) as well as oxidant (H2O2, diamide) and heat stress treatments. In contrast, the SeMeCo community collectively showed to be similarly tolerant to stress as wild‐type populations. Moreover, stress heterogeneity did not establish as sole consequence of metabolic genotype (auxotrophic background) of the single cell, but was observed only for cells that cooperated according to their metabolic capacity. We therefore conclude that phenotypic heterogeneity and cell to cell differences in stress tolerance are emergent properties when cells cooperate in metabolism.

Pharmacogenetics for Safe Codeine Use in Sickle Cell Disease.

After postoperative deaths in children who were prescribed codeine, several pediatric hospitals have removed it from their formularies. These deaths were attributed to atypical cytochrome P450 2D6 (CYP2D6) pharmacogenetics, which is also implicated in poor analgesic response. Because codeine is often prescribed to patients with sickle cell disease and is now the only Schedule III opioid analgesic in the United States, we implemented a precision medicine approach to safely maintain codeine as an option for pain control. Here we describe the implementation of pharmacogenetics-based codeine prescribing that accounts for CYP2D6 metabolizer status. Clinical decision support was implemented within the electronic health record to guide prescribing of codeine with the goal of preventing its use after tonsillectomy or adenoidectomy and in CYP2D6 ultra-rapid and poor metabolizer (high-risk) genotypes. As of June 2015, CYP2D6 genotype results had been reported for 2468 unique patients. Of the 830 patients with sickle cell disease, 621 (75%) had a CYP2D6 genotype result; 7.1% were ultra-rapid or possible ultra-rapid metabolizers, and 1.4% were poor metabolizers. Interruptive alerts recommended against codeine for patients with high-risk CYP2D6 status. None of the patients with an ultra-rapid or poor metabolizer genotype were prescribed codeine. Using genetics to tailor analgesic prescribing retained an important therapeutic option by limiting codeine use to patients who could safely receive and benefit from it. Our efforts represent an evidence-based, innovative medication safety strategy to prevent adverse drug events, which is a model for the use of pharmacogenetics to optimize drug therapy in specialized pediatric populations.

Natural variation of root exudates in Arabidopsis thaliana-linking metabolomic and genomic data.

Many metabolomics studies focus on aboveground parts of the plant, while metabolism within roots and the chemical composition of the rhizosphere, as influenced by exudation, are not deeply investigated. In this study, we analysed exudate metabolic patterns of Arabidopsis thaliana and their variation in genetically diverse accessions. For this project, we used the 19 parental accessions of the Arabidopsis MAGIC collection. Plants were grown in a hydroponic system, their exudates were harvested before bolting and subjected to UPLC/ESI-QTOF-MS analysis. Metabolite profiles were analysed together with the genome sequence information. Our study uncovered distinct metabolite profiles for root exudates of the 19 accessions. Hierarchical clustering revealed similarities in the exudate metabolite profiles, which were partly reflected by the genetic distances. An association of metabolite absence with nonsense mutations was detected for the biosynthetic pathways of an indolic glucosinolate hydrolysis product, a hydroxycinnamic acid amine and a flavonoid triglycoside. Consequently, a direct link between metabolic phenotype and genotype was detected without using segregating populations. Moreover, genomics can help to identify biosynthetic enzymes in metabolomics experiments. Our study elucidates the chemical composition of the rhizosphere and its natural variation in A. thaliana, which is important for the attraction and shaping of microbial communities.

Analysis of Polymorphism of Angiotensin System Genes (ACE, AGTR1, and AGT) and Gene ITGB3 in Patients with Arterial Hypertension in Combination with Metabolic Syndrome.

Changes in the frequencies of genotypes and mutant alleles of ACE, AGTR1, AGT, and ITGB3 genes were analyzed in patients with arterial hypertension coupled with metabolic syndrome (N=15) and compared with population data and corresponding parameters in patients with isolated hypertension (N=15). Increased frequency of genotype ID of ACE gene (hypertension predictor) was confirmed for both groups. In case of isolated hypertension, M235M genotype (gene AGT) was more frequent, in case of hypertension combined with metabolic syndrome, the frequency of genotypes A1166C and C1166C of the gene AGTR1 was higher in comparison with population data. Comparison of mutant allele frequencies in the two groups showed that at the 90% significance level allele T of the AGT gene was more frequent in hypertension coupled with metabolic syndrome (OR=1.26) and genotype A1166A of the AGTR1 gene was more frequent in the group with isolated hypertension.

