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）是成反比的， 与主动脉和冠状动脉钙化的严重程度相关， 动脉粥样硬化已经提出了几个共同的途径来连接这些 两种失调本项目的总体目标是评估 BMD与冠状动脉和主动脉钙化的关系， 通过电子束CT测量，在一个大型阿米什人家系的700名成员中， Amish Family Osteoporosis Study（AFOS）的一部分。通过 以家庭为中心，我们可以梳理出遗传因素的各自贡献， 和非遗传因素的影响。AFOS启动了 在1997年，为了确定影响骨质疏松症易感性的基因， 家庭确定骨折风险。通过NIH提供的资金， AFOS亲本研究中，我们将391个高度多态性短串联重复序列进行基因分型 (STR)标记间隔约10厘米的间隔，并执行全基因组 扫描检测与变异相关的数量性状位点（QTL） 骨密度和相关性状。旧秩序阿米什人是理想的资助和 建议的研究，因为他们是一个封闭的创始人人口谁是相对 基因同质，有非常大的家庭规模，并有充分的记录 家谱 本文提出的研究将使用现有的BMD测量方法， 沿着AFOS中的性状和基因型以及新收集的 血管钙化这项研究是AFOS的自然延伸， 一个强大的跨学科研究团队， 在心血管疾病和骨质疏松症方面的记录， 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，以确定 共同的基因或共同的环境对这种关联的贡献， 家庭接下来我们将评估遗传和非遗传 CAC的血管钙化决定因素的变异性 这些家庭。我们将评估个人和共同的贡献 脂质氧化导致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。这些结果将补充 在骨相关表型上获得类似的分析。最后我们 将确定与BMD变异相关的染色体区域是否也 与血管钙化变异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。等 这些见解可能导致阐明特定的遗传途径， 在未来用于早期识别高风险个体， 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.