Osteocalcin and Metabolic Risk Factors. The Framingham Study

描述（由申请人提供）：基于最近在啮齿动物中的发现，首次发现骨钙素（OC），一种由成骨细胞独特分泌的主要骨形成蛋白，可能通过增强b细胞增殖、胰岛素产生、胰岛素敏感性和脂联素表达作为瘦素调节成骨细胞的反馈环，在能量代谢的内分泌调节中发挥关键作用。这一新的证据表明，骨细胞不仅在骨骼局部发挥作用，而且可能参与胰岛素抵抗和代谢综合征的发病机制。然而，OC如何与脂肪细胞，胰腺2细胞和其他参与葡萄糖稳态功能的分子相互作用的潜在机制仍不清楚。生物学证据的存在将通常相当不同的疾病的“内表型”联系起来，提出了另一种可能性，即疾病可能不像人们通常认为的那样相互独立。我们的研究试图将两个系统联系起来：骨骼和能量代谢。因此，这一提议的基本假设是，存在调节血清OC和代谢风险因素（代谢综合征风险因素聚集：包括向心性肥胖、高血糖、血脂异常和高血压在内的风险因素的组合）的共享遗传变异。在这项应用中，我们提出了一个全基因组关联（GWA）的方法在心脏研究中，以确定（1）新的遗传变异的血清OC和（2）共同的遗传决定因素与直接多效性影响血清OC和代谢危险因素（包括腰围、收缩压、空腹甘油三酯、空腹HDL胆固醇、空腹血糖、空腹血浆胰岛素、脂联素浓度和胰岛素抵抗指数如HOMA-IR和QUICKI）。将使用最先进的GWA分析方法，包括多表型GWA分析，使用最近开发的遗传性方法的原则，基于先验信息的加权假设，以及新开发的结构建模来推断直接的多效性效应。生物信息学方法，如通路网络分析、基因组富集测试和eSNP分析也将被应用。我们将使用已经收集的表型数据和可用的高密度550 K Affyssin基因分型数据。拟议的工作将利用丰富的可用数据和大样本量的心脏研究。这将是第一个使用GWA方法试图从动物身上翻译OC发现的人类研究，这将为产生新的假设提供机会，以了解串扰背后的信号通路和潜在的生物学机制，因为还不完全了解这种骨蛋白如何调节葡萄糖代谢，胰岛素分泌和胰岛素敏感性。在人类中证实这些发现也可能对妇女有重要的意义，她们通常患有骨质疏松症和心血管疾病危险因素聚集的病态并发症，有时甚至是致命的并发症，代谢综合征。 公共卫生相关性：近年来的动物实验研究表明，骨钙素是一种重要的骨蛋白，参与能量代谢的内分泌调节。然而，骨钙素如何与脂肪细胞和胰腺2细胞相互作用的潜在机制仍不清楚。我们的研究将是第一个使用最先进的全基因组关联方法的人类研究，试图识别骨钙素和代谢风险因素共享的新型遗传变异，这将为潜在的分子靶点提供有价值的见解，这将有助于进一步了解骨骼和能量代谢之间的潜在通信机制。

DESCRIPTION (provided by applicant): Based on a recent discovery in rodents, for the first time, osteocalcin (OC), a major bone formation protein uniquely secreted by osteoblasts, may play a crucial role in endocrine regulation of energy metabolism by enhancing b-cell proliferation, insulin production, insulin sensitivity and adiponectin expression as a feedback loop of Leptin's regulation of osteoblasts. This new evidence suggests that bone cells not only function locally on the skeleton, but may also be involved in the pathogenesis of insulin resistance and the metabolic syndrome. However, the underlying mechanisms for how OC interacting with adipocytes, pancreatic 2 cells and other molecules functionally involved in glucose homeostasis are still unclear. The existence of biological evidence linking "endo-phenotypes" of often quite distinct diseases raises another possibility that diseases may not be as independent of each other as is often assumed. Our study attempts to link two systems: bone and energy metabolisms. Thus the underlying hypothesis of this proposal is that there are shared genetic variants that regulate both serum OC and metabolic risk factors (metabolic syndrome risk factor clustering: a combination of risk factors including central obesity, hyperglycemia, dyslipidemia, and hypertension). In this application we are proposing a genome-wide association (GWA) approach in the Framingham Heart Study to identify (1) novel genetic variants for serum OC and (2) shared genetic determinants with directly pleiotropic effects on both serum OC and metabolic risk factors (including waist circumference, systolic blood pressure, fasting triglycerides, fasting HDL cholesterol, fasting plasma glucose, fasting plasma insulin, adiponectin concentrations and insulin resistance indices such as HOMA-IR and QUICKI). The state-of-the-art GWA analytical approaches will be used including the multipe-phenotyping GWA analysis using a recent developed Principle of Heritability method, weighted hypotheses based on prior information, and a newly developed structure modeling to infer the directly pleotropic effects. Bioinformatics approaches, such as pathway network analyses, gene- set enrichment test, and eSNP analyses will also be applied. We will use already collected phenotype data and available high-density 550K Affymetrix genotyping data. The proposed work will take advantage of the rich available data and large sample size of the Framingham Heart Study. This will be the first human study using GWA approach to attempt to translate the OC findings from animals, which will afford the opportunity to generate new hypotheses to understand the signaling pathways and underlying biological mechanisms behind the crosstalk, as it is not fully understood how this bone protein regulates glucose metabolism, insulin secretion and insulin sensitivity. Confirmation of these findings in humans could also have important implications for women who commonly suffer from the morbid and sometimes mortal complications of both osteoporosis and cardiovascular disease risk factor clustering, metabolic syndrome. PUBLIC HEALTH RELEVANCE: Recent animal studies have showed that osteocalcin, an important bone protein, involves in the endocrine regulation of energy metabolism. However, the underlying mechanisms for how osteocalcin interacting with adipocytes and pancreatic 2 cells are still unclear. Our study will be the first human study using state-of-the-art genome-wide association approaches to attempt to identify novel genetic variants shared by both osteocalcin and metabolic risk factors, which will provide valuable insight into potential molecular targets that will help further understanding the underlying mechanisms of communication between skeleton and energy metabolism.