Genetic Epidemiology of Musculoskeletal Aging

描述(由申请人提供)：与年龄相关的瘦体重下降在病理上表现为骨质疏松，导致骨折和骨质疏松症，导致肌肉无力和功能丧失。身体成分的这些变化最终与身体功能和执行日常生活任务的能力下降有关。Health ABC的这项研究是对3075名年龄在70-79岁的男性和女性(52%是女性，42%是非裔美国人)进行的纵向研究，对身体成分、力量和功能进行了最先进的测量。在Health ABC队列中，我们将评估50个生理候选基因的变异对骨(骨密度和骨质量)和肌肉(肌肉质量、力量和质量)表型和性能的贡献。我们将：(1)评估肌肉和骨骼表型与六种类固醇代谢和作用以及生长因子和细胞因子结构和作用所涉及的位点变异的相关性；(2)评估候选基因变异与肌肉和骨骼表型量化指标的年化变化之间的关联；(3)评估影响肌肉和骨骼表型的基因之间以及基因和环境之间的交互作用；以及(4)检查候选基因变异与表现指标之间的关联。高通量基因分型将使用最近开发的荧光偏振技术。为了检验肌肉骨骼表型和遗传多态之间的关系，我们将使用适合横断面和纵向数据的统计模型。对于横断面分析，我们的主要工具将是一般线性模型(回归、方差分析和Manova)。将对主要效果、相互作用和计划的对比进行评估。将检查残差、离群值和影响点，并进行敏感性分析。对于连续结果的纵向数据分析，将采用标准随机效应模型。这些模型考虑了受试者之间的异质性，因此提高了测量遗传效应的精确度。我们将使用一种通用的分析方法进行关联研究，即基因组控制，以使我们的结论对种群亚结构的影响具有稳健性。这些研究将有助于我们了解与年龄相关的瘦体重下降的机制，并可能识别出预防干预的高风险个体。

DESCRIPTION (provided by applicant): Age related declines in lean body mass become pathologically significant as osteoporosis, leading to fractures and sarcopenia, leading to muscle weakness and loss of function. These changes in body composition are ultimately associated with declines in physical function and the ability to perform tasks of daily living. The Health ABC study is a longitudinal study of 3,075 men and women aged 70-79 (52 percent women and 42 percent African American) with state of the art measures of body composition, strength and function. In Health ABC cohort, we will estimate the contribution of variation at 50 physiological candidate genes on bone (bone mineral density and bone quality) and muscle (muscle mass, strength and quality) phenotypes and performance. We will: (1) evaluate the association of muscle and bone phenotypes with variation in loci involved in six steroid metabolism and action and in growth factor and cytokine structure and action; (2) evaluate the association between candidate gene variation and annualized changes in quantitative measures of muscle and bone phenotypes; (3) evaluate the interaction between genes and between genes and environments in influencing muscle and bone phenotypes; and (4) examine the association between variation at candidate genes and measures of performance. High throughput genotyping will use the recently developed fluorescence polarization technique. To examine the relationship between musculoskeletal phenotypes and genetic polymorphisms, we will use statistical models appropriate for cross-sectional and longitudinal data. For cross-sectional analyses, our major tools will be general linear model (regression, ANOVA, and MANOVA). Main effects, interactions and planned contrasts will be assessed. Residuals, outliers and influential points will be examined and sensitivity analyses performed. For longitudinal data analysis of continuous outcomes, will employ standards random effects models. The models account for heterogeneity between subjects and consequently increase the precision with which genetic effects are measured. We will employ a general analytic method for association studies, genomic control, to make our conclusions robust against the impact of population substructure. These studies will contribute to our knowledge of the mechanisms of age related loss of lean body mass and may identify individuals at elevated risk for preventive intervention.