GENETIC ANALYSIS OF HIP FRAGILITY

描述（由申请人提供）：遗传影响占骨矿物质密度和骨脆性群体方差的大部分。考虑到髋部骨折是最昂贵的腰椎骨折，无论是在医疗保健成本和人力成本方面（即，发病率和死亡率），应该有相当大的兴趣，在动物模型研究遗传影响髋关节脆性。我们最近确定了两种品系的大鼠，哥本哈根2331（COP）和DA，其股骨颈的生物力学特性有相当大的变化。我们建议使用这些大鼠品系，以确定基因负责髋关节脆性的变化。我们将检验三个假设：（1）COP和DA大鼠在6月龄时达到股骨颈强度和骨量峰值。我们的目标是确定在股骨颈强度处于峰值的年龄时，遗传对生物力学特性和骨结构的影响。Sprague-Dawley大鼠在5-9月龄的窗口内达到峰值骨量和强度。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 - 10月龄大鼠股骨的生物力学性能、几何结构和显微结构，以确定峰值相关的年龄;（2）可以确定大鼠的染色体区域，其包含调节股骨颈强度和显微结构的基因。将COP和DA祖大鼠交配，并将其F1杂种后代杂交以产生含有500-600个个体的F2群体。将根据股骨颈生物力学、几何学和显微结构测量结果对这些大鼠进行表型分析。将进行数量性状基因座（QTL）分析，以确定影响变异表型的遗传基因座。我们预计这些分析将确定几个QTL包含基因的影响股骨颈脆性;（3）股骨干和颈部脆性的调控，至少部分，由不同的遗传位点。将进一步表征COP x DA F2群体的股骨中段骨脆性，将进行QTL分析以鉴定导致表型变异的遗传基因座。我们预计这些分析将确定一些以前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.