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，骨密度(BMD)与 与主动脉和冠状动脉钙化严重程度相关的标志物 动脉粥样硬化。已经提出了几种常见的路径来连接这些 两种疾病。这个项目的总体目标是评估 骨密度与冠状动脉和主动脉钙化的关系 一个阿米什大家系700名成员的电子束CT测量 已参与阿米什家庭骨质疏松症研究(AFOS)。通过 聚焦于家庭，我们可以梳理出基因各自的贡献 以及非遗传因素导致了这种特征的聚集。AFOS是由 在1997年发现影响骨质疏松症易感性的基因 已确定有骨折风险的家庭。通过美国国立卫生研究院提供给 AFOS父母研究，我们将对391个高度多态的短串联重复序列进行基因分型 (STR)标记以大约10 cM的间隔间隔并执行全基因组 扫描检测与变异相关的数量性状基因座(QTL) 在骨密度及相关性状上。旧秩序阿米什人是有钱人和 建议的研究，因为他们是相对封闭的创始人群体 基因相同，有非常大的家庭成员，并且有很好的记录 家谱。 这里提出的研究将使用现有的骨密度测量方法，相关 AFO中的性状、基因类型以及新收集的 血管钙化。这项研究是AFO的自然延伸，带来了 汇聚一支强大的跨学科研究团队，拥有大量 在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，确定 共同基因或共享环境对这种关联的贡献 家人。接下来，我们将评估遗传遗传力和非遗传性 血管钙化决定因素在冠状动脉钙化中的作用 这些家庭。我们将评估个人和联合的贡献 脂质氧化为BMD和血管钙化CAC。使用广泛的 基因分型，我们将进行全基因组扫描 冠状动脉和主动脉钙化CAC。这些结果将是互补的 对与骨相关的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 与血管钙化的变化或另一个可能的关节有关 决定因素，如CAC(或对脂质氧化)。这些研究将提供 对联合决定因素骨质疏松症和动脉粥样硬化的见解。是这样的 洞察力可能导致阐明特定的遗传途径，这些途径可以 在未来被利用来早期识别高危个人，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.