GENETIC ANALYSIS OF HIP FRAGILITY

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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.