GENETIC ANALYSIS OF HIP FRAGILITY

描述（由申请人提供）：遗传影响是骨矿物质密度和骨脆性的人群差异的主要原因。考虑到髋部骨折是最昂贵的骨质疏松性骨折，无论是在医疗保健成本还是在人力成本（即发病率和死亡率）方面，人们都应该对研究遗传对髋部脆弱性影响的动物模型产生很大的兴趣。我们最近鉴定了两种大鼠品系：哥本哈根 2331 (COP) 和 DA，它们的股骨颈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鉴定导致髋部脆弱性变化的基因。我们将测试三个假设：(1) COP 和 DA 大鼠在六个月时达到股骨颈强度和骨量的峰值。我们的目标是确定股骨颈强度达到峰值时的遗传对生物力学特性和骨骼结构的影响。 Sprague-Dawley 大鼠在 5-9 个月龄的时间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 至 10 个月龄大鼠的股骨生物力学特性、几何形状和微观结构，以确定与峰值相关的年龄； (2)可以确定大鼠的含有调节股骨颈强度和微观结构的基因的染色体区域。 COP 和 DA 祖鼠将进行交配，并将其 F1 杂交后代进行杂交，形成包含 500-600 只个体的 F2 群体。这些大鼠将根据股骨颈生物力学、几何和微观结构测量进行表型分析。将进行数量性状位点（QTL）分析，以确定影响变异表型的遗传位点。我们预计这些分析将鉴定出几个含有影响股骨颈脆性基因的 QTL； (3)股骨干和颈脆性至少部分地由不同的基因位点调节。将进一步对 COP x DA F2 群体股骨中轴处的骨脆性进行 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鉴定出一些先前与目标 2 中股骨颈脆性相关的 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.