Calcium-phosphorus metabolism and the risk of cardiovascular disease

描述（由申请人提供）：本申请的目的是回答有关钙-磷稳态在心血管疾病发展中的作用的临床和科学重要问题。首先，我们将确定甲状旁腺激素（PTH）与冠心病（CHD）和高血压的发展之间的关系。通过直接或间接作用于骨骼、肾脏和肠道，甲状旁腺激素在钙和磷平衡中起着核心作用。然而，PTH受体也在血管平滑肌和内皮中表达，PTH增加内皮功能障碍和动脉粥样硬化相关因子的表达，如内皮素-1（晚期糖基化终产物受体）和IL-6。其次，我们将阐明25-羟基维生素D （25[OH]D）、钙、磷、甲状旁腺激素、肌酐水平与冠心病发生之间的独立关系。以往关于钙磷代谢与冠心病风险的前瞻性研究并没有同时测量这些相关因素。最后，我们的目的是解决目前存在的关于补充钙的使用，磷的摄入量和冠心病发生的风险的争议。我们计划在卫生专业人员随访研究（HPFS； N=51,529名男性）和护士健康研究（NHS； N=121,700名女性）中开展前瞻性巢式病例对照研究，研究血浆中完整甲状旁腺激素、25(OH)D、钙和磷水平与冠心病和高血压风险之间的独立关系。我们还计划进行前瞻性队列研究，研究补充钙的使用、磷的摄入和冠心病的发生之间的关系。由于先前的数据表明PTH与男性高血压之间存在关联，而绝经前女性则没有，因此我们将确定PTH对绝经后女性高血压风险的影响是否因使用绝经后激素而异。该应用首次大规模前瞻性研究PTH对无原发性甲状旁腺功能亢进或慢性肾病患者冠心病风险的影响。该应用程序的独特优势包括：1)更新，详细的暴露信息积累在很长一段时间内，2)存档等离子体，和3)大样本量提供高统计能力。公共卫生相关性：我们期望我们的钙和磷代谢研究为心血管疾病的发展提供新的见解，并确定一些新的和可改变的冠心病危险因素。我们的发现可能会刺激未来的研究，最终允许调节钙磷平衡的因素作为预防冠心病和高血压的目标。

DESCRIPTION (provided by applicant): The goal of this application is to answer clinically and scientifically important questions about the role of calcium-phosphorus homeostasis in the development of cardiovascular disease. First, we will determine the associations between parathyroid hormone (PTH) and the development of coronary heart disease (CHD) and hypertension. By direct or indirect actions on bone, kidney, and intestine, PTH plays a central role in calcium and phosphorus balance. However, the PTH receptor also is expressed in vascular smooth muscle and the endothelium, and PTH increases the endothelial expression of factors implicated in endothelial dysfunction and atherosclerosis, such as endothelin-1, the receptor of advanced glycation end products, and IL-6. Second, we will clarify the independent associations between plasma levels of 25-hydroxyvitamin D (25[OH]D), calcium, phosphorus, PTH, creatinine and incident CHD. Previous prospective studies of calcium-phosphorus metabolism and CHD risk did not simultaneously measure these interrelated factors. Finally, we aim to resolve existing controversies about supplemental calcium use, phosphorus intake and the risk of incident CHD. We plan to conduct prospective nested case-control studies of the independent associations between plasma levels of intact PTH, 25(OH)D, calcium, and phosphorus and the risk of CHD and hypertension in the Health Professionals Follow-up Study (HPFS; N=51,529 men) and the Nurses' Health Study (NHS; N=121,700 women). We also plan to conduct prospective cohort studies examining the relations between supplemental calcium use, phosphorus intake, and incident CHD. Because previous data suggest an association between PTH and hypertension in men but not pre-menopausal women, we will determine whether the impact of PTH on the risk of hypertension in post-menopausal women varies by use of post-menopausal hormones. This application represents the first large-scale prospective effort to examine the impact of PTH on CHD risk in individuals without primary hyperparathyroidism or chronic kidney disease. The unique strengths of this application include 1) updated, detailed exposure information accumulated prospectively over long periods, 2) archived plasma, and 3) large sample sizes providing high statistical power. PUBLIC HEALTH RELEVANCE: We expect our studies of calcium and phosphorus metabolism to provide new insights into the development of cardiovascular disease and to identify several novel and modifiable coronary heart disease risk factors. Our findings may stimulate future research that eventually allows factors regulating calcium- phosphorus balance to serve as targets for the prevention of coronary heart disease and hypertension.