GENETIC ANALYSIS OF HIP FRAGILITY

描述(由申请人提供)：遗传影响是骨矿密度和骨脆性总体差异的主要原因。考虑到髋部骨折是骨质疏松性骨折中最昂贵的一种，无论是从医疗保健成本还是从人类成本(即发病率和死亡率)来看，应该有相当大的兴趣建立动物模型来研究遗传因素对髋关节脆性的影响。我们最近发现了两个品系的大鼠，哥本哈根2331(COP)和DA，它们的股骨颈的生物力学特性有相当大的差异。我们建议使用这些大鼠品系来识别导致髋关节脆性变化的基因。我们将检验三个假设：(1)COP和DA大鼠在6个月龄时达到股骨颈强度和骨量的峰值。我们的目标是确定在股骨颈力量达到峰值的年龄对生物力学特性和骨结构的遗传影响。SD大鼠在5-9个月龄时达到骨量和强度的峰值。据推测，COP和DA菌株遵循相似的骨骼生长曲线。我们将测量2到10个月龄大鼠的股骨生物力学性能、几何形状和微结构，以确定与峰值相关的年龄；(2)可以为大鼠确定含有调节股骨颈强度和微结构的基因的染色体区域。COP和DA祖鼠将交配，它们的F1杂交后代将产生一个包含500-600只个体的F2群体。这些大鼠将根据股骨颈的生物力学、几何和微观结构测量进行表型鉴定。将进行数量性状座位(QTL)分析，以确定影响变异表型的遗传座位。我们预计，这些分析将确定包含影响股骨颈脆性的基因的几个QTL；以及(3)股骨干和股骨颈脆性至少部分由不同的基因位点调控。COP x DA F2群体将进一步表征股骨中段的骨脆性，将进行QTL分析，以确定导致表型变异的遗传位点。我们预计，这些分析将确定一些以前在AIM 2中与股骨颈脆性相关的QTL，以及专门影响股骨干表型的新QTL。

DESCRIPTION (provided by applicant): Genetic influences account for the majority of the population variance in bone mineral density and bone fragility. Considering that hip fracture is the most expensive of osteoporotic fractures, both in terms of health care cost and in human costs (i.e., morbidity and mortality), there should be considerable interest in an animal model for studying genetic influences on hip fragility. We recently identified two strains of rats, Copenhagen 2331 (COP) and DA, which have considerable variation in the biomechanical properties of their femoral necks. We propose to use these rat strains to identify genes responsible for the variation in hip fragility. We will test three hypotheses: (1) COP and DA rats reach peak femoral neck strength and bone mass at six months of age. Our goal is to determine genetic influences on the biomechanical properties and bone structure at an age when femoral neck strength is at its peak. Sprague-Dawley rats achieve peak bone mass and strength within a window of 5-9 months of age. Presumably, COP and DA strains follow similar skeletal growth curves. We will measure femoral biomechanical properties, geometry and microstructure in rats ranging from 2 to 10 months of age to determine the age associated with peak values; (2) chromosomal regions harboring genes that regulate femoral neck strength and microstructure can be determined for rats. COP and DA progenitor rats will be mated and their F1 hybrid offspring intercrossed to create an F2 population containing 500-600 individuals. These rats will be phenotyped based upon femoral neck biomechanical, geometrical and microstructural measurements. Quantitative trait loci (QTL) analyses will be performed to identify the genetic loci influencing variation phenotypes. We anticipate that these analyses will identify several QTLs containing genes that influence femoral neck fragility; and (3) femoral shaft and neck fragility are regulated, at least in part, by different genetic loci. The COP x DA F2 population will be further characterized for bone fragility at the femoral midshaft QTL analyses will be performed to identify the genetic loci contributing to the variation in the phenotypes. We anticipate that these analyses will identify some QTLs previously linked to femoral neck fragility in Aim 2, as well as novel QTLs specifically influencing femoral shaft phenotypes.