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Kazuki Nakagita, Kyoichi Wada, Yutaro Mukai, Takaya Uno, Ryoji Nishino, Sachi Matsuda, Hiromi Takenaka, Nobue Terakawa, Akira Oita, Mitsutaka Takada
PURPOSE: This study aimed to investigate relationships between times in therapeutic range (TTR) or warfarin sensitivity indexes (WSI) and VKORC1-1639G>A and CYP2C9 polymorphisms in patients with left ventricular assist devices (LVAD). METHODS: Severe heart failure patients who received LVAD from January 1, 2013 to October 31, 2017 were recruited. Relationships between TTR or WSI and VKORC1-1639G>A and CYP2C9 gene polymorphisms were investigated immediately after LVAD implantation (period 1) and immediately prior to hospital discharge (period 2)...
May 21, 2018: European Journal of Clinical Pharmacology
Zhouping Wang, Li Zhang, Ping Huang, Xiaoqiong Gu, Xiaofei Xie, Yanfei Wang, Wei Li, Qiyi Zeng
INTRODUCTION: Warfarin therapy is recommended in children with giant coronary artery aneurysms (GCAAs) after Kawasaki disease (KD). Large individual variability makes it difficult to predict the warfarin dose. Polymorphisms in the vitamin K expoxide reductase 1 (VKORC1) and cytochrome P4502C9 (CYP2C9) genes have been reported to influence the warfarin dose. We investigated the effects of the VKORC1 and CYP2C9 genotypes on the warfarin dose in pediatric patients with giant CAAs after KD...
May 8, 2018: Thrombosis Research
Riccardo E Marioni, Sarah E Harris, Qian Zhang, Allan F McRae, Saskia P Hagenaars, W David Hill, Gail Davies, Craig W Ritchie, Catharine R Gale, John M Starr, Alison M Goate, David J Porteous, Jian Yang, Kathryn L Evans, Ian J Deary, Naomi R Wray, Peter M Visscher
Alzheimer's disease (AD) is a public health priority for the 21st century. Risk reduction currently revolves around lifestyle changes with much research trying to elucidate the biological underpinnings. We show that self-report of parental history of Alzheimer's dementia for case ascertainment in a genome-wide association study of 314,278 participants from UK Biobank (27,696 maternal cases, 14,338 paternal cases) is a valid proxy for an AD genetic study. After meta-analysing with published consortium data (n = 74,046 with 25,580 cases across the discovery and replication analyses), three new AD-associated loci (P < 5 × 10-8 ) are identified...
May 18, 2018: Translational Psychiatry
Jiao Li, Wenlong Yang, Zhonghui Xie, Kun Yu, Yuhua Chen, Kaijun Cui
BACKGROUND: The anticoagulation of atrial fibrillation catheter ablation during the perioperative stage does matter and should be treated with discretion. We aimed to assess impact of three important genes participating in vitamin K cycle (i.e. VKORC1 rs9923231, CYP4F2 rs2108622 and NQO1 rs1800566) on the daily stable warfarin dose requirement in Sichuan Han Chinese patients with catheter ablation of atrial fibrillation. METHODS: A total of 222 atrial fibrillation patients taking stable warfarin therapy after catheter ablation operation were enrolled in this study...
May 18, 2018: BMC Cardiovascular Disorders
Abdelhak Elkhazraji, El Arbi Bouaiti, Hassan Boulahyaoui, Christiana Philippa Nahmtchougli, Hafid Zahid, Mounia Bensaid, Azeddine Ibrahimi, Nezha Messaoudi
We investigated the impact of non-genetics factors, and single nucleotide polymorphisms (SNPs) in VKORC1, CYP2C9, CYP4F2, and GGCX on acenocoumarol dosage in Moroccan adult's patients, in order to develop an algorithm to predict acenocoumarol dose for Moroccan patients. Our study consisted of 217 Moroccan patients taking a maintenance dose of acenocoumarol for various indications. The patients were genotyped for VKORC1 -1639 G>A, VKORC1 1173 C>T, CYP2C9*2, CYP2C9*3, CYP4F2 1347 G>A and GGCX 12970 C>G SNPs...
2018: Drug Discoveries & Therapeutics
Syed Shahzad Hasan, Chia Siang Kow, Louise E Curley, Darrin L Baines, Zaheer-Ud-Din Babar
Anticoagulants refer to a variety of agents that inhibit one or more steps in the coagulation cascade. Generally, clinical conditions that require the prescribing of an oral anticoagulant increase in frequency with age. However, a major challenge of anticoagulation use among older patients is that this group of patients also experience the highest bleeding risk. To date, economic evaluation of prescribing of anticoagulants that includes the novel or newer oral anticoagulants (NOACs) in older adults has not been conducted and is warranted...
