scholarly journals VKORC1 and CYP2C9 genotype and patient characteristics explain a large proportion of the variability in warfarin dose requirement among children

Blood ◽  
2012 ◽  
Vol 119 (3) ◽  
pp. 868-873 ◽  
Author(s):  
Tina T. Biss ◽  
Peter J. Avery ◽  
Leonardo R. Brandão ◽  
Elizabeth A. Chalmers ◽  
Michael D. Williams ◽  
...  
Keyword(s):  
Interindividual Variability ◽  
Tertiary Care ◽  
Warfarin Dose ◽  
Patient Characteristics ◽  
Similar Proportion ◽  
Limited Information ◽  
Dose Requirement ◽  
Cross Sectional ◽  
Warfarin Dose Requirement ◽  
Warfarin Dosing

Abstract Although genetic and environmental factors explain approximately half of the interindividual variability in warfarin dose requirement in adults, there is limited information available in children. In a cross-sectional study of anticoagulated children from 5 tertiary care centers, 120 children with a stable warfarin dose were genotyped for VKORC1 (−1639G > A; rs9923231), CYP2C9 (*2 and *3 alleles; rs1799853 and rs1057910), and CYP4F2 (V433M; rs2108622) polymorphisms. Clinical and demographic features were recorded. Multiple regression analysis of the data showed that, although CYP4F2 made no contribution to the dose model, 72.4% of the variability in warfarin dose requirement is attributed to by patient height, genetic polymorphisms in VKORC1 and CYP2C9, and indication for warfarin. The recently published International Warfarin Pharmacogenetics Consortium pharmacogenetic-based warfarin dosing algorithm (based on data derived from anticoagulated adults) consistently overestimated warfarin dose for our cohort of children. A similar proportion of the interindividual variability in warfarin dose is explained by genetic factors in children compared with adult patients, although height is a greater predictor in children. A pharmacogenomic approach to warfarin dosing has the potential to improve the efficacy and safety of warfarin therapy in children. However, algorithms should be derived from data in children if their potential benefit is to be realized.

Association between polymorphisms in microRNA seed region and warfarin stable dose

2020 ◽  
pp. postgradmedj-2019-137197
Author(s):  
Maryam Hosseindokht ◽  
Hamed Zare ◽  
Rasoul Salehi ◽  
Leyla Pourgholi ◽  
Shayan Ziaee ◽  
...  
Keyword(s):  
Fragment Length Polymorphism ◽  
Interindividual Variability ◽  
Warfarin Dose ◽  
Optimal Dose ◽  
Seed Region ◽  
Dose Requirement ◽  
Vitamin K Cycle ◽  
Warfarin Dose Requirement ◽  
Potential Factor ◽  
Warfarin Maintenance Dose

BackgroundThe optimal dose of anticoagulant warfarin varies among patients to achieve the target international normalised ratio. Although genetic variations related to warfarin pharmacokinetics and vitamin K cycle are important factors associated with warfarin dose requirements, these variations do not completely explain the large interindividual variability observed in the most populations, suggesting that additional factors may contribute to this variability. microRNAs have recently been introduced as regulators of drug function genes, and therefore, may be involved in drug responses. In this study, we aimed to evaluate the possible association between variants in the seed region of microRNAs, which target the genes involved in the action of warfarin and warfarin dose requirement.Methods526 samples were collected from Iranian patients. Four selected polymorphisms in the seed region of microRNAs (rs2910164, rs66683138, rs12416605 and rs35770269 in miR-146a, miR-3622a, miR-938 and miR-449c, respectively) were genotyped by PCR-restriction fragment length polymorphism method.Resultsrs2910164 C/G in the seed region of miR-146a was associated with warfarin dose requirement (p<0.001); the patients with GG genotype had the higher mean dose of warfarin (40.6 mg/week, compared with 33.9 and 31.8 mg/week for GC and CC genotypes, respectively). The association of other polymorphisms with warfarin dose requirement was not statistically significant.Conclusionrs2910164 C/G in the seed region of miR-146a is associated with warfarin maintenance dose, likely by disrupting interaction between miR-146a and ATP-binding cassette subfamily B member 1 gene, ABCB1. Therefore, this polymorphism may possibly be a potential factor for assessment of warfarin dose requirements.

