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https://www.readbyqxmd.com/read/27887741/evaluation-of-16-genotype-guided-warfarin-dosing-algorithms-in-310-korean-patients-receiving-warfarin-treatment-poor-prediction-performance-in-vkorc1-1173c-carriers
#1
Mina Yang, Rihwa Choi, June Soo Kim, Young Keun On, Oh Young Bang, Hyun-Jung Cho, Soo-Youn Lee
PURPOSE: The purpose of this study was to evaluate the performance of 16 previously published warfarin dosing algorithms in Korean patients. METHODS: The 16 algorithms were selected through a literature search and evaluated using a cohort of 310 Korean patients with atrial fibrillation or cerebral infarction who were receiving warfarin therapy. FINDINGS: A large interindividual variation (up to 11-fold) in warfarin dose was observed (median, 25 mg/wk; range, 7-77 mg/wk)...
November 22, 2016: Clinical Therapeutics
https://www.readbyqxmd.com/read/27879469/frequency-of-common-vkorc1-polymorphisms-and-their-impact-on-warfarin-dose-requirement-in-pakistani-population
#2
Aisha Qayyum, Muzammil Hasan Najmi, Qaisar Mansoor, Muhammad Irfan, Abdul Khaliq Naveed, Andleeb Hanif, Ali Raza Kazmi, Muhammad Ismail
Polymorphisms in vitamin K epoxide reductase complex subunit 1 (VKORC1) gene lead to interindividual variability in warfarin dose requirement. The characterization of genotype frequency distribution is required in different populations for construction of customized dosing algorithms to enhance the efficacy and reduce the toxicity of warfarin therapy. This study was carried out in Pakistani population to evaluate the contribution of common VKORC1 polymorphisms to warfarin therapy. A total of 550 stable patients taking warfarin were enrolled after medical history, physical examination, and laboratory investigations...
November 21, 2016: Clinical and Applied Thrombosis/hemostasis
https://www.readbyqxmd.com/read/27855133/influence-of-genotype-on-warfarin-maintenance-dose-predictions-produced-using-a-bayesian-dose-individualization-tool
#3
Shamin M Saffian, Stephen B Duffull, Rebecca L Roberts, Robert C Tait, Leanne Black, Kirstin A Lund, Alison H Thomson, Daniel F B Wright
BACKGROUND: A previously established Bayesian dosing tool for warfarin was found to produce biased maintenance dose predictions. In this study, we aimed (1) to determine whether the biased warfarin dose predictions previously observed could be replicated in a new cohort of patients from 2 different clinical settings, (2) to explore the influence of CYP2C9 and VKORC1 genotype on predictive performance of the Bayesian dosing tool, and (3) to determine whether the previous population used to develop the kinetic-pharmacodynamic model underpinning the Bayesian dosing tool was sufficiently different from the test (posterior) population to account for the biased dose predictions...
December 2016: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/27826798/contribution-of-pharmacogenetic-testing-to-modeled-medication-change-recommendations-in-a-long-term-care-population-with-polypharmacy
#4
Elaine A Sugarman, Ali Cullors, Joel Centeno, David Taylor
BACKGROUND: Among long-term care facility residents, polypharmacy is common, and often appropriate, given the need to treat multiple, complex, chronic conditions. Polypharmacy has, however, been associated with increased healthcare costs, adverse drug events, and drug interactions. The current study evaluates the potential medication cost savings of adding personalized pharmacogenetic information to traditional medication management strategies. METHODS: One hundred and twelve long-term care residents completed pharmacogenetic testing for targeted variants in the following genes: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4/CYP3A5, HTR2A, HTR2C, SLC6A4, SLC6A2 COMT, OPRM1, SLCO1B1, VKORC1 and MTHFR...