May 9, 2018: Expert Review of Pharmacoeconomics & Outcomes Research
Christine Kimbacher, Christian Paar, Andrea Freystetter, Joerg Berg
BACKGROUND: Genotyping for clinically important single nucleotide polymorphisms (SNPs) is performed by many clinical routine laboratories. To support testing, quality controls and reference materials are needed. Those may be derived from residual patient samples, left over samples of external quality assurance schemes, plasmid DNA or DNA from cell lines. DNAs from cell lines are commutable and available in large amounts. METHODS: DNA from 38 cell lines were examined for suitability as controls in 11 SNP assays that are frequently used in a clinical routine laboratory: FV (1691G>A), FII (20210G>A), PAI-1 4G/5G polymorphism, MTHFR (677C>T, 1298A>C), HFE (H63D, S65C, C282Y), APOE (E2, E3, E4), LPH (-13910C>T), UGT1A1 (*28, *36, *37), TPMT (*2, *3A, *3B, *3C), VKORC1 (-1639G>A, 1173C>T), CYP2C9 (*2, *3, *5)...
May 1, 2018: Clinical Laboratory
Surendra Kumar, Ashish Kant Dubey, Jayantee Kalita, Usha Kant Misra
Objective: To analyze the clinical importance of VKORC1 polymorphism and its correlation with stability of oral anticoagulation. Patients and Methods: In a hospital-based study, the patients on oral anticoagulant (OAC) were included during 2013-2016. The patients received OAC for cardioembolic stroke, cerebral venous sinus thrombosis (CVST), and prevention of deep vein thrombosis (DVT). Demographic, clinical, and neurological findings were recorded. Stability of anticoagulation was determined by percentage of time international normalized ratio (INR) values were in therapeutic range...
April 2018: Journal of Neurosciences in Rural Practice
Zhiying Luo, Rong Liu, Bao Sun, Xinming Zhou, Zhaoqian Liu, Honghao Zhou, Heng Xu, Xi Li, Wei Zhang
OBJECTIVE: To identify warfarin dose-associated DNA methylation changes, we conducted the first genomewide DNA methylation association study. METHOD: A total of 22 patients who required an extreme warfarin dosage from VKORC1 -1639AA & CYP2C9*1*1 genotype group were enrolled in this study. The Illumina Infinium HumanMethylation450 platform was used to perform genome-scale DNA methylation profiling, identifying differentially methylated CpG sites by a nonparametric test...
May 1, 2018: Die Pharmazie
Fernanda Rodrigues-Soares, Fernanda S G Kehdy, Julia Sampaio-Coelho, Poliana X C Andrade, Carolina Céspedes-Garro, Camila Zolini, Marla M Aquino, Mauricio L Barreto, Bernardo L Horta, Maria Fernanda Lima-Costa, Alexandre C Pereira, Adrián LLerena, Eduardo Tarazona-Santos
We present allele frequencies involving 39 pharmacogenetic biomarkers studied in Brazil, and their distribution on self-reported race/color categories that: (1) involve a mix of perceptions about ancestry, morphological traits, and cultural/identity issues, being social constructs pervasively used in Brazilian society and medical studies; (2) are associated with disparities in access to health services, as well as in their representation in genetic studies, and (3), as we report here, explain a larger portion of the variance of pharmaco-allele frequencies than geography...
May 1, 2018: Pharmacogenomics Journal
Xiaohui Ma, Da-Wei Wang, Ning Li, Lan Liu, Lin Tian, Chan Luo, Lin Cong, Zhiyong Feng, Xiao-Hui Liu, Ying Song
BACKGROUND: Anticoagulant rodenticides have been widely used in rodent control in China for over 30 years and resistant Norway rats have been reported. Mutations in the vitamin K epoxide reductase complex, subunit 1 (Vkorc1) gene can cause anticoagulant resistance in rodents. In this study, we analyzed the Vkorc1 polymorphisms of 681 Norway rats collected in Zhanjiang and Harbin City in China from 2008 to 2015 and evaluated the warfarin resistance frequency. RESULTS: Analysis revealed 4 mutations including 3 not previously reported...
April 17, 2018: Pest Management Science
G Shen, S Li, W Cui, S Liu, Q Liu, Y Yang, M Gross, W Li
The human genome encodes two paralogs of vitamin-K-epoxide reductase, VKORC1 and VKORL1, that support blood coagulation and other vitamin-K-dependent processes. Warfarin inhibits both enzymes, but VKORL1 is relatively resistant to warfarin OBJECTIVES: To understand the difference between VKORL1 and VKORC1, and the cause of warfarin-resistant (WR) mutations in VKORC1 METHODS: We performed systematic mutagenesis and analyzed warfarin responses with a cell-based activity assay. Mass spectrometry analyses were used to detect cellular redox state RESULTS: VKORC1 and VKORL1 adopt a similar intracellular redox state with four-transmembrane-helix topology...
April 17, 2018: Journal of Thrombosis and Haemostasis: JTH
Haifa Jmel, Lilia Romdhane, Yosra Ben Halima, Meriem Hechmi, Chokri Naouali, Hamza Dallali, Yosr Hamdi, Jingxuan Shan, Abdelmajid Abid, Henda Jamoussi, Sameh Trabelsi, Lotfi Chouchane, Donata Luiselli, Sonia Abdelhak, Rym Kefi
Genetic variation is an important determinant affecting either drug response or susceptibility to adverse drug reactions. Several studies have highlighted the importance of ethnicity in influencing drug response variability that should be considered during drug development. Our objective is to characterize the genetic variability of some pharmacogenes involved in the response to drugs used for the treatment of Metabolic Syndrome (MetS) in Tunisia and to compare our results to the worldwide populations. A set of 135 Tunisians was genotyped using the Affymetrix Chip 6...
