VITAMIN K, VKORC1 POLYMORPHISMS, AND OSTEOPOROTIC FRACTURES

这个子项目是众多研究子项目之一

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Vitamin K serves as a co-factor for the enzyme gamma glutamyl-carboxylase, which modifies glutamate reidues on proteins into gamm-carboxy glutamic acid (Gla) redies that aid in binding to calcium. Osteocalcin, the most abundant non-collagenous protein in bone, receives multiple Gla residues which help it bind to hydroxyapatite mineral in bone. Undercarboxylated osteocalcin (ucOC) lacks sufficient Gla residues and is associated with an increased risk for osteoporotic fracture. The role of vitamin K in maintaining bone integrity also is supported by observational studies of vitamin K antagonists such as warfarin, which are associated with increased fractures. (Gage et al., 2006). When gamma glutamyl-carboxylase forms Gla residues on proteins, vitamin K is changed to vitamin K epoxide. VKORC1 is part of the enzyme vitamin K epoxide reductase that is pivotal to the recycling of vitamin K epoxide into to the form used by gamma glutamyl-carboxylase. VKORC1 is also the site of warfarin antagonism and explains 25% of the variability in warfarin dosing among patients prescribed this therapy. Specifically, those with VKORC1 haplotype A polymorphisms have a 2-3 fold decreased expression of the VKORC1 gene compared to those with VKORC1 haplotype B polymorphisms. (Rieder et al. 2005). Therefore, with vitamin K having a role in bone metabolism, we hypothesize (hypothesis 1) that certain VKORC1 polymorphisms, or gene mutations, may place individuals at greater risk for osteoporotic fractures or reduced bone mineral density. To date, no studies have examined the role of vitamin K related genes in bone. Aim 1 will seek to determine the role of a VKORC1 promotor polymorphism (-1639A) in osteoporotic fracture. Cases (Aim 1) will be postmenopausal women who have suffered an osteoporotic fracture and controls will be postmenopausal women with normal bone density and no fractures. Through use of linear regression we will compare those with and without fracture to the frequency of the polymorphism of interest. In Aim 2, post-menopausal women with a history fo osteoporotic fractures will be supplemented with increasing doses of vitamin K2 to determine the interaction between vitamin K2 supplementation and the VKORC1 polymoriphism on levels of ucOC. In Aim 2, a repeated measures regression will help determine if the wild-type polymorphism results in a greater decline in ucOC levels after supplementation compared with the mutant.