title: Comparative genetics of warfarin resistance.
abstract: Warfarin and other 4-hydroxycoumarin-based 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.
authors.affiliation: Prof. Dr. Johannes Oldenburg, Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Sigmund Freud Str. 25, 53105 Bonn, Germany, E-mail: johannes.oldenburg@ukb.uni-bonn.de, Tel. +49/(0)228/287 51 75, Fax +49/(0)228/287 51 76.
authors.forename: J
authors.initials: J
authors.lastname: Oldenburg
authors.forename: C R
authors.initials: CR
authors.lastname: Müller
authors.forename: S
authors.initials: S
authors.lastname: Rost
authors.forename: M
authors.initials: M
authors.lastname: Watzka
authors.forename: C G
authors.initials: CG
authors.lastname: Bevans
mesh_terms: D000925:Anticoagulants / Q000627:therapeutic use; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008661:Metabolism, Inborn Errors / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D013927:Thrombosis / Q000188:drug therapy* / Q000235:genetics*; D064417:Vitamin K Epoxide Reductases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D014859:Warfarin / Q000627:therapeutic use*
chemical_list: D000925:Anticoagulants; D014859:Warfarin; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases
keywords: 3-epoxide reductase complex subunit 1; Genetics; VKORC1; vitamin K 2; warfarin resistance