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The genetics of vitamin K antagonists

The Pharmacogenomics Journal volume 4, pages 224–225 (2004)Cite this article

By the same mechanism, coumarins are effective rodenticides, causing fatal bleeding in coumarin-naïve rodents. Studies of wild-caught, coumarin-resistant rats have provided important clues to the location of VKOR. For example, Kohn and Pelz crossed a coumarin-resistant rat with a susceptible albino strain and studied the seventh generation of backcrossed offspring.3 Using linkage analysis, they placed Rw, the gene for warfarin resistance in the rat, near one of several microsatellite markers. Then, using comparative ortholog mapping, they identified three candidate human chromosome locations for Rw, one of which was on the short arm of chromosome 16.

The second clue to the location of VKOR came from a study of familial multiple coagulation factor deficiency (FMFD). FMFD is an extremely rare, autosomal recessive, bleeding disorder characterized by inadequate γ-carboxylation of coagulation factors II, VII, IX, and X. Fregin et al4 investigated two kindreds with FMFD with suspected VKOR complex mutations due to biochemical evidence of elevated vitamin K epoxide/vitamin K hydroquinone ratios. Genome-wide scanning based on micro-satellite markers and linkage analysis identified a marker in the centromeric region of chromosome 16 with a LOD score of approximately 3, and haplotype analysis confirmed homozygosity for chromosome region 16p12–q21 in one of the families. Mapping studies of Rw in the rat and a similar gene in mice (war) identified a homologous region on human chromosome 16, and several known genes that flank Rw and War are located on the short arm of chromosome 16.3

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Acknowledgements

This review was supported by NIH grant R01 HL71083.

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Authors and Affiliations

  1. Division of General Medical Sciences, Washington University School of Medicine, St. Louis, MO, USA

    B F Gage

  2. Division of Laboratory Medicine at Washington University School of Medicine, St. Louis, MO, USA

    C S Eby

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  1. B F Gage
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  2. C S Eby
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Correspondence to B F Gage.

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The authors have no financial or other conflict of interest.

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Gage, B., Eby, C. The genetics of vitamin K antagonists. Pharmacogenomics J 4, 224–225 (2004). https://doi.org/10.1038/sj.tpj.6500258

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