Identification of the gene for vitamin K epoxide reductase

Abstract

Vitamin K epoxide reductase (VKOR) is the target of warfarin, the most widely prescribed anticoagulant for thromboembolic disorders. Although estimated to prevent twenty strokes per induced bleeding episode, warfarin is under-used because of the difficulty of controlling dosage and the fear of inducing bleeding. Although identified in 1974 (ref. 2), the enzyme has yet to be purified or its gene identified. A positional cloning approach has become possible after the mapping of warfarin resistance to rat chromosome 1 (ref. 3) and of vitamin K-dependent protein deficiencies to the syntenic region of human chromosome 16 (ref. 4). Localization of VKOR to 190 genes within human chromosome 16p12-q21 narrowed the search to 13 genes encoding candidate transmembrane proteins, and we used short interfering RNA (siRNA) pools against individual genes to test their ability to inhibit VKOR activity in human cells. Here, we report the identification of the gene for VKOR based on specific inhibition of VKOR activity by a single siRNA pool. We confirmed that MGC11276 messenger RNA encodes VKOR through its expression in insect cells and sensitivity to warfarin. The expressed enzyme is 163 amino acids long, with at least one transmembrane domain. Identification of the VKOR gene extends our understanding of blood clotting, and should facilitate development of new anticoagulant drugs.

Analysis of vkorc1 polymorphisms in Norway rats using the roof rat as outgroup

“…vkorc1 ) has been mapped [16,17]. The identification of the vkorc1 as the molecular target for anticoagulants [5-7,11] now should enable the design of studies to verify selection at the resolution of individual nucleotide sites, but such studies need to be designed such to enable the application of rigorous test for natural selection.…”

“…[4] for review and additional references). A warfarin-sensitive subcomponent of VKOR is encoded by the vitamin K epoxide reductase complex subunit 1 ( vkorc1 ) gene [5,6]. …”

Adaptative evolution of the Vkorc1 gene in Mus musculus domesticus is influenced by the selective pressure of anticoagulant rodenticides

“…While the VKOR activity was described in the 1970s, the VKORC1 enzyme catalyzing this activity was identified in 2004 only by two different teams (Li et al., 2004; Rost et al., 2004) Rost et al., 2004). This enzyme of 163 amino acids is coded by the vkorc1 gene.…”

Reversal of vitamin K antagonists prior to urgent surgery

“…7,8 The gene for VKOR encodes for several isoforms of the protein with varying sensitivities to the VKA inhibition. As a result of VKA inhibition of VKOR, the liver synthesizes partially carboxylated and de-carboxylated proteins with reduced activity, but clot formation is not completely inhibited.…”