VKORC1 Asp36Tyr warfarin resistance marker is common in Ethiopian individuals

Aklillu, Eleni; Leong, Cheryl; Loebstein, Ronen; Halkin, Hillel; Gak, Eva

doi:10.1182/blood-2008-01-135863

Cited by 39 publications

(32 citation statements)

References 9 publications

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“…Three of the four warfarin-resistant mutations that we isolated are located in the MtbVKOR-coding region. Consistent with our suggestion that bacterial and human VKOR share common features is the finding that these three mutations alter amino acid residues that correspond to the same or similar sites as those found among humans who require higher doses of warfarin (7,(18)(19)(20)(21)(22)(23). These mutations do not alter expression of the protein and therefore may be affecting the binding of warfarin to the protein or altering the redox activity of the protein to overcome the inhibition.…”

Section: Discussionsupporting

confidence: 84%

“…A comparison of the sequences of MtbVKOR with that of human VKORC1 reveals an alignment in which Asp50 corresponds to Asp36 in humans. In Ashkenazi Jewish and Ethiopian populations, an Asp36-to-Tyr change is associated with warfarin resistance (18,19). Although the Aspto-Glu mutation represents a rather conservative change, both this and the Tyr replacement found in the human enzyme result in bulkier residues, which may interfere with the binding of warfarin.…”

Section: Warfarin-resistance Mutations In the M Tuberculosis Vkor Homentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of bacterial disulfide bond formation by the anticoagulant warfarin

Dutton

Wayman

Wei

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Blood coagulation in humans requires the activity of vitamin K epoxide reductase (VKOR), the target of the anticoagulant warfarin (Coumadin). Bacterial homologs of VKOR were recently found to participate in a pathway leading to disulfide bond formation in secreted proteins of many bacteria. Here we show that the VKOR homolog from the bacterium Mycobacterium tuberculosis, the causative agent of human tuberculosis, is inhibited by warfarin and that warfarin-resistant mutations of mycobacterial VKOR appear in similar locations to mutations found in human patients who require higher doses of warfarin. Deletion of VKOR results in a severe growth defect in mycobacteria, and the growth of M. tuberculosis is inhibited by warfarin. The bacterial VKOR homolog may represent a target for antibiotics and a model for genetic studies of human VKOR. We present a simple assay in Escherichia coli, based on a disulfide-sensitive β-galactosidase, which can be used to screen for stronger inhibitors of the M. tuberculosis VKOR homolog.vitamin K epoxide reductase | DsbB | DsbA | Mycobacterium tuberculosis T he stability of many secreted proteins depends on the presence of structural disulfide bonds. Disulfide bond formation in Escherichia coli requires two cell-envelope proteins, DsbA and DsbB (1). The periplasmic protein DsbA, a thioredoxin family member, is the direct catalyst of disulfide bond formation. The cytoplasmic membrane protein DsbB maintains DsbA in the oxidized, active state by transferring electrons from DsbA to membrane-bound quinones. Unlike E. coli, many other bacteria do not have a DsbB protein encoded in their genomes, but instead have an alternative pathway for disulfide bond formation (2, 3). In place of DsbB, these bacteria use a homolog of an enzyme required for blood coagulation in humans. This enzyme is vitamin K epoxide reductase (VKOR), the target of the most widely used oral anticoagulant, warfarin (Coumadin).We previously showed that the VKOR homolog from Mycobacterium tuberculosis was capable of replacing DsbB in E. coli and thereby restoring disulfide bond formation to an E. coli ΔdsbB strain (2). Similar results were obtained with a VKOR homolog from a cyanobacterium (3). Although bacterial VKOR homologs do not show sequence similarity to DsbB, these results suggest that they may be carrying out similar reactions to those of DsbB: the oxidation of DsbA-like proteins followed by the reduction of quinones.Although the cellular processes in which the bacterial VKOR (and DsbB) and human VKOR are involved (disulfide bond formation and blood coagulation) are quite different, the enzymatic reactions that they can carry out are analogous. In both cases, the enzymes mediate the transfer of electrons from a thioredoxin-like protein to a quinone. Human VKOR can transfer electrons from protein disulfide isomerase, also a thioredoxin family member and the primary catalyst for disulfide bond formation in eukaryotic secreted proteins, to vitamin K, a quinone, in the endoplasmic reticulum membrane (4-8). This reaction...