scholarly journals Regulatory polymorphism in vitamin K epoxide reductase complex subunit 1 (VKORC1) affects gene expression and warfarin dose requirement

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1013-1021 ◽  
Author(s):  
Danxin Wang ◽  
Huizi Chen ◽  
Kathryn M. Momary ◽  
Larisa H. Cavallari ◽  
Julie A. Johnson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mrna Expression ◽  
Warfarin Dose ◽  
Candidate Snps ◽  
Promoter Regions ◽  
Dose Requirement ◽  
Genotype Effect ◽  
Warfarin Dose Requirement ◽  
Warfarin Dosing

Abstract Warfarin dose requirements have been associated with 2 main haplotypes in VKORC1, but the responsible polymorphisms remain unknown. To search for regulatory polymorphisms, we measured allelic mRNA expression of VKORC1 in human liver, heart, and B lymphocytes. The observed 2-fold allelic mRNA expression imbalance narrowed possible candidate SNPs to −1639G>A and 1173C<T. This genotype effect was observed selectively in the liver but not in heart or lymphocytes. In vitro expression of VKORC1 gene constructs, including coding and promoter regions, failed to reveal any genotype effect on transcription and mRNA processing. Chromatin immunoprecipitation with antibodies against acetyl-histone3 and K4-trimethyl-histone3 revealed preferential association of the promoter −1639 G allele with active chromatin, consistent with enhanced mRNA expression. The minor −1639 A allele generates a suppressor E-box binding site, apparently regulating gene expression by a mechanism undetectable with reporter gene assays. A clinical association study demonstrated that promoter SNP −1639G>A, and the tightly linked intron1 SNP 1173C>T, predict warfarin dose more accurately than intron 2 SNP 1542G>C in blacks. Increased warfarin dose requirement in blacks was accounted for by lower frequency of the −1639 A allele. Therefore, −1639G>A is a suitable biomarker for warfarin dosing across ethnic populations.

The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen

Blood ◽  
2005 ◽  
Vol 106 (7) ◽  
pp. 2329-2333 ◽  
Author(s):  
Elizabeth A. Sconce ◽  
Tayyaba I. Khan ◽  
Hilary A. Wynne ◽  
Peter Avery ◽  
Louise Monkhouse ◽  
...  
Keyword(s):  
Body Size ◽  
Warfarin Dose ◽  
Patient Characteristics ◽  
International Normalized Ratio ◽  
Dosing Regimen ◽  
Dose Requirement ◽  
Cyp2c9 Genotype ◽  
Daily Dose ◽  
Warfarin Dosing ◽  
The Impact

AbstractCurrent dosing algorithms do not account for genetic and environmental factors for warfarin dose determinations. This study investigated the contribution of age, CYP2C9 and VKORC1 genotype, and body size to warfarin-dose requirements. Studied were 297 patients with stable anticoagulation with a target international normalized ratio (INR) of 2.0 to 3.0. Genetic analyses for CYP2C9 (*2 and *3 alleles) and VKORC1 (-1639 polymorphism) were performed and venous INR and plasma R- and S-warfarin concentrations determined. The mean warfarin daily dose requirement was highest in CYP2C9 homozygous wild-type patients, compared with those with the variant *2 and *3 alleles (P &lt; .001) and highest in patients with the VKORC1 (position -1639) GG genotype compared with those with the GA genotype and the AA genotype (P &lt; .001). Mean warfarin daily dose requirements fell by 0.5 to 0.7 mg per decade between the ages of 20 to 90 years. Age, height, and CYP2C9 genotype significantly contributed to S-warfarin and total warfarin clearance, whereas only age and body size significantly contributed to R-warfarin clearance. The multivariate regression model including the variables of age, CYP2C9 and VKORC1 genotype, and height produced the best model for estimating warfarin dose (R2 = 55%). Based upon the data, a new warfarin dosing regimen has been developed. The validity of the dosing regimen was confirmed in a second cohort of patients on warfarin therapy.