Impact of Ageing on Serum Concentrations of Risperidone and Its Active Metabolite in Patients with Known CYP2D6 Genotype

The aim of this study was to investigate the impact of ageing on serum concentrations of risperidone and 9-hydroxyrisperidone in patients with known CYP2D6 genotype. We included retrospective therapeutic drug monitoring data from 464 genotyped patients with measured serum concentrations of risperidone and 9-hydroxyrisperidone after oral administration. Patients were divided into two age subgroups, that is ≤65 (n = 396) and >65 years (n = 68), and dose-adjusted concentrations (C:D ratios) were compared using multiple linear regression analyses with CYP2D6 genotype and gender as covariates. Moreover, absolute concentrations and prescribed daily doses were compared between age subgroups by simple, univariate Mann-Whitney tests. Age had no effect on C:D ratio of risperidone (p > 0.4), but C:D ratios of 9-hydroxyrisperidone and risperidone + 9-hydroxyrisperidone (total active moiety) were estimated to be 2.6 and 2.0 times higher in patients >65 versus ≤65 years (p < 0.001). Female gender and a CYP2D6 poor metabolizer (PM) genotype were also associated with significantly higher C:D ratio of the total active moiety (p < 0.01). Despite lower dosing in patients >65 versus ≤65 years (median 1.5 versus 3.0 mg/day, p < 0.0001), absolute concentration of the total active moiety did not differ between the age subgroups (median 52.5 versus 47.0 nmol/L, p > 0.6). In conclusion, ageing implies significantly increased dose-adjusted serum concentration of risperidone active moiety, and treatment intensity is not generally reduced by halving the oral dose in the elderly. Tolerability of risperidone therapy should therefore be closely monitored in older patients, and female CYP2D6 PMs >65 years might be a particularly vulnerable subgroup of adverse effects.

High Frequency of CYP2D6 Ultrarapid Metabolizer Genotype in the Finnish Population.

CYP2D6 participates in the biotransformation of many commonly used drugs. Large genetic variability in CYP2D6 results in a wide interindividual variability in the response to CYP2D6 substrate drugs. Previous studies have assessed the phenotype and genotype distributions of CYP2D6 in relatively small Finnish population samples. The aim of our study was to investigate the frequencies of CYP2D6 genotypes in a larger Finnish population cohort of 857 healthy volunteers. The volunteers were genotyped for 10 CYP2D6 genetic variants (*2, *3, *4, *5, *6, *9, *10, *17, *39, *41) and copy number variation performed with TaqMan genotyping assays and copy number assay targeting exon 9. CYP2D6 phenotypes were inferred from the genotype data with the classical and activity score methods. According to the classical method, a large majority of the study cases were extensive metabolizers (EM; 87.3%; 95% confidence interval 84.9-89.3) and the second largest group was ultrarapid metabolizers (UM; 7.2%; 5.7-9.2%). Intermediate (IM) and poor metabolizers (PM) were in clear minority (3.0%; 2.1-4.4% and 2.3%; 1.5-3.6%, respectively). The activity score method yielded similar phenotype predictions. These results show that the frequency of UM genotype is higher and that of PM and IM genotype is lower in the Finnish population than in other North European populations. Accordingly, CYP2D6 genetic profile of the Finnish population differs from its geographically close neighbours, which has implications for the effective and safe use of drugs metabolized by CYP2D6.

