Low trauma fractures are a major public health problem in the elderly. The most powerful, measurable determinant of fracture risk is low bone mass and the most important determinant of late life bone mass is peak bone mass (PBM). The heritability of PBM is high, estimates ranging from 50-88 percent. Both association studies with candidate genes and linkage studies with dense genetic markers covering the whole human genome have merit in searching for genes underlying variation in PBM. We will conduct both types of studies to: 1) identify genomic regions (-5cM in length) responsible for -15 percent or more of variation in PBM; 2) test whether the vitamin D receptor (VDR) genomic region is responsible for -15 percent or more of the variation in PBM using linkage studies; 3) test whether genomic regions containing 29 candidate genes underlie variation in PBM using an association study approach. We will obtain 212 full sib pairs extremely discordant for PBM (EDSP) and 866 full sib pairs extremely concordant for low PBM (ECSP). All sib pairs and their parents (1803 individuals) will be genotyped at 361 highly polymorphic microsatellite markers about evenly spaced across the human genome using an automated fluorescence based genotyping system. Additionally, we will genotype 29 candidate genes. Identifying genetic loci underlying PBM variation is the first step in unraveling the major genetic cause of low bone mass, the main measurable phenotype associated with osteoporosis. It will expedite the characterization of mutations and their functional products responsible for low PLB, and also help later studies of the interaction of genetic and environmental causes of low PBM. This knowledge is essential for development of preventive interventions and/or cures for osteoporosis that can be based on individuals' specific genotypes.
Showing the most recent 10 out of 72 publications
