Comparative genetics of warfarin resistance

Summary

Warfarin and other 4-hydroxycoumarinbased oral anticoagulants targeting vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1) are administered to humans, mice and rats with different purposes in mind – to act as pesticides in high-dosage baits for killing rodents, but also to save lives when administered in low dosages as antithrombotic drugs in humans. However, high-dosage warfarin used to control rodent populations has resulted in numerous mutations causing warfarin resistance. Currently, six single missense mutations in mice, 12 distinct missense mutations in rats, as well as compound heterozygous or homozygous mutations with up to six distinct missense mutations per Vkorc1 allele have been described. Warfarin resistance missense mutations for human VKORC1 have also been found world-wide, but differ characteristically from those in rodents. In humans, 26 distinct mutations have been characterized, but occur only rarely either in heterozygous or, even rarer, in homozygous form.

In this review, we summarize the known VKORC1 missense mutations causing warfarin and other 4-hydroxycoumarin drug resistance, identify genomics databases as new sources of data, explore possible underlying genetic mechanisms, and summarize similarities and differences between warfarin resistant VKORC1 variants in humans and rodents.

Zusammenfassung

Warfarin und andere 4-Hydroxycumarin-basierte orale Antikoagulanzien, die VKORC1 (Vitamin-K-2,3-epoxid-Reductase-Komplex Untereinheit 1) inhibieren, werden bei Menschen und den Nagern Maus und Ratte angewandt: als Rodentizid in hoher Dosierung und als antithrombotische Substanzen beim Menschen in niedriger Dosierung. Bald nach der Hochdosisanwendung bei Nagern kam es zu Resistenzen, die durch Mutationen in VKORC1 hervorgerufen werden. Zurzeit sind 6 Missense-Mutationen bei Mäusen, 12 Missense-Mutationen bei Ratten, einschließlich compound heterozygoter oder homozygoter Mutationen mit bis zu 6 Missense-Mutationen pro Vkorc1-Allel bekannt. Ebenfalls wurden weltweit 26 Warfarin-resistente Missense-Mutationen beim Menschen im VKORC1-Gen in heterozygoter, selten in homozygoter Ausprägung beschrieben.

In dieser Übersicht fassen wir die VKORC1-Missense-Mutationen zusammen, die zur Resistenz gegen Warfarin und andere 4-Hydroxycumarine führen. Des Weiteren berichten wir über VKORC1-Varianten in genomischen Datenbanken, Mechanismen der Resistenzentwicklung und vergleichen die zu Warfarin-Resistenz führenden VKORC1-Varianten beim Menschen und bei Nagern.

Keywords

Genetics - vitamin K 2,3-epoxide reductase complex subunit 1 - VKORC1 - warfarin resistance

Schlüsselwörter

Genetik - Vitamin-K-2,3-epoxid-ReductaseKomplex Untereinheit 1 - VKORC1 - Warfarinresistenz

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