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风险。骨矿物质密度（BMD）可以在临床环境中容易地测量，并且低BMD与骨质疏松性骨折的风险增加相关。心血管疾病（CVD）是工业化社会中死亡的主要原因，并且已经确定升高HDL胆固醇可以降低心血管疾病的风险。研究表明，低BMD可作为CVD的独立预测因子，CVD患者更容易出现低BMD。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。这些都表明，这两种疾病可能有共同的原因。BMD和血清HDL水平均被证明是受遗传调节的。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会影响骨密度和血清高密度脂蛋白水平，因此很难确定心血管疾病和骨质疏松症之间的遗传联系。小鼠是绘制复杂性状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相关的数量性状基因座（QTL），它们与血清高密度脂蛋白（HDL）的QTL一致。此外，这两个BMD QTL与膳食胆固醇摄入量相互作用。Chr 1 QTL已缩小到一个基因，Chr 8 QTL已缩小到4个候选基因。在本申请中，将开发Chr 1上候选基因的敲除小鼠以证实：1）该基因是Chr 1上BMD QTL的基础; 2）该QTL与膳食胆固醇摄入相互作用以影响BMD;以及3）该相同基因调节血清HDL水平。在第二个目标中，将确定第8染色体上BMD QTL的潜在基因，并证实该位点的单个基因调节BMD和HDL QTL的假设。 公共卫生相关性：低骨矿物质密度（BMD）与骨质疏松性骨折的风险增加有关，低水平的HDL胆固醇与心脏病的风险增加有关。这项研究将帮助我们更好地理解和识别同时调节BMD和HDL胆固醇水平的基因。了解心脏病和骨质疏松症的共同遗传原因将导致新的和更好的治疗方法，并提高我们筛查和预防这些常见和使人衰弱的疾病的能力。

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. PUBLIC HEALTH RELEVANCE: Low bone mineral density (BMD) is associated with increased risk of osteoporotic fracture, and low levels of HDL cholesterol are associated with increased risk for heart disease. This research will help us better comprehend and identify the genes that simultaneously regulate BMD and HDL cholesterol levels. Understanding the shared genetic causes of heart disease and osteoporosis will lead to new and better treatments and improve our ability to screen for and prevent these common and debilitating diseases.