Effect of mid-dose efavirenz concentrations and CYP2B6 genotype on viral suppression in patients on first-line antiretroviral therapy

The therapeutic range for efavirenz plasma concentrations is unclear and some studies found no correlation with viral non-suppression. Efavirenz concentrations are variable, driven in part by polymorphisms in CYP2B6. We hypothesised that efavirenz mid-dosing concentrations, together with CYP2B6 metaboliser genotype, could predict viral non-suppression. Participants starting first-line efavirenz-based antiretroviral therapy were monitored for 48 weeks. HIV-RNA and efavirenz mid-dose interval concentrations were determined at Weeks 16 and 48. CYP2B6 metaboliser genotype status was determined by 516G→T and 983T→C polymorphisms. Cox proportional hazards modelling was used to predict viral non-suppression and to determine the most predictive efavirenz mid-dosing concentration threshold. In total, 180 participants were included. Median efavirenz concentrations were 2.3 mg/L (IQR 1.6–4.6 mg/L) and 2.2 mg/L (IQR 1.5–3.9 mg/L) at Weeks 16 and 48, respectively. Moreover, 49 (27.2%), 84 (46.7%) and 39 (21.7%) participants had extensive, intermediate or slow CYP2B6 metaboliser genotype, respectively. Log2 efavirenz concentrations [adjusted hazard ratio (aHR) = 0.77, 95% CI 0.67–0.89] and baseline CD4 cell count (aHR = 0.994, 95% CI 0.989–0.998), but not CYP2B6 genotype, were predictive of viral non-suppression. For every doubling of efavirenz concentration there was a 23% decrease in the hazard of non-suppression. A threshold of 0.7 mg/L was found to be the efavirenz mid-dosing concentration that was most predictive of non-suppression. Mid-dosing efavirenz concentrations are predictive of viral non-suppression, but the currently recommended lower therapeutic limit (1 mg/L) is higher than our finding. Knowledge of CYP2B6 metaboliser genotype is not required for prediction of virological outcomes.

Relationship between ATP-binding cassette subfamily B member 1 and cytochrome P450 2C19 polymorphisms and the effect of clopidogrel post percutaneous coronary intervention in patients with acute coronary syndrome

To observe the relationship between ATP-binding cassette subfamily B member 1 (ABCB1) and cytochrome P450 (CYP)2C19 polymorphisms and the effect of clopidogrel post percutaneous coronary intervention in patients with coronary artery disease. A total of 300 consecutive patients with acute coronary syndrome undergoing selected percutaneous coronary intervention in General Hospital of the People's Liberation Army from October 2010 to August 2012 and treated with clopidogrel were enrolled and retrospectively analyzed. Antiplatelet responsiveness of clopidogrel was estimated by thrombelastograph. The patients were divided into 3 groups: remarkable efficacy group (adenosine diphosphate pathway inhibition rate >80%, 105 cases), effective group (adenosine diphosphate pathway inhibition rate of 50%-80%, 100 cases), and poor responsiveness group (adenosine diphosphate pathway inhibition rate <50%, 95 cases). CYP2C19 and ABCB1 polymorphisms were detected by PCR combined with restrictive fragment length polymorphism (PCR-RELP) method in all patients. A total of 200 patients were performed by high performance liquid chromatography with electrospray tandem mass spectrum methods (HTLC-MS/MS), which was applied for determining the plasma concentration level of clopidogrel metabolites between remarkable efficacy group and poor responsiveness group. Major adverse cardiovascular events and bleeding events were observed through follow-up. (1) There were significantly differences in gender, smoking and alanine transaminase level among 3 groups(P<0.01 or 0.05). (2)There was no significant difference in the ratio of TT, CC and CT genotype of ABCB1 gene among 3 groups(P>0.05). There was significant difference in the ratio of poor, middle and strong metabolizer genotype of CYP2C19 gene (P<0.05). (3)Recurrent angina rates were 8.6%(9/105), 6.0%(6/100) and 18.9%(18/95) (P<0.05), and bleeding events rates were 1.0% (1/105), 1.0%(1/100) and 8.4%(8/95)respectively (P<0.01) in remarkable efficacy group, effective group and poor responsiveness group during the 1 year follow up. There were no significant difference in rates of myocardial infarction, heart failure, ischemic stroke and death among 3 groups (all P>0.05) during follow up. Rates of major adverse cardiovascular events and bleeding events were similar in patients with TT, CC and CT genotype of ABCB1 (14.6%(13/89), 12.8(19/148)and 11.6%(5/43), P>0.05). Rates of major adverse cardiovascular events and bleeding events were 9.5%(2/21), 17.8(27/152) and 7.5%(8/107) in poor, middle and strong metabolizer genotype of CYP2C19 gene patients (P<0.05). (4) Plasma concentration of clopidogrel was significantly lower and relative concentration of acid metabolites was significantly higher in poor responsiveness group than in remarkable efficacy group(P<0.01 or 0.05). There was no significantly different in plasma relative concentration of 2-oxo-clopidogrel between remarkable efficacy group and poor responsiveness group. ABCB1 gene polymorphism is not but CYP2C19 gene polymorphisms is related with antiplatelet responsiveness of clopidogrel and clinical cardiovascular disease events in patients with acute coronary syndrome undergoing selected percutaneous coronary intervention.

