Fetuin-A and Incident Cardiovascular Disease, Fracture, and Diabetes

描述(由申请人提供)：心血管疾病(CVD)、骨质疏松症和糖尿病在老年人中非常常见，是导致大量发病率和死亡率的原因。对它们的发展负责的机制还没有完全阐明。每条路径都有重叠。探索每种疾病共同途径中的机制将为导致每种疾病的生物学提供新的见解，并最终可能导致预防这些疾病的新的治疗目标。胎球蛋白-A是一种肝脏分泌性蛋白，其主要功能是调节钙磷在血管和骨骼中的沉积。胎球蛋白-A还直接和间接地诱导外周胰岛素抵抗。我们在定义胎球蛋白-A的流行病学和阐明其在人类亚临床脑血管病、骨病和糖尿病的发展中的作用方面做出了重大贡献。虽然这些初步研究提供了重要的新见解，但现有的许多数据是横截面的，因此胎球蛋白-A与疾病结局的时间关系在很大程度上是未经证实的。这项应用将确定胎球蛋白-A与老年人心血管疾病死亡率、骨折和糖尿病的预期相关性。这项研究将作为兰乔·贝尔纳多研究中的一项嵌套研究有效地进行；该研究是在社区老年人中建立的观察队列。这项研究将对1992-96年间储存的血液样本进行胎球蛋白-A测量。从那时起，受试者一直被纵向跟踪，为心血管疾病死亡率、骨质疏松性骨折和糖尿病事件提供了超过15年的随访。我们将利用这一丰富的资源：(1)确定胎球蛋白-A水平是否与心血管疾病有关；(2)确定胎球蛋白-A水平是否与发生的骨质疏松性骨折有关；(3)确定在社区生活的老年人中，胎球蛋白-A水平与发生的糖尿病之间的联系是否通过脂联素和体脂的纵向变化来调节。公共卫生相关性：虽然心血管疾病、骨质疏松症和糖尿病是老年人的常见和病态疾病，但我们对其发病机制的了解仍然不完整。这项流行病学研究的结果将为其发病机制提供新的见解，并最终可能为其预防或治疗确定新的治疗靶点。

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD), osteoporosis, and diabetes are exceedingly common in older persons, and are responsible for substantial morbidity and mortality. Mechanisms responsible for their development are not fully elucidated. There are overlaps in the pathways to each. Exploring mechanisms at points in the pathways common to each will provide novel insights to the biology leading to each disease, and may ultimately lead to novel therapeutic targets for their prevention. Fetuin-A is a hepatic secretory protein with the principal function of regulating calcium and phosphorus deposition in the vasculature and bone. Fetuin-A also directly and indirectly induces peripheral insulin resistance. We have made major contributions to defining the epidemiology of fetuin-A and elucidating its role in the development of subclinical CVD, bone disease, and diabetes in human populations. While these preliminary studies have provided important new insights, much of the existing data has been cross-sectional, and therefore the temporal relationship of fetuin-A with disease outcomes is largely unproven. This application will determine the prospective associations of fetuin-A with CVD mortality, fractures, and diabetes in older persons. The study will be efficiently conducted as a nested study within the Rancho Bernardo Study; an established observational cohort among community living older persons. The study will make fetuin-A measurements on stored blood specimens from 1992-96. Subjects have been followed longitudinally from that time forward, providing over 15 years of follow-up for CVD mortality, osteoporotic fractures, and incident diabetes. We will utilize this rich resource to: (1) Determine whether fetuin-A levels are associated with cardiovascular disease; (2) Determine whether fetuin-A levels are associated with incident osteoporotic fractures; and (3) Determine whether the association of fetuin-A levels with incident diabetes mellitus is mediated through adiponectin and longitudinal changes in body fat, in community-living older persons. PUBLIC HEALTH RELEVANCE: While cardiovascular disease, osteoporosis, and diabetes represent common and morbid disease in older persons, our understanding of their pathogenesis remains incomplete. The results of this epidemiologic study will provide novel insights into their pathogenesis and may ultimately identify novel therapeutic targets for their prevention or treatment.