Impact of disordered mineral metabolism on stroke and cognitive impairment

矿物质代谢紊乱对中风和认知障碍的影响

• 批准号: 8699858
• 负责人: Orlando M Gutierrez
• 金额: $ 22.46万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8699858
• 关键词: 1,25 (OH) vitamin D; 25-hydroxyvitamin D; Accounting; Adult; Adverse effects; African American; Biological Markers; Black race; Blood specimen; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cerebrovascular Disorders; Cessation of life; Clinical; Cognitive; Data; Deficiency Diseases; Diabetes Mellitus; Disease; Epidemiology; General Population; Health; Healthcare; Heart Diseases; High Prevalence; Homeostasis; Hormones; Hypertension; Impaired cognition; Individual; Inflammation; Insulin Resistance; Interleukin-6; Intervention Trial; Leptin; Link; Measures; Mediating; Mediator of activation protein; Metabolism; Minerals; Modeling; Outcome; Parathyroid gland; Participant; Pathway interactions; Phosphorus; Plasma; Play; Prospective Studies; Proteins; Race; Reasons for Geographic And Racial Differences in Stroke; Risk Factors; Role; Sampling; Specific qualifier value; Stroke; Stroke prevention; Testing; Ursidae Family; Vitamin D; Vitamin D Deficiency; Work; adiponectin; adverse outcome; blood pressure regulation; bone; calcium phosphate; cerebrovascular; cohort; design; disability; experience; fibroblast growth factor 23; geographic difference; high risk; improved; indexing; inorganic phosphate; insulin sensitivity; multidisciplinary; novel; novel therapeutics; nutrition; phosphorus metabolism; racial difference; resistin

DESCRIPTION (provided by applicant): Stroke and cognitive impairment are major causes of death and disability in the US and disproportionately impact blacks. While traditional stroke risk factors such as hypertension and diabetes contribute to racial disparities in cerebrovascular outcomes, they are not sufficient to completely explain these findings, suggesting that non-traditional risk factors play an important role. Disturbances in vitamin D and phosphorus metabolism have emerged as non-traditional risk factors for adverse cardiovascular outcomes. Low 25-hydroxyvitamin D (25D) levels are associated with heart disease and death via broad effects on inflammation, insulin resistance and blood pressure control. Disturbances in phosphorus metabolism stimulate the secretion of fibroblast growth factor 23 (FGF23), a bone-derived hormone that maintains phosphorus homeostasis in part by inhibiting the conversion of 25D to its activated metabolite, 1,25-dihydroxyvitamin D (1,25D). Our group and others showed that higher FGF23 levels were associated with adverse outcomes through direct and indirect effects promoting cardiovascular disease and 1,25D deficiency. Moreover, preliminary data from our group suggest that low vitamin D is an independent risk factor for stroke and cognitive impairment. The primary focus of the current proposal is to build upon this prior work by determining whether low plasma 25D levels and excess plasma FGF23 levels are associated with incident stroke and cognitive impairment in a large, national cohort (Aim 1). In addition, since disorders of vitamin D and phosphorus metabolism are more common and severe in blacks than whites, we will determine if they partly underlie racial disparities in stroke (Aim 2). Finally, given that inflammation, insulin resistance and hypertension are key risk factors for cerebrovascular disease, and are interconnected with disturbances in vitamin D and phosphorus metabolism, we will determine whether they partly mediate the associations of 25D and FGF23 with stroke and cognitive decline. We will test these hypotheses by measuring plasma 25D, FGF23 and other key mediators of mineral metabolism including 1,25D, parathyroid hormone, calcium and phosphate in stored blood samples from a specified case cohort of 2,085 participants of the REasons for Geographic and Racial Differences in Stroke (REGARDS) study, a national prospective study of black and white adults designed to identify novel risk factors for racial disparities in stroke. The case-cohort to be used for this study has available measures of inflammation and insulin resistance, making it uniquely well-suited to test our hypotheses. The results of these studies may have an important impact on the treatment and/or prevention of stroke and cognitive decline. Indeed, 25D deficiency and FGF23 excess are common in the general population, disproportionately impact blacks, and can be treated with safe and relatively inexpensive therapies. Thus, if vitamin D deficiency and excess FGF23 are risk factors for cerebrovascular disease, this would support intervention trials testing the treatment of these disorders in reducing rates of incident stroke and cognitive impairment, particularly among black individuals.

描述（由申请人提供）：中风和认知障碍是美国死亡和残疾的主要原因，对黑人的影响不成比例。虽然传统的中风危险因素，如高血压和糖尿病有助于脑血管结局的种族差异，但它们不足以完全解释这些发现，这表明非传统危险因素起着重要作用。维生素D和磷代谢紊乱已成为心血管不良结局的非传统危险因素。低水平的25-羟基维生素D（25 D）通过对炎症，胰岛素抵抗和血压控制的广泛影响与心脏病和死亡有关。磷代谢紊乱刺激成纤维细胞生长因子23（FGF 23）的分泌，FGF 23是一种骨源性激素，部分通过抑制25 D转化为其活化代谢物1，25-二羟基维生素D（1，25 D）来维持磷稳态。我们的研究小组和其他研究表明，较高的FGF 23水平通过促进心血管疾病和1，25 D缺乏的直接和间接作用与不良结局相关。此外，我们小组的初步数据表明，低维生素D是中风和认知障碍的独立危险因素。当前提案的主要重点是在此之前的工作基础上，通过确定低血浆25 D水平和过量血浆FGF 23水平是否与大型国家队列中的卒中和认知障碍事件相关（目标1）。此外，由于维生素D和磷代谢紊乱在黑人中比白人更常见和严重，我们将确定它们是否部分地成为中风种族差异的基础（目标2）。最后，鉴于炎症、胰岛素抵抗和高血压是脑血管疾病的关键危险因素，并且与维生素D和磷代谢紊乱相互关联，我们将确定它们是否部分介导25 D和FGF 23与中风和认知能力下降的相关性。我们将通过测量血浆25 D、FGF 23和其他矿物质代谢的关键介质（包括储存的血液样本中的1，25 D、甲状旁腺激素、钙和磷酸盐）来检验这些假设，这些血液样本来自中风的地理和种族差异的原因（REGARDS）研究的2，085名参与者的指定病例队列，一项针对黑人和白色成年人的全国性前瞻性研究，旨在确定中风种族差异的新风险因素。用于本研究的病例队列具有可用的炎症和胰岛素抵抗指标，使其非常适合于测试我们的假设。这些研究的结果可能对中风和认知能力下降的治疗和/或预防产生重要影响。事实上，25 D缺乏和FGF 23过量在一般人群中很常见，对黑人的影响不成比例，并且可以用安全且相对便宜的疗法进行治疗。因此，如果维生素D缺乏和过量的FGF 23是脑血管疾病的危险因素，这将支持干预试验测试这些疾病的治疗，以降低中风和认知障碍的发病率，特别是在黑人个体中。