GENETICS OF BONE LOSS AND BONE STRENGTH IN WOMEN & MEN

女性骨质流失和骨质强度的遗传学

• 批准号: 7020553
• 负责人: MUNRO PEACOCK
• 金额: $ 45.5万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7020553
• 关键词: African American; aging; biomechanics; bone density; caucasian American; computed axial tomography; developmental genetics; family genetics; gender difference; gene expression; genetic mapping; genetic polymorphism; genetic screening; genetic susceptibility; human subject; longitudinal human study; osteoporosis; patient oriented research; phenotype; quantitative trait loci; racial /ethnic difference; siblings

We have shown that QTL for both bone mineral density (BMD) and structure appear to be sex-specific. These potentially important findings will be corroborated by enlarging the current sample size of brothers from 700 to 1,000 pairs and comparing these with data we have collected in 1,225 sister pairs. Bone size is an important factor in determining bone strength and hence fracture risk. We have shown that there is a significant increase in the rate of bone expansion at the femoral neck that it is heritable, and that linkage analysis has identified a number of QTL. No comparable data have been collected in men. We will perform a 5 year longitudinal study in brother pairs to establish if there are sex-specific genes for expansion of bone size. Quantitative computerized tomography (CT) at the proximal femur provides volumetric BMD of cortical and trabecular bone, structural phenotypes, and mechanical phenotypes related to in vivo bone strength. We have found significant differences between white and black men in cortical BMD. In women, we have found QTL for cortical and trabecular volumetric BMD at femoral neck. To corroborate these key findings we propose to increase our sample size by 300 pairs of brothers and 300 pairs of sisters for CT phenotypes. Achievement of these specific aims will provide fundamental information on the presence of sex-specific genes underlying the normal variation in bone density, bone structure, and in vivo biomechanical phenotypes, all key components of bone strength and risk of fracture. Further, it will provide information on the genes underlying differences in bone strength between American whites and blacks. It is expected that these proposed studies will greatly contribute to our understanding for the reasons for the higher risk of osteoporotic fracture in women than men and in American whites than blacks. Importantly the genes responsible for these differences are likely to provide targets for novel and more specific therapy aimed at prevention and treatment of osteoporotic fracture.

我们已经表明，骨密度（BMD）和结构的QTL似乎是性别特异性的。这些潜在的重要发现将通过将目前兄弟的样本量从700对扩大到1,000对，并将这些数据与我们在1,225对姐妹中收集的数据进行比较来证实。骨大小是决定骨强度和骨折风险的重要因素。我们已经证明，股骨颈的骨膨胀率显著增加，这是可遗传的，并且连锁分析已经确定了一些QTL。在男性中未收集到可比数据。我们将在兄弟对中进行为期5年的纵向研究，以确定是否有性别特异性基因用于骨骼尺寸的扩展。股骨近端的定量计算机断层扫描（CT）提供皮质骨和松质骨的体积BMD、结构表型和与体内骨强度相关的机械表型。我们发现白色人和黑人男性在皮质骨密度方面存在显著差异。在女性中，我们发现了股骨颈皮质和骨小梁体积BMD的QTL。为了证实这些关键发现，我们建议增加300对兄弟和300对姐妹篇的CT表型的样本量。这些特定目标的实现将提供有关性别特异性基因存在的基本信息，这些基因是骨密度、骨结构和体内生物力学表型的正常变化的基础，骨强度和骨折风险的所有关键组成部分。此外，它还将提供以下信息： 美国白人和黑人之间骨骼强度差异的潜在基因。预计这些拟议的研究将大大有助于我们了解女性比男性和美国白人比黑人更高的骨质疏松性骨折风险的原因。重要的是，负责这些差异的基因可能为旨在预防和治疗骨质疏松性骨折的新的和更具体的治疗提供靶点。