Age-related osteoporotic fracture is largely due to the universal reduction in bone strength that occurs with age. Bone density is the main component of bone strength. About 80% of variance in bone density is due to heritable factors that appear to be regulated by relatively few genes. Polymorphisms of the vitamin D receptor gene have been reported by one group, but unable to be confirmed by us, to be in linkage with both bone mineral density and bone turnover in whites. Blacks have higher bone density and lower bone turnover than whites but heritability and linkage of these phenotypes have not been studied. The overall goal is to establish that heritable factors account for a similar proportion of variance in bone strength in blacks and whites, and to identify genetic markers for bone strength and bone turnover. Our goal will be achieved by testing two hypotheses. Hypothesis 1: Heritability of bone strength and bone turnover in blacks are of the same order as that in whites. This will be tested in 200 black and 200 white healthy female sib-pairs, i.e. a total of 800 subjects. Quantitative phenotypes will include: bone mineral density at several skeletal sites, geometric and architectural variables at the hip, ultrasound transmission in the os calcis; concentration of biochemical markers of bone formation and resorption in blood and urine; serum concentration of calcium-regulating hormones; and calcium absorption. Heritability for these phenotypes will be calculated using the sib-pair model and compared between blacks and whites. Hypothesis 2: Variant alleles of a limited number of genes determine the heritability of bone strength and turnover and are responsible for the differences in bone strength and turnover between blacks and whites. This will be tested in the populations studied in hypothesis 1. Genotyping will use highly informative (dC-dA)n.(dG-dT)n microsatellites. Chromosomal regions closely flanking candidate genes, initially focusing on the vitamin D receptor gene, will be examined in detail. Later, genome-wide maps will be developed. Quantitative phenotypes will be examined for linkage to genotypes using a sib-pair analysis in which the genetic markers will be examined as identical-by-descent to determine those significantly shared above expectation. These protocols optimize the search for genetic markers of bone strength, which will provide the fundamental knowledge to develop new preventative and therapeutic regimens for age-related osteoporotic fracture.
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