<i>VKORC1</i> mutations in patients with partial resistance to phenprocoumon

Schmeits, Peter C. J.; Hermans, Mirjam H. A.; Geest-Daalderop, Johanna H. H. van; Poodt, Jeroen; Nolting, Pernette R. W. De Sauvage; Conemans, J. M. H.

doi:10.1111/j.1365-2141.2009.08017.x

Cited by 14 publications

(16 citation statements)

References 13 publications

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“…This variability being partly due to genetic polymorphisms in the Vkorc1 gene, numerous studies have been performed to detect new Vkorc1 mutations in patients resistant to AVK. These studies allowed to detect in humans 27 mutations in the coding sequence of the Vkorc1 gene (Bodin, Horellou, Flaujac, Loriot, & Samama, 2005; Bodin, Perdu, Diry, Horellou, & Loriot, 2008; D'Andrea et al., 2005; Harrington, Siddiq, Allford, Shearer, & Mumford, 2011; Harrington et al., 2008; Loebstein et al., 2007; Osman, Enström, Arbring, Söderkvist, & Lindahl, 2006; Peoc'h, Pruvot, Gourmel, Dit Sollier, & Drouet, 2009; Rieder et al., 2005; Rishavy, Usubalieva, Hallgren, & Berkner, 2011; Rost et al., 2004; Schmeits et al., 2010; Watzka et al., 2011; Wilms, Touw, Conemans, Veldkamp, & Hermans, 2008). In rats, 15 missense mutations in the Vkorc1 gene of Rattus norvegicus have been described in Europe (Grandemange, Lasseur, Longin‐Sauvageon, Benoit, & Berny, 2010; Haniza et al., 2015; Pelz et al., 2005, 2012; Rost et al., 2004).…”

Section: Discussionmentioning

confidence: 99%

Adaptative evolution of theVkorc1gene inMus musculus domesticusis influenced by the selective pressure of anticoagulant rodenticides

Goulois

Lambert

Legros³

et al. 2017

Ecology and Evolution

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Anticoagulant rodenticides are commonly used to control rodent pests worldwide. They specifically inhibit the vitamin K epoxide reductase (VKORC1), which is an enzyme encoded by the Vkorc1 gene, involved in the recycling of vitamin K. Therefore, they prevent blood clotting. Numerous mutations of Vkorc1 gene were reported in rodents, and some are involved in the resistant to rodenticides phenotype. Two hundred and sixty‐six mice tails were received from 65 different locations in France. Coding sequences of Vkorc1 gene were sequenced in order to detect mutations. Consequences of the observed mutations were evaluated by the use of recombinant VKORC1. More than 70% of mice presented Vkorc1 mutations. Among these mice, 80% were homozygous. Contrary to brown rats for which only one predominant Vkorc1 genotype was found in France, nine missense single mutations and four double mutations were observed in house mice. The single mutations lead to resistance to first‐generation antivitamin K (AVKs) only and are certainly associated with the use of these first‐generation molecules by nonprofessionals for the control of mice populations. The double mutations, probably obtained by genetic recombination, lead to in vitro resistance to all AVKs. They must be regarded as an adaptive evolution to the current use of second‐generation AVKs. The intensive use of first‐generation anticoagulants probably allowed the selection of a high diversity of mutations, which makes possible the genetic recombination and consequently provokes the emergence of the more resistant mutated Vkorc1 described to date.

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Section: Discussionmentioning

confidence: 99%

Adaptative evolution of theVkorc1gene inMus musculus domesticusis influenced by the selective pressure of anticoagulant rodenticides

Goulois

Lambert

Legros³

et al. 2017

Ecology and Evolution

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“…Since 2004, 26 different OACR-associated missense mutations in human VKORC1 (hVKORC1) have been reported. 3,7,[9][10][11][12][13][14][15][16] However, the molecular mechanism of OAC inhibition of VKORC1 and how mutations in this enzyme lead to OAC resistance are still unclear. Historically, investigations of wild-type and mutant hVKORC1 have relied on the "classical" in vitro dithiothreitol-driven VKOR assay to measure VKORC1 function and assess OAC inhibition.…”

Section: Introductionmentioning

confidence: 99%

Human VKORC1 mutations cause variable degrees of 4-hydroxycoumarin resistance and affect putative warfarin binding interfaces

