VITAMIN K, VKORC1 POLYMORPHISMS, AND OSTEOPOROTIC FRACTURES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 维生素K是伽马谷氨酰-羧基酶的辅助因子，该酶将蛋白质上的谷氨酸修饰成有助于与钙结合的伽马-羧基谷氨酸(GLA)。骨钙素是骨骼中含量最丰富的非胶原蛋白，它能接受多种GLA残基，帮助其与骨骼中的羟基磷灰石矿物结合。不足羧化的骨钙素(UcOC)缺乏足够的GLA残基，与骨质疏松性骨折的风险增加有关。维生素K在维持骨骼完整性方面的作用也得到了对维生素K拮抗剂(如华法林)的观察研究的支持，这些拮抗剂与骨折的增加有关。(Gage等人，2006年)。 当伽玛谷氨酰羧基酶在蛋白质上形成GLA残基时，维生素K就变成了维生素K环氧化物。VKORC1是维生素K环氧化物还原酶的一部分，该酶对维生素K环氧化物循环为伽马谷氨酰羧基酶的形式起关键作用。VKORC1也是华法林拮抗作用的部位，并解释了开这种疗法的患者中华法林剂量变化的25%。具体地说，与VKORC1单倍型B多态相比，具有VKORC1单倍型A多态的患者VKORC1基因的表达降低了2-3倍。(Rieder等人)2005)。因此，随着维生素K在骨骼代谢中的作用，我们假设(假设1)某些VKORC1基因多态性或基因突变可能会使个人面临更大的骨质疏松性骨折或骨密度降低的风险。 到目前为止，还没有研究检查维生素K相关基因在骨骼中的作用。目的1试图确定VKORC1启动子多态性(-1639A)在骨质疏松性骨折中的作用。病例(目标1)将是遭受骨质疏松性骨折的绝经后妇女，对照将是骨密度正常且没有骨折的绝经后妇女。通过使用线性回归，我们将比较那些有骨折和没有骨折的人的感兴趣的多态频率。 在目标2中，有骨质疏松性骨折病史的绝经后妇女将补充更多剂量的维生素K2，以确定补充维生素K2与VKORC1基因多态性对ucoC水平的相互作用。在目标2中，重复测量回归将有助于确定野生型多态是否导致补充后ucoC水平比突变体更大的下降。

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.