November 8, 2016: Drugs & Aging
https://www.readbyqxmd.com/read/27824210/vkcfd2-from-clinical-phenotype-to-molecular-mechanism
#5
K J Czogalla, M Watzka, J Oldenburg
Vitamin K 2,3-epoxide reductase complex, subunit 1 (VKORC1) is an enzyme essential for the vitamin K cycle. VKORC1 catalyses the reduction of vitamin K 2,3-epoxide to the quinone form of vitamin K and further to vitamin K hydroquinone. The generated vitamin K hydroquinone serves as substrate for the enzyme γ-glutamyl-carboxylase which modifies all vitamin K-dependent proteins, allowing them to bind calcium ions necessary for physiological activity. Vitamin K-dependent proteins include the coagulation factors FII, FVII, FIX, FX, and proteins C, S und Z...
November 8, 2016: Hämostaseologie
https://www.readbyqxmd.com/read/27789970/pharmacogenetic-polymorphism-as-an-independent-risk-factor-for-frequent-hospitalizations-in-older-adults-with-polypharmacy-a-pilot-study
#6
Joseph Finkelstein, Carol Friedman, George Hripcsak, Manuel Cabrera
Pharmacogenetic testing identifies genetic biomarkers that are predictive of individual sensitivity to particular drugs. A significant proportion of medications that are widely prescribed for older adults are metabolized by enzymes that are encoded by highly polymorphic genes. Pharmacogenetic testing is increasingly used to optimize the medication regimen; however, its potential in older adults with polypharmacy has not been systematically explored. Following the initial case-series study, this study hypothesized that frequently hospitalized older adults with polypharmacy have higher frequency of pharmacogenetic polymorphism as compared to older adults with polypharmacy who are rarely admitted to a hospital...
2016: Pharmacogenomics and Personalized Medicine
https://www.readbyqxmd.com/read/27765905/integrative-genomics-reveals-hypoxia-inducible-genes-that-are-associated-with-a-poor-prognosis-in-neuroblastoma-patients
#7
Mark A Applebaum, Aashish R Jha, Clara Kao, Kyle M Hernandez, Gillian DeWane, Helen R Salwen, Alexandre Chlenski, Marija Dobratic, Christopher J Mariani, Lucy A Godley, Nanduri Prabhakar, Kevin White, Barbara E Stranger, Susan L Cohn
Neuroblastoma is notable for its broad spectrum of clinical behavior ranging from spontaneous regression to rapidly progressive disease. Hypoxia is well known to confer a more aggressive phenotype in neuroblastoma. We analyzed transcriptome data from diagnostic neuroblastoma tumors and hypoxic neuroblastoma cell lines to identify genes whose expression levels correlate with poor patient outcome and are involved in the hypoxia response. By integrating a diverse set of transcriptome datasets, including those from neuroblastoma patients and neuroblastoma derived cell lines, we identified nine genes (SLCO4A1, ENO1, HK2, PGK1, MTFP1, HILPDA, VKORC1, TPI1, and HIST1H1C) that are up-regulated in hypoxia and whose expression levels are correlated with poor patient outcome in three independent neuroblastoma cohorts...
October 17, 2016: Oncotarget
https://www.readbyqxmd.com/read/27763679/theory-based-pkpd-of-s-and-r-warfarin-and-effects-on-inr-influence-of-body-size-composition-and-genotype-in-cardiac-surgery-patients
#8
Ling Xue, Nick Holford, Xiao-Liang Ding, Zhen-Ya Shen, Chen-Rong Huang, Hua Zhang, Jing-Jing Zhang, Zhe-Ning Guo, Cheng Xie, Ling Zhou, Zhi-Yao Chen, Lin-Sheng Liu, Li-Yan Miao
AIMS: The aims of this study are to apply a theory based mechanistic model to describe the pharmacokinetics (PK) and pharmacodynamics (PD) of S- and R-warfarin. METHODS: Clinical data were obtained from 264 patients. Total concentrations for S- and R-warfarin were measured by ultra-high performance liquid tandem mass spectrometry. Genotypes were measured using pyrosequencing. A sequential population pharmacokinetic parameter with data method was used to describe the international normalized ratio (INR) time course...
