Bone geometry is a valid measure of bone fragility and risk of osteoporotic fractures. The primary aim of this study is to identify and evaluate genes determining geometrical properties of bone. This study will take advantage of existing hand x-rays and dual x-ray absorptiometry scans of the hip from participants of the Framingham Heart Study, one of the longest running cohort studies in the world. Well-described pedigrees from the Framingham Study along with an existing genome scan, including microsatellites uniformly distributed throughout the genome, will allow us to perform a study of the genetic sources of variation in bone geometry. Elucidation of genetic and molecular mechanisms underlying bone structure and strength will ultimately lead to the identification of the individuals at highest risk of osteoporotic fractures who can be targeted for therapeutic interventions. The specific hypotheses of this study are: - Genetic factors explain a significant portion of variability in geometric indices that will be derived as part of this project in both the weight-beating femur and in non weight-beating metacarpals. - Significant linkage with chromosomal loci will be found for indices of bone geometry at femur and metacarpals. - Common genetic sources will be found for femoral and metacarpal indices, with pleiotropic effect also on bone mineral density of femur and quantitative ultrasound of heel that are already investigated as part of the Framingham Osteoporosis Study. Initial linkage results will be refined by genotyping additional markers in genomic regions with LOD scores suggestive of linkage with femoral and metacarpal geometric indices. Our goal is to fine-tune localization of quantitative trait loci by examining polymorphic markers within these regions. Linkage analysis will also be combined with family based tests of association with candidate genes that lie under the peak, with additional mapping with single nucleotide polyrnorphisms.
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