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: 8539109
• 负责人: Orlando M Gutierrez
• 金额: $ 25.27万
• 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/8539109
• 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，对黑人的影响尤为严重。虽然高血压和糖尿病等传统中风危险因素导致脑血管结果的种族差异，但它们不足以完全解释这些发现，表明非传统危险因素发挥着重要作用。维生素 D 和磷代谢紊乱已成为不良心血管结局的非传统危险因素。 25-羟基维生素 D (25D) 水平低会通过对炎症、胰岛素抵抗和血压控制产生广泛影响而与心脏病和死亡相关。磷代谢紊乱会刺激成纤维细胞生长因子 23 (FGF23) 的分泌，这是一种骨源性激素，部分通过抑制 25D 转化为其活化代谢物 1,25-二羟基维生素 D (1,25D) 来维持磷稳态。我们的小组和其他人表明，较高的 FGF23 水平通过直接和间接促进心血管疾病和 1,25D 缺乏而与不良后果相关。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先前的工作基础上，通过确定低血浆 25D 水平和过量血浆 FGF23 水平是否与大型全国队列中的中风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且更严重，因此我们将确定它们是否是中风种族差异的部分原因（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 25D 和 FGF23 与中风和认知能力下降的关联。我们将通过测量储存的血液样本中的血浆 25D、FGF23 和其他矿物质代谢的关键介质（包括 1,25D、甲状旁腺激素、钙和磷酸盐）来检验这些假设，该样本来自 2,085 名地理和种族差异原因研究参与者的特定病例组。中风（REGARDS）研究是一项针对黑人和白人成年人的全国性前瞻性研究，旨在确定中风种族差异的新危险因素。用于本研究的病例队列具有炎症和胰岛素抵抗的可用测量方法，使其非常适合检验我们的假设。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，25D 缺乏症和 FGF23 过量在普通人群中很常见，对黑人的影响尤为严重，并且可以通过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 FGF23 过多是脑血管疾病的危险因素，这将支持测试这些疾病的治疗方法以降低中风和认知障碍发生率的干预试验，特别是在黑人中。