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Section: Discussionsupporting

confidence: 84%

Section: Warfarin-resistance Mutations In the M Tuberculosis Vkor Homentioning

confidence: 99%

Inhibition of bacterial disulfide bond formation by the anticoagulant warfarin

Dutton

Wayman

Wei

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…This mutation was first reported in a case of a patient requiring more than 10 mg per day of warfarin, and was later described by Loebstein et al [7] and appears to be comparatively common amongst Jewish ethnic groups [9]. It is noteworthy that the family members and the patient reported in this study, and carrying the haplotype including these mutations, belongs to the Ashkenasi Jewish group and originated from Eastern Europe.…”

supporting

confidence: 55%

“…Common genetic polymorphisms in VKORC1 are associated with both a low dose requirement (and a high risk of over anticoagulation) as well as a high dose requirement [1][2][3][4][5][6][7]. Rare missense mutations appear to be the cause of partial or complete resistance to vitamin K antagonists (VKA) in both humans and rats [1,[8][9][10]. In the present study, we report genetic variations in VKORC1 as the molecular basis for the high dose requirement of warfarin and other VKA in six patients that received long-term treatment with unusually high doses of various oral anticoagulants (warfarin, acenocoumarol, fluindione and phenprocoumon).…”

mentioning

confidence: 99%

Multiple genetic alterations in vitamin K epoxide reductase complex subunit 1 gene (VKORC1) can explain the high dose requirement during oral anticoagulation in humans

Bodin

Perdu

Diry

et al. 2008

Journal of Thrombosis and Haemostasis

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“…Further, about 15% of non-Jewish Ethiopians carry this variant, although the study did not attempt to correlate this variant and warfarin dose. 20 In contrast, this variant was much less common in both African and Yemenite Jews. 19 In the present study, sequencing the coding region of VKORC1 did not identify novel DNA variants that account for warfarin resistance in the Marshfield Cohort, which is predominately of German and Northern European ancestry.…”

Section: Vkorc1 -1fmentioning

confidence: 92%

Absence of Novel CYP4F2 and VKORC1 Coding Region DNA Variants in Patients Requiring High Warfarin Doses

Burmester

Berg²,

Glurich³

et al. 2011

Clinical Medicine & Research

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Objective:Warfarin is an FDA-approved oral anticoagulant for long-term prevention of thromboembolism. Substantial inter-individual variation in dosing requirements and the narrow therapeutic index of this widely-prescribed drug make safe initiation and dose stabilization challenging. Single nucleotide polymorphisms (SNPs) occurring in CYP2C9, VKORC1, and CYP4F2 genes are known to impact dose, and VKORC1 and CYP4F2 polymorphisms are associated with higher therapeutic dose requirements in our cohort. However, the most advanced regression models using personal, clinical, and genetic factors to predict individual stable dose account for only 50% to 60% of the observed variability in stable theapeutic dose in Caucasians. Design and Methods:In this study, we used DNA sequence analysis to determine whether additional variants in CYP4F2 and VKORC1 gene coding regions contribute to variable dosing requirements among individuals for whom the actual dose was the highest relative to regression modelpredicted dose. Results and Conclusions:No novel DNA variants in the coding regions of these genes were identified among subjects requiring high warfarin doses, suggesting that other factors yet to be defined contribute to variability in warfarin dose requirements in this subset of our cohort. Al though warfarin is the most commonly used drug for chronic prevention of thromboembolic events and stroke, it also ranks high among drugs that cause serious adverse events. 1,2 The narrow therapeutic index coupled with substantial inter-individual variability in warfarin dose requirement puts patients at increased risk for hemorrhagic events, and the variability in dose requirements has been attributed to inter-individual differences in medical, personal, and genetic factors. Some factors known to contribute to this variability include valve replacement, diabetes, body surface area (BSA), age, and DNA variants in three enzymes whose activity impacts vitamin K-dependent synthesis of coagulation factors: CYP2C9, VKORC1, and CYP4F2.3-7 Regression models that incorporate these factors have been developed to predict stable dose in order to improve clinical management (eg, time in thereapeutic range) and reduce thrombotic and hemorrhagic events. However, because these algorithms collectively explain only 50% to 60% of dose variability in Caucasians, 8,9 efforts are continuing to identify additional genetic and clinical factors that systematically impact warfarin dose requirements.

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VKORC1 Asp36Tyr warfarin resistance marker is common in Ethiopian individuals

Cited by 39 publications

References 9 publications

Inhibition of bacterial disulfide bond formation by the anticoagulant warfarin

Inhibition of bacterial disulfide bond formation by the anticoagulant warfarin

Multiple genetic alterations in vitamin K epoxide reductase complex subunit 1 gene (VKORC1) can explain the high dose requirement during oral anticoagulation in humans

Absence of Novel CYP4F2 and VKORC1 Coding Region DNA Variants in Patients Requiring High Warfarin Doses

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