Risk Factors for and Tissue Biomarker Expression in Primary Hyperparathyroidism

描述(申请人提供)：原发性甲状旁腺功能亢进症(PHPT)影响多达2%的绝经后妇女，并导致骨密度降低、骨折和肾结石。尽管PHPT的发病率和发病率很高，但其发病机制尚不清楚。我们建议的研究是第一次大规模的前瞻性研究，旨在研究PHPT的潜在可改变的危险因素。我们的目标是对PHPT产生新的见解，从而可能导致预防和治疗这种常见且昂贵的疾病的新方法。散发性PHPT的甲状旁腺腺瘤是单克隆性的，提示这些肿瘤起源于具有与生长相关的突变的单个细胞。因此，我们对AIMS 1和AIMS 2中PHPT风险的前瞻性研究将检查慢性刺激甲状旁腺激素释放和/或导致甲状旁腺增生的因素。我们最近在护士健康研究(NHS)I中报告了较低的钙摄入量与PHPT事件风险的增加相关。在目标1中，我们将对NHS I和NHS II中没有PHPT基线的145,000名妇女进行前瞻性队列研究，以描述身体大小、绝经、饮食因素(包括维生素D、镁、蛋白质和维生素A)、药物(包括环磷酰胺和噻嗪利尿剂)和随后发生PHPT的风险之间的独立关联。到目前为止，还没有研究前瞻性地检查PHPT的血浆危险因素。利用诊断前收集的储存血液样本，我们有独特的能力在NHS I和II(N=450例，900名对照)的嵌套前瞻性病例对照研究中调查这些因素。在目标2中，我们假设较高的血浆磷、较低的25-羟基维生素D(25[OH]D)和较低的FGF23独立地与PHPT事件的风险增加相关。我们还假设，未结合或“游离”的25(OH)D(由总的25[OH]D、维生素D结合蛋白和白蛋白估计)与风险的相关性比总的25(OH)D更强。在目标3中，我们将使用组织微阵列免疫组织化学染色来定量200名患有PHPT的NHS I和II参与者切除的、扩大的甲状旁腺中细胞周期蛋白D1和钙感应受体(CaSR)的表达。我们假设，1)较高的cycd1和较低的CaSR表达与甲状旁腺重量增加相关，甲状旁腺重量是疾病严重程度的决定因素，2)较高的BMI、绝经、吸烟和较少使用非甾体抗炎药与较高的cycd1表达相关，以及3)较低的维生素D累积摄入量和较高的BMI与较低的CaSR表达相关。这将是第一次研究PHPT诊断前评估的环境因素与甲状旁腺蛋白随后的组织表达之间的相关性，甲状旁腺蛋白可能在PHPT的发病机制和/或严重程度中发挥重要作用。

DESCRIPTION (provided by applicant): Primary hyperparathyroidism (pHPT) affects up to 2% of post-menopausal women and causes decreased bone mineral density, bone fractures, and kidney stones. Despite the high prevalence and morbidity of the disease, the pathogenesis of pHPT remains unclear. Our proposed studies represent the first large-scale prospective effort to examine potentially modifiable risk factors for pHPT. We aim to produce new insights into pHPT that may lead to new approaches to prevention and treatment of this common and costly disease. The parathyroid adenomas of sporadic pHPT are monoclonal, suggesting that these neoplasms originate from single cells with a growth conferring mutation. Thus, our prospective studies of pHPT risk in Aims 1 and 2 will examine factors that chronically stimulate PTH release and/or cause parathyroid gland hyperplasia. We recently reported that lower calcium intake was associated with increased risk of incident pHPT in the Nurses Health Study (NHS) I. In Aim 1, we will conduct prospective cohort studies of > 145,000 women in NHS I and II without pHPT at baseline to delineate independent associations between body size, menopause, dietary factors (including vitamin D, magnesium, protein, and vitamin A), medications (including loop and thiazide diuretics), and the subsequent risk of incident pHPT. No study to date has prospectively examined plasma risk factors for pHPT. Using stored blood samples collected prior to diagnosis, we have the unique ability to investigate such factors in nested, prospective case- control studies in NHS I and II (N = 450 cases, 900 controls). In Aim 2, we hypothesize that higher plasma phosphorus, lower 25-hydroxyvitamin D (25[OH]D), and lower FGF23 are independently associated with increased risk of incident pHPT. We also hypothesize that unbound, or "free" 25(OH)D (estimated by total 25[OH]D, vitamin D binding protein, and albumin) is more strongly associated with risk than total 25(OH)D. In Aim 3, we will use tissue microarray immunohistochemical staining to quantify expression of cyclin D1 and the calcium sensing receptor (CaSR) in resected, enlarged parathyroid glands of 200 NHS I and II participants with pHPT. Cyclin D1 (cycD1), an integral component of cell-cycle regulation, is highly expressed in ~ 40% of parathyroid adenomas, and lower CaSR on enlarged parathyroid glands may represent a cause, rather than a consequence, of pHPT. We hypothesize that 1) higher cycD1 and lower CaSR expression are associated with increased parathyroid gland weight, a determinant of disease severity, 2) higher BMI, menopause, smoking, and lower use of NSAIDs are associated with higher cycD1 expression, and 3) lower cumulative intake of vitamin D and higher BMI are associated with lower CaSR expression. This will be the first study to examine associations between environmental factors assessed before pHPT diagnosis and the subsequent tissue expression of parathyroid proteins that may play important roles in the pathogenesis and/or severity of pHPT.