Co-localizing Quantitative Trait Loci for Bone Mineral Density and HDL in Mice

描述（由申请人提供）：一半的美国人患有骨质疏松症或有严重的骨质疏松症风险。骨密度（BMD）可以很容易地在临床环境中测量，骨密度低与骨质疏松性骨折的风险增加有关。在工业化社会，心血管疾病（CVD）是导致死亡的主要原因之一，而高密度脂蛋白胆固醇的升高可以降低患心血管疾病的风险。研究表明，低骨密度可以作为CVD的独立预测指标，而患有CVD的患者更有可能患有低骨密度。吸烟、缺乏锻炼和吃高脂肪的“西方”饮食会增加患心血管疾病和骨质疏松症的风险。综上所述，这两种疾病可能有共同的病因。骨密度和血清高密度脂蛋白水平均受基因调控。对人类的初步研究表明，这两种表型存在共同的遗传原因，但是，由于环境和生活方式因素影响BMD和血清HDL水平，确定CVD和骨质疏松症之间的遗传联系一直很困难。小鼠是绘制复杂性状的基因图谱的绝佳模型，而且，与人类研究不同的是，在使用小鼠的研究中，环境可以根据需要进行控制和调节。在小鼠1号和8号染色体上发现了两个与骨密度有关的QTL，它们与血清高密度脂蛋白QTL一致。此外，这两种BMD QTL都与膳食胆固醇摄入量相互作用。Chr 1 QTL已缩小到1个基因，Chr 8 QTL已缩小到4个候选基因。在本应用中，将开发Chr 1上候选基因的敲除小鼠，以确认：1)该基因是Chr 1上BMD QTL的基础；2)该QTL与膳食胆固醇摄入量相互作用影响骨密度；3)这个基因调节血清高密度脂蛋白水平。在第二个目标中，将确定Chr 8上BMD QTL的基础基因，并证实该位点上的单个基因同时调节BMD和HDL QTL的假设。

DESCRIPTION (provided by applicant): Half of all Americans either have or are at serious risk for developing osteoporosis. Bone mineral density (BMD) can be readily measured in a clinical setting, and low BMD is associated with increased risk of osteoporotic fracture. Cardiovascular disease (CVD) is a major cause of death in industrialized societies, and it is well established that raising HDL cholesterol reduces the risk of cardiovascular disease. Studies have shown that low BMD can be used as an independent predictor of CVD, and patients with CVD are more likely to have low BMD. Smoking, lack of exercise and eating a high fat "Western" diet increases the risk of developing both CVD and osteoporosis. Together these suggest that there may be shared causes for these two diseases. Both BMD and serum HDL levels have been shown to be genetically regulated. Preliminary studies in humans have suggested the existence of shared genetic causes for both of these phenotypes, but, as environmental and lifestyle factors influence both BMD and serum HDL levels, identifying the genetic link between CVD and osteoporosis has been difficult. The mouse is an excellent model for mapping genes that underlie complex traits, and, unlike in human studies, environment can be controlled and modulated as needed in studies using the mouse. Two quantitative trait loci (QTL) for BMD have been identified on mouse Chromosome 1 and 8 that are coincident for QTL for serum HDL. Furthermore, both of these BMD QTL interact with dietary cholesterol intake. The Chr 1 QTL has been narrowed down to one gene, and the Chr 8 QTL has been narrowed down to 4 candidate genes. In this application, a knockout mouse for the candidate gene on Chr 1 will be developed to confirm that: 1) this gene underlies the BMD QTL on Chr 1; 2) this QTL interacts with dietary cholesterol intake to affect BMD; and 3) this same gene regulates serum HDL levels. In the second Aim, the gene underlying the BMD QTL on Chr 8 will be identified, and the hypothesis that a single gene at this locus regulates both the BMD and HDL QTL will be confirmed.