Joint Determinants of Bone Density and CVD Calcification

描述（由申请人提供）： 越来越多的证据表明骨质疏松症和动脉粥样硬化之间存在联系。 最近的研究表明，骨矿物质密度 (BMD) 成反比 与主动脉和冠状动脉钙化、标志物的严重程度相关 动脉粥样硬化。已经提出了几种共同的途径来连接这些 两种疾病。该项目的总体目标是评估 BMD与冠状动脉和主动脉钙化之间的关系， 通过电子束 CT 对一个大型阿米什血统的 700 名成员进行了测量 已经参加阿米什家庭骨质疏松症研究（AFOS）。由 以家庭为中心，我们可以梳理出遗传因素各自的贡献 和非遗传因素对这种特征的聚集。 AFOS 启动 1997年确定了影响骨质疏松症易感性的基因 确定家庭的骨折风险。通过 NIH 提供的资金 AFOS亲本研究，我们将对391高度多态性短串联重复进行基因分型 (STR) 标记以大约 10 cM 的间隔排列，并进行全基因组分析 扫描以检测与变异相关的数量性状基因座 (QTL) BMD 和相关特征。旧秩序阿米什人是有资金和有资金的人的理想选择 提出的研究，因为他们是一个封闭的创始人群体，相对而言 遗传同质，家族规模非常大，并且有充分的记录 家谱。 这里提出的研究将使用 BMD 的可用措施，相关 AFOS 中的性状和基因型以及新收集的测量值 血管钙化。这项研究是 AFOS 的自然延伸，带来了 汇集了一支强大的跨学科研究团队，拥有大量 心血管疾病和骨质疏松症方面的记录和专业知识 流行病学、统计遗传学和分子遗传学。 提出的具体目标是确定 BMD 是否与 冠状动脉和主动脉钙化 CAC，如果是，则确定 共同基因或共享环境对这种关联的贡献 家庭。接下来我们将评估遗传性和非遗传性 对 CAC 血管钙化决定因素的变异性的贡献 这些家庭。我们将评估个人和共同贡献 脂质氧化为 BMD 和血管钙化 CAC。使用广泛的 基因分型将可用，我们将进行全基因组扫描 冠状动脉和主动脉钙化CAC。这些结果将补充 对骨相关表型进行了类似的分析。最后，我们 将确定与 BMD 变异相关的染色体区域是否也存在 与血管钙化的变化或其他可能的关节有关 决定因素，如 CAC（或脂质氧化）。这些研究将提供 对骨质疏松症和动脉粥样硬化的联合决定因素的见解。这样的 见解可能有助于阐明特定的遗传途径，这些途径可以 未来可用于早期识别高风险个体，例如 以及开发新的预防和治疗方法。

DESCRIPTION (provided by applicant): There is growing evidence of a link between osteoporosis and atherosclerosis. Recent studies document that bone mineral density (BMD) is inversely correlated with severity of aortic and coronary artery calcification, markers of atherosclerosis. Several common pathways have been proposed to link these two disorders. The overall objective of this project is to evaluate the relationship between BMD and coronary artery and aortic calcification, measured by Electron Beam CT, in 700 members of a large Amish pedigrees already participating in the Amish Family Osteoporosis Study (AFOS). By focusing on families, we can tease out the respective contributions of genetic and non-genetic factors to this clustering of traits. The AFOS was initiated in 1997 to identify genes influencing susceptibility to osteoporosis in families ascertained for fracture risk. Through NIH funding available to the AFOS parent study, we will genotype 391 highly polymorphic short tandem repeat (STR) markers spaced at approximately 10 cM intervals and perform a genome-wide scan to detect quantitative trait loci (QTLs) associated with variation in BMD and related traits. The Old Order Amish are ideal for the funded and proposed studies since they are a closed founder population who are relatively genetically homogeneous, have very large family sizes, and well-documented genealogies. The study proposed here will use the available measures of BMD, related traits, and genotypes in the AFOS along with the newly collected measures of vascular calcification. This study, a natural extension of the AFOS, brings together a strong interdisciplinary team of researchers with a substantial track record in both cardiovascular disease and osteoporosis and expertise in epidemiology, statistical genetics, and molecular genetics. The specific goals proposed are to determine if BMD is correlated with coronary artery and aortic calcification CAC and, if so, to determine the contribution of common genes or shared environments to this association in families. We will next assess genetic heritability and non-genetic contributions to variability in vascular calcification determinants of CAC in these families. We will assess the individual and joint contributions of lipid oxidation to BMD and vascular calcification CAC. Using the extensive genotyping that will be available, we will perform a genome wide scan of coronary artery and aortic calcification CAC. These results will complement the similar analyses obtained on the bone-related phenotypes. Finally, we will determine if chromosomal regions linked to variation in BMD are also linked to variation in vascular calcification or to another possible joint determinant such as CAC (or to lipid oxidation). These studies will provide insights into joint determinants osteoporosis and atherosclerosis. Such insights could lead to elucidation of specific genetic pathways that can be exploited in the future for early identification of high-risk individuals, as well as development of new preventive and therapeutic approaches.