Impact of disordered mineral metabolism on stroke and cognitive impairment

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会导致脑血管预后的种族差异，但它们不足以完全解释这些发现，这表明非传统危险因素发挥了重要作用。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）水平低与心脏病和死亡有关，对炎症、胰岛素抵抗和血压控制有广泛影响。磷代谢紊乱会刺激成纤维细胞生长因子23 （FGF23）的分泌，FGF23是一种骨源性激素，通过抑制25D向其活性代谢物1,25-二羟基维生素D （1,25D）的转化，在一定程度上维持磷的稳态。我们的研究小组和其他研究小组表明，FGF23水平升高与不良结局相关，直接或间接地促进心血管疾病和1,25 d缺乏症。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。当前研究的主要重点是在先前研究的基础上，在一个大型的国家队列中确定低血浆25D水平和过量血浆FGF23水平是否与卒中和认知障碍相关（目的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在一定程度上导致了中风的种族差异（目的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。我们将通过测量血浆25D、FGF23和其他矿物质代谢的关键介质（包括1,25 d、甲状旁腺激素、钙和磷酸盐）来检验这些假设，这些矿物质代谢介质来自2085名参与者的特定病例队列，这些参与者来自REGARDS研究的地理和种族差异的原因（REGARDS）研究，这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可用的炎症和胰岛素抵抗测量方法，使其非常适合测试我们的假设。这些研究的结果可能对中风和认知能力下降的治疗和/或预防有重要影响。事实上，25D缺乏和FGF23过量在普通人群中很常见，对黑人的影响尤为严重，可以用安全且相对便宜的治疗方法进行治疗。因此，如果维生素D缺乏和过量的FGF23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方法，以降低中风和认知障碍的发生率，特别是在黑人中。

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.