scholarly journals Multi‐site Investigation of Genetic Determinants of Warfarin Dose Variability in Latinos

2020 ◽  
Author(s):  
Nihal El Rouby ◽  
Leiliane Rodrigues Marcatto ◽  
Karla Claudio ◽  
Letícia Camargo Tavares ◽  
Heidi Steiner ◽  
...  
Keyword(s):  
Warfarin Dose ◽  
Site Investigation ◽  
Genetic Determinants ◽  
Dose Variability

scholarly journals Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups

Blood ◽  
2010 ◽  
Vol 115 (18) ◽  
pp. 3827-3834 ◽  
Author(s):  
Nita A. Limdi ◽  
Mia Wadelius ◽  
Larisa Cavallari ◽  
Niclas Eriksson ◽  
Dana C. Crawford ◽  
...  
Keyword(s):  
Linear Regression ◽  
Warfarin Dose ◽  
Population Level ◽  
Racial Groups ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Dose Prediction ◽  
Similar Dose ◽  
Warfarin Dosing ◽  
Dose Variability

Abstract Warfarin-dosing algorithms incorporating CYP2C9 and VKORC1 −1639G>A improve dose prediction compared with algorithms based solely on clinical and demographic factors. However, these algorithms better capture dose variability among whites than Asians or blacks. Herein, we evaluate whether other VKORC1 polymorphisms and haplotypes explain additional variation in warfarin dose beyond that explained by VKORC1 −1639G>A among Asians (n = 1103), blacks (n = 670), and whites (n = 3113). Participants were recruited from 11 countries as part of the International Warfarin Pharmacogenetics Consortium effort. Evaluation of the effects of individual VKORC1 single nucleotide polymorphisms (SNPs) and haplotypes on warfarin dose used both univariate and multi variable linear regression. VKORC1 −1639G>A and 1173C>T individually explained the greatest variance in dose in all 3 racial groups. Incorporation of additional VKORC1 SNPs or haplotypes did not further improve dose prediction. VKORC1 explained greater variability in dose among whites than blacks and Asians. Differences in the percentage of variance in dose explained by VKORC1 across race were largely accounted for by the frequency of the −1639A (or 1173T) allele. Thus, clinicians should recognize that, although at a population level, the contribution of VKORC1 toward dose requirements is higher in whites than in nonwhites; genotype predicts similar dose requirements across racial groups.

THE EFFECTS OF GENETIC AND NON GENETIC FACTORS ON WARFARIN DOSE RESPONSE IN VENOUS THROMBOEMBOLISM

2021 ◽  
pp. 4-5
Author(s):  
Bala Tripura Sundari . A ◽  
R. Sivaraj ◽  
Sunil Kumar Pandey
Keyword(s):  
Venous Thromboembolism ◽  
Dose Response ◽  
Oral Anticoagulant ◽  
Genetic Factors ◽  
Reference Lists ◽  
Warfarin Dose ◽  
Google Scholar ◽  
Factors Associated ◽  
Treatment And Prevention ◽  
Dose Variability

BACKGROUND Warfarin is the most commonly used oral anticoagulant for the treatment and prevention of thromboembolic disorders. Pharmacogenomics studies have shown that variants in CYP2C9 and VKORC1 genes are strongly and consistently associated with warfarin dose variability. METHODOLOGY In this review, we included patients on stable warfarin dose and had the genetics and non-genetics factors associated with mean warfarin dose. We searched PubMed, Medline, Scopus, Google scholar and reference lists of relevant reviews. CONCLUSION Genetic and non-genetic factors affects the dose of warfarin. Genetic factors and Non genetic factors plays a signicant role and that may affects the dose of warfarin

CYP2C9 and VKORC1 polymorphisms influence warfarin dose variability in patients on long-term anticoagulation

2012 ◽  
Vol 69 (4) ◽  
pp. 789-797 ◽  
Author(s):  
Paulo Caleb Junior Lima Santos ◽  
Carla Luana Dinardo ◽  
Isolmar Tadeu Schettert ◽  
Renata Alonso Gadi Soares ◽  
Liz Kawabata-Yoshihara ◽  
...  
Keyword(s):  
Warfarin Dose ◽  
Dose Variability

scholarly journals Pharmacogenetic warfarin dose refinements remain significantly influenced by genetic factors after one week of therapy

