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

小鼠骨矿物质密度和 HDL 的定量性状基因座的共定位

• 批准号: 8277798
• 负责人: Cheryl Lynne Ackert-Bicknell
• 金额: $ 31.05万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-20 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8277798
• 关键词: Affect; Age; Alleles; American; Bioinformatics; Bone Density; Boxing; Candidate Disease Gene; Cardiovascular Diseases; Cause of Death; Cholesterol; Chromosome Mapping; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 8; Clinical; Complex; Congenic Mice; Developed Countries; Development; Diagnosis; Diet; Dietary Cholesterol; Disease; Distal; Eating; Environment; Environmental Risk Factor; Exercise; Fatty acid glycerol esters; Genes; Genetic; Genetic Polymorphism; Goals; Haplotypes; Heart Diseases; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Inbred Strains Mice; Intake; Integrin alpha Chains; Knockout Mice; Knowledge; Lead; Link; Maps; Measures; Metabolism; Modeling; Mus; Osteoblasts; Osteoclasts; Osteoporosis; Patients; Phenotype; Physiology; Public Health; Quantitative Trait Loci; Research; Risk; Risk Factors; Serum; Smoking; Societies; Techniques; Testing; adipocyte differentiation; alanylaspartic acid; aspartylglutamate; bone; bone morphogenic protein; cardiovascular disorder risk; disease diagnosis; embryonic stem cell; extracellular; feeding; glutamylalanine; heart disease risk; human GPT2 protein; improved; knockout gene; lifestyle factors; lipoprotein lipase; novel; osteoporosis with pathological fracture; polypeptide; prevent; procollagen C-endopeptidase; public health relevance; trait

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.

描述（由申请人提供）：一半的美国人患有骨质疏松症或有患骨质疏松症的严重风险。骨矿物质密度 (BMD) 可以在临床环境中轻松测量，低 BMD 与骨质疏松性骨折风险增加相关。心血管疾病（CVD）是工业化社会的一个主要原因，众所周知，提高高密度脂蛋白胆固醇可以降低心血管疾病的风险。研究表明，低BMD可以作为CVD的独立预测因子，CVD患者更有可能患有低BMD。吸烟、缺乏运动和吃高脂肪的“西方”饮食会增加患心血管疾病和骨质疏松症的风险。这些共同表明这两种疾病可能有共同的原因。骨密度和血清高密度脂蛋白水平均已被证明受到基因调节。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，因此很难确定 CVD 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，并且与人类研究不同的是，在使用小鼠的研究中，可以根据需要控制和调节环境。已在小鼠 1 号和 8 号染色体上鉴定出两个 BMD 数量性状基因座 (QTL)，它们与血清 HDL 的 QTL 一致。此外，这两个 BMD QTL 都与膳食胆固醇摄入量相互作用。 Chr 1 QTL 已缩小至 1 个基因，Chr 8 QTL 已缩小至 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BMD； 3) 这个相同的基因调节血清高密度脂蛋白水平。在第二个目标中，将鉴定 Chr 8 上 BMD QTL 的基因，并证实该基因座上的单个基因调节 BMD 和 HDL QTL 的假设。 公众健康相关性：低骨矿物质密度 (BMD) 与骨质疏松性骨折的风险增加相关，而低水平的 HDL 胆固醇则与心脏病风险增加相关。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带来新的、更好的治疗方法，并提高我们筛查和预防这些常见疾病和使人衰弱的疾病的能力。