October 20, 2016: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27753953/os-08-03-pharmacogenetic-markers-of-survival
#9
Vera Erdman, Ilsia Tuktarova, Timur Nasibullin, Ianina Timasheva, Olga Mustafina
OBJECTIVE: Physiological and biochemical changes during aging alter drug metabolism. Drug intake is increased with age because of cumulative morbidity, in particular, high prevalence of cardiovascular diseases. Antihypertensive medications are the most commonly used drugs. Individual drug sensitivity or resistance may be influenced by the variance of the "pharmacological response" genes.Our purpose was to search for the polymorphic variants of "pharmacological response" genes associated with survival in different age periods...
September 2016: Journal of Hypertension
https://www.readbyqxmd.com/read/27751997/vkorc1-gene-vitamin-k-epoxide-reductase-polymorphisms-are-associated-with-cardiovascular-disease-in-chronic-kidney-disease-patients-on-hemodialysis
#10
Noha A Osman, Nevine El-Abd, Mohamed Nasrallah
Vitamin K is necessary for the carboxylation of clotting factors and matrix Gla protein (MGP). Vitamin K epoxide reductase (VKOR) is the enzyme responsible for recirculation of Vitamin K increasing its tissue availability. Polymorphisms of VKOR may alter the function of MGP, thereby influencing vascular calcification. We conducted this study to investigate the relationship of VKORC1 gene single nucleotide polymorphisms (SNP's) to vascular calcification and clinically overt cardiovascular disease in chronic kidney disease (CKD) patients on hemodialysis (HD)...
September 2016: Saudi Journal of Kidney Diseases and Transplantation
https://www.readbyqxmd.com/read/27750332/-how-to-individualize-drug-therapy-based-on-pharmacogenetic-information-a-systematic-review-of-published-guidelines
#11
Susanne Hafner, Sabine Haubensak, Tanusree Paul, Oliver Zolk
Background | Differences (polymorphisms) in genes encoding drug targets, drug transport proteins, or drug metabolizing enzymes may be responsible, among other factors, for the observed variation in patients' responses to medications. The field of pharmacogenetics aims to identify patients at higher genetically-determined risk of adverse effects or poor response to medication. This information would allow for modification of dosage or substitution with alternative therapy. However, there is a lack of awareness of pharmacogenetic clinical practise guidelines...
October 2016: Deutsche Medizinische Wochenschrift
https://www.readbyqxmd.com/read/27743182/linkage-disequilibrium-between-the-cyp2c19-2-17-and-cyp2c9-1-alleles-and-impact-of-vkorc1-cyp2c9-cyp2c19-gene-polymorphisms-and-gene-gene-interactions-on-warfarin-therapy
#12
Koroush Khalighi, Gang Cheng, Seyedabbas Mirabbasi, Bahar Khalighi, Yin Wu, Wuqiang Fan
Warfarin therapy is complicated by its large inter-individual and intra-individual variability. Both genetic and non-genetic factors can affect warfarin therapy. This study aims to investigate the allele distribution of VKORC1, CYP2C9 and CYP2C19, contribution of different allele variants and possible gene-gene interaction on warfarin therapy. Four hundreds and ninety-two patients were enrolled and single nucleotide polymorphisms for vitamin K epoxide reductase complex subunit 1 (VKORC1), cytochrome P450 CYP2C9 and cytochrome P450 CYP2C19 were genotyped...
October 14, 2016: Journal of Thrombosis and Thrombolysis
https://www.readbyqxmd.com/read/27740916/can-pharmacogenetics-help-patients-under-chronic-treatment-with-coumarin-anticoagulants
#13
Isabel López, Estela Sangüesa, Yves Vancraenendonck, Estefanía Zuriaga, María Pilar Ribate, Cristina Belén García
Vitamin K antagonists are highly effective antithrombotic drugs. However, appropriate dosing is difficult to establish owing to its narrow therapeutic window as well as widespread inter- and intra-individual variability in dosage. Compared with dosing solely based on clinical information, pharmacogenetics can help improve the therapy with coumarins by decreasing the time to reach a stable dose and reducing the risk of bleeding. Most of the studies about genotyping of patients using vitamin K antagonists have focused on predicting the stable dose...
