Association of Genetic Polymorphisms of CYP2C9 and VKORC1 with Bleeding Following Warfarin: A Case-Control Study

Sridharan, Kannan; Modi, Tanvi; Bendkhale, Shital R; Kulkarni, D.B.; Gogtay, Nithya J; Thatte, Urmila M

doi:10.2174/1574884711666160118095322

Cited by 16 publications

(18 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…21 Thus, the presence of variant genotypes of CYP2C9 (*2 and *3) and VKORC1 (rs9923231 and rs9934438) is associated with increased risk of bleeding in warfarin users. [22][23][24] Of note, CYP2C9*2 and *3 variants have an activity of about 70% and 5%, respectively. 25 In fact, the CYP2C9*3 allele have a twofold higher risk of major bleeding in warfarin users.…”

Section: Discussionmentioning

confidence: 99%

Pharmacogenetics of vitamin K antagonists and bleeding risk prediction in atrial fibrillation

Serna

Rivera‐Caravaca

Gónzález-Conejero

et al. 2018

Eur J Clin Investigation

View full text Add to dashboard Cite

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. A baseline venous blood sample was obtained for DNA extraction. We gave an extra point to the HAS-BLED score if the patient was a simultaneous carrier of the VKORC1 and CYP2C9 polymorphisms related to bleeding, and we called this modified score "GEN|HAS-BLED." During a median follow-up of 7.6 years (IQR 5.6-8.0), all major bleeding events were recorded. Results: During follow-up, 106 (16.2%) patients experienced a major bleeding (2.81%/y; 42 intracranial haemorrhages and 44 gastrointestinal bleeding) and 24 (3.7%) died from major bleeding (0.48%/y). Cox regression analyses demonstrated a significant association between HAS-BLED or GEN|HAS-BLED and major bleeds, both as continuous or categorical scores. Comparison of receiver operating characteristic (ROC) curves shows that original HAS-BLED clinical score had better predictive ability than GEN|HAS-BLED (0.660, 95% CI 0.622-0.696 vs 0.645, 95% CI 0.607-0.682; P = .030). Discrimination and reclassification analyses showed that GEN|HAS-BLED did not improve sensitivity compared with the original score and even showed significant negative reclassification. Conclusion: Adding pharmacogenetic factors (ie polymorphisms of the VKORC1 and CYP2C9 genes) to the HAS-BLED score does not improve the prediction or discrimination performance for major bleeding. K E Y W O R D Satrial fibrillation, CYP2C9, haemorrhage, polymorphisms, VKORC1 Serna and Rivera-Caravaca equally contributed to this study. Rold an and Mar ın are joint senior authors.

show abstract

Section: Discussionmentioning

confidence: 99%

Pharmacogenetics of vitamin K antagonists and bleeding risk prediction in atrial fibrillation

Serna

Rivera‐Caravaca

Gónzález-Conejero

et al. 2018

Eur J Clin Investigation

View full text Add to dashboard Cite

show abstract

“…Estudo in vitro [6] envolvendo cultura de células geneticamente modificadas com variantes da enzima CYP2C9 de origem humana demonstrou que a presença desses alelos leva a uma diminuição entre 20% a 96% da atividade enzimática. Além disso, são cada vez mais crescentes as evidências que apontam um aumento significativo na chance de ocorrência de eventos adversos em indivíduos portadores dos alelos *2 ou *3, como eventos hemorrágicos com o uso da Varfarina [7], confirmando a funcionalidade e implicação clínica relevante dos alelos *2 e *3.…”

Section: N T R O D U ç ã Ounclassified

Experiences From an Extension Program: Awareness of the Population About the Importance and Use of Pharmacogenetics

