Calcium-phosphorus metabolism and the risk of cardiovascular disease

描述(由申请人提供)：本申请的目标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上的重要问题。首先，我们将确定甲状旁腺激素(PTH)与冠心病(CHD)和高血压的关系。甲状旁腺激素通过直接或间接作用于骨骼、肾脏和肠道，在钙磷平衡中发挥核心作用。然而，PTH受体也在血管平滑肌和内皮细胞中表达，PTH增加与内皮功能障碍和动脉粥样硬化相关的因子的表达，如晚期糖基化终产物受体内皮素-1和IL-6。其次，我们将阐明血浆25-羟基维生素D(25[OH]D)、钙、磷、甲状旁腺素、肌酐水平与冠心病发病的独立关系。先前关于钙磷代谢和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，我们的目标是解决现有的关于补充钙的使用、磷的摄入量和发生冠心病的风险的争议。我们计划在健康专业人员随访研究(HPFS；N=51,529名男性)和护士健康研究(NHS；N=121,700名女性)中，对血浆完整的甲状旁腺素、25(OH)D、钙和磷水平与冠心病和高血压风险之间的独立相关性进行前瞻性嵌套病例对照研究。我们还计划进行前瞻性队列研究，研究补充钙的使用、磷的摄入量和冠心病事件之间的关系。由于先前的数据表明甲状旁腺激素与男性高血压有关，而绝经前女性没有，我们将确定甲状旁腺素对绝经后女性高血压风险的影响是否因绝经后激素的使用而不同。这项应用是首次大规模前瞻性研究甲状旁腺激素对没有原发性甲状旁腺功能亢进或慢性肾脏疾病的个体的冠心病风险的影响。这一应用的独特优势包括1)更新的、长期积累的详细曝光信息，2)存档的等离子，以及3)提供高统计能力的大样本。公共卫生相关性：我们希望我们对钙和磷代谢的研究为心血管疾病的发展提供新的见解，并确定几个新的和可修改的冠心病危险因素。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成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.