High frequency of CYP2D6 ultrarapid metabolizer genotypes in an Ashkenazi Jewish population from Argentina.

A twofold higher frequency of CYP2D6 ultrarapid metabolizers (estimated from genotype: gUMs) was reported among Ashkenazi Jews (AJ) living in New York (USA) than in other North American Caucasians, which might be important to guide the prescription for CYP2D6 substrates in AJ communities around the world. This study was aimed to determine whether the high frequency of CYP2D6 gUMs described in AJ from USA was replicated in AJ from Argentina when compared with other multiethnic admixture Argentines (GA). The frequency of the most common allelic variants and of CYP2D6 gUMs (>2 active genes) and poor metabolizers (0 active genes, gPMs) was also compared among the studied Argentine populations. CYP2D6 genotyping was performed in 173 AJ and 246 GA DNA samples of unrelated donors from the metropolitan area of Buenos Aires. CYP2D6 alleles (*2, *3, *4, *5, *6, *10, *17, *35, *41 and multiple copies), genotypes and functional phenotype frequencies were determined. The frequencies of gUMs and gPMs in AJ from Argentina were 11.5% and 5.2%, respectively, whereas in GA, the frequencies of gUM and gPMs were 6.5% and 4.9%, respectively. Comparisons between AJ and GA showed that gUMs frequencies were twofold higher (P<0.05) in AJ than GA. CYP2D6*35 allele was more frequent in GA than AJ, whereas CYP2D6*41 and *1xN were more frequent in AJ than in GA (P<0.05). This study supports the previously reported high frequency of gUMs on another Ashkenazi population in New York. The present findings also support the interethnic variability of CYP2D6 genetic polymorphism in the overall Argentine population.

Rapid metabolizer genotype of CYP2C19 is a risk factor of being refractory to proton pump inhibitor therapy for reflux esophagitis.

Proton pump inhibitors (PPIs) are mainly metabolized by cytochrome P450 2C19 (CYP2C19) and used as the first-line therapy for gastroesophageal reflux disease (GERD). However, while several studies have examined the influence of CYP2C19 polymorphism on GERD treatment with PPIs, most have had small sample sizes and were conducted in a single center. Here, we used meta-analysis to investigate whether or not the CYP2C19 rapid metabolizer (RM) genotype is a risk factor for GERD patients being refractory to PPI therapy. PubMed and other electronic databases were systematically searched up to August 2014 using the following terms: "GERD and CYP2C19", "esophagitis and CYP2C19", and "non-erosive reflux disease and CYP2C19." Searches were limited to publications in English, and two investigators evaluated eligible studies and extracted data. The total efficacy rate of PPIs for GERD, including reflux esophagitis (RE) and non-erosive reflux disease, was 56.4% (95% confidence interval [CI]; 53.9-58.9%, 870/1543) in intention-to-treat analysis and 63.8% (95%CI; 61.3-66.2%, 950/1489) in per-protocol analysis. Efficacy rates varied significantly between CYP2C19 genotypes (intention-to-treat analysis: RMs, 52.2% [315/604]; intermediate metabolizers, 56.7% [298/526]; poor metabolizers [PMs], 61.3% [138/225]; P = 0.047). Among RE patients, CYP2C19 RMs had an increased risk of being refractory to PPI therapy compared with PMs (odds ratio: 1.661, 95% CI: 1.023-2.659, P = 0.040). The present meta-analysis demonstrates that CYP2C19 RMs with RE have an increased risk of being refractory to PPI therapy compared with PMs. Individualized dosing regimen with PPIs based on CYP2C19 genotype might be a valid therapeutic strategy for overcoming insufficient gastric acid inhibition.