Genetic Analysis of Osteoporosis Risk Factors

骨质疏松症危险因素的遗传分析

• 批准号: 7118744
• 负责人: STEFAN A. CZERWINSKI
• 金额: $ 45.43万
• 依托单位: WRIGHT STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7118744
• 关键词: bone density; chromosomes; clinical research; disease /disorder proneness /risk; gene environment interaction; genetic polymorphism; genetic susceptibility; human genetic material tag; human subject; linkage mapping; osteoporosis; phenotype; quantitative trait loci; statistics /biometry

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.

拟议的研究是针对计划公告PA-02-110的“遗传结构，生物学变异和复杂表型”提交的。 骨质疏松症是一种衰老的疾病，其特征是骨骼质量低和骨组织的结构恶化，导致骨骼脆弱性和增加骨折的敏感性（NIH共识陈述，2000年）。如今，骨质疏松症是美国最普遍的代谢骨病，近1000万人患有折磨，另有3400万人处于危险之中。近年来，人们对理解骨质疏松风险的复杂遗传基础引起了极大的兴趣。尽管我们对骨质疏松症风险的遗传学的了解越来越多，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，评估骨质疏松症风险中最广泛使用的措施是骨矿物质密度（BMD），因为它与断裂风险的相关性很高。除了BMD之外，骨骼质量的各个方面也是骨折风险的重要预测指标。这些措施包括骨转换率以及骨骼结构的特征。 这些特征中的一些可能具有共同的遗传途径。拟议的研究研究了来自大型扩展血统的2,000名成年人样本中BMD的遗传决定因素和骨质质量的测量。拟议研究的主要目标是鉴定影响BMD的基因和骨质质量的测量，以及鉴定对这些特征的关节影响的基因。具体来说，我们将：1）确定 哪些遗传和特定环境因素会影响BMD的变化以及骨质质量的测量； 2）通过定量性状连锁分析确定具有影响BMD的基因的染色体区域和骨质质量的测量。此外，我们将使用多元定量性状链接分析来确定具有关节影响BMD的染色体区域以及对骨骼质量的测量； 3）细微地图通过定量性状链接分析识别的五个最有希望的QTL的区域。 这项提出的研究的结果表征，量化和定位对BMD的遗传作用以及骨质质量测量的结果，将为随后的研究提供重要的发现，目的是鉴定影响BMD的真正功能性多态性以及随后的骨质疏松风险。此外，这些发现将有可能导致在评估骨质疏松症的风险，预防和治疗方面的新​​发展。