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Warfarin has been widely used for over 50 years as a rodent poison in pest control and also in human medicine as a prescribed anticoagulant for preventing thrombosis.The vitamin K epoxide reductase complex subunit 1 (VKORC1) and the P450 enzymes CYP2C9 and CYP4F2 have been revealed as three main pharmacogenetic determinants of warfarin dosage in humans.Although many resistant Vkorc1 variants have been identified in rats and mice,its not clear whether the P450 gene variants are also strongly associated with warfarin resistance.Here we examine the possible orthologue genes (Vkorc1,Cyp2c11,Cyp4f1,Cyp4f4 and Cyp4f18) of human pharmacogenetic determinants for their variations and associations in 19 resistant Norway rat populations in Germany,as well as modelling panmictic virtual populations to control population stratification.We found all resistant populations carry either Y139C or S56P variant in the Vkorc1 gene.Association analysis indicated the Vkorc1 variant was strongly associated with warfarin resistance in 68%-93%local populations and all virtual populations,followed by the Cyp2c11 variant in~21%local populations and one virtual population,then the Cyp4f4 variant in 5%-7%local populations and one virtual population.Our findings indicate natural selection on Vkorc1 has led to establishment of a high proportion of resistant rats in the study area.The Cyp2c11 and Cyp4f4 variants also appear under warfarin selection but have not been established firmly in the region due to strong effect on drift.