Risk Factors for and Tissue Biomarker Expression in Primary Hyperparathyroidism

原发性甲状旁腺功能亢进症的危险因素和组织生物标志物表达

• 批准号: 9036383
• 负责人: ERIC N TAYLOR
• 金额: $ 41.38万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9036383
• 关键词: 25-hydroxyvitamin D; Affect; Albumins; Biological Markers; Blood specimen; Body Size; Bone Density; Calcium; Calcium-Sensing Receptors; Case Study; Case-Control Studies; Cell Cycle Regulation; Cell Proliferation; Cells; Cohort Studies; Cyclin D1; Demographic Factors; Development; Diagnosis; Diet; Dietary Factors; Disease; Diuretics; Endocrine System Diseases; Environmental Risk Factor; Estrogens; Excision; Fracture; Growth; Health; High Prevalence; Hypercalcemia; Hyperparathyroidism; Hyperplasia; Individual; Intake; Interleukin-6; Kidney Calculi; Lead; Life Style; Magnesium; Measures; Menopause; Morbidity - disease rate; Mutation; Neoplasms; Non-Steroidal Anti-Inflammatory Agents; Nurses' Health Study; Obesity; PTGS2 gene; PTH gene; Parathyroid Adenoma; Parathyroid gland; Participant; Pathogenesis; Pharmaceutical Preparations; Phosphorus; Plasma; Play; Positioning Attribute; Postmenopause; Prevention approach; Probability; Prospective Studies; Proteins; Reporting; Resected; Risk; Risk Factors; Role; Sampling; Serum; Severities; Severity of illness; Smoking; Somatic Mutation; Staining method; Stains; Testing; Thiazide Diuretics; Tissue Microarray; Tissues; Variant; Vitamin A; Vitamin D; Vitamin D-Binding Protein; Weight; Woman; calcium intake; common treatment; insight; lifestyle factors; modifiable risk; molecular phenotype; novel strategies; prospective; protein expression; receptor expression; thiazide; tissue biomarkers; urinary

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.

描述（由申请人提供）：原发性甲状旁腺功能亢进症（PHPT）影响多达2％的绝经后妇女，并导致骨矿物质密度，骨折和肾结石降低。尽管该疾病的患病率很高和发病率，但pHPT的发病机理仍不清楚。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的潜在可修改风险因素。我们旨在对PHPT产生新的见解，这可能会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，这表明这些肿瘤来自具有生长赋予突变的单个细胞。因此，我们对目标1和2中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，较低的钙摄入量与护士健康研究（NHS）I的发生风险增加有关。利尿剂），以及随后发生pHPT的风险。迄今为止，还没有研究对PHPT的血浆风险因素进行了前瞻性检查。使用在诊断之前收集的储存的血液样本，我们具有在NHS I和II中嵌套的前瞻性病例控制研究中研究此类因素的独特能力（n = 450例，900例对照）。在AIM 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与出现PHPT的风险增加有关。我们还假设未结合或“自由” 25（OH）D（由25 [OH] D估计，维生素D结合蛋白和白蛋白）与风险相比，比总计25（OH）d更加密切。在AIM 3中，我们将使用组织微阵列免疫组织化学染色来量化细胞周期蛋白D1和钙传感受体（CASR）的表达，并在具有PHPT的200 NHS I和II参与者的切除的，增大的甲状旁腺增大。 Cyclin D1（CyCD1）是细胞周期调节的组成部分，在约40％的甲状旁腺腺瘤中高度表达，甲状旁腺肿大的CASR较低的CASR可能代表PHPT的原因，而不是结果。我们假设1）较高的CYCD1和CASR表达较高与甲状旁腺重量的增加有关，疾病严重程度的决定因素，2）较高的BMI，更年期，吸烟和NSAID的使用较低与CYCD1表达和较高的Cycd1表达相关，而3）累积的累积性较低的BMI累积累积与较低的BMI相关。这将是首次研究PHPT诊断前评估的环境因素与随后在PHPT的发病机理和/或严重程度中起重要作用的甲状旁腺蛋白的组织表达之间的关联。