2018: PloS One
Ahmed M L Bedewy, Salah A Sheweita, Mostafa Hasan Mostafa, Lamia Saeed Kandil
[This corrects the article DOI: 10.1007/s12288-016-0725-4.].
April 2018: Indian Journal of Hematology & Blood Transfusion
Ahmed M L Bedewy, Salah Showeta, Mostafa Hasan Mostafa, Lamia Saeed Kandil
Warfarin is the most commonly used drug for chronic prevention of thromboembolic events, it also ranks high among drugs that cause serious adverse events. The variability in dose requirements has been attributed to inter-individual differences in medical, personal, and genetic factor. Cytochrome P-450 2C9 is the principle enzyme that terminates the anticoagulant effect of warfarin by catalyzing the conversion of the pharmacologically more potent S-enantiomer to its inactive metabolites. Warfarin exerts its effect by inhibition of vitamin K epoxide reductase...
April 2018: Indian Journal of Hematology & Blood Transfusion
Thomas J Baranski, Aldi T Kraja, Jill L Fink, Mary Feitosa, Petra A Lenzini, Ingrid B Borecki, Ching-Ti Liu, L Adrienne Cupples, Kari E North, Michael A Province
Human GWAS of obesity have been successful in identifying loci associated with adiposity, but for the most part, these are non-coding SNPs whose function, or even whose gene of action, is unknown. To help identify the genes on which these human BMI loci may be operating, we conducted a high throughput screen in Drosophila Melanogaster. Starting with 78 BMI loci from two recently published GWAS meta-analyses, we identified fly orthologs of all nearby genes (± 250KB). We crossed RNAi knockdown lines of each gene with flies containing tissue-specific drivers to knock down (KD) the expression of the genes only in the brain and the fat body...
April 2, 2018: PLoS Genetics
Mark A Rishavy, Kevin W Hallgren, Lee Wilson, Savita Singh, Kurt W Runge, Kathleen L Berkner
The anticoagulant warfarin inhibits the vitamin K oxidoreductase (VKORC1), which generates vitamin K hydroquinone (KH2 ) required for the carboxylation and consequent activation of vitamin K-dependent (VKD) proteins. VKORC1 produces KH2 in two reactions: reduction of vitamin K epoxide (KO) to quinone (K) and then KH2 , and our dissection of full reduction versus the individual reactions revealed a surprising mechanism of warfarin inhibition. Warfarin inhibition of KO to K reduction and carboxylation that requires full reduction were compared in wild type VKORC1 or mutants (Y139H, Y139F) that cause warfarin resistance...
March 28, 2018: Blood
Katrin J Czogalla, Kerstin Liphardt, Klara Höning, Veit Hornung, Arijit Biswas, Matthias Watzka, Johannes Oldenburg
Vitamin K reduction is catalyzed by 2 enzymes in vitro: the vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1) and its isozyme VKORC1-like1 (VKORC1L1). In vivo, VKORC1 reduces vitamin K to sustain γ-carboxylation of vitamin K-dependent proteins, including coagulation factors. Inhibition of VKORC1 by oral anticoagulants (OACs) is clinically used in therapy and in prevention of thrombosis. However, OACs also inhibit VKORC1L1, which was previously shown to play a role in intracellular redox homeostasis in vitro...
March 27, 2018: Blood Advances
María José Serna, José Miguel Rivera-Caravaca, Rocío Gonzalez-Conejero, María Asunción Esteve-Pastor, Mariano Valdés, Vicente Vicente, Gregory Y H Lip, Vanessa Roldán, Francisco Marín
BACKGROUND: Polymorphisms in the vitamin K epoxide reductase complex 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) genes increase the bleeding risk in anticoagulated atrial fibrillation (AF) patients. Here, we aimed to investigate whether VKORC1 and CYP2C9 polymorphisms improved the predictive performance for major bleeding using the HAS-BLED score. MATERIAL AND METHODS: We recruited 652 consecutive AF patients stable on vitamin K antagonist (INR 2.0-3.0) during at least the previous 6 months...
March 25, 2018: European Journal of Clinical Investigation
Basim Mohammad Ayesh, Ahmed Shaker Abu Shaaban, Abdalla Asaf Abed
Aim: To evaluate applicability of CYP2C9*2 , *3 and VKORC1-1639G > A based algorithm to predict warfarin stable dose (WSD) in a group of Palestinian patients. Patients & methods: Warfarin doses were retrospectively calculated for 101 Palestinian patients under warfarin therapy using three models. Performance of the three models was assessed in 47 patients found to take WSD. Results: Frequency of CYP2C9*2 , *3 and VKORC1-1639G > A alleles is 13...
March 2018: Future Science OA
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