{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T09:10:46Z","timestamp":1791277846278,"version":"4.1.0"},"reference-count":54,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2005,8,1]],"date-time":"2005-08-01T00:00:00Z","timestamp":1122854400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2005,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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 &amp;gt;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.<\/jats:p>","DOI":"10.1534\/genetics.104.040360","type":"journal-article","created":{"date-parts":[[2005,5,7]],"date-time":"2005-05-07T00:59:15Z","timestamp":1115427555000},"page":"1839-1847","source":"Crossref","is-referenced-by-count":280,"title":["The Genetic Basis of Resistance to Anticoagulants in Rodents"],"prefix":"10.1093","volume":"170","author":[{"given":"Hans-Joachim","family":"Pelz","sequence":"first","affiliation":[{"name":"Biologische Bundesanstalt fu\u0308r Land-und Forstwirtschaft, Institut fu\u0308r Nematologie und Wirbeltierkunde, 48161 Mu\u0308nster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Rost","sequence":"additional","affiliation":[{"name":"Institut fu\u0308r Humangenetik, Universita\u0308t Wu\u0308rzburg, Biozentrum, 97074 Wu\u0308rzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirja","family":"Hu\u0308nerberg","sequence":"additional","affiliation":[{"name":"Institut fu\u0308r Humangenetik, Universita\u0308t Wu\u0308rzburg, Biozentrum, 97074 Wu\u0308rzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Fregin","sequence":"additional","affiliation":[{"name":"Institut fu\u0308r Humangenetik, Universita\u0308t Wu\u0308rzburg, Biozentrum, 97074 Wu\u0308rzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann-Charlotte","family":"Heiberg","sequence":"additional","affiliation":[{"name":"Danish Pest Infestation Laboratory, Danish Institute of Agricultural Sciences, DK-2800 Kgs. Lyngby, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristof","family":"Baert","sequence":"additional","affiliation":[{"name":"Institute for Forestry and Game Management, 9500 Geraardsbergen, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan D","family":"MacNicoll","sequence":"additional","affiliation":[{"name":"Central Science Laboratory, Defra, Sand Hutton, York YO41 1LZ, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin V","family":"Prescott","sequence":"additional","affiliation":[{"name":"School of Animal and Microbial Sciences, The University of Reading, Whiteknights, Reading RG6 6AJ, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Sophie","family":"Walker","sequence":"additional","affiliation":[{"name":"Institut National de la Recherche Agronomique (INRA), Unite\u0301 de Phytopharmacie et Me\u0301diateurs Chimiques, 78026 Versailles, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Oldenburg","sequence":"additional","affiliation":[{"name":"Institut fu\u0308r Transfusionsmedizin und Immunha\u0308matologie, DRK Blutspendedienst Baden-Wu\u0308rttemberg-Hessen, 60526 Frankfurt\/M, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clemens R","family":"Mu\u0308ller","sequence":"additional","affiliation":[{"name":"Institut fu\u0308r Humangenetik, Universita\u0308t Wu\u0308rzburg, Biozentrum, 97074 Wu\u0308rzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2005,8,1]]},"reference":[{"key":"2022010712442315400_BIB1","first-page":"271","volume":"16","year":"1980","journal-title":"Ann. Ist. Super. Sanita"},{"key":"2022010712442315400_BIB2"},{"key":"2022010712442315400_BIB3","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1021\/bi00733a015","volume":"12","year":"1973","journal-title":"Biochemistry"},{"key":"2022010712442315400_BIB4","first-page":"517","volume":"188","year":"1960","journal-title":"Nature"},{"key":"2022010712442315400_BIB5","doi-asserted-by":"crossref","first-page":"29068","DOI":"10.1074\/jbc.272.46.29068","volume":"272","year":"1997","journal-title":"J. Biol. Chem."},{"key":"2022010712442315400_BIB6","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1055\/s-0037-1615151","volume":"80","year":"1998","journal-title":"Thromb. Haemost."},{"key":"2022010712442315400_BIB7","first-page":"99","volume":"42","year":"1994","journal-title":"Dierplagen en Milieu"},{"key":"2022010712442315400_BIB8","first-page":"1668","volume":"3746","year":"1961","journal-title":"Minic. Engin. Lond."},{"key":"2022010712442315400_BIB9","first-page":"771","volume":"968","year":"1966","journal-title":"New Sci."},{"key":"2022010712442315400_BIB10","doi-asserted-by":"crossref","first-page":"3229","DOI":"10.1182\/blood-2002-03-0698","volume":"100","year":"2002","journal-title":"Blood"},{"key":"2022010712442315400_BIB11","first-page":"809","volume":"56","year":"1993","journal-title":"J. Wildl. Manage."},{"key":"2022010712442315400_BIB12","doi-asserted-by":"crossref","first-page":"454","DOI":"10.2307\/3809316","volume":"58","year":"1994","journal-title":"J. Wildl. Manage."},{"key":"2022010712442315400_BIB13","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.tibs.2004.04.004","volume":"29","year":"2004","journal-title":"Trends Biochem. Sci."},{"key":"2022010712442315400_BIB14","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1038\/215877a0","volume":"215","year":"1967","journal-title":"Nature"},{"key":"2022010712442315400_BIB15","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1038\/224284a0","volume":"224","year":"1969","journal-title":"Nature"},{"key":"2022010712442315400_BIB16","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1258\/002367773781008614","volume":"7","year":"1973","journal-title":"Lab. Anim."