Parathyroid Hormone: Genetic Architecture and Clinical Consequences

项目摘要 该提案描述了一个为期3年的职业发展计划和研究战略， 候选人将加强她的临床流行病学专业知识与基因组科学的研究能力， 生物信息学和研究甲状旁腺激素浓度的遗传基础。 主要研究者已在华盛顿大学（UW）获得流行病学博士学位， 博士后培训在肾脏研究所，肾脏科，医学系，在 华盛顿大学她将通过有重点的职业发展计划和以下方面的培训来扩展她的科学技能： 分子遗传学应用于成人甲状旁腺激素失调。布鲁斯·普萨蒂博士是 医学在华盛顿大学，并将指导主要研究者的科学和职业发展。Psaty博士是一位 全球公认的心血管疾病遗传流行病学领导者。的一个顾问委员会 科学家，包括Deborah Nickerson博士，他在应用强大的方法方面具有专业知识， 一代测序技术和Ronit Katz博士谁是一个公认的生物统计学家，将提供 额外的职业和项目指导。此外，密集的研讨会，课程在华盛顿大学和寒冷 春港实验室，UT Health的奖学金计划，研讨会，期刊俱乐部和特定的分析 技术培训将伴随着充足的受保护的研究时间。学术环境在 肾内科在UW支持独立，翻译研究人员的发展。 科学研究将集中在循环甲状旁腺激素（PTH）的遗传机制， 甲状旁腺激素紊乱具有重要的临床意义 后果原发性甲状旁腺功能亢进通常与骨病、肾结石和 胃肠动力障碍继发性甲状旁腺功能亢进在慢性肾脏疾病中的进展 (CKD)，有助于CKD-矿物质和骨骼疾病的发病机制。在一般人群中， 血清PTH浓度与高血压、左心室肥大和骨折有关。 钙稳态的必需调节激素。 的 甲状旁腺激素的潜在调节机制尚不清楚，存在明显的相互作用， PTH的个体差异与已知因素无关。PTH全基因组关联研究进展 浓度显示与CYP 24 A1基因附近的常见变异体存在稳健和强相关性。 CYP 24 A1编码活性维生素D的主要分解代谢酶，并在钙代谢中起关键作用。 代谢，通过发现失活突变作为高钙血症的原因而突出， 肾结石这些数据代表了维生素D催化剂与PTH调节相关的第一个证据。 该项目的具体目标是通过以下方式扩展这些发现：1）识别与以下疾病相关的罕见变异： 循环PTH，2）精确定位与PTH浓度相关的功能变体，和3）估计 血清甲状旁腺激素浓度与高血压、心力衰竭和骨折的非混杂因果关系 使用孟德尔随机化方法。

PROJECT SUMMARY This proposal describes a 3-year career development program and research strategy through which the Candidate will bolster her clinical epidemiology expertise with research capacity in genome science and bioinformatics and investigate the genetic underpinnings of parathyroid hormone concentrations. The principal investigator has completed a PhD at the University of Washington (UW) in Epidemiology, and post-doctoral training at the Kidney Research Institute, Division of Nephrology, Department of Medicine at the UW. She will expand upon her scientific skills through a focused career development plan and training in molecular genetics as applied to parathyroid hormone dysregulation in adults. Dr. Bruce Psaty is Professor of Medicine at UW and will mentor the principal investigator's scientific and career development. Dr. Psaty is a globally recognized leader in the genetic epidemiology of cardiovascular disease. An advisory committee of scientists, including Dr. Deborah Nickerson who has expertise in the applying robust methods for next- generation sequencing technology and Dr. Ronit Katz who is a well-established biostatistician, will provide additional career and project guidance. In addition, intensive workshops, coursework at UW and the Cold Spring Harbor Laboratory, a fellowship program at UT Health, seminars, journal clubs, and specific analytic technique training will accompany ample protected research time. The academic environment in the Department of Nephrology at UW supports the development of independent, translational investigators. Scientific investigations will focus on the genetic mechanisms of circulating parathyroid hormone (PTH), the Disorders of PTH have important clinical consequences. Primary hyperparathyroidism is classically associated with bone disease, kidney stones, and gastrointestinal dysmotility. Secondary hyperparathyroidism develops progressively in chronic kidney disease (CKD), contributing to the pathogenesis of CKD-mineral and bone disorder. In the general population, higher serum PTH concentrations are associated with hypertension, left ventricular hypertrophy, and fractures. essential regulatory hormone for calcium homeostasis. The underlying regulatory mechanism for of parathyroid hormone is unknown and there exists marked inter- individual variation in PTH independent of known factors. A recent genome-wide association study of PTH concentrations revealed a robust and strong association for a common variant near the CYP24A1 gene. CYP24A1 encodes the primary catabolic enzyme for active vitamin D and plays a critical role in calcium metabolism, highlighted by the discovery of inactivating mutations as a cause of hypercalcemia and nephrolithiasis. These data represent the first evidence that vitamin D catabolism is related to PTH regulation. The specific goals of this project are to extend these findings, by: 1) identifying rare variants associated with circulating PTH, 2) pinpointing functional variants associated with PTH concentrations, and 3) estimating the unconfounded causal association of serum PTH concentrations with hypertension, heart failure, and fracture using a Mendelian randomization approach.