Although osteoporosis is commonly associated with older women, osteoporosis is also a substantial health problem among older men. In contrast to our understanding of osteoporosis in women, considerably less is known about the etiology and prevention of osteoporosis in men. The goal of the current project is to improve our understanding of the complex genetic regulation of bone strength among older men. To achieve this goal, we propose to study the association between variation in bone strength related traits and variation in 43 genes related to steroid hormone production and action and to growth factor and cytokine structure and function. We have prioritized candidate genes based on prior evidence that genetic variation at these loci influences bone strength related traits and/or biological evidence that these genes are important for skeletal integrity. The proposed study is very efficient because it uses existing data and stored specimens from 2,484 ethnically diverse participants in the Osteoporotic Fractures in Men (MrOS) Study, a multi-center observational study of the determinants of skeletal health in men aged 65 and older. Participants are well characterized with respect to clinical and epidemiologic factors including body composition, medical conditions, habits (smoking, alcohol consumption, physical activity), dietary intake, and use of medications. Volumetric bone mineral density, bone size and skeletal geometry measurements were made at the proximal femur, femoral shaft and lumbar spine using state-of-the-art three-dimensional quantitative computed tomography. Detailed protocols, extensive training of staff, and well-established quality control procedures ensured high quality data collection. We will use these data and biological specimens and high-throughput molecular methods to: 1) evaluate the association of the bone strength related traits with variation in the candidate loci; 2) analyze the interaction between selected genes in influencing the bone strength related traits; and 3) examine the interaction between genes and selected environmental exposures. Finally, we will employ contemporary statistical genetic methods to make our conclusions robust against false positive discoveries due to population substructure and multiple hypothesis testing. The improved understanding of the genetic regulation of bone strength that will emerge from the proposed project will yield fundamental insight into the basic mechanisms of male osteoporosis.
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