},{"key":"2022010712442315400_BIB17"},{"key":"2022010712442315400_BIB18","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/0022-474X(76)90025-4","volume":"12","year":"1976","journal-title":"J. Stored Prod. Res."},{"key":"2022010712442315400_BIB19","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1017\/S0022172400070820","volume":"89","year":"1982","journal-title":"J. Hyg."},{"key":"2022010712442315400_BIB20"},{"key":"2022010712442315400_BIB21"},{"key":"2022010712442315400_BIB22"},{"key":"2022010712442315400_BIB23","first-page":"481","volume":"18","year":"1988","journal-title":"Eur. Plant Protect. Org. Bull."},{"key":"2022010712442315400_BIB24"},{"key":"2022010712442315400_BIB25","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1007\/s003359901073","volume":"10","year":"1999","journal-title":"Mamm. Genome"},{"key":"2022010712442315400_BIB26","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1038\/nature02254","volume":"427","year":"2004","journal-title":"Nature"},{"key":"2022010712442315400_BIB27"},{"key":"2022010712442315400_BIB28","first-page":"273","volume":"143","year":"1964","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2022010712442315400_BIB29","first-page":"89","volume":"11","year":"1984","journal-title":"Proc. Vertebrate Pest Conf."},{"key":"2022010712442315400_BIB30","doi-asserted-by":"crossref","first-page":"22298","DOI":"10.1016\/S0021-9258(18)41669-9","volume":"267","year":"1992","journal-title":"J. Biol. Chem."},{"key":"2022010712442315400_BIB31","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/0304-4165(85)90156-4","volume":"840","year":"1985","journal-title":"Biochim. Biophys. Acta"},{"key":"2022010712442315400_BIB32"},{"key":"2022010712442315400_BIB33","first-page":"701","volume":"23","year":"1993","journal-title":"Eur. Plant Protect. Org. Bull."},{"key":"2022010712442315400_BIB34","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1258\/002367779780937852","volume":"13","year":"1979","journal-title":"Lab. Anim."},{"key":"2022010712442315400_BIB35"},{"key":"2022010712442315400_BIB36","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1002\/ps.2780430111","volume":"43","year":"1995","journal-title":"Pesticide Sci."},{"key":"2022010712442315400_BIB37","doi-asserted-by":"crossref","first-page":"243","DOI":"10.7601\/mez.32.243","volume":"32","year":"1981","journal-title":"Jap. J. Sanit. Zool."},{"key":"2022010712442315400_BIB38","doi-asserted-by":"crossref","first-page":"6347","DOI":"10.1016\/S0021-9258(19)42259-X","volume":"249","year":"1974","journal-title":"J. Biol. Chem."},{"key":"2022010712442315400_BIB39"},{"key":"2022010712442315400_BIB40"},{"key":"2022010712442315400_BIB41","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1055\/s-0037-1613115","volume":"87","year":"2002","journal-title":"Thromb. Haemost."},{"key":"2022010712442315400_BIB42","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/nature02214","volume":"427","year":"2004","journal-title":"Nature"},{"key":"2022010712442315400_BIB43","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1017\/S0022172400069370","volume":"87","year":"1981","journal-title":"J. Hyg."},{"key":"2022010712442315400_BIB44","doi-asserted-by":"crossref","first-page":"2770","DOI":"10.1016\/S0021-9258(17)33555-X","volume":"251","year":"1976","journal-title":"J. Biol. Chem."},{"key":"2022010712442315400_BIB45","first-page":"39","volume":"9","year":"1978","journal-title":"Search"},{"key":"2022010712442315400_BIB46","first-page":"49","volume":"32","year":"1982","journal-title":"Environ. Health Rev."},{"key":"2022010712442315400_BIB47","doi-asserted-by":"crossref","first-page":"2730","DOI":"10.1073\/pnas.71.7.2730","volume":"71","year":"1974","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2022010712442315400_BIB48","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/ps.2780430112","volume":"43","year":"1995","journal-title":"Pesticide Sci."},{"key":"2022010712442315400_BIB49"},{"key":"2022010712442315400_BIB50"},{"key":"2022010712442315400_BIB51","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1017\/S0022172400055078","volume":"76","year":"1976","journal-title":"J. Hyg."},{"key":"2022010712442315400_BIB52","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.1172\/JCI112182","volume":"76","year":"1985","journal-title":"J. Clin. Invest."},{"key":"2022010712442315400_BIB53"},{"key":"2022010712442315400_BIB54","doi-asserted-by":"crossref","first-page":"E88","DOI":"10.1093\/nar\/29.17.e88","volume":"29","year":"2001","journal-title":"Nucleic Acids Res."}],"container-title":["Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/genetics\/article-pdf\/170\/4\/1839\/42066769\/genetics1839.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/genetics\/article-pdf\/170\/4\/1839\/42066769\/genetics1839.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,7]],"date-time":"2022-01-07T13:15:27Z","timestamp":1641561327000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/genetics\/article\/170\/4\/1839\/6060484"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2005,8,1]]},"references-count":54,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2005,8,1]]},"published-print":{"date-parts":[[2005,8,1]]}},"URL":"https:\/\/doi.org\/10.1534\/genetics.104.040360","relation":{},"ISSN":["1943-2631"],"issn-type":[{"value":"1943-2631","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2005,8,1]]},"published":{"date-parts":[[2005,8,1]]}}}