Factors affecting the interindividual variability of warfarin dose requirement in adult Korean patients

2007 ◽  
Vol 8 (4) ◽  
pp. 329-337 ◽  
Author(s):  
Hyun-Jung Cho ◽  
Kie-Ho Sohn ◽  
Hyang-Mi Park ◽  
Kyung-Hoon Lee ◽  
BoYoung Choi ◽  
...  
Keyword(s):  
Interindividual Variability ◽  
Warfarin Dose ◽  
Dose Requirement ◽  
Factors Affecting ◽  
Korean Patients ◽  
Warfarin Dose Requirement

The effects of CYP2C9 and VKORC1 gene polymorphisms on warfarin maintenance dose in Turkish cardiac patients

2020 ◽  
Author(s):  
Cansu Selcan Akdeniz ◽  
Mehtap Cevik ◽  
Ismail Polat Canbolat ◽  
Selen Yurdakul ◽  
Penbe Cagatay ◽  
...  
Keyword(s):  
Warfarin Dose ◽  
Individual Variability ◽  
Considerable Proportion ◽  
Wild Type ◽  
Dose Requirement ◽  
Study Results ◽  
Warfarin Dose Requirement ◽  
Turkish Patients ◽  
Vkorc1 Gene ◽  
Warfarin Maintenance Dose

Aim: Our aim was to examine the effect of CYP2C9 and VKORC1 polymorphisms on warfarin dose requirements in Turkish patients. Materials & methods: 24 warfarin prescribed patients were included and analyzed for eight VKORC1 and 6 CYP2C9 polymorphisms in the study. Results: Patients with CYP2C9 *1/*1 and VKORC1 -1639 GG and GA genotypes required higher warfarin doses in comparison to wild type VKORC1 genotype. Patients with CYP2C9 *1/*3 and VKORC1 -1639 GG genotypes simultaneously, required the lowest dose of warfarin (4.64 mg/day). Patients with CYP2C9 *1/*1 and VKORC1 9041 AA genotype were found to require higher warfarin doses. Conclusion: Our results provide additional evidence to support the hypothesis that CYP2C9 *2, *3, VKORC1 9041 G > A polymorphisms explain considerable proportion of inter-individual variability in warfarin dose requirement.

scholarly journals Severe Fatigue is Highly Prevalent in Patients with IPF or Sarcoidosis

2020 ◽  
Vol 9 (4) ◽  
pp. 1178 ◽  
Author(s):  
Ada E. M. Bloem ◽  
Rémy L. M. Mostard ◽  
Naomi Stoot ◽  
Jan H. Vercoulen ◽  
Jeannette B. Peters ◽  
...  
Keyword(s):  
Functional Activity ◽  
Depression Scale ◽  
Patient Characteristics ◽  
Respiratory Illness ◽  
Cross Sectional Study ◽  
Pulmonary Sarcoidosis ◽  
Limited Information ◽  
Activity Impairment ◽  
Cross Sectional ◽  
Severe Fatigue

