Risk Factors for and Tissue Biomarker Expression in Primary Hyperparathyroidism

描述（由申请人提供）：原发性甲状旁腺功能亢进（pHPT）影响高达2%的绝经后妇女，并导致骨密度降低、骨折和肾结石。尽管pHPT的患病率和发病率很高，但其发病机制仍不清楚。我们提出的研究代表了第一个大规模的前瞻性努力，以检查pHPT的潜在可改变的风险因素。我们的目标是对pHPT产生新的见解，这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的，这表明这些肿瘤起源于具有生长赋予突变的单细胞。因此，我们在目标1和2中对pHPT风险的前瞻性研究将检查长期刺激PTH释放和/或引起甲状旁腺增生的因素。我们最近报道，在护士健康研究（NHS）I中，钙摄入量减少与pHPT事件风险增加相关。在目标1中，我们将对基线时没有pHPT的NHS I和II中> 145，000名妇女进行前瞻性队列研究，以描述体型，绝经，饮食因素（包括维生素D，镁，蛋白质和维生素A），药物（包括袢和噻嗪类利尿剂）和随后的pHPT事件风险之间的独立关联。迄今为止，没有研究前瞻性地检查pHPT的血浆风险因素。使用在诊断前收集的储存血液样本，我们具有独特的能力，在NHS I和II的巢式前瞻性病例对照研究中调查这些因素（N = 450例病例，900例对照）。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FGF 23与pHPT事件风险增加独立相关。我们还假设未结合或“游离”25（OH）D（通过总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25（OH）D更强。在目标3中，我们将使用组织微阵列免疫组化染色，以定量表达细胞周期蛋白D1和钙敏感受体（CaSR）切除，扩大甲状旁腺的200 NHS I和II参与者pHPT。细胞周期蛋白D1（cycD 1）是细胞周期调控的一个组成部分，在约40%的甲状旁腺腺瘤中高度表达，增大的甲状旁腺上的较低CaSR可能是pHPT的原因，而不是结果。我们假设1）较高的cycD 1和较低的CaSR表达与甲状旁腺重量增加相关，甲状旁腺重量增加是疾病严重程度的决定因素，2）较高的BMI、绝经、吸烟和较低的NSAID使用与较高的cycD 1表达相关，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。这将是第一个研究pHPT诊断前评估的环境因素与随后的甲状旁腺蛋白组织表达之间的关联，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.