2012 ◽  
Vol 107 (02) ◽  
pp. 232-240 ◽  
Author(s):  
Petra Lenzini ◽  
Mia Wadelius ◽  
Andrea Jorgensen ◽  
Stephen Kimmel ◽  
Paul Ridker ◽  
...  
Keyword(s):  
Treatment Response ◽  
Genetic Factors ◽  
Validation Cohort ◽  
Warfarin Dose ◽  
Absolute Error ◽  
Clinical Algorithm ◽  
Response Index ◽  
Dose Variability ◽  
Index Treatment ◽  
Refinement Algorithm

SummaryBy guiding initial warfarin dose, pharmacogenetic (PGx) algorithms may improve the safety of warfarin initiation. However, once international normalised ratio (INR) response is known, the contribution of PGx to dose refinements is uncertain. This study sought to develop and validate clinical and PGx dosing algorithms for warfarin dose refinement on days 6–11 after therapy initiation. An international sample of 2,022 patients at 13 medical centres on three continents provided clinical, INR, and genetic data at treatment days 6–11 to predict therapeutic warfarin dose. Independent derivation and retrospective validation samples were composed by randomly dividing the population (80%/20%). Prior warfarin doses were weighted by their expected effect on S-warfarin concentrations using an exponential-decay pharmacokinetic model. The INR divided by that “effective” dose constituted a treatment response index. Treatment response index, age, amiodarone, body surface area, warfarin indication, and target INR were associated with dose in the derivation sample. A clinical algorithm based on these factors was remarkably accurate: in the retrospective validation cohort its R2 was 61.2% and median absolute error (MAE) was 5.0 mg/week. Accuracy and safety was confirmed in a prospective cohort (N=43). CYP2C9 variants and VKORC1–1639 G→A were significant dose predictors in both the derivation and validation samples. In the retrospective validation cohort, the PGx algorithm had: R2= 69.1% (p<0.05 vs. clinical algorithm), MAE= 4.7 mg/week. In conclusion, a pharmacogenetic warfarin dose-refinement algorithm based on clinical, INR, and genetic factors can explain at least 69.1% of therapeutic warfarin dose variability after about one week of therapy.

scholarly journals VKORC1 Asp36Tyr geographic distribution and its impact on warfarin dose requirements in Egyptians

2013 ◽  
Vol 109 (06) ◽  
pp. 1045-1050 ◽  
Author(s):  
Mohamed Hossam A. Shahin ◽  
Larisa H. Cavallari ◽  
Minoli A. Perera ◽  
Sherief I. Khalifa ◽  
Anne Misher ◽  
...  
Keyword(s):  
African Americans ◽  
Middle Eastern ◽  
Linear Regression Analysis ◽  
Warfarin Dose ◽  
The United States ◽  
Eastern Africa ◽  
Dose Requirement ◽  
Population Prevalence ◽  
Warfarin Dose Requirement ◽  
Dose Variability

SummaryThe VKORC1 Asp36Tyr single nucleotide polymorphism (SNP) is one of the most promising predictors of high warfarin dose, but data on its population prevalence is incomplete. We determined the frequency of this SNP in participants from seven countries on four continents and investigated its effect on warfarin dose requirement. One thousand samples were analysed to define the population prevalence of this SNP. Those samples included individuals from Egypt, Ghana, Sudan, Kenya, Saudi Arabia, Peru and African Americans from the United States. A total of 206 Egyptian samples were then used to investigate the effect of this SNP on warfarin dose requirements. This SNP was most frequent among Kenyans and Sudanese, with a minor allele frequency (MAF) of 6% followed by Saudi Arabians and Egyptians with a MAF of 3% and 2.5%, respectively. It was not detected in West Africans, based on our data from Ghana, and a large cohort of African Americans. Egyptian carriers of the VKORC1 Tyr36 showed higher warfarin dose requirement (57.1 ± 29.4 mg/week) than those with the Asp36Asp genotype (35.8 ± 16.6 mg/week; p=0.03). In linear regression analysis, this SNP had the greatest effect size among the genetic factors (16.6 mg/week increase in dose per allele), and improved the warfarin dose variability explained in Egyptians (model R2 from 31% to 36.5%). The warfarin resistant VKORC1 Asp36Tyr appears to be confined to north-eastern Africa and nearby Middle-Eastern populations, but in those populations where it is present, it has a significant influence on warfarin dose requirement and the percent of warfarin dose variability that can be explained.

scholarly journals A Genome-Wide Association Study Confirms VKORC1, CYP2C9, and CYP4F2 as Principal Genetic Determinants of Warfarin Dose