December 1, 2016: Drug Metabolism and Personalized Therapy
https://www.readbyqxmd.com/read/27740732/identification-of-novel-variants-associated-with-warfarin-stable-dosage-by-use-of-a-two-stage-extreme-phenotype-strategy
#14
Z Luo, X Li, M Zhu, J Tang, Z Li, X Zhou, G Song, Z Liu, H Zhou, W Zhang
: Essentials Required warfarin doses for mechanical heart valves vary greatly. A two-stage extreme phenotype design was used to identify novel warfarin dose associated mutation. We identified a group of variants significantly associated with extreme warfarin dose. Four novel identified mutations account for 2.2% of warfarin dose discrepancies. SUMMARY: Background The variation among patients in warfarin response complicates the management of warfarin therapy, and an improper therapeutic dose usually results in serious adverse events...
October 14, 2016: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/27703968/g-1639a-but-not-c1173t-vkorc1-gene-polymorphism-is-related-to-ischemic-stroke-and-its-various-risk-factors-in-ukrainian-population
#15
Yevhen I Dubovyk, Viktoriia Yu Harbuzova, Alexander V Ataman
Vitamin K epoxide reductase complex subunit 1 (VKORC1) is integral 163-amino acid long transmembrane protein which mediates recycling of vitamin K 2,3-epoxide to vitamin K hydroquinone and it is necessary for activation of vitamin K-dependent proteins (VKDPs). Herein, the association between G-1639A (rs9923231) and C1173T (rs9934438) single-nucleotide polymorphisms (SNPs) of the VKORC1 gene and ischemic stroke (IS) was tested in Ukrainian population. Genotyping was performed in 170 IS patients and 124 control subjects (total 294 DNA samples) using PCR-RFLP (polymerase chain reaction with following restriction fragment length polymorphism analysis) method...
2016: BioMed Research International
https://www.readbyqxmd.com/read/27681307/uniparental-disomy-causes-deficiencies-of-vitamin-k-dependent-proteins
#16
M A Dasi, R Gonzalez-Conejero, S Izquierdo, J Padilla, J L Garcia, N Garcia-Barberá, B Argilés, M E de la Morena-Barrio, J M Hernández-Sánchez, J M Hernández-Rivas, V Vicente, J Corral
BACKGROUND: Inherited deficiency of all vitamin K-dependent coagulant factors (VKCFD) is a rare autosomal recessive disorder caused by mutations in γ-glutamyl carboxylase (GGCX) or vitamin K-epoxide reductase (VKORC1) with great heterogeneity both in terms of clinical presentation and response to treatment. OBJECTIVE: To characterize the molecular basis of VKCFD in a Spanish family. METHODS & RESULTS: Sequencing of candidate genes, comparative genomic hybridization and massive sequencing identified a new mechanism causing VKCFD in the proband...
September 28, 2016: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/27643348/os-08-03-pharmacogenetic-markers-of-survival
#17
Vera Erdman, Ilsia Tuktarova, Timur Nasibullin, Ianina Timasheva, Olga Mustafina
OBJECTIVE: Physiological and biochemical changes during aging alter drug metabolism. Drug intake is increased with age because of cumulative morbidity, in particular, high prevalence of cardiovascular diseases. Antihypertensive medications are the most commonly used drugs. Individual drug sensitivity or resistance may be influenced by the variance of the "pharmacological response" genes.Our purpose was to search for the polymorphic variants of "pharmacological response" genes associated with survival in different age periods...
