VITAMIN K, VKORC1 POLYMORPHISMS, AND OSTEOPOROTIC FRACTURES

维生素 K、VKORC1 多态性和骨质疏松性骨折

• 批准号: 7603365
• 负责人: BRIAN F GAGE
• 金额: $ 0.64万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2007-09-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7603365
• 关键词: Binding; Bone Density; Calcium; Computer Retrieval of Information on Scientific Projects Database; Disease regression; Dose; Enzymes; Fracture; Frequencies; Funding; Gene Mutation; Genes; Genetic Polymorphism; Glutamates; Glutamic Acid; Grant; Haplotypes; Hydroxyapatites; Individual; Institution; Linear Regressions; Measures; Minerals; Observational Study; Osteocalcin; Patients; Postmenopause; Proteins; Recording of previous events; Recycling; Research; Research Personnel; Resources; Risk; Role; Site; Source; Supplementation; United States National Institutes of Health; Vitamin K; Vitamin K 2; Vitamins; Warfarin; Woman; bone; bone metabolism; gamma-glutamyl carboxylase; interest; mutant; osteoporosis with pathological fracture; promoter; vitamin K epoxide reductase; vitamin K1 oxide

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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 维生素K是γ-谷氨酰-羧化酶的辅助因子，该酶将蛋白质上的谷氨酸残基修饰成γ-羧基谷氨酸（Gla）残基，从而有助于与钙结合。 骨钙素是骨中含量最丰富的非胶原蛋白，它接受多个Gla残基，这些残基帮助它与骨中的羟基磷灰石矿物结合。 羧化不足的骨钙素（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在维持骨完整性方面的作用也得到了维生素K拮抗剂（如华法林）的观察性研究的支持，这些拮抗剂与骨折增加有关。 (Gage例如，2006年）。 当γ-谷氨酰羧化酶在蛋白质上形成Gla残基时，维生素K被转化为维生素K环氧化物。 VKORC 1是维生素K环氧化物还原酶的一部分，该酶对于将维生素K环氧化物再循环成γ谷氨酰羧化酶所使用的形式至关重要。 VKORC 1也是华法林拮抗作用的部位，并解释了接受该治疗的患者中华法林剂量变异性的25%。 具体地，与具有VKORC 1单倍型B多态性的那些相比，具有VKORC 1单倍型A多态性的那些具有2-3倍降低的VKORC 1基因表达。 （里德尔等人，2005年）。 因此，由于维生素K在骨代谢中起作用，我们假设（假设1）某些VKORC 1多态性或基因突变可能会使个体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将试图确定VKORC 1启动子多态性（-1639A）在骨质疏松性骨折中的作用。 病例（目标1）将是患有骨质疏松性骨折的绝经后妇女，对照组将是骨密度正常且无骨折的绝经后妇女。 通过使用线性回归，我们将比较那些有和没有骨折的频率的多态性的利益。 在目标2中，具有骨质疏松性骨折史的绝经后女性将补充增加剂量的维生素K2，以确定维生素K2补充和VKORC 1多形性对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与突变体相比，野生型多态性是否导致补充后ucOC水平的更大下降。