ArticleBMC genetics2014
Confirmation of warfarin resistance of naturally occurring VKORC1 variants by coexpression with coagulation factor IX and in silico protein modelling.
Article in BMC genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers, 2 of them syntheses that pooled it.
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Who cites it
7 citing papers in PubMed, 2 syntheses or guidelines pooled it, 18 citations in OpenAlex.
- Recommendations for Clinical Warfarin Genotyping Allele Selection: A Report of the Association for Molecular Pathology and the College of American Pathologists.The Journal of molecular diagnostics : JMD · 2020Guideline
- Polymorphism related to cardiovascular risk in hemodialysis subjects: a systematic review.Jornal brasileiro de nefrologiaPooled it
- Structural disruption of VKORC1 by resistance mutations reveals a conserved hydrophobic pattern essential for warfarin binding: insights from molecular dynamics analyses.Molecular diversity · 2026Article
- Development of a sandwich enzyme-linked immunosorbent assay (ELISA) to quantify γ-glutamyl-carboxylated clotting factor IX and assess redox susceptibility of anticoagulant chemicals.The Journal of veterinary medical science · 2022Article
- Association of Warfarin Therapy withIranian journal of pharmaceutical research : IJPR · 2017Article
- Structural Modeling Insights into Human VKORC1 Phenotypes.Nutrients · 2015Review
- Zebrafish vitamin K epoxide reductases: expression in vivo, along extracellular matrix mineralization and under phylloquinone and warfarin in vitro exposure.Fish physiology and biochemistry · 2015Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundVKORC1 has been identified some years ago as the gene encoding vitamin K epoxide reductase (VKOR) - the target protein for coumarin derivates like warfarin or phenprocoumon. Resistance against warfarin and other coumarin-type anticoagulants has been frequently reported over the last 50 years in rodents due to problems in pest control as well as in thrombophilic patients showing variable response to anticoagulant treatment. Many different mutations have already been detected in the VKORC1 gene leading to warfarin resistance in rats, mice and in humans. Since the conventional in vitro dithiothreitol (DTT)-driven VKOR enzymatic assay often did not reflect the in vivo status concerning warfarin resistance, we recently developed a cell culture-based method for coexpression of VKORC1 with coagulation factor IX and subsequent measurement of secreted FIX in order to test warfarin inhibition in wild-type and mutated VKORC1.
resultsIn the present study, we coexpressed wild-type factor IX with 12 different VKORC1 variants which were previously detected in warfarin resistant rats and mice. The results show that amino acid substitutions in VKORC1 maintain VKOR activity and are associated with warfarin resistance. When we projected in silico the amino acid substitutions onto the published three-dimensional model of the bacterial VKOR enzyme, the predicted effects matched well the catalytic mechanism proposed for the bacterial enzyme.
conclusionsThe established cell-based system for coexpression of VKORC1 and factor IX uses FIX activity as an indicator of carboxylation efficiency. This system reflects the warfarin resistance status of VKORC1 mutations from anticoagulant resistant rodents more closely than the traditional DTT-driven enzyme assay. All mutations studied were also predicted to be involved in the reaction mechanism.
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