Abstract
BackgroundPolymorphisms in the vitamin K-epoxide reductase complex subunit 1 gene, Vkorc1, could affect blood coagulation and other vitamin K-dependent proteins, such as osteocalcin (bone Gla protein, BGP). Here we sequenced the Vkorc1 gene in 40 mouse priority strains. We analyzed Vkorc1 haplotypes with respect to prothrombin time (PT) and bone mineral density and composition (BMD and BMC); phenotypes expected to be vitamin K-dependent and represented by data in the Mouse Phenome Database (MPD).FindingsIn the commonly used laboratory strains of Mus musculus domesticus we identified only four haplotypes differing in the intron or 5' region sequence of the Vkorc1. Six haplotypes differing by coding and non-coding polymorphisms were identified in the other subspecies of Mus. We detected no significant association of Vkorc1 haplotypes with PT, BMD and BMC within each subspecies of Mus. Vkorc1 haplotype sequences divergence between subspecies was associated with PT, BMD and BMC.ConclusionPhenotypic variation in PT, BMD and BMC within subspecies of Mus, while substantial, appears to be dominated by genetic variation in genes other than the Vkorc1. This was particularly evident for M. m. domesticus, where a single haplotype was observed in conjunction with virtually the entire range of PT, BMD and BMC values of all 5 subspecies of Mus included in this study. Differences in these phenotypes between subspecies also should not be attributed to Vkorc1 variants, but should be viewed as a result of genome wide genetic divergence.
Highlights
Polymorphisms in the vitamin K-epoxide reductase complex subunit 1 gene, Vkorc1, could affect blood coagulation and other vitamin K-dependent proteins, such as osteocalcin
Phenotypic variation in prothrombin time (PT), bone mineral density (BMD) and bone mineral content (BMC) within subspecies of Mus, while substantial, appears to be dominated by genetic variation in genes other than the Vkorc1. This was evident for M. m. domesticus, where a single haplotype was observed in conjunction with virtually the entire range of PT, BMD and BMC values of all 5 subspecies of Mus included in this study
Vkorc1 genetic polymorphisms in mouse priority strains We identified 10 haplotypes that were defined by 84 Single nucleotide polymorphisms (SNPs) and 153 indels [see Additional file 1]
Summary
Polymorphisms in the vitamin K-epoxide reductase complex subunit 1 gene, Vkorc, could affect blood coagulation and other vitamin K-dependent proteins, such as osteocalcin (bone Gla protein, BGP). We analyzed Vkorc haplotypes with respect to prothrombin time (PT) and bone mineral density and composition (BMD and BMC); phenotypes expected to be vitamin K-dependent and represented by data in the Mouse Phenome Database (MPD). The warfarin-sensitive vitamin K epoxide reductase enzyme complex (VKOR) converts vitamin K 2,3-epoxide to vitamin K hydroquinone, a required cofactor for the post-translational gamma-carboxylation of several blood coagulation factors and other vitamin K-dependent proteins, such as osteocalcin (bone Gla protein, BGP) and matrix Gla protein (MGP) [1,2]. The vitamin K epoxide reductase complex subunit 1 gene (Vkorc1) appears to be a critical component of the VKOR [5,6]. Genetic polymorphisms in the Vkorc could affect antico-
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