Genetic Analysis of Osteoporosis Risk Factors

该研究是根据PA-02-110“遗传结构、生物变异和复杂表型”项目公告提交的。 骨质疏松症是一种以低骨量和骨组织结构退化为特征的衰老性疾病，导致骨脆性和骨折易感性增加（NIH共识声明，2000）。今天，骨质疏松症是美国最普遍的代谢性骨病，有近1000万人患病，另有3400万人处于危险之中。近年来，人们对了解骨质疏松症风险的复杂遗传基础产生了相当大的兴趣。尽管我们对骨质疏松症风险的遗传学知识不断增加，但确定所涉及的特定多态性仍然是一个难以捉摸的目标。 传统上，在骨质疏松症风险评估中最广泛使用的测量是骨矿物质密度（BMD），因为它与骨折风险高度相关。除了BMD，骨质量方面也是骨折风险的重要预测因素;这些指标包括骨转换率以及骨结构特征。 其中一些特征可能具有共同的遗传途径。该研究调查了来自大型扩展家系的2,000名成年人样本中BMD和骨质量测量的遗传决定因素。这项研究的主要目的是鉴定影响骨密度和骨质量的基因，以及鉴定对这些性状有联合影响的基因。具体而言，我们将：1）确定 所述遗传和特定环境因素影响BMD和骨质量测量的变化; 2）使用数量性状连锁分析鉴定含有影响BMD和骨质量测量的基因的染色体区域。此外，我们将使用多变量数量性状连锁分析来确定对BMD和骨质量测量具有联合影响的染色体区域;以及3）精细定位通过数量性状连锁分析确定的五个最有希望的QTL周围的区域。 这项研究的结果表征，量化和定位遗传对骨密度和骨质量的措施的影响，将提供重要的发现，为后续的研究，旨在确定真正的功能多态性影响骨密度和随后的骨质疏松症的风险。此外，这些发现将有可能导致骨质疏松症的风险评估，预防和治疗的新发展。

The proposed study is submitted in response to program announcement PA-02-110, "Genetic Architecture, Biological Variation and Complex Phenotypes". Osteoporosis is a disease of aging characterized by low bone mass and structural deterioration of bone tissue, leading to bone fragility and an increased susceptibility to fractures (NIH Consensus Statement, 2000). Today, osteoporosis is the most prevalent metabolic bone disease in the United States with nearly 10 million people afflicted and another 34 million at risk. In recent years there has been considerable interest in understanding the complex genetic basis of osteoporosis risk. Despite our increasing knowledge of the genetics of osteoporosis risk, identifying the specific polymorphisms involved has continued to be an elusive goal. Traditionally, the most widely used measure in the assessment of osteoporosis risk is bone mineral density (BMD) because of its high correlation with fracture risk. In addition to BMD, aspects of bone quality are also important predictors of fracture risk; these measures include rate of bone turnover as well as characteristics of bone architecture. Some of these traits are likely to share common genetic pathways. The proposed study investigates the genetic determinants of BMD and measures of bone quality in a sample of 2,000 adults from large extended pedigrees. The main goal of the proposed study is the identification of genes influencing BMD and measures of bone quality, as well as the identification of genes that have joint influences on these traits. Specifically, we will: 1) determine the extent to which genetic and specific environmental factors influence variation in BMD and measures of bone quality; 2) identify chromosomal regions harboring genes influencing BMD and measures of bone quality using quantitative trait linkage analysis. Additionally, we will identify chromosomal regions with joint influences on BMD and measures of bone quality using multivariate quantitative trait linkage analysis; and 3) fine map the regions surrounding the five most promising QTL identified through quantitative trait linkage analysis. The results of this proposed study characterizing, quantifying, and localizing genetic effects on BMD and measures of bone quality will provide important findings for subsequent research aimed at the identification of the true functional polymorphisms influencing BMD and subsequent osteoporosis risk. Furthermore, these findings will have the potential to lead to new developments in the assessment of risk, prevention, and treatment of osteoporosis.