September 2016: Journal of Hypertension
https://www.readbyqxmd.com/read/27636550/a-european-spectrum-of-pharmacogenomic-biomarkers-implications-for-clinical-pharmacogenomics
#18
Clint Mizzi, Eleni Dalabira, Judit Kumuthini, Nduna Dzimiri, Istvan Balogh, Nazli Başak, Ruwen Böhm, Joseph Borg, Paola Borgiani, Nada Bozina, Henrike Bruckmueller, Beata Burzynska, Angel Carracedo, Ingolf Cascorbi, Constantinos Deltas, Vita Dolzan, Anthony Fenech, Godfrey Grech, Vytautas Kasiulevicius, Ľudevít Kádaši, Vaidutis Kučinskas, Elza Khusnutdinova, Yiannis L Loukas, Milan Macek, Halyna Makukh, Ron Mathijssen, Konstantinos Mitropoulos, Christina Mitropoulou, Giuseppe Novelli, Ioanna Papantoni, Sonja Pavlovic, Giuseppe Saglio, Jadranka Setric, Maja Stojiljkovic, Andrew P Stubbs, Alessio Squassina, Maria Torres, Marek Turnovec, Ron H van Schaik, Konstantinos Voskarides, Salma M Wakil, Anneke Werk, Maria Del Zompo, Branka Zukic, Theodora Katsila, Ming Ta Michael Lee, Alison Motsinger-Rief, Howard L Mc Leod, Peter J van der Spek, George P Patrinos
Pharmacogenomics aims to correlate inter-individual differences of drug efficacy and/or toxicity with the underlying genetic composition, particularly in genes encoding for protein factors and enzymes involved in drug metabolism and transport. In several European populations, particularly in countries with lower income, information related to the prevalence of pharmacogenomic biomarkers is incomplete or lacking. Here, we have implemented the microattribution approach to assess the pharmacogenomic biomarkers allelic spectrum in 18 European populations, mostly from developing European countries, by analyzing 1,931 pharmacogenomics biomarkers in 231 genes...
2016: PloS One
https://www.readbyqxmd.com/read/27632229/genetic-determinants-of-variability-in-warfarin-response-after-the-dose-titration-phase
#19
Otito F Iwuchukwu, Andrea H Ramirez, Yaping Shi, Erica A Bowton, Vivian K Kawai, Jonathan S Schildcrout, Dan M Roden, Joshua C Denny, C Michael Stein
OBJECTIVES: Genetic factors contribute considerably toward variability in warfarin dose requirements and are important in the dose-titration phase; their effects on the stability of anticoagulation later in therapy are not known. METHODS: Using deidentified electronic medical records linked to a DNA-biobank, we studied 140 African-Americans and 943 European-Americans after the warfarin dose-titration phase. We genotyped 12 single nucleotide polymorphisms in genes (CYP2C9, VKORC1, CYP4F2, GGCX, EPHX1, CALU) associated with altered warfarin dose requirements and tested their associations with international normalized ratio variability (INRVAR) and percent time in therapeutic range in European-Americans and African-Americans...
November 2016: Pharmacogenetics and Genomics
https://www.readbyqxmd.com/read/27622442/prediction-of-sensitivity-to-warfarin-based-on-vkorc1-and-cyp2c9-polymorphisms-in-patients-from-different-places-in-colombia
#20
Ricardo A Cifuentes, Juan Murillo-Rojas, Esperanza Avella-Vargas
INTRODUCTION: In the search to prevent hemorrhages associated with anticoagulant therapy, a major goal is to validate predictors of sensitivity to warfarin. However, previous studies in Colombia that included polymorphisms in the VKORC1 and CYP2C9 genes as predictors reported different algorithm performances to explain dose variations, and did not evaluate the prediction of sensitivity to warfarin.  OBJECTIVE: To determine the accuracy of the pharmacogenetic analysis, which includes the CYP2C9 *2 and *3 and VKORC1 1639G>A polymorphisms in predicting patients' sensitivity to warfarin at the Hospital Militar Central, a reference center for patients born in different parts of Colombia...
2016: Biomédica: Revista del Instituto Nacional de Salud
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