Originally published as Genetics Published Articles Ahead of Print on May 6, 2005.

Genetics, Vol. 170, 1839-1847, August 2005, Copyright © 2005
doi:10.1534/genetics.104.040360

The Genetic Basis of Resistance to Anticoagulants in Rodents

Hans-Joachim Pelz^*,1, Simone Rost^,1, Mirja Hünerberg, Andreas Fregin, Ann-Charlotte Heiberg, Kristof Baert, Alan D. MacNicoll^**, Colin V. Prescott, Anne-Sophie Walker, Johannes Oldenburg and Clemens R. Müller^,2

^* Biologische Bundesanstalt für Land-und Forstwirtschaft, Institut für Nematologie und Wirbeltierkunde, 48161 Münster, Germany
Institut für Humangenetik, Universität Würzburg, Biozentrum, 97074 Würzburg, Germany
Danish Pest Infestation Laboratory, Danish Institute of Agricultural Sciences, DK-2800 Kgs. Lyngby, Denmark
Institute for Forestry and Game Management, 9500 Geraardsbergen, Belgium
^** Central Science Laboratory, Defra, Sand Hutton, York YO41 1LZ, United Kingdom
School of Animal and Microbial Sciences, The University of Reading, Whiteknights, Reading RG6 6AJ, United Kingdom
Institut National de la Recherche Agronomique (INRA), Unité de Phytopharmacie et Médiateurs Chimiques, 78026 Versailles, France
Institut für Transfusionsmedizin und Immunhämatologie, DRK Blutspendedienst Baden-Württemberg-Hessen, 60526 Frankfurt/M, Germany

² Corresponding author: Institut für Humangenetik, Universität Würzburg, Biozentrum, Am Hubland, 97074 Würzburg, Germany.
E-mail: crm{at}biozentrum.uni-wuerzburg.de

Anticoagulant compounds, i.e., derivatives of either 4-hydroxycoumarin (e.g., warfarin, bromadiolone) or indane-1,3-dione (e.g., diphacinone, chlorophacinone), have been in worldwide use as rodenticides for >50 years. These compounds inhibit blood coagulation by repression of the vitamin K reductase reaction (VKOR). Anticoagulant-resistant rodent populations have been reported from many countries and pose a considerable problem for pest control. Resistance is transmitted as an autosomal dominant trait although, until recently, the basic genetic mutation was unknown. Here, we report on the identification of eight different mutations in the VKORC1 gene in resistant laboratory strains of brown rats and house mice and in wild-caught brown rats from various locations in Europe with five of these mutations affecting only two amino acids (Tyr139Cys, Tyr139Ser, Tyr139Phe and Leu128Gln, Leu128Ser). By recombinant expression of VKORC1 constructs in HEK293 cells we demonstrate that mutations at Tyr139 confer resistance to warfarin at variable degrees while the other mutations, in addition, dramatically reduce VKOR activity. Our data strongly argue for at least seven independent mutation events in brown rats and two in mice. They suggest that mutations in VKORC1 are the genetic basis of anticoagulant resistance in wild populations of rodents, although the mutations alone do not explain all aspects of resistance that have been reported. We hypothesize that these mutations, apart from generating structural changes in the VKORC1 protein, may induce compensatory mechanisms to maintain blood clotting. Our findings provide the basis for a DNA-based field monitoring of anticoagulant resistance in rodents.

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