Moraes¹,

Lacchini²

2017

Rev. Cult. Ext. USP

View full text Add to dashboard Cite

A expressão "farmacogenética" indica a existência de variações na sequência de DNA que podem influenciar a maneira como o corpo responde aos medicamentos, tanto em relação à eficácia terapêutica quanto à ocorrência de reações adversas aos medicamentos. Apesar de muito bem estabelecida e aplicada internacionalmente, o uso da farmacogenética ainda não é uma realidade no Brasil, especialmente no SUS. O objetivo geral desse trabalho foi produzir uma cartilha informativa sobre farmacogenética e aplicar essa cartilha para a população frequentadora do campus da USP de Ribeirão Preto, e fornecer de forma gratuita aos participantes um exame genético com a determinação dos alelos *2 e *3 da enzima CYP2C9, tema da cartilha. O presente projeto de extensão foi feito em paralelo a uma pesquisa clínica cujos resultados serão submetidos para revistas científicas e não serão reproduzidos aqui. Os participantes receberam informações gerais sobre farmacogenética de forma oral, em seguida leram a cartilha e a avaliaram através de um questionário. Esse estudo mostrou que, com o uso de materiais e método simples, é possível trazer a farmacogenética até mesmo para leigos, e isto pode ser uma importante abordagem para estimular o uso dessas informações por profissionais da saúde.Palavras-chave: Citocromo P-450 CYP2C9. Farmacogenética. Efeitos Colaterais. Reações Adversas Relacionadas a Medicamentos. A B S T R A C TThe term "pharmacogenetics" indicates the existence of variations in the DNA sequence that may influence the way our body responds to drugs, both in terms of therapeutic efficacy and the occurrence of adverse drug reactions. Although very well established and applied internationally, the use of pharmacogenetics is not yet a reality in Brazil, especially in SUS. The general objective of this work was to produce an

show abstract

“…[1] Warfarin exerts huge inter-individual variability owing to differences in the demographic characteristics, genetics, diet and concomitant drugs. [2] Warfarin is initiated usually at 5 mg and prothrombin time international normalized ratio (PT-INR) has been recommended to be tested at least four times in the first week of therapy. [3] Clinical and pharmacogenetic algorithms from International Warfarin Pharmacogenetics Consortium (IWPC) were validated and widely followed in many institutions for identifying the appropriate initial warfarin dose.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Stable Doses of Warfarin in a Patient Cohort

2020

Self Cite

View full text Add to dashboard Cite

Background Definitions for stable dose of warfarin varies in the reported studies. International warfarin pharmacogenetic consortium (IWPC) algorithm was generated from the data based on these definitions. Objective In the present study, we primarily evaluated whether any significant differences exist between the definitions for stable warfarin dose. Methods A prospective cross-sectional study in adults receiving warfarin for at least 3 months was carried out. Stable doses of warfarin as defined in previous studies were compared with the standard definition. Bland-Altman plots, Pearson’s correlation and intra-class coefficients (ICC) were used to assess the correlation, reliability and agreements between the doses. Results Sixty-four patients were recruited. Twenty definitions were obtained from the previous studies. We observed that all but one showed very high or high positive correlations; and either excellent or good ICC. No significant differences between the doses initiated and predicted by IWPC algorithm. Conclusion We observed similar stable doses between the definitions except for one. Hence, IWPC algorithm may not have any bias associated with inclusion of any studies with variable definitions for stable warfarin dose.

show abstract

Association of Genetic Polymorphisms of CYP2C9 and VKORC1 with Bleeding Following Warfarin: A Case-Control Study

Abstract: A significant association between CYP2C9 (1,2,*3) genotype and VKORC1 (1639 G>A) haplotype status has been found with increased bleeding tendency to warfarin. This may help to individualize therapy.

Cited by 16 publications

References 0 publications

Pharmacogenetics of vitamin K antagonists and bleeding risk prediction in atrial fibrillation

Pharmacogenetics of vitamin K antagonists and bleeding risk prediction in atrial fibrillation

Experiences From an Extension Program: Awareness of the Population About the Importance and Use of Pharmacogenetics

Evaluation of Stable Doses of Warfarin in a Patient Cohort

Contact Info

Product

Resources

About

Association of Genetic Polymorphisms of CYP2C9 and VKORC1 with Bleeding Following Warfarin: A Case-Control Study

Abstract: A significant association between CYP2C9 (*1,*2,*3) genotype and VKORC1 (1639 G>A) haplotype status has been found with increased bleeding tendency to warfarin. This may help to individualize therapy.

Cited by 16 publications

References 0 publications

Pharmacogenetics of vitamin K antagonists and bleeding risk prediction in atrial fibrillation

Pharmacogenetics of vitamin K antagonists and bleeding risk prediction in atrial fibrillation

Experiences From an Extension Program: Awareness of the Population About the Importance and Use of Pharmacogenetics

Evaluation of Stable Doses of Warfarin in a Patient Cohort

Contact Info

Product

Resources

About

Abstract: A significant association between CYP2C9 (1,2,*3) genotype and VKORC1 (1639 G>A) haplotype status has been found with increased bleeding tendency to warfarin. This may help to individualize therapy.