In patients with interstitial lung disease (ILD) next to dyspnea, fatigue is expected to be the most prevalent symptom. Surprisingly, the prevalence of severe fatigue has been scarcely studied in ILD patients and limited information on its associated factors is available. This study aimed to determine the prevalence of severe fatigue in patients with idiopathic pulmonary fibrosis (IPF) or pulmonary sarcoidosis and to identify the relationship between fatigue, patient characteristics, and clinical parameters. In this cross-sectional study, fatigue (checklist individual strength-fatigue (CIS-Fat)), demographics, lung function, dyspnea (modified-Medical Research Council (mMRC)), sleepiness (Epworth Sleepiness Scale), anxiety/depression (hospital anxiety and depression scale (HADS-A/HADS-D)), catastrophizing (fatigue catastrophizing scale (FCS)), functional activity impairment (respiratory illness quality-of-life (QoL-RIQ-Activity)), and health status (EuroQol five-dimensional descriptive system (EQ-5D-5L)) were assessed in outpatients with ILD. Mean CIS-Fat scores were 34.1 (SD ± 11.2) in 59 IPF patients and 40.0 (12.3) in 58 sarcoidosis patients. Severe fatigue (SD ± ≥36 points) was present in IPF patients (47.5%) and sarcoidosis (69%). In IPF, CIS-Fat correlated strongly (ρ > 0.5; p < 0.01) with FCS, QoL-RIQ-Activity, and EQ-5D-5L-Health and moderately (0.3 < ρ < 0.5; p < 0.01) with EQ-5D-5L-Index, mMRC, and HADS-D. In sarcoidosis, CIS-Fat correlated strongly with EQ-5D-5L-Health, QoL-RIQ-Activity, EQ-5D-5L-Index, HADS-D, and mMRC and moderately with FCS and hospitalization <12 months. Severe fatigue is highly prevalent in ILD patients and is associated with dyspnea, depression, catastrophizing, functional activity impairments, and QoL.

scholarly journals Vitamin K antagonists in children with heart disease: height and VKORC1 genotype are the main determinants of the warfarin dose requirement

Blood ◽  
2012 ◽  
Vol 119 (3) ◽  
pp. 861-867 ◽  
Author(s):  
Caroline Moreau ◽  
Fanny Bajolle ◽  
Virginie Siguret ◽  
Dominique Lasne ◽  
Jean-Louis Golmard ◽  
...  
Keyword(s):  
Vitamin K ◽  
Dose Response ◽  
Maintenance Dose ◽  
Vitamin K Antagonists ◽  
Warfarin Dose ◽  
International Normalized Ratio ◽  
Individual Variability ◽  
Dose Requirement ◽  
Warfarin Dose Requirement ◽  
Main Determinants

Abstract Managing vitamin K antagonist (VKA) therapy is challenging in children because of a narrow therapeutic range and wide inter- and intra-individual variability in dose response. Only a few small studies have investigated the effect of nongenetic and genetic factors on the dose response to VKAs in children. In a cohort study including 118 children (median age 9 years; range, 3 months-18 years) mostly with cardiac disease, we evaluated by multivariate analysis the relative contribution of nongenetic factors and VKORC1/CYP2C9/CYP4F2 genotypes on warfarin (n = 83) or fluindione (n = 35) maintenance dose and the influence of these factors on the time spent within/above/below the range. The results showed that height, target international normalized ratio and VKORC1 and CYP2C9 genotypes were the main determinants of warfarin dose requirement, accounting for 48.1%, 4.4%, 18.2%, and 2.0% of variability, respectively, and explaining 69.7% of the variability. Our model predicted the warfarin dose within 7 mg/wk in 86.7% of patients. None of the covariates was associated with the time spent above or below the international normalized ratio range. Whether this model predicts accurately the effective maintenance dose is currently being investigated.

scholarly journals Warfarin dose requirement in patients having severe thrombosis or thrombophilia

2019 ◽  
Vol 85 (8) ◽  
pp. 1684-1691 ◽  
Author(s):  
Tuukka A. Helin ◽  
Lotta Joutsi‐Korhonen ◽  
Heidi Asmundela ◽  
Mikko Niemi ◽  
Arto Orpana ◽  
...  
Keyword(s):  
Warfarin Dose ◽  
Dose Requirement ◽  
Warfarin Dose Requirement
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