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，并且是造成大量发病率和死亡率的原因。导致其发展的机制尚未得到充分阐明。每个通道都有重叠。探索每一种疾病的共同通路中的机制将为导致每种疾病的生物学提供新的见解，并可能最终为预防这些疾病提供新的治疗靶点。胎儿素a是一种肝脏分泌蛋白，其主要功能是调节血管和骨骼中的钙和磷沉积。Fetuin-A也直接或间接诱导外周胰岛素抵抗。我们在定义胎儿蛋白a的流行病学和阐明其在亚临床心血管疾病、骨病和糖尿病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，但现有的许多数据都是横断面的，因此胎儿蛋白a与疾病结局的时间关系在很大程度上尚未得到证实。这项应用将确定胎儿蛋白a与老年人心血管疾病死亡率、骨折和糖尿病的潜在关联。该研究将作为Rancho Bernardo研究的巢式研究有效地进行；在社区生活老年人中建立观察队列。该研究将对1992年至1996年储存的血液样本进行胎儿素a测量。从那时起，受试者进行了纵向随访，提供了超过15年的心血管疾病死亡率、骨质疏松性骨折和偶发糖尿病的随访。我们将利用这一丰富的资源：(1)确定胎儿素a水平是否与心血管疾病相关；(2)确定胎儿素a水平与骨质疏松性骨折发生率是否相关；(3)在社区生活的老年人中，确定是否通过脂联素和体脂的纵向变化介导了胎儿素- a水平与糖尿病发病率的关联。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常见和病态的疾病，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，并可能最终确定预防或治疗这些疾病的新治疗靶点。

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.