PLoS Genetics ◽  
2009 ◽  
Vol 5 (3) ◽  
pp. e1000433 ◽  
Author(s):  
Fumihiko Takeuchi ◽  
Ralph McGinnis ◽  
Stephane Bourgeois ◽  
Chris Barnes ◽  
Niclas Eriksson ◽  
...  
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Warfarin Dose ◽  
Genome Wide Association ◽  
Genetic Determinants ◽  
Genome Wide ◽  
A Genome

scholarly journals The effect of genetic and nongenetic factors on warfarin dose variability in Qatari population

2019 ◽  
Vol 20 (2) ◽  
pp. 277-284 ◽  
Author(s):  
Loulia Bader ◽  
Ahmad Mahfouz ◽  
Mohammed Kasem ◽  
Shaban Mohammed ◽  
Sumayya Alsaadi ◽  
...  
Keyword(s):  
Warfarin Dose ◽  
Dose Variability

scholarly journals The Creating an Optimal Warfarin Nomogram (CROWN) Study

2012 ◽  
Vol 107 (01) ◽  
pp. 59-68 ◽  
Author(s):  
Todd S. Perlstein ◽  
Samuel Z. Goldhaber ◽  
Kerrie Nelson ◽  
Victoria Joshi ◽  
T. Morgan ◽  
...  
Keyword(s):  
Therapeutic Range ◽  
Significant Proportion ◽  
Warfarin Dose ◽  
Clinical Trial Registration ◽  
Therapeutic Anticoagulation ◽  
Dosing Algorithm ◽  
Epoxide Reductase ◽  
Secondary Endpoints ◽  
Warfarin Dosing ◽  
Dose Variability

SummaryA significant proportion of warfarin dose variability is explained by variation in the genotypes of the cytochrome P450 CYP2C9 and the vitamin K epoxide reductase complex, VKORC1, enzymes that influence warfarin metabolism and sensitivity, respectively. We sought to develop an optimal pharmacogenetic warfarin dosing algorithm that incorporated clinical and genetic information. We enroled patients initiating warfarin therapy. Genotyping was performed of the VKORC1, –1639G>A, the CYP2C9*2, 430C>T, and the CYP2C9*3, 1075C>A genotypes. The initial warfarin dosing algorithm (Algorithm A) was based upon established clinical practice and published warfarin pharmacogenetic information. Subsequent dosing algorithms (Algorithms B and Algorithm C) were derived from pharmacokinetic / pharmacodynamic (PK/PD) modelling of warfarin dose, international normalised ratio (INR), clinical and genetic factors from patients treated by the preceding algorithm(s). The primary outcome was the time in the therapeutic range, considered an INR of 1.8 to 3.2. A total of 344 subjects are included in the study analyses. The mean percentage time within the therapeutic range for each subject increased progressively from Algorithm A to Algorithm C from 58.9 (22.0), to 59.7 (23.0), to 65.8 (16.9) percent (p = 0.04). Improvement also occurred in most secondary endpoints, which included the per-patient percentage of INRs outside of the therapeutic range (p = 0.004), the time to the first therapeutic INR (p = 0.07), and the time to achieve stable therapeutic anticoagulation (p < 0.001). In conclusion, warfarin pharmacogenetic dosing can be optimised in real time utilising observed PK/PD information in an adaptive fashion.Clinical Trial Registration: ClinicalTrials.gov (NCT00401414)

Prioritizing rs7294 as a mirSNP contributing to warfarin dosing variability

2020 ◽  
Vol 21 (4) ◽  
pp. 257-267
Author(s):  
Linda Koshy ◽  
S Harikrishnan ◽  
PR Sudhakaran
Keyword(s):  
Linkage Disequilibrium ◽  
Association Studies ◽  
Meta Analysis ◽  
Warfarin Dose ◽  
In Silico Analysis ◽  
Population Based ◽  
Genome Wide Association Studies ◽  
Warfarin Dosing ◽  
Dosing Accuracy ◽  
Dose Variability

Aim: The role of mirSNPs in the 3′UTR of VKORC1, CYP2C9 and CYP4F2 genes that could influence warfarin dose variability via a discrete miRNA-mediated mechanism remains unexplained. Methods: Genotypic data in the 1000 Genomes dataset were analyzed for pair-wise linkage disequilibrium and allelic enrichment. Results: MirSNP rs7294 in the 3′UTR of VKORC1 gene displayed varying strengths of linkage disequilibrium with rs9923231 and rs9934438 across populations, albeit consistently associated with higher warfarin dose requirements based on genome-wide association studies, meta-analysis and population-based association studies. In silico analysis predicted altered hybrid stability for the hsa-miR-133a-3p conserved binding site, providing evidence for miRNA-mediated gene regulation. Conclusion: The results support the inclusion of rs7294 as a functional variable for population-specific dosing algorithms to improve dosing accuracy.

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