Genetic Analysis of Osteoporosis Risk Factors

这项拟议的研究是根据项目公告PA-02-110“遗传结构、生物变异和复杂表型”提交的。 骨质疏松症是一种老年性疾病，其特征是骨量减少和骨组织结构恶化，导致骨骼脆性和骨折易感性增加(NIH Consensus Statement，2000)。今天，骨质疏松症是美国最常见的代谢性骨骼疾病，有近1000万人患有骨质疏松症，另有3400万人面临风险。近年来，人们对了解骨质疏松风险的复杂遗传基础有相当大的兴趣。尽管我们对骨质疏松症风险的遗传学知识越来越多，但确定涉及的特定基因多态仍然是一个难以实现的目标。 传统上，骨质疏松症风险评估中应用最广泛的指标是骨密度，因为它与骨折风险高度相关。除了骨密度，骨质量方面也是骨折风险的重要预测指标；这些指标包括骨转换率和骨结构特征。 这些特征中的一些可能具有共同的遗传途径。这项拟议的研究调查了来自大型家系的2000名成年人的骨密度和骨质量测量的遗传决定因素。这项研究的主要目标是确定影响骨密度的基因和骨质量指标，以及确定对这些特征有共同影响的基因。具体地说，我们将：1)确定 哪些遗传和特定环境因素影响骨密度和骨质量指标的变异；2)利用数量性状连锁分析确定含有影响骨密度和骨质量指标的基因的染色体区域。此外，我们将利用多变量数量性状连锁分析确定联合影响骨密度和骨质量指标的染色体区域；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。 这项拟议的研究结果对骨密度和骨质量的遗传效应进行了表征、量化和定位，将为后续旨在识别影响骨密度和随后的骨质疏松症风险的真正功能多态性的研究提供重要的发现。此外，这些发现将有可能导致骨质疏松症风险评估、预防和治疗方面的新发展。

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.