Czogalla¹,

Biswas²,

Wendeln³

et al. 2013

Blood

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Key Points• In vitro analysis of VKORC1 mutations perfectly reflects patients' warfarin resistance phenotypes.• In silico docking of warfarin on a VKORC1 model reveals a putative docking site in agreement with the locations of OACR-associated mutations.Since the discovery of warfarin-sensitive vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1), 26 human VKORC1 (hVKORC1) missense mutations have been associated with oral anticoagulant resistance (OACR). Assessment of warfarin resistance using the "classical" dithiothreitol-driven vitamin K 2,3-epoxide reductase (VKOR) assay has not reflected clinical resistance phenotypes for most mutations. Here, we present half maximal inhibitory concentrations (IC 50 ) results for 21 further hVKORC1 mutations obtained using a recently validated cell-based assay (J Thromb Haemost 11(5):872). In contrast to results from the dithiothreitol-driven VKOR assay, all mutations exhibited basal VKOR activity and warfarin IC 50 values that correspond well to patient OACR phenotypes. Thus, the present assay is useful for functional investigations of VKORC1 and oral anticoagulant inhibition of the vitamin K cycle. Additionally, we modeled hVKORC1 on the previously solved structure of a homologous bacterial enzyme and performed in silico docking of warfarin on this model. We identified one binding site delineated by 3 putative binding interfaces. These interfaces comprise linear sequences of the endoplasmic reticulum-lumenal loop (Ser52-Phe55) and the first (Leu22-Lys30) and fourth (Phe131-Thr137) transmembrane helices. All known OACR-associated hVKORC1 mutations are located in or around these putative interfaces, supporting our model. (Blood. 2013;122(15):2743-2750

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“…The identification of the genes encoding cytochrome P-450 2C9 enzyme ( CYP2C9 ), the principal metabolizing enzyme of the coumarins, and vitamin K epoxide reductase enzyme ( VKORC1 ), the molecular target for coumarins, has strongly stimulated the research on pharmacogenetics of coumarins in the last decade. Several variants in CYP2C9 (CYP2C9 *2 and especially the CYP2C9 *3 allele) and VKORC1 genes (especially the 1639G>A polymorphism) are associated with effective coumarin derivative dose [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]. CYP2C9 and VKORC1 seem the only genes with relevant effects on coumarin response [10], except the rs2108622 polymorphism in the gene encoding cytochrome P450, family 4, subfamily F, polypeptide 2 ( CYP4F2 ) which could also influence warfarin dose [9].…”

Section: Introductionmentioning

confidence: 99%

A Novel, Single Algorithm Approach to Predict Acenocoumarol Dose Based on CYP2C9 and VKORC1 Allele Variants

et al. 2010

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The identification of CYP2C9 and VKORC1 genes has strongly stimulated the research on pharmacogenetics of coumarins in the last decade. We assessed the combined influence of CYP2C9 *2 and *3, and VKORC1 c.-1639G>A, 497C>G, and 1173C>T variants, on acenocoumarol dosage using a novel algorithm approach, in 193 outpatients who had achieved stable anticoagulation. We constructed an “acenocoumarol-dose genotype score” (AGS, maximum score = 100) based on the number of alleles associated with higher acenocoumarol dosage carried by each subject for each polymorphism. The mean AGS was higher in the high-dose (>28mg/week) compared with the low-dose (<7mg/week) group (mean(SEM) of 84.1±3.4 vs. 62.2±4.8, P = 0.008). An AGS>70 was associated with an increased odds ratio (OR) of requiring high acenocoumarol dosage (OR: 3.347; 95%CI: 1.112–10.075; P = 0.032). In summary, although more research is necessary in other patient cohorts, and this algorithm should be replicated in an independent sample, our data suggest that the AGS algorithm could be used to help discriminating patients requiring high acenocoumarol doses to achieve stable anti-coagulation.

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VKORC1 mutations in patients with partial resistance to phenprocoumon

Cited by 14 publications

References 13 publications

Adaptative evolution of theVkorc1gene inMus musculus domesticusis influenced by the selective pressure of anticoagulant rodenticides

Adaptative evolution of theVkorc1gene inMus musculus domesticusis influenced by the selective pressure of anticoagulant rodenticides

Human VKORC1 mutations cause variable degrees of 4-hydroxycoumarin resistance and affect putative warfarin binding interfaces

A Novel, Single Algorithm Approach to Predict Acenocoumarol Dose Based on CYP2C9 and